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Oncology Intelligence

EGFR
EGFR
HER2(38) HER3(39)
Mutations that lead to EGFR overexpression and mutation is associated with a number of cancers, including lung cancer, anal cancers, and GBM.(9, 10, 15, 17, 18) Mutations in the EGFR kinase domain are found in approximately 10% of NSCLCs that are sensitive to treatment with gefitinib and erlotinib.(5-8) Whereas ErbB1 and ErbB2 (EGFR and HER2) are frequently overexpressed in BC and correlate with a poor prognosis, ErbB4 (HER4) expression in BCs actually correlates with a favorable prognosis.(11) While EGFR and HER2 is associated with increased cell growth, malignant transformation, and progression, HER4 proteolytic fragments that slows growth and stimulates differentiation of breast cells.(12)
ErbB family receptor activation initiates a number of downstream signaling pathways, such as MAPK, STAT, and the modulation of calcium channels, among others. These downstream signaling activations modulate cell proliferation, survival, adhesion, migration and differentiation.(1, 2)
The EGFR family are RTKs, including EGFR, HER2/c-neu, Her3 and Her4. EGFR is the cell-surface receptor, consisting of a glycosylated, extracellular N-terminal part containing a ligand binding site and a dimerization arm, a transmembrane segment, and an intracellular part containing a TYK domain and a C-terminal tail with several phosphorylation sites.(3,4)
EGFR is activated by binding specific ligands, including EGF and TGF. EGFR has 3 known natural ligands: EGF, TGF-α, and amphiregulin.(13) EGFR dimerization stimulates its intrinsic intracellular PTK activity. Autophosphorylation elicits downstream activation via downstream signaling proteins, which initiate several signal transduction cascades, principally the MAPK, Akt, and JNK pathways, leading to DNA synthesis and cell proliferation.(14, 15) There are 3 important signaling outputs of activated EGFR homo- or heterodimers: KRAS status is a predictor of response to EGFR targeted therapies.(19) KRAS acts as a molecular on/off switch for the recruitment and activation of proteins necessary for the propagation of growth factor and other receptor signals, such as c-Raf and PI3K.(19) When an activating mutation occurs in the KRAS gene, the RAS G-protein activates the MAPK signaling cascade downstream of EGFR. This may bypass the need for ligand binding to EGFR, conferring resistance to therapies like cetuximab or panitumumab which target the EGFR extracellularly.(19) However, many patients develop resistance.(15, 20-22) Agents targeting EGFR fall into a middle ground: some of them are extremely successful for specific types of cancer, and in a subset of patients.(16)
HER2 is a protein that in humans is encoded by the ERbB2 gene, a known proto-oncogene located at the long arm of human chromosome 17. HER2 is a member of the EGFR family. HER2 is named because it has a similar structure to human EGFR or HER1. The expression of HER2 is regulated by signaling through ERs.(23) ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR.(4) Signaling pathways activated by HER2 include: MAPK, PI3K/Akt, phospholipase C PKC, and STAT.(23, 24)
The behavior of ErbB2 regarding endocytic downregulation differs significantly from that of EGFR, and it is generally accepted that ErbB2 avoids efficient endocytic downregulation. Another efficient way to induce endocytosis and lysosomal degradation of ErbB2 is inhibition of the chaperone HSP90. ErbB2 is one of the most prominent client proteins of the chaperone HSP90, and this interaction is considered as a potentially valuable pharmacological target.(3)
Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of BC and in recent years it has evolved to become an important biomarker and target of therapy for the disease.(23) It is strongly associated with increased disease recurrence and poor prognosis. Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer.(23, 25) There is mounting evidence of the role of HER2 overexpression in patients with gastric cancer.(26)
Estradiol and Tamoxifen acting through the ER down-regulate the expression of HER2. However, when the ratio of the co-activator AIB-3 exceeds that of the co-repressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant BC.(23) The duration of response to trastuzumab-based therapy ranges from 5 to 9 months, suggesting that acquired resistance often develops.(27) It is revealed that patients with ER+/HER2+ compared with ER-/HER2+ BCs may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.(23) Research has identified dysregulation of the downstream PI3K-AKT-mTOR pathway, accumulation of the truncated kinase active p95-HER2, and alternative RTK signaling as mediators of trastuzumab resistance.(27) Recognizing that activation of the PI3K pathway, through loss of PTEN or mutational activation of PIK3CA, is a common mechanism of trastuzumab resistance, facile and reliable assays to detect these molecular lesions are actively being developed to identify patients most likely to benefit from PI3K-based treatment options.(27)
RTK erbB-3 is an enzyme that in humans is encoded by the ERBB3 gene. HER3 stands out among this family as the only member lacking catalytic kinase function. It can bind this ligand but not convey the signal into the cell through protein phosphorylation. Like many of the receptor tyrosine-kinases, ERBB3 is activated by extracellular ligand. Ligands known to bind to ERBB3 include heregulin. It forms heterodimers with other EGF receptor family members that do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation.(28)
Overexpression of HER3 has been reported in numerous cancers, including PC, bladder, and BCs.(28) Cancers with driving HER3 amplifications or mutations have not been found, and studies of its expression in tumors have been only weakly provocative. However, substantial evidence suggests that its non-catalytic functions are critically important in many cancers driven by its HER family partners. Furthermore, new insights into the mechanism of activation in the HER family has provided clear evidence of functionality in the HER3 kinase domain.(29) An increasing body of evidence shows that HER3 plays a critical role in EGFR- and HER2-driven tumors. In particular, HER3 lies upstream of a critically important tumorigenic signalling pathway with extensive ability for feedback and cross-talk signaling, and targeting approaches that fail to account for this important trans-target of EGFR and HER2 can be undermined by its resiliency and resourcefulness.(30)
RTK erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene.(31) It is a member of the EGF receptor subfamily. ERBB4 is a single-pass type I transmembrane protein with multiple furin-like cysteine rich domains, a TYK domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins-2 and -3, heparin-binding EGF-like growth factor, and cellulin. Ligand binding induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment.(31) Following ligand binding and receptor activation, EGFR is endocytosed and transported to lysosomes where the receptor is degraded.(3) ErbB4/HER4 appears to impair growth by inducing a G2/M checkpoint, perhaps one involving BRCA1.(12)
There are several mechanisms whereby cancer cells can obtain uncontrolled ErbB receptor signaling, including increased receptor expression, activating mutations, and escape of endocytic receptor downregulation.(3, 32-36) ErbB2 and ErbB4 are likely to use the same activation mechanism.(5, 37) Because ErbB4-deficient mammary epithelial cells fail to demonstrate activation of STAT5a, even in the context of an intact PRL-PRLR-JAK2-STAT5a signaling axis, it was determined that ErbB4 must be an obligate mediator of STAT5a activation in the mammary gland.(12)


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References

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News
11:00 PM|Urabe, Masayuki; Ushiku, Tetsuo; Seto, Yasuyuki; Fukayama, Masashi|The American Journal of Surgical Pathology - Current Issue|Labels: EGFR, gastric
imageTrastuzumab-based chemotherapy is now a standard approach for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. However, histopathologic changes after treatment have yet to be elucidated. This study aims to characterize the histologic response of gastric cancer to trastuzumab treatment and its correlation with HER2 status. Twenty-one advanced HER2-positive gastric cancers treated with trastuzumab-based chemotherapy, including 10 surgically resected specimens and 11 biopsy samples from patients with inoperable tumors, were evaluated for the histologic responses and HER2 status of residual cells. We also reviewed, as controls, 10 cases undergoing surgical resection of tumors after chemotherapy without trastuzumab. Complete and partial histologic responses were obtained in 2 and 8 of the surgical cases, respectively. HER2-positive neoplastic cells were recognized at least focally in the 8 cases. Notably, the proportion of HER2-positive cells was always higher in superficial (mucosal/submucosal) layers than in deeper layers. Three specimens contained HER2-positive neoplastic cells exclusively in the superficial area or intravascular space, whereas deeply invasive or metastatic components almost completely disappeared or were HER2 negative when still present. In contrast, HER2-negative cells or residual tumor cells in control cases tended to survive as well or better in deeply invasive areas or in metastases than in superficial areas. Biopsy samples from nonoperative patients remained HER2 positive after treatment in 8 of 11 patients. Our observations suggest that HER2-positive neoplastic cells tend to survive within superficial areas or intravascular spaces after trastuzumab therapy, even when deeply invasive or metastatic lesions responded well to therapy.
8:43 PM|Current Molecular Pharmacology (Volume 9 - Issue 3)|Labels: EGFR, breast cancer
Significant advances have been made in our understanding of the mechanisms of innate and adaptive immunity and the mechanisms by which tumors escape from the normal process of immune surveillance. However, effectively harnessing the power of the immune system to specifically target the tumor cells has proven quite difficult, in large part due to the fact that tumors are composed of patient’s own cells, expressing antigens recognized as “self” and thus escaping the immune surveillance. For breast cancer treatment, the first successful inroads in immunotherapy came with the introduction of monoclonal antibodies against a membrane receptor for the epidermal growth factor receptor family (HER2). In 1998 the first monoclonal antibody against the Her 2 antigen was approved for clinical use (trastuzumab). Clinical trials combining trastuzumab with various chemotherapy regimens have consistently shown improvement in survival in both metastatic as well as early stage breast cancer. Another promising approach has been the development of anti HER 2 vaccines. More recently the discovery of immune modulating antibodies (checkpoint inhibitors) and their success in the treatment of cancers such as melanoma and renal cell carcinoma has lead to renewed interest in immune therapies in cancer in general and new clinical trials exploring the role of immune therapies in breast cancer.
8:43 PM|Current Molecular Pharmacology (Volume 9 - Issue 3)|Labels: EGFR, lung cancer
Lung cancer is among the most prevalent and deadly cancers. Although the development of targeted drugs, erlotinib and crizotinib, has improved lung cancer management, survival rates of lung cancer patients have not shown significant improvement over the past decade. Better therapeutic options are required to treat lung cancer patients. Immunotherapy is a maturing and rapidly growing field, which has recently contributed many novel strategies for addressing cancer treatment. Here, we discuss the current state of cancer vaccines, immune checkpoint blockers, and adoptive cellular therapies, as novel clinical treatment strategies for non-small cell lung cancer. The durability of clinical activity in a subset of patients has led to a great deal of excitement and optimism.
Friday, September 23, 2016 10:47 AM|Janku, F., Kurzrock, R.|Clinical Cancer Research Online First Articles|Labels: EGFR, biomarker diagnostic

In cancer, plasma-derived cell-free DNA can be used for detection of oncogenic aberrations relevant for treatment selection. A cell-free DNA-based test for EGFR mutations has been approved as an alternative to tumor tissue analysis in lung cancer. Testing for other aberrations, including copy number alterations, continues to be investigated.

Friday, September 23, 2016 10:47 AM|Scarborough, H. A., Helfrich, B. A., Casas-Selves, M., Schuller, A., Grosskurth, S. E., Kim, J., Tan, A.-C., Chan, D. C., Zhang, Z., Zaberezhnyy, V., Bunn, P. A., DeGregori, J.|Clinical Cancer Research Online First Articles|Labels: EGFR, lung cancer

Purpose: The emergence of EGFR-inhibitors such as gefitinib, erlotinib and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR-inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors. Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its anti-tumor activity, impingement on canonical Wnt signaling and effects on gene expression. We performed pharmacokinetic (PK) and pharmacodynamic (PD) profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results: In combination with EGFR-inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR-inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. PK and PD profiling of AZ1366-treated orthotopic tumors demonstrated clinically-relevant serum drug levels and intratumoral target inhibition. Finally, co-administration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model. Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a co-treatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC.

Friday, September 23, 2016 1:05 AM|Google News on 'breast cancer'|Labels: EGFR, breast cancer, regulatory

Investor's Business Daily

Puma Races To Eight-Month High On Breast Cancer Drug Success
Investor's Business Daily
Puma Biotechnology (PBYI) stock rocketed to an eight-month high Thursday after the U.S. Food and Drug Administration on Tuesday approved its new application for neratinib, a breast cancer treatment drug. An estimated 36,000 patients in the U.S. and U.K ...
FDA Accepts NDA for Neratinib in HER2+ Early Stage Breast CancerCancer Therapy Advisor

all 62 news articles »
Thursday, September 22, 2016 6:00 PM|Frank Dombrowski|International Journal of Molecular Sciences|Labels: EGFR, liver cancer
Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.
Thursday, September 22, 2016 1:42 PM|Bryan Finnigan|Biotech|Labels: EGFR, breast cancer, regulatory

Credit Suisse Has increased its target price for Puma Biotechnology, Inc (NYSE: PBYI) from $54 to $111, maintaining an Outperform Rating. The increased price target is based on the firm's greater sales expectations for the breast cancer treatment drug neratinib.

“We view the FDA's acceptance of neratinib's NDA as a key de-risking event,” said analyst Kennen MacKay, “further supported by management's guidance ...

Full story available on Benzinga.com

Thursday, September 22, 2016 9:16 AM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: EGFR, RAS, CRC, clinical trial
European Journal of Surgical Oncology, Volume 42, Issue 10, 2016 Oct | Köhne, C.-H.; Poston, G.; Folprecht, G.;...
Introduction Improvements in surgical intervention have significantly contributed to the enhanced survival of patients with metastatic colorectal cancer (mCRC) that has been observed over the past 15 years. The prognosis for patients presenting wi...
Wednesday, September 21, 2016 6:00 PM|Elizabeth Smyth|Public Health & Healthcare|Labels: EGFR, gastric
Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients.
Wednesday, September 21, 2016 4:00 PM|Oxnard, Thress, Alden, Lawrance, Paweletz, Cantarini, Yang, Barrett, Janne|Journal of Clinical Oncology Current Issue|Labels: EGFR, lung cancer
Purpose

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib.

Methods

Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAMing. Plasma genotyping accuracy was assessed by using tumor genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analyzed in all T790M-positive or T790M-negative patients.

Results

Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumors, T790M was detected in plasma of 18 (31%). ORR and median PFS were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M-negative plasma had overall favorable outcomes (ORR, 46%; median PFS, 8.2 months), tumor genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months).

Conclusion

In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine presence or absence of T790M.

Tuesday, September 20, 2016 1:01 PM|Onclive Articles|Labels: EGFR, breast cancer, regulatory
The FDA has accepted a new drug application for neratinib as an extended adjuvant therapy for patients with HER2-positive breast cancer following prior treatment with postoperative trastuzumab.
Tuesday, September 20, 2016 5:28 AM|Google News on 'breast cancer'|Labels: EGFR, breast cancer, regulatory

Yahoo Finance

Pfizer (PFE) Breast Cancer Drug Ibrance Wins CHMP Backing
Yahoo Finance
Ibrance is under review in the EU for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer. The CHMP has indicated that Ibrance is to be used ...

and more »
Background: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. Methods: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). Results: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). Conclusion: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.
Chemotherapy 2017;62:71-79
Tuesday, September 20, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: EGFR, breast cancer, clinical trial, regulatory
Puma Biotechnology Inc. (NYSE:PBYI) gained $6.21 (11%) to $65.16 on Tuesday after it said FDA accepted an NDA for oral neratinib (PB272) to treat patients with early stage HER2-amplified breast cancer previously treated with Herceptin trastuzumab. Puma said the PDUFA date for the candidate is July 21, 2017. Puma's application includes data from the Phase III ExteNET trial, in which neratinib met the primary endpoint of extending disease-free survival (DFS) at two years vs. placebo. In an updated analysis announced in July, Puma said five-year invasive DFS rates were 90.4% for neratinib and 87.9% for placebo (HR=0.74, p=0.017) (see BioCentury Extra, July 22).The company has exclusive, worldwide rights to neratinib from Pfizer Inc. (NYSE:PFE). It is an oral inhibitor of HER1, HER2 and HER4 kinases.The Genentech unit of Roche (SIX:ROG; OTCQX:RHHBY) markets Herceptin.
Contributors : Bernard Omolo ; Mingli Yang ; Fang Y Lo ; Michael J Schell ; Sharon Austin ; Kellie Howard ; Anup Madan ; Timothy J Yeatman
Series Type : Expression profiling by high throughput sequencing
Organism : Homo sapiens

Background: The KRAS gene is mutated in about 40% of colorectal cancer (CRC) cases, which has been clinically validated as a predictive mutational marker of intrinsic resistatnce to anti-EGFR inhibitor (EGFRi) therapy. Since nearly 60% of patients with a wild type KRAS fail to respond to EGFRi treatment, there is a need to develop more reliable molecular signatures to better predict response. Here we address the challenge of adapting a gene expression signature predictive of RAS pathway activation, created using fresh frozen (FF) tissues, for use with more widely available formalin fixed paraffin-embedded (FFPE) tissues.
Methods: In this study, we evaluated the translation of an 18-gene RAS pathway signature score from FF to FFPE in 54 CRC cases, using a head-to-head comparison of five technology platforms. FFPE-based technologies included the Affymetrix GeneChip (Affy), NanoString nCounter(NanoS), Illumina whole genome RNASeq (RNA-Acc), Illumina targeted RNASeq(t-RNA), and Illumina stranded Total RNA-rRNA-depletion (rRNA).
Results: Using Affy_FF as the "gold" standard, initial analysis of the 18-gene RAS scores on all 54 samples shows varying pairwise Spearman correlations, with (1) Affy_FFPE(r=0.233, p=0.090); (2) NanoS_FFPE(r=0.608, p<0.0001); (3) RNA-Acc_FFPE(r=0.175, p=0.21); (4) t-RNA_FFPE (r=-0.237, p=0.085); and (5) t-RNA (r=-0.012, p=0.93). These results suggest that only NanoString has successful FF to FFPE translation. The subsequent removal of identified "problematic" samples (n=15) and gene (n=2) further improves the correlations of Affy_FF with three of the five technologies: Affy_FFPE (r=0.672, p<0.0001); NanoS_FFPE (r=0.738, p<0.0001); and RNA-Acc_FFPE (r=0.483, p=0.002).
Conclusions: Of the five technology platforms tested, NanoString technology provides a more faithful translation of the RAS pathway gene expression signature from FF to FFPE than the Affymetrix GeneChip and multiple RNASeq technologies. Moreover, NanoString was the most forgiving technology in the analysis of samples with presumably poor RNA quality. Using this approach, the RAS signature score may now be reasonably applied to FFPE clinical samples.

Mucoepidermoid carcinoma as a subtype of salivary gland cancer is rare and the number of patients is insufficient to elaborate therapy regimens in case of relapsed or metastatic disease. In this report we are presenting the case of an 18-year-old adolescent with a high grade mucoepidermoid carcinoma of the parotid gland, suffering from multiple local and distinct relapses despite adequate surgical and radiation treatment. After initial treatment with surgery and radiation the patient showed local and distant metastases. He received a novel multimodal treatment including epidermal growth factor receptor-antibody cetuximab in combination with cisplatin leading to partial remission followed with consolidating chemotherapy including ifosfamid, cisplatin and adriamycin. Due to the high risk of recurrent disease, high dose chemotherapy containing carboplatin and etoposide followed by autologous stem cell transplantation was initiated, additionally re-irradiation was accomplished. The treatment led to sustained complete remission for 2 years and 9 months. This novel treatment approach resulting in long time survival may offer new treatment options for other high risk patients suffering from relapsed mucoepidermoid carcinoma.
Friday, September 16, 2016 4:27 PM|Ji-Yeon Lee, Ho Hur, Hyo Jung Yun, Yeejeong Kim, Seoyeon Yang, Seung Il Kim, Myoung Hee Kim|International Journal of Biological Sciences|Labels: EGFR, breast cancer

HOX transcription factors play an important role in determining body patterning and cell fate during embryogenesis. Accumulating evidence has shown that these genes act as positive and/or negative modulators in many types of cancer, including breast cancer, in a tissue-specific manner. We have previously reported that HOXB5 is aberrantly overexpressed in breast cancer tissues and cell lines. Here, we investigated the biological roles and clinical relevance of HOXB5 in breast cancer. Immunohistochemical analysis of HOXB5 on tissue microarray (TMA) including 34 normal and 67 breast cancer specimens revealed that HOXB5 was highly expressed in cancer tissues, particularly from estrogen receptor (ER)-positive breast cancer patients. An online survival analysis confirmed the correlation between HOXB5 expression and poor distant metastasis-free survival in ER-positive, but not in ER-negative, breast cancer. In vitro studies indicated that HOXB5 silencing in ER-positive cells significantly decreased cell proliferation and anchorage-independent cell growth. In contrast, overexpression of HOXB5 displayed EMT characteristics with a greater invasive ability, higher cell proliferation and colony formation in soft agar. HOXB5 knockdown or overexpression led to changes in the expression levels of RET, ERBB2, and EGFR, but not of ESR1. In conclusion, we suggest that HOXB5 acts as a positive modulator most likely by promoting cell proliferative response and invasiveness in ER-positive breast cancer. These results would help predict prognosis of breast cancer and identify a new valuable therapeutic target.

Friday, September 16, 2016 4:27 PM|David J. Clark, Yuping Mei, Shisheng Sun, Hui Zhang, Austin J. Yang, Li Mao|Theranostics|Labels: EGFR, RAS

Protein glycosylation plays a fundamental role in a multitude of biological processes, and the associated aberrant expression of glycoproteins in cancer has made them attractive biomarkers and therapeutic targets. In this study, we examined differentially expressed glycoproteins in cell lines derived from three different states of lung tumorigenesis: an immortalized bronchial epithelial cell (HBE) line, a non-small cell lung cancer (NSCLC) cell line harboring a Kirsten rat sarcoma viral oncogene homolog (KRAS) activation mutation and a NSCLC cell line harboring an epidermal growth factor receptor (EGFR) activation deletion. Using a Triple SILAC proteomic quantification strategy paired with hydrazide chemistry N-linked glycopeptide enrichment, we quantified 118 glycopeptides in the three cell lines derived from 82 glycoproteins. Proteomic profiling revealed 27 glycopeptides overexpressed in both NSCLC cell lines, 6 glycopeptides overexpressed only in the EGFR mutant cells and 19 glycopeptides overexpressed only in the KRAS mutant cells. Further investigation of a panel of NSCLC cell lines found that Cellular repressor of E1A-stimulated genes (CREG1) overexpression was closely correlated with KRAS mutation status in NSCLC cells and could be down-regulated by inhibition of KRAS expression. Our results indicate that CREG1 is a down-stream effector of KRAS in a sub-type of NSCLC cells and a novel candidate biomarker or therapeutic target for KRAS mutant NSCLC.

Friday, September 16, 2016 3:02 PM|Onclive Articles|Labels: EGFR, breast cancer, regulatory
The Committee for Medicinal Products for Human Use has recommended approval of palbociclib for patients with HR-positive, HER2-negative metastatic breast cancer, either in combination with an aromatase inhibitor in the frontline setting, or combined with fulvestrant after progression on endocrine therapy.
Friday, September 16, 2016 10:23 AM|Xinxin Zhang, Lei Du, Feifang Zhao, Qiuju Wang, Shiming Yang, Lin Ma|International Journal of Biological Sciences|Labels: EGFR, pharyngeal

Purpose: The present clinical trial was designed to evaluate the efficacy and safety of concurrent helical tomotherapy (HT) with cetuximab followed by adjuvant chemotherapy with docetaxel and cisplatin (TP) in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma.

Materials and Methods: This phase II clinical trial included 43 patients with Stage III/IV LANC (33 Stage III and 10 Stage IV). The treatment consisted of concurrent HT with cetuximab (400 mg/m2 loading dose and weekly 250mg/m2), followed by four cycles of chemotherapy [docetaxel (70 mg/m2 on Day 1) and cisplatin (40 mg/m2 on Days 1 and 2 every 3 weeks). Side effects were evaluated with CTCAE criteria (Common Terminology Criteria for Adverse Events 3.0).

Results: The median follow-up duration was 48.0 months [95% confidence interval (CI) 41.7-58.0 months], the 2-year locoregional failure-free rate (LFFR), progression-free survival (PFS), distant failure-free rate (DFFR) and overall survival (OS) were 95.2%, 79.1%, 88.1% and 93.0% respectively; the 3-year LFFR, DFFR, PFS and OS were 92.7%, 85.6%, 72.0% and 85.7% respectively. The most common grade 3 toxicities were oropharyngeal mucositis (81.4%) and RT-related dermatitis (7.0%). No patients had more than grade 3 radiation related toxicities and no patients required nasogastric feeding. One patient experienced grade 3 osteonecrosis at 18 months after treatment.

Conclusions: Concurrent HT with cetuximab followed by adjuvant chemotherapy with TP is an effective strategy for the treatment of LANC with encouraging survival rates and minimal side effects.

Friday, September 16, 2016 8:07 AM|R. Chandrasekaran|Biotech|Attachments|Labels: CDK, EGFR, breast cancer, regulatory

Pfizer Inc. (NYSE: PFE), Amgen, Inc. (NASDAQ: AMGN) and Eli Lilly and Co (NYSE: LLY) received favorable opinions from the European Medicines Agency in response to their respective applications.

Pfizer's IBRANCE®

Pfizer disclosed that the European Medicines Agency (EMA)'s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending its IBRANCE® (palbociclib) for marketing authorization. The drug candidate is for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer.

Related Link: Wedbush Answers "So, Now What?" For Novavax Shareholders

Amgen's Parsabiv™ ...

Full story available on Benzinga.com

Thursday, September 15, 2016 5:10 PM|Hirofumi Mukai, Toshiaki Saeki, Kenjiro Aogi, Yoichi Naito, Nobuaki Matsubara, Takashi Shigekawa, Shigeto Ueda, Seiki Takashima, Fumikata Hara, Tomonari Yamashita, Shoichi Ohwada, Yasutsuna Sasaki|Cancer Science|Labels: EGFR, breast cancer, clinical trial
Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.) We examined the safety and pharmacokinetics of patritumab, a human anti-HER3 monoclonal antibody that has shown anticancer activity in preclinical models, in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. No dose-limiting toxicities were observed, and the target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses, but we recommend the 18 mg/kg dose for future studies.
Thursday, September 15, 2016 7:42 AM|T.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: EGFR, breast cancer

Dual FASN and EGFR Blockade in TNBC
Giro-Perafita, A Palomeras, S, Lum, D. H, Blancafort, A, Vinas, G, Oliveras, G, Perez-Bueno, F, Sarrats, A, Welm, A. L, Puig, T.
Clinical Cancer Research, Vol. 22, No. 18 (2016) pp. 4687 - 4697
Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC. Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models. Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity. Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC. Clin Cancer Res; 22(18); 4687&ndash;97. &copy;2016 AACR.

Wednesday, September 14, 2016 6:37 PM|Oncology|Labels: EGFR, lung cancer
Lung cancer is among the most prevalent and deadly cancers. Although the development of targeted drugs, erlotinib and crizotinib, has improved lung cancer management, survival rates of lung cancer patients have not shown significant improvement over the past decade. Better therapeutic options are required to treat lung cancer patients. Immunotherapy is a maturing and rapidly growing field, which has recently contributed many novel strategies for addressing cancer treatment. Here, we discuss the current state of cancer vaccines, immune checkpoint blockers, and adoptive cellular therapies, as novel clinical treatment strategies for non-small cell lung cancer. The durability of clinical activity in a subset of patients has led to a great deal of excitement and optimism.
Wednesday, September 14, 2016 5:17 PM|Andreas Hilgeroth|RSC - Med. Chem. Commun. latest articles|Labels: EGFR, IGFR

Med. Chem. Commun., 2016, Advance Article
DOI: 10.1039/C6MD00329J, Research Article
Cornelius Hempel, Abdulkarim Najjar, Frank Totzke, Christoph Schachtele, Wolfgang Sippl, Christoph Ritter, Andreas Hilgeroth
Small-molecule inhibitors of cancer-relevant receptor tyrosine kinases EGFR and IGF-1R have been discovered.
To cite this article before page numbers are assigned, use the DOI form of citation above.
The content of this RSS Feed (c) The Royal Society of Chemistry
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, breast cancer, clinical trial
This phase I trial studies the side effects and best dose of multiantigen deoxyribonucleic acid (DNA) plasmid-based vaccine in treating patients with human epidermal growth factor receptor 2 (HER2)-negative stage III-IV breast cancer. Multiantigen DNA plasmid-based vaccine may target immunogenic proteins expressed in breast cancer stem cells which are the component of breast cancer that is resistant to chemotherapy and has the ability to spread. Vaccines made from DNA may help the body build an effective immune response to kill tumor cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, breast cancer, clinical trial
This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug is still being studied and that research doctors are trying to find out more about it-such as the safest dose to use, the side effects it may cause, and if the drug is effective for treating different types of cancer. It also means that the FDA has not approved this drug for use patients undergoing adjuvant treatment for HER2+ breast cancer. Trastuzumab emtansine (T-DM1) is a drug that may stop cancer cells from growing. This drug has been used in other research studies and information from those other research studies suggests that this drug may help to prevent the recurrence of breast cancer in this research study. The use of T-DM1 in this research study is experimental, which means it is not approved by any regulatory authority for the adjuvant treatment of HER2-positive breast cancer. However, it FDA-approved for metastatic HER2-positive breast cancer. T-DM1 has caused cancer cells to die in laboratory studies. In preclinical studies, this drug has prevented or slowed the growth of breast cancer. The breast cancer treatments (paclitaxel and Trastuzumab) used in this study are considered part of standard-of-care regimens in early breast cancer. A standard treatment means that this is a treatment that would be accepted by the majority of the medical community as a suitable treatment for your type of breast cancer. In this research study, the investigators are looking to see if the study drug T-DM1 will have less side effects than traditional HER2-positive breast cancer treatment of trastuzumab and paclitaxel. The investigators are also hoping to learn about the long term benefits and disease-free survival of participants who take the study drug T-DM1 in comparison to those participants to take the combination of trastuzumab and paclitaxel.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, mTOR, brain cancer
This research study is a Feasibility clinical trial. In this trial, researchers are trying to figure out whether a medication can be chosen based on rapid testing done on tumor tissue. Information from a feasibility or pilot trial will hopefully help researchers plan larger trials in the future to determine the effect of this therapy.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, pancreatic cancer, clinical trial
This phase I/Ib trial studies the side effects and best dose of afatinib dimaleate when given together with capecitabine in treating patients with solid tumors, pancreatic cancer, or biliary cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment and has not responded to previous treatment. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving afatinib dimaleate together with capecitabine may be a better treatment for solid tumors, pancreatic cancer, or biliary cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, mTOR, breast cancer, clinical trial
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate, goserelin acetate, leuprolide acetate, anastrozole, letrozole, or exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet know whether hormone therapy is more effective when given with or without everolimus in treating breast cancer. PURPOSE: This randomized phase III trial studies how well giving hormone therapy together with or without everolimus work in treating patients with breast cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, PI3K, breast cancer, clinical trial
The purpose of the study is to determine whether treatment with a PI3K inhibitor plus letrozole leads to an increase in pathologic response compared to treatment with placebo plus letrozole in patients with Breast cancer
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, breast cancer
The main purpose of this study is to see whether CDX-011 (glembatumumab vedotin, an antibody-drug conjugate) is effective in treating patients who have advanced Triple-Negative Breast Cancer (TNBC; i.e., tumors lacking expression of estrogen, progesterone and HER2 receptors), and whose tumor cells make a protein called glycoprotein NMB (gpNMB), which CDX-011 binds to. The study will also further characterize the safety of CDX-011 treatment in this patient population.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, breast cancer, clinical trial
The purpose of this study is to determine whether patients treated with margetuximab plus chemotherapy have longer progression free survival and overall survival than patients treated with trastuzumab plus chemotherapy.
Wednesday, September 14, 2016 11:10 AM|Mayo Clinic Cancer Center - Research news|Labels: EGFR, breast cancer
JACKSONVILLE, Fla. — A marker of immune function that predicts for better outcomes in patients treated with chemotherapy for triple negative breast cancer is also linked to improved prognosis in patients treated with chemotherapy for HER2-positive breast cancer. But that marker — the quantity of tumor-infiltrating lymphocytes (S-TILs) in a biopsy — appears irrelevant when [...]
Wednesday, September 14, 2016 11:10 AM|Mayo Clinic Cancer Center - Research news|Labels: EGFR, breast cancer
Years After Treatment for HER2-Positive Early Stage Breast Cancer Trastuzumab Shows Life-Altering Benefit  JACKSONVILLE, Fla. — After following breast cancer patients for an average of eight-plus years, researchers say that adding trastuzumab (Herceptin) to chemotherapy significantly improved the overall and disease-free survival of women with early stage HER2-positive breast cancer. They found that the use of [...]
Wednesday, September 14, 2016 11:10 AM|Sini J Kalapurakal, James Malone, K. Thomas Robbins, Lucinda Buescher, John Godwin, Krishna Rao|Journal of Cancer|Labels: EGFR, skin cancer

Objectives: Non-melanoma skin cancer is the most common malignancy in US, with an annual incidence of in excess of 1.5 million cases. In the majority of cases, locoregional treatment is curative and systemic therapy is not indicated. Platinum-based chemotherapy regimens have been used most commonly in refractory cases. The use of cetuximab, a monoclonal antibody targeting epidermal growth factor receptor [EGFR], has been reported for skin cancer treatment. This current study evaluated eight cases of locally advanced and refractory basal cell or squamous cell cancers which were treated with cetuximab.

Methods: This is a retrospective study on eight patients who had received cetuximab for treatment of cutaneous carcinoma since 2007 at Southern Illinois University School of Medicine (SIU-SOM) Medical Oncology clinic.

Results: Three of the four patients with basal cell carcinoma and two of the four patients with squamous cell carcinoma maintained remission on treatment.. The main side effect was acneiform rash which required termination of treatment for one patient and dose reduction in another.

Conclusion: The study indicates that cetuximab may have a beneficial role for patients with non-melanoma cutaneous carcinomas that are refractory to standard therapy.

Wednesday, September 14, 2016 11:10 AM|Jan Trøst Jørgensen, Maria Hersom|Journal of Cancer|Labels: EGFR, gastric, biomarker diagnostic

Through the recent conduct of the ToGA trial, HER2 has shown to be predictive for the treatment with trastuzumab in advanced gastric and gastro-oesophageal cancer. When it comes to the prognostic properties the situation is different. Despite the fact that it is more than 20 years ago since the first studies demonstrating an association between a positive HER2 status and poor prognosis were published the issue is still controversial. In this current systematic review a large number of studies on HER2 and gastric cancer have been reviewed. The studies included in this review should fulfill the following two criteria. First criterion: The number of patients in each study should be ≥ 100, and the HER2 status should have been determined either by immunohistochemistry (IHC) or in situ hybridization (ISH). Second criterion: The selected articles should include an analysis of the association between the HER2 status and survival or relevant clinicopathological characteristics. Forty-two publications with a total of 12,749 patients fulfilled the two criteria and were reviewed in detail. The majority of the publications (71%) showed that a HER2-postive status measured either by IHC or ISH was associated with poor survival and/or clinicopathological characteristics, such as serosal invasion, lymph node metastases, disease stage, or distant metastases. Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer.

Wednesday, September 14, 2016 11:10 AM|Xin Yao, Janet Hosenpud, Christopher R. Chitambar, John Charlson, Yee Chung Cheng|Journal of Cancer|Labels: EGFR, breast cancer, clinical trial

Background: Neoadjuvant chemotherapy with concurrent docetaxel, doxorubicin and cyclophosphamide is commonly used for patients with locally advanced breast cancer. Epirubicin is another anthracycline used in breast cancer but the concurrent use of epirubicin and taxane is not well-established. We conducted a single institution, phase II study to assess the efficacy and safety of concurrent docetaxel, epirubicin and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen in breast cancer. Methods: Patients with newly diagnosed locally advanced breast cancer defined as T2 >3 cm, T3, T4 with any N, or any T with N1-3 were eligible. A chemotherapy regimen of docetaxel 75mg/m2, epirubicin 75mg/m2 and cyclophosphamide 600mg/m2 was given with filgrastim support every 3 weeks for 6 cycles. The primary end-point was pathologic complete response rate. Results: Twenty patients were enrolled from 2003 to 2006. The median age was 51 (29-70) year-old. Eight patients were premenopausal. Ten patients had positive hormone receptors. Four patients had HER2 positive receptor. Nineteen patients completed six cycles of TEC chemotherapy. The pathologic complete response rate was 25%. Eight of sixteen patients with N1-3 disease had pathological negative lymph nodes. With a median follow up of 57.5 (16-71) months, four patients relapsed including one death from recurrence. The estimated 5 year relapse-free survival was 79.3% and the 5-year overall survival was 94.7%. No patient had cardiac failure or death during treatment. The most common grade 3-4 toxicity was neutropenia (35%). Conclusion: TEC regimen is a well- tolerated and effective neoadjuvant chemotherapy regimen for locally advanced breast cancer that results in a pathologic complete response rate of 25%.

Wednesday, September 14, 2016 7:55 AM|KISS, I., MLCOCHOVA, J., BORTLICEK, Z., POPRACH, A., DRABEK, J., VYCHYTILOVA-FALTEJSKOVA, P., SVOBODA, M., BUCHLER, T., BATKO, S., RYSKA, A., HAJDUCH, M., SLABY, O.|Anticancer Research current issue|Labels: EGFR, CRC

Background: In metastatic colorectal cancer (mCRC), panitumumab is generally considered to be ineffective after the progression on cetuximab therapy. However, few studies have demonstrated that a small subset of mCRC patients may benefit from panitumumab in this setting. Patients and Methods: In our study, wild-type KRAS mCRC patients, enrolled into the nationwide Czech registry CORECT between January 2007 and December 2012, were screened for panitumumab therapy after progression on cetuximab. Results: We identified 26 mCRC in the registry with well documented progression on cetuximab in combination with irinotecan-based chemotherapy (FOLFIRI or irinotecan alone) who received panitumumab monotherapy. Partial response (PR) was achieved in 3 (11.5%) patients and stable disease (SD) in 7 (26.9%) patients after 8 weeks of therapy. Thirteen (50.0%) patients had evidence of progressive disease (PD) and in 3 (11.5%) cases response was not available. Furthermore, we confirmed that higher expression levels of newly described biomarker, miR-31-5p, in tumor are significantly associated with shorter progression-free survival (PFS) in patients treated with cetuximab (p=0.038); however, we did not observe association between miR-31-5p and response to panitumumab in mCRC patients after progression on cetuximab. Conclusion: It remains possible that a subset of mCRC patients may benefit from panitumumab after progression on cetuximab.

Wednesday, September 14, 2016 7:55 AM|RACHAR, V., CZEJKA, M., KITZMUELLER, M., BUCHNER, P., LICHTNECKERT, M., GREIL, R., GEILER, H., DITTRICH, C.|Anticancer Research current issue|Labels: EGFR, CRC, clinical trial

Aim: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX). Patients and Methods: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m2 bid p.o.), followed by CCB plus CTX (loading dose (LD)=400 mg/m2 followed by 250 mg/m2 weekly i.v. maintenance dose) (Arm A; n=12 patients (patients)) or CCB plus CTX followed by CCB alone (Arm B; n=12 patients). Plasma samples were collected from the cubital vein and CCB, 5’-desoxy-5-fluorocytidine (5’-DFCR) and 5’-desoxy-5 fluorouridine (5’-DFUR) were quantified by a sensitive, selective reversed phase high-performance liquid chromatography (HPLC) assay. Non-compartment pharmacokinetic parameters have been calculated by Phoenix WinNonlin. Results: No clinically relevant impact of CTX on CCB pharmacokinetic parameters and metabolic conversion could be detected in both arms after statistical evaluation (ANOVA). Conclusion: From the pharmacokinetic point of view, co-administration of CTX to CCB seems to be safe.

Wednesday, September 14, 2016 7:55 AM|HOLUBEC, L., POLIVKA, J., SAFANDA, M., KARAS, M., LISKA, V.|Anticancer Research current issue|Labels: EGFR, CRC

Monoclonal antibodies binding the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, are widely used targeted therapeutics for the treatment of patients with colorectal cancer. The clinical significance of these drugs has so far been associated with combined chemotherapy or radiation. It has been shown that these treatment strategies have their clinical limitations and do not fully exploit the immunomodulatory effect of these drugs. In this review, we discuss the mechanisms of immunomodulation together with the anticancer immune response to the monoclonal antibodies targeted to the EGFR. The combination of anti-EGFR monoclonal antibodies with other immunotherapeutic treatment modalities certainly brings new opportunities for targeted therapy in patients with colorectal cancer.

Wednesday, September 14, 2016 5:40 AM|Hiroyuki Minemura, Kiyoshi Takagi, Ai Sato, Hikaru Takahashi, Yasuhiro Miki, Yukiko Shibahara, Mika Watanabe, Takanori Ishida, Hironobu Sasano, Takashi Suzuki|Cancer Science|Labels: EGFR, P53, breast cancer
CITED2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2) is a member of CITED family and involved in various cellular functions during development and differentiation. Mounting evidence suggests importance of CITEDs in the progression of human malignancies, but significance of CITED2 protein has not yet been examined in breast carcinoma. Therefore, in this study, we examined clinical significance and biological functions of CITED2 in breast carcinoma by immunohistochemistry and in vitro studies. CITED2 immunoreactivity was detected in the breast carcinoma tissues, and it was significantly higher compared to the morphologically normal mammary glands. CITED2 immunoreactivity was significantly associated with stage, pathological T factor, lymph node metastasis, histological grade, HER2 and Ki-67, and inversely correlated with estrogen receptor. Moreover, the immunohistochemical CITED2 status was significantly associated with increased incidence of recurrence and breast cancer-specific death of the breast cancer patients, and multivariate analyses demonstrated CITED2 status as an independent worse prognostic factor for disease-free and breast cancer-specific survival. Subsequent in vitro experiments showed that CITED2 expression significantly increased proliferation activity and migration property in MCF-7 and SKBR-3 breast carcinoma cells. Moreover, CITED2 caused chemoresistance to epirubicin and 5-fluorouracil, but not paclitaxel, in these cells, and it inhibited p53 accumulation after 5-fluorouracil treatment in MCF-7 cells. These results suggest that CITED2 plays important roles in the progression and chemoresistance of breast carcinoma and CITED2 status is a potent prognostic factor in breast cancer patients. This article is protected by copyright. All rights reserved.
Tuesday, September 13, 2016 11:38 PM|Adriana Priscila Trapé, Shuying Liu, Andrea Carolina Cortes, Naoto T. Ueno, Ana Maria Gonzalez-Angulo|Journal of Cancer|Labels: CDK, EGFR, breast cancer

Among patients with hormone receptor (HR)-positive breast cancer, those with residual disease after neoadjuvant chemotherapy have a higher risk of relapse and poorer survival than those with a complete response. Previous studies have revealed a correlation between activation of cell cycle-regulating pathways in HR-positive breast cancer, particularly cyclin-dependent kinase (CDK) 4 and 6/cyclin D1 signaling, and resistance to standard therapies. Although CDK4/6 inhibition by palbociclib in combination with endocrine therapy has shown potent antiproliferative effects in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the potential role of palbociclib in re-sensitizing chemotherapy-resistant HR-positive breast cancer is not well defined. We hypothesized that CDK4/6 inhibition by palbociclib re-sensitizes HR-positive/HER2-negative residual breast cancer to taxane-based adjuvant therapy. Using cell counting, flow cytometry, and western blotting, we evaluated the efficacy of palbociclib alone and in concurrent or sequential combination with paclitaxel in parental and paclitaxel-resistant T47D HR-positive/HER2-negative breast cancer cells. The CDK4/6 pathway was constitutively active in both parental and paclitaxel-resistant T47D cells; thus, both cell types were highly sensitive to the inhibitory effects of single-agent palbociclib on cell growth and cell cycle progression. However, palbociclib did not re-sensitize resistant cells to paclitaxel-induced G2/M arrest and cell death in any of the combinations tested. Our results suggest that CDK4/6 inhibition by palbociclib does not re-sensitize HR-positive/HER2-negative residual breast cancer to chemotherapy. Nevertheless, the fact that CDK4/6 activation remained intact in paclitaxel-resistant cells indicates that patients who have HR-positive/HER2-negative residual disease after taxane-based neoadjuvant chemotherapy may still benefit from palbociclib in combination with other regimens, such as endocrine therapies, for adjuvant therapy.

Tuesday, September 13, 2016 11:38 PM|Ya-Ping Xu, Gang Lin, Xiao-Jiang Sun, Mao-Hui Yan, Gu Zhang, Jin-Lin Hu, Wen-Yong Sun, Jin-Ming Yu|Journal of Cancer|Labels: EGFR, MET, esophageal cancer

Background: Epidermal growth factor receptor (EGFR), c-Met, and human epidermal growth factor receptor 2 (HER2) are overexpressed in a variety of human cancers, and may serve as biomarkers for disease prognosis. We examined whether high expression of these molecular markers correlates with poor disease prognosis in esophageal squamous cell cancer (ESCC). Materials and Methods: Expression of EGFR, c-Met, and HER2 protein was detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients. The overall survival (OS) rates were calculated according to the Kaplan-Meier method, and the log-rank test was used to evaluate differences between survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses. Results: The median survival of all patients was 46 months. There was no significant difference in OS in terms of HER2 and EGFR status (P = 0.177 and P=0.061, respectively). However, there was a significant difference in OS between c-Met high expression patients and c-Met low expression or negative patients (median: 41.9 months vs. 56.7 months; P = 0.001). Multivariate analysis also showed that, of the covariates analyzed, c-Met high expression was the only prognostic factor for OS (HR: 0.459 [95 % confidence interval: 0.287-0.733]; P = 0.001). Patients with ESCC that had concurrent overexpression of EGFR and c-Met had significantly worse survival than ESCC that displayed overexpression of either EGFR or c-Met individually or that did not have overexpression of either protein (P=0.000). Conclusions: Overexpression of HER2 and EGFR individually is not significantly associated with poor prognosis in ESCC. High expression of c-Met may be indicative of a poorer prognosis in ESCC. In order to promote efficient and rapid development of therapeutic methods in ESCC, further studies are necessary to explore the role of c-Met.

Tuesday, September 13, 2016 11:38 PM|Ivette J. Suárez-Arroyo, Tiffany J. Rios-Fuller, Yismeilin R. Feliz-Mosquea, Mercedes Lacourt-Ventura, Daniel J. Leal-Alviarez, Gerónimo Maldonado-Martinez, Luis A. Cubano, Michelle M. Martínez-Montemayor|Journal of Cancer|Labels: EGFR, breast cancer

The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors.

Tuesday, September 13, 2016 8:19 PM|Antonino Grassadonia, Marta Caporale, Nicola Tinari, Marinella Zilli, Michele DeTursi, Teresa Gamucci, Patrizia Vici, Clara Natoli|Journal of Cancer (RSS 2.0)|Labels: EGFR, mTOR, breast cancer, clinical trial

Inhibition of aberrantly activated pathways cross-talking with hormone receptor (HR) improves response to endocrine therapy in patients with HR-positive advanced breast cancer. We performed a Pubmed database systematic review to ascertain the existence of a better clinical response when combining endocrine therapy with targeted agents in the neoadjuvant setting. Preclinical studies or trials evaluating toxicity were excluded.

We found nine phase II trials that fulfilled the research criteria. The endocrine agents used were third generation aromatase inhibitors (AIs), anastrozole, letrozole or exemestane. The investigated targeted agents were inhibitors of tyrosine kinase receptors such as gefitinib, imatinib or trastuzumab/lapatinib, inhibitors of mTOR, such as everolimus, inhibitors of COX-2, such as celecoxib, and inhibitors of angiogenesis, such as bevacizumab. The response rate (RR) observed combining endocrine and targeted agents ranged between 36% and 90%.

Overall the studies failed to show a remarkable advantage in RR in the combination group compared to historical control subjects receiving AIs alone.

Tuesday, September 13, 2016 8:19 PM|Yuan-Yuan Li, Sze-Kwan Lam, Chun-Yan Zheng, James Chung-Man Ho|Journal of Cancer (RSS 2.0)|Labels: EGFR, lung cancer

Lung cancer is the top cancer killer worldwide. Tyrosine kinase inhibitors (TKIs), for example erlotinib, are commonly used to target epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC). Autophagy is a cellular response to stress, serving as a protective mechanism during anticancer therapy. The tumor microenvironment (TME) is composed of non-tumor cells that include fibroblasts. Our study aimed to investigate the effect of TME on autophagy and TKI sensitivity. Following cell sorting after direct co-culturing, autophagy and cytokine production were observed in both HCC827 and MRC-5 cells. The synergistic combination of erlotinib and chloroquine (autophagy inhibitor) was observed under TME. Tumor growth was significantly suppressed with combined erlotinib/chloroquine compared with erlotinib in HCC827 xenografts.

Tuesday, September 13, 2016 8:19 PM|Sreeja C Sekhar, Tomonari Kasai, Ayano Satoh, Tsukasa Shigehiro, Akifumi Mizutani, Hiroshi Murakami, Bishoy YA El-Aarag, David S. Salomon, Anna Massaguer, Rafael de Llorens, Masaharu Seno|Journal of Cancer|Labels: EGFR, breast cancer

The oncogenic tyrosine kinase receptor ErbB2 is a prognostic factor and target for breast cancer therapeutics. In contrast with the other ErbB receptors, ErbB2 is hardly internalized by ligand induced mechanisms, indicating a prevalent surface expression. Elevated levels of ErbB2 in tumor cells are associated with its defective endocytosis and down regulation. Here we show that caveolin-1 expression in breast cancer derived SKBR-3 cells (SKBR-3/Cav-1) facilitates ligand induced ErbB2 endocytosis using an artificial peptide ligand EC-eGFP. Similarly, stimulation with humanized anti ErbB2 antibody Trastuzumab (Herceptin) was found to be internalized and co-localized with caveolin-1 in SKBR-3/Cav-1 cells. Internalized EC-eGFP and Trastuzumab in SKBR-3/Cav-1 cells were then delivered via caveolae to the caveolin-1 containing early endosomes. Consequently, attenuated Fc receptor mediated ADCC functions were observed when exposed to Trastuzumab and EC-Fc (EC-1 peptide conjugated to Fc part of human IgG). On the other hand, this caveolae dependent endocytic synergy was not observed in parental SKBR-3 cells. Therefore, caveolin-1 expression in breast cancer cells could be a predictive factor to estimate how cancer cells are likely to respond to Trastuzumab treatment.

Tuesday, September 13, 2016 8:19 PM|Yee Chung Cheng, Gabriela Rondón, Paolo Anderlini, Issa F. Khouri, Richard E. Champlin, Naoto T. Ueno|Journal of Cancer|Labels: EGFR, breast cancer

We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (AHST) for patients with HER2-positive metastatic breast cancer. Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results.

Tuesday, September 13, 2016 8:19 PM|Akiko Nakayama, Shinji Takagi, Tadashi Yusa, Masahiro Yaguchi, Akira Hayashi, Toshiya Tamura, Youichi Kawakita, Tomoyasu Ishikawa, Yoshikazu Ohta|Journal of Cancer|Labels: EGFR, breast cancer

Breast cancer therapy has improved following the development of drugs with specific molecular targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model. TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases.

Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: EGFR, breast cancer
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Morimoto, T.; Michishita, S.
Background : T-DM1 is the standard regimen for advanced or recurrent HER2 positive breast cancer patients in the second line. The purpose of this study is to evaluate the effect of T-DM1 therapy as the late line for HER2 positive breast cancer pat...
Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: EGFR, breast cancer
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Rahouma, M.; Abou El-Kasem, F.; Aziz, H.;...
Background : It is well known that presence of ER, PR or HER2neu is associated with better response to hormonal Tx & Herceptin. Looking from a different angle, we thought to detect predictors of PR and HER2neu Positivity Prior to Biopsy in adv...
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Wagner, A.D.; Kang, Y.K.; Van Dieren, J.;...
Background : Around 10–20% of patients with gastric cancer (GCa) have HER2+ tumors. The addition of trastuzumab to cisplatin/fluoropyrimidine based regimen improved survival in metastatic HER2+ GCa. When pertuzumab was added to trastuzumab and che...
Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: EGFR, gastric
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Ciesielski, M.; Szajewski, M.; Kruszewski, W.J.;...
Background : In gastric cancer, HER2 protein overexpression is considered to be conducive to the higher proliferation activity of tumour cells. Tumour formation is associated with angiogenesis in order to secure an abundant supply of oxygen and gl...
Tuesday, September 13, 2016 4:00 PM|Cheng, Murakami, Yang, He, Nakagawa, Kang, Kim, Wang, Enatsu, Puri, Orlando, Yang|Journal of Clinical Oncology Current Issue|Labels: EGFR, lung cancer
Purpose

To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non–small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations.

Patients and Methods

Chemotherapy-naïve for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m2 on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65).

Results

PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable.

Conclusion

P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation–positive patients new treatment options and improved clinical outcomes compared with the current standard of care.

Tuesday, September 13, 2016 4:00 PM|Urata, Katakami, Morita, Kaji, Yoshioka, Seto, Satouchi, Iwamoto, Kanehara, Fujimoto, Ikeda, Murakami, Daga, Oguri, Goto, Imamura, Sugawara, Saka, Nogami, Negoro, Nakagawa, Nakanishi|Journal of Clinical Oncology Current Issue|Labels: EGFR, lung cancer, clinical trial
Purpose

The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non–small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs.

Patients and Methods

Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS).

Results

Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinib were 6.5 and 7.5 months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P = .257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P = .768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation–positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P = .424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib).

Conclusion

The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.

Tuesday, September 13, 2016 2:05 PM|Patrizia Vici, Laura Pizzuti, Teresa Gamucci, Domenico Sergi, Francesca Conti, Germano Zampa, Pietro Del Medico, Roy De Vita, Marcello Pozzi, Claudio Botti, Simona Di Filippo, Federica Tomao, Isabella Sperduti, Luigi Di Lauro|Journal of Cancer|Labels: EGFR, breast cancer

Purpose: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer. In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines. We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice.

Methods: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres. Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks. In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel.

Results: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy. In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%. A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%) pCR was observed (p=0.14). Treatments were well tolerated. The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity.

Conclusions: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice.

Tuesday, September 13, 2016 10:22 AM|Google News on 'breast cancer'|Labels: EGFR, breast cancer

Science Daily

How a diabetes drug might stop breast cancer
Futurity: Research News
Scientists have discovered a way to fight the overexpression of a protein associated with the growth of breast cancer. They say pioglitazone, a drug that is typically used to treat type 2 diabetes, may offer a way to dial down levels of the protein NAF ...
New tools join breast cancer fightScience Daily
Circulating Breast Cancer Cells Can Switch HER2 Gene On-Off to Evade TreatmentBreast Cancer News
Breast cancer breakthrough: Spread of disease could be stopped with DIABETES drugExpress.co.uk
Medical Xpress
all 9 news articles »
Monday, September 12, 2016 6:00 PM|José Leone|International Journal of Molecular Sciences|Labels: CDK, EGFR, VEGF, breast cancer
The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.
Sunday, September 11, 2016 11:00 PM|Guo, Xiaoqing; Meng, Yue; Sheng, Xiaotong; Guan, Yuan; Zhang, Fenglei; Han, Zhen; Kang, Yuying; Tai, Guihua; Zhou, Yifa; Cheng, Hairong|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: EGFR, Jnk, TNF, CRC
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in many tumor cells while leaving normal cells intact and is thus an attractive candidate for antitumor therapies. This paper reports that the combination of tunicamycin plus TRAIL produced a strong synergistic effect in TRAIL-sensitive human colon cancer HCT116 cells and TRAIL-resistant HT-29 cells. On a cellular mechanistic level, tunicamycin-enhanced TRAIL-induced apoptosis by death receptor (DR) 5 upregulation and DR4 deglycosylation. Knockdown of DR5 but not DR4 expression by specific shRNAs or siRNAs significantly increased tunicamycin-mediated and TRAIL-mediated cell viability. DR5 induction was regulated by C/EBP homologous protein (CHOP) and JNK as CHOP siRNA or JNK inhibitor SP600125 considerably abolished the DR5 induction. In addition, tunicamycin inhibited epidermal growth factor receptor glycosylation and the downstream signaling pathways, Akt and extracellular signal-regulated kinases activation, which might also be required for TRAIL sensitization by tunicamycin. In summary, tunicamycin effectively enhanced TRAIL-induced apoptosis might through JNK-CHOP-mediated DR5 upregulation and the inhibition of the epidermal growth factor receptor pathway. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Thursday, September 8, 2016 10:00 PM|Food and Drug Adminstration (FDA): CDRHNew|Labels: EGFR, lung cancer, biomarker diagnostic
The cobas® EGFR Mutation Test v2 is an automated molecular assay designed to detect the presence of mutations in the epidermal growth factor receptor (EGFR) gene in cancer-spreading (metastatic) non-small cell lung cancer (NSCLC). In normal tissue, the...
Thursday, September 1, 2016 10:05 PM|Liikanen, I., Tähtinen, S., Guse, K., Gutmann, T., Savola, P., Oksanen, M., Kanerva, A., Hemminki, A.|Molecular Cancer Therapeutics current issue|Labels: EGFR

Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with full-length trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-24-tras, coding for human trastuzumab antibody heavy- and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259–69. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Wang, X., Wong, J., Sevinsky, C. J., Kokabee, L., Khan, F., Sun, Y., Conklin, D. S.|Molecular Cancer Therapeutics current issue|Labels: Btk, EGFR, breast cancer

We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292, and CGI-1746, reduce breast cancer cell survival and prevent drug-resistant clones from arising. Ibrutinib treatment impacts HER2+ breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4. Consequently, the activation of AKT and ERK signaling pathways are also blocked leading to a G1–S cell-cycle delay and increased apoptosis. Importantly, inhibition of BTK prevents activation of the AKT signaling pathway by NRG or EGF that has been shown to promote growth factor–driven lapatinib resistance in HER2+ breast cancer cells. HER2+ breast cancer cell proliferation is blocked by ibrutinib even in the presence of these factors. AVL-292, which has no effect on EGFR family activation, prevents NRG- and EGF-dependent growth factor–driven resistance to lapatinib in HER2+ breast cancer cells. In vivo, ibrutinib inhibits HER2+ xenograft tumor growth. Consistent with this, immunofluorescence analysis of xenograft tumors shows that ibrutinib reduces the phosphorylation of HER2, BTK, Akt, and Erk and histone H3 and increases cleaved caspase-3 signals. As BTK-C and HER2 are often coexpressed in human breast cancers, these observations indicate that BTK-C is a potential therapeutic target and that ibrutinib could be an effective drug especially for HER2+ breast cancer. Mol Cancer Ther; 15(9); 2198–208. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Bertino, E. M., McMichael, E. L., Mo, X., Trikha, P., Davis, M., Paul, B., Grever, M., Carson, W. E., Otterson, G. A.|Molecular Cancer Therapeutics current issue|Labels: EGFR, CRC, HNN, clinical trial

mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m2 i.v. every two weeks with lenalidomide given orally days 1–21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily, days 1–21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244–50. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|LaBonte, M. J., Yang, D., Zhang, W., Wilson, P. M., Nagarwala, Y. M., Koch, K. M., Briner, C., Kaneko, T., Rha, S.-Y., Gladkov, O., Urba, S. G., Sakaeva, D., Pishvaian, M. J., Hsieh, R.-K., Lee, W.-P., Lenz, H.-J.|Molecular Cancer Therapeutics current issue|Labels: EGFR, gastric, biomarker diagnostic, clinical trial

An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m2 twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P = 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther; 15(9); 2251–8. ©2016 AACR.

Wednesday, August 31, 2016 11:00 PM|Agrawal, Anil; Ziolkowski, Piotr; Grzebieniak, Zygmunt; Jelen, Michal; Bobinski, Piotr; Agrawal, Siddarth|Applied Immunohistochemistry & Molecular Morphology - Current Issue|Labels: EGFR, breast cancer
imageObjectives: The aim of the study was to estimate the implications of androgen receptor (AR) expression in estrogen receptor (ER)-positive subset of invasive breast carcinoma patients. Patients and Methods: We assessed the AR expression in a subset of 96 predominantly ER-positive invasive breast carcinomas and correlated this expression pattern with several clinical and pathologic parameters: histologic type and grade, tumor size, lymph node status, progesterone receptor (PgR) status, and human epidermal growth factor receptor type 2 (HER2) overexpression and evaluated the association of these parameters with 10-year survival using univariate and multivariate analyses. Data used for analysis were derived from medical records. Immunohistochemical analysis for AR, ER, PgR, and HER2 were carried out and semiquantitative evaluation of stainings was performed. Results: AR expression was demonstrated in 43.7% of patients. AR was significantly related to well-differentiated tumors and positive PgR/HER2 status. No statistical difference was demonstrated in AR expression in relation to tumor size, lymph node status, menopausal status, and tumor histologic type. AR expression was not an independent prognostic factor related to 10-year survival in ER-positive cancers. In multivariate analyses, older age at diagnosis, larger tumor size, and positive lymph node status were significantly associated with poorer 10-year survival. Conclusions: AR expression is significantly associated with ER/PgR/HER2 status and positively related to well-differentiated tumors. Although AR status in ER-positive cancers is not an independent prognostic factor, it might provide important additional information on prognosis and become a promising object for targeted therapy.
Wednesday, August 31, 2016 10:05 PM|A. H.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: EGFR, esophageal cancer

New Strategies in Esophageal Cancer
Wang, V. E Grandis, J. R, Ko, A. H.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4283 - 4290
Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting HER2 and VEGFR in selected patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, although large-scale exome and whole-genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both esophageal adenocarcinoma and SCC and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features. Clin Cancer Res; 22(17); 4283&ndash;90. &copy;2016 AACR.

Wednesday, August 31, 2016 10:05 PM|Wang, V. E., Grandis, J. R., Ko, A. H.|Clinical Cancer Research recent issues|Labels: EGFR, esophageal cancer

Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting HER2 and VEGFR in selected patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, although large-scale exome and whole-genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both esophageal adenocarcinoma and SCC and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features. Clin Cancer Res; 22(17); 4283–90. ©2016 AACR.

Wednesday, August 31, 2016 6:00 PM|Terence Van Raay|Cancers|Labels: EGFR, WNT
The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2), there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO) for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef) reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling.
Tuesday, August 30, 2016 6:00 PM|Chi-Wen Luo|International Journal of Molecular Sciences|Labels: EGFR, INT, breast cancer
Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival.
Thursday, August 25, 2016 7:16 AM|Google News on 'breast cancer'|Labels: EGFR, breast cancer

Science Daily

Dynamic Nature of Breast Cancer Resistance: The HER2 Switch
AJMC.com Managed Markets Network
Research at Massachusetts General Hospital has provided clues to drug resistance in breast cancer—the smart tumor cells switch between a human epidermal growth factor receptor 2 (HER2)-negative to a HER2-positive state, which can result in disease ...
Breast cancer cells found to switch molecular characteristicsScience Daily
Harvard Breast Cancer Study of HER2 Expression Identifies New Potential Treatment OptionsGenomeWeb

all 6 news articles »
Thursday, August 25, 2016 6:57 AM|Google News on 'cancer for a feed'|Labels: EGFR, regulatory

EMA accepts Mylan, Biocon Trastuzumab biosimilar for review
India Today
New Delhi, Aug 25 (PTI) European Medicines Agency (EMA) has accepted for review Mylans application to market biosimilar Trastuzumab, co-developed with Biocon, that is used to treat certain breast and gastric cancers. This is the second biosimilar ...

and more »
Wednesday, August 24, 2016 6:00 PM|Qing-Hai Ye, Wen-Wei Zhu, Ju-Bo Zhang, Yi Qin, Ming Lu, Guo-Ling Lin, Lei Guo, Bo Zhang, Zhen-Hai Lin, Stephanie Roessler, Marshonna Forgues, Hu-Liang Jia, Lu Lu, Xiao-Fei Zhang, Bao-Feng Lian, Lu Xie, Qiong-Zhu Dong, Zhao-You Tang, Xin Wei Wang, Lun-Xiu Qin|Cancer Cell|Labels: EGFR, liver cancer
Ye et al. identify GOLM1 as a key promoter of hepatocellular carcinoma (HCC) metastasis and determine its critical roles in the recycling, spatial redistribution, and signaling kinetics of EGFR/RTKs. In human HCC, GOLM1 expression is correlated with early recurrence, metastasis, and poor patient survival.
Monday, August 22, 2016 8:40 AM|Zhu, A. X., Kang, Y.-K., Rosmorduc, O., Evans, T. R. J., Santoro, A., Ross, P., Gane, E., Vogel, A., Jeffers, M., Meinhardt, G., Pena, C. E. A.|Clinical Cancer Research Online First Articles|Labels: EGFR, liver cancer, biomarker diagnostic

Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial.

Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples.

Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n = 243; sorafenib plus placebo, n = 251). Treatment arm–independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P = 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P = 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P = 0.0233; e-adj P = 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P = 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P = 0.030; e-adj P = 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib.

Conclusions: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS. Clin Cancer Res; 1–10. ©2016 AACR.

Friday, August 19, 2016 2:22 AM|News-Medical.Net Erlotinib News Feed|Comments|Labels: EGFR, lung cancer, regulatory
Afatinib (trade name: Giotrif) has been approved since April 2016 for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) of squamous histology who have already received chemotherapy.
Sunday, August 14, 2016 10:05 PM|Keller, J., Nimnual, A. S., Varghese, M. S., VanHeyst, K. A., Hayman, M. J., Chan, E. L.|Molecular Cancer Research recent issues|Labels: EGFR, brain cancer

EGFR is a popular therapeutic target for many cancers. EGFR inhibitors have been tested in children with refractory neuroblastoma. Interestingly, partial response or stable disease was observed in a few neuroblastoma patients. As EGFR mutations are biomarkers for response to anti-EGFR drugs, primary neuroblastoma tumors and cell lines were screened for mutations. A novel EGFR extracellular domain deletion mutant, EGFR768, was discovered and the biologic and biochemical properties of this mutant were characterized and compared with wild-type and EGFRvIII receptors. EGFR768 was found to be constitutively active and localized to the cell surface. Its expression conferred resistance to etoposide and drove proliferation as well as invasion of cancer cells. While EGFR768 had similarity to EGFRvIII, its biologic and biochemical properties were distinctly different from both the EGFRvIII and wild-type receptors. Even though erlotinib inhibited EGFR768, its effect on the mutant was not as strong as that on wild-type EGFR and EGFRvIII. In addition, downstream signaling of EGFR768 was different from that of the wild-type receptor. In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFR768. The EGFR768 also possesses distinct biologic and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant.

Implications: Neuroblastoma expressed a novel EGFR mutant which possesses distinct biologic and biochemical properties that might have therapeutic implications. Mol Cancer Res; 14(8); 740–52. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Wei, P.-L., Tseng, C.-S., Chen, C.-C., Chiu, C.-J., Hsiao, G.|Clinical Cancer Research recent issues|Labels: EGFR, CRC

Background: Previously we have demonstrated the novel microtube array membrane (MTAM) can serves as an excellent substrate for a rapid, in vivo anti-cancer drug screening assay based on the hollow fiber assay (HFA), with higher cell-drug sensitivity, cell-host interaction, plus the clear angiogenesis, owing to its unique structural characteristics. In current study, the patient derived tumor cells (PDTC) were subjected to MTAM/X based screening platform. Patient derived colon cancer sample was treated and loaded into MTAM, studied first in cell growth and characterization, and later the cell toxicity by several representative cancer drugs, both in vitro and in vivo. The goal of this study is to explore the potential of utilizing MTAM/X with PDX for rapid, reliable, lower cost personalized anti-cancer drug selection platform.

Materials and Methods: Nano-porous PLLA MTAMs (npMTAM) were fabricated via a co-axial electrospinning and characterized morphologically first, then mechanical and permeation properties were determined. The nano-porous microstructure was also characterized by porosimeter. PTDC (colon cancer, 0.5 cm3) was obtained surgically and treated with enzyme-containing medium, homogenized before loaded into npMTAM at 105-106 cell per sample. The subcutaneous implantation of these MTAMs were conducted with 4 MTAMs per model (BALB/c) one day before the drug treatment. Regiments used according to the recommended dosage were cisplatin, 5 FU and Erbitux. In vitro and in vivo PDTC growth within MTAM were determined via MTT assay. The in vivo drug cytotoxicity towards PDTC was then determined by MTT in a 9-day period, in the meantime, the supportive results of angiogenesis was characterized via imaging process.

Results: Nano-porous PLLA MTAMs were successfully prepared with a tube wall thickness of 2-3 microns and pore size of 100-200 nm. PDTC (colon cancer) was loaded into npMTAM within 2 hours after surgical collection. The in vitro and in vivo growth of PDTC in npMTAM was observed clearly in a two weeks period. Upon the administration of 5 FU, Cisplatin and Erbitux to the test model, cell growth was altered, however in different fashion. 5FU show early cell cytotoxicity, however, loss its inhibition capability afterwards. Erbitux showed no sign of inhibition. Finally greatest inhibition of this particular patient tumor was found with cisplatin. Extent of angiogenesis was found to be in consist with MTT data. The overall time needed to generate the final results is within 2 weeks.

Conclusions: Testing PDTC in vivo within npMTAM based assay (PDXiMTAM), we demonstrated the feasibility of in vivo personalized cancer drug selection platform can be achieved in a reasonable time periods of 2 weeks. Selection from a group of four regiments, cisplatin demonstrated its highest cytotoxicity towards this specific tumor. This will be a very practical assay in clinical setting to identify most effective drug at personal level. Our results therefore suggest that such assay could be further developed in timely treatment selection. A double blind, cohort clinical trial of 60 patients with colon cancer is currently ongoing to validate PDXiMTAM.

Citation Format: Po-Li Wei, Chia-Shiuan Tseng, Chien-Chung Chen, Chien-Jin Chiu, George Hsiao. The implication of patient derived tumor cell (PDTC) tested/screened with novel microtube array membrane (MTAM)-based hollow fiber assay (HFA).. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A33.

Sunday, August 14, 2016 10:05 PM|Jen, J., Mansfield, A., Eiken, P. W., Stoddard, S., Pierson, K., Hou, X., Ren, H. Z., Molina, J., Yi, J., Yang, P.|Clinical Cancer Research recent issues|Labels: ALK, EGFR, lung cancer

Mutations in the EGFR gene or transcript fusion involving EML4-ALK result in oncogenic activation of these oncogenes driving lung adenocarcinoma growth in tumors carrying such an alteration. For lung adenocarcinoma with these genetic changes, small-molecule tyrosine kinase inhibitors have been highly effective at reducing tumor burden and improve the outcome of the patients. Unfortunately, drug resistance eventually develops in these tumors and challenges remain in controlling lung cancer recurrence after targeted therapy.

To overcome recurrence, we initiated a prove-of-principle study to evaluate the feasibility of an integrated strategy utilizing genomic profiles of the tumor and patient-specific tumor xenografts derived (PDX) from biopsies for ex vivo evaluation of antitumor drugs to help guide personalized treatment of lung cancer in patients who have developed resistance to targeted therapy drugs. Our study has three main objectives. 1) Use tumor biopsies obtained at the time of recurrence for oncogene mutation and RNAseq analyses to identify molecular changes in oncogenes and gene pathways that can be potentially targeted. 2) Evaluate drug efficacy and optimize personalized therapy for each patient using PDX models. 3) Assess clinical feasibility and our experience using integrated approaches for lung cancer patients who failed targeted therapy.

This study was approved by the Mayo Clinic Institutional Review Board (IRB) and utilizes both clinical and research biopsies. A dedicated nurse study coordinator reviews clinical patient list and history on weekly basis and informs the study team of each potential candidate patient. A total of 30 patients having ALK positive lung cancers have been identified and followed up from nearly 500 potentially ALK positive cases between April 2014 to Sept. 2015. Most patients were never smokers but six were former smokers and two were current smokers. Age at diagnoses ranged from 27-78 years (median = 61). Seven patients (23%) were 45 years or younger at the time of diagnosis. A total of 22 patients are currently being treated with crizotinib while eight are on ceritinib or alectinib. For each biopsy, tumor tissues are obtained using a 20 gauge needle, transferred on ice in preserving media and implanted within one hour into 6-8 week old NOD/SCID mice. Many patients have been on treatment for 2-3 years with stable disease so they do not require biopsy. Using a similar strategy, we also obtained biopsies from patients with EGFR gene mutations in their tumors and have progressed while on targeted therapy.

A total of seven cases have been implanted. We will report our experiences in patient selection, clinical follow up, patient consent, PDX development, time from biopsy to tumor establishment, and the results of molecular analyses. Our study enabled us to gain new insights regarding the molecular changes associated with recurring tumors after they have failed targeted therapy as well as clinical experiences on how to utilize state-of-the art approaches and comprehensive genomic information to further improve cancer patient care upon disease progression.

Acknowledgements: This work is supported in part by the Hillsberg Award from the National Foundation for Cancer Research and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine.

Citation Format: Jin Jen, Aaron Mansfield, Patrick W. Eiken, Shawn Stoddard, Karlyn Pierson, Xiaonan Hou, Hong Zheng Ren, Julian Molina, Joanne Yi, Ping Yang. Integrated Approaches to Treating Lung Adenocarcinoma Resistant to Targeted Therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B34.

Sunday, August 14, 2016 10:05 PM|Lewis, M. T., Dobrolecki, L. E., Hilsenbeck, S. G., Simon, L. M., Shaw, C. A.|Clinical Cancer Research recent issues|Labels: EGFR, breast cancer

Background: Clinical oncology trials in humans have major limitations, not the least of which is the inability to treat a single tumor with multiple drugs simultaneously to identify the most effective treatment options. In theory, this and other limitations can be overcome using an "animal clinical trial" platform that exploits collections of human cancer patient-derived xenograft (PDX) models.

Clinically, breast cancers are divided into three distinct groups: those that express the estrogen hormone receptor (ER+) (which typically also express the progesterone hormone receptor (PR+), those that are amplified or overexpress the ErbB2 (HER2) oncogene (HER2+), and those that express none of these three markers (termed triple negative breast cancer TNBC).

Unlike ER+ and HER2+ breast cancers, there are currently no targeted therapies against TNBC. Treatment of TNBC entails surgery coupled with radio- or chemotherapy, or both. Chemotherapy options include Taxanes (e.g. Docetaxel, Paclitaxel), Anthracyclin based therapies (Adriamycin/Doxorubicin plus Cytoxan (cyclophosphamide) (AC), and more recently, and platinum-based agents (e.g. Cisplatin, Carboplatin). However, other than BRCA1/2 mutation status correlating with increased efficacy of platinum-based agents, there are currently no clinically useful predictors of differential treatment response among these three commonly used chemotherapeutics.

Hypothesis: We hypothesized that a molecular predictor of differential chemotherapy response could be developed using human breast cancer patient-derived xenografts as the discovery platform.

Materials and Methods: We tested this hypothesis in an "animal clinical trial" using 20 PDX treated with three chemotherapies vs. control. Molecular correlates of response were identified in RNAseq and proteomic data, and are being validated in a separate cohort of PDX.

Results: We show that animal clinical trials are feasible, and can be conducted efficiently, using minimal staff. Further, we extend our previous analysis showing that treatment responses observed clinically are recapitulated in the PDX lines, thereby establishing clinical relevance of observed responses. Finally, we demonstrate that PDX show largely non-overlapping sensitivity to only one of the three agents tested, with corresponding largely non-overlapping molecular signatures delineating those PDX that respond to a given treatment from those that do not. Validation studies in newly developed PDX lines are ongoing.

Conclusions: Together, these data suggest that PDX models should be useful for generating predictors of treatment response. Ultimately, if robust genetic, epigenetic, or molecular predictors of differential treatment response can be identified and applied clinically, it may be possible to avoid ineffective treatments, minimize exposure to cytotoxic agents, and ultimately increase survivorship.

Citation Format: Michael T. Lewis, Lacey E. Dobrolecki, Susan G. Hilsenbeck, Lukas M. Simon, Chad A. Shaw. Identification of molecular predictors of differential chemotherapy response using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B04.

Sunday, August 14, 2016 10:05 PM|Pavia-Jimenez, A., Chen, W., Hill, H., Christie, A., Yousuf, Q., Williams, N., Xie, X.-J., Kapur, P., Brugarolas, J.|Clinical Cancer Research recent issues|Labels: EGFR, kidney cancer

Renal cell carcinoma (RCC) is diagnosed in over 50,000 Americans annually and in the metastatic setting remains largely incurable. The development of new drugs is hampered by the lack of suitable preclinical animal models reproducing the characteristics of human tumors. To date, we have implanted tumors from over 700 kidney cancer patients orthotopically in mice. Our models include common tumor types, such as clear cell and papillary, but also rare tumor types such as translocation carcinomas and fumarate hydratase (FH)-deficient renal tumors from HLRCC patients. We have shown that tumor fragments implanted orthotopically into NOD/SCID mice result in tumors that reproduce: (i) histology, (ii) gene expression, (iii) DNA copy number alterations and (iv) mutations. Tumorgraft (TG)-bearing mice also reproduce paraneoplastic syndromes (paraneoplastic hypercalcemia). Furthermore, TGs recapitulate the treatment responsiveness of RCC in patients. We performed pharmacokinetic studies to determine appropriate administration regimens resulting in comparable exposures. TGs responded to drugs effective against RCC in patients (sunitinib and sirolimus, which accounts for 70% of the circulating drug after temsirolimus administration) and were resistant to ineffective drugs (erlotinib). TGs provide a superb platform to evaluate promising novel therapeutics. Data will be presented on the application of our TG platform to the evaluation of a first-in-class inhibitor of arguably the most important driver of RCC, the HIF-2 transcription factor. TGs were used to assess activity, validate a putative pharmacodynamic biomarker, identify biomarkers of sensitivity, and to assess the development of resistance. By leveraging a large and diverse TG platform, preclinical drug testing may be rigorously conducted, the most promising agents may be identified, and future clinical development may be effectively informed.

Citation Format: Andrea Pavia-Jimenez, Wenfang Chen, Haley Hill, Alana Christie, Qurratulain Yousuf, Noelle Williams, Xian-Jin Xie, Payal Kapur, James Brugarolas. Renal cancer tumorgrafts: A validated model to evaluate novel targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA10.

Tuesday, August 9, 2016 12:44 AM|Cancer News Headlines - Yahoo! News|Attachments|Labels: EGFR, lung cancer, clinical trial

A sign is seen at an AstraZeneca site in MacclesfieldAstraZeneca's cancer drug pipeline suffered a setback on Tuesday when the experimental drug selumetinib failed to meet its goal in a late-stage trial for lung cancer. Hopes for the medicine had already been reduced after it failed in another study for treating a rare cancer of the eye in July 2015, although it may still have a role in a type of thyroid cancer and in cancers growing along nerve tissue. Selumetinib is viewed as less important than AstraZeneca's recently launched cancer drugs Tagrisso and Lynparza, and its closely watched experimental product durvalumab.


Friday, August 5, 2016 12:14 PM|Srivastava, R. M., Trivedi, S., Concha-Benavente, F., Gibson, S. p., Reeder, C., Ferrone, S., Ferris, R. L.|Clinical Cancer Research Online First Articles|Labels: EGFR, HNN, clinical trial

Purpose:Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in head and neck cancer (HNC) patients. Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcRIIIa, which is important for inducing anti-tumor cellular immunity. Cetuximab activated NK cells upregulate the costimulatory receptor CD137 (4-1BB) which, when triggered by agonistic mAb urelumab, might enhance NK cell functions, to promote T cell based immunity. Experimental Design:CD137 expression on tumor infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were employed in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. Results:CD137 agonist mAb urelumab enhanced cetuximab-activated NK cell survival, DC maturation and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab treated HNC patients, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of HNC patients treated with cetuximab plus urelumab. Conclusions:These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.

Thursday, August 4, 2016 1:31 AM|Ken Saito, Hidekazu Iioka, Chie Kojima, Mikako Ogawa, Eisaku Kondo|Cancer Science|Labels: EGFR, P53
p14ARF is one of the major tumor suppressors conventionally identified both as the mdm2-binding molecule restoring p53 function in the nucleus, and as a nucleophosmin-binding partner inside the nucleolous to stabilize ribosomal RNA. However, its recently reported mitochondrial localization has pointed to novel properties as a tumor suppressor. At the same time, functional peptides are gaining much attention in nanomedicine for their in vivo utility as non-invasive biologics. We previously reported the p14ARF-specific peptide that restored the sensitivity to gefitinib on the gefitinib-resistant lung cancer cells. Based on the information of this prototype peptide, here we generated the more powerful anti-tumor peptide “r9-CatB-p14 MIS,” which comprises the minimal inhibitory sequence of the mitochondrial targeting p14ARF protein in combination with the proteolytic cleavage site for cathepsin B, which is activated in various tumor cells, fused with the nine-polyarginine-domain for cell penetration, and demonstrated its novel action of regulating mitochondrial function in accordance with localization of endogenous p14ARF. The p14 MIS peptide showed a potent tumor inhibiton in vitro and in vivo against not only lung cancer cells but also tumor cells of diverse lineages, via modulating mitochondrial membrane potential, with minimal cytotoxicity to non-neoplastic cells and tissues. Hence, this mitochondrially targeted p14 peptide agent provides a novel basis for non-invasive peptide-based antitumor therapeutics. Action mode of the novel tumor suppressor peptide, “p14 MIS”, on cancer cells.
Introduction

Many second-line treatments for advanced non-small-cell lung cancer (NSCLC) have been assessed in randomised controlled trials, but which treatments work the best remains unclear. Novel treatments are being rapidly developed. We need a comprehensive up-to-date evidence synthesis of all these treatments. We present the protocol for a live cumulative network meta-analysis (NMA) to address this need.

Methods and analysis

We will consider trials of second-line treatments in patients with advanced NSCLC with wild-type or unknown epidermal growth factor receptor status. We will consider any single agent of cytotoxic chemotherapy, targeted therapy, combination of cytotoxic chemotherapy and targeted therapy and any combination of targeted therapies. The primary outcomes will be overall survival and progression-free survival. The live cumulative NMA will be initiated with a NMA and then iterations will be repeated at regular intervals to keep the NMA up-to-date over time. We have defined the update frequency as 4 months, based on an assessment of the pace of evidence production on this topic. Each iteration will consist of six methodological steps: adaptive search for treatments and trials, screening of reports and selection of trials, data extraction, assessment of risk of bias, update of the network of trials and synthesis, and dissemination. We will set up a research community in lung cancer, with different groups of contributors of different skills. We will distribute tasks through online crowdsourcing. This proof-of-concept study in second-line treatments of advanced NSCLC will allow one for assessing the feasibility of live cumulative NMA and opening the path for this new form of synthesis.

Ethics and dissemination

Ethical approval is not required because our study will not include confidential participant data and interventions. The description of all the steps and the results of this live cumulative NMA will be available online.

Trial registration number

CRD42015017592.

Monday, August 1, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: EGFR, breast cancer, clinical trial

According to results from a phase II study, abemaciclib shows single-agent activity in women with metastatic HER2-negative, ER-positive breast cancer whose disease has progressed on endocrine therapy and chemotherapy. The objective response rate to this investigational CDK4/6 inhibitor was 19.7%, with 28.2% of responses lasting at least a year.

Sunday, July 31, 2016 11:00 PM|Burtness, Barbara; Powell, Mark; Catalano, Paul; Berlin, Jordan; Liles, Darla K.; Chapman, Andrew E.; Mitchell, Edith; Benson, Al B.|American Journal of Clinical Oncology - Most Popular Articles|Labels: EGFR, pancreatic cancer, clinical trial
imageObjectives: The primary objective was to determine the response rate in patients with metastatic pancreatic cancer treated in first line with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and the rate of thromboembolic events with prophylactic enoxaparin sodium. Patients and Methods: Patients were eligible who had measurable, metastatic adenocarcinoma of the pancreas, and normal bilirubin. All patients received anticoagulation. Docetaxel (35 mg/m2) and irinotecan (50 mg/m2) were administered once a week for 4 weeks followed by 2 weeks rest (Arm A) alone or with the addition of cetuximab (Arm B). The primary endpoint was response rate. Results: A total of 87 eligible patients were enrolled and treated. Grade 3/4 toxicity was observed in 74% of patients in Arm A and 76% in Arm B. The principal grade 3/4 toxicity was diarrhea. Response rates were 4.5% in Arm A and 7% in Arm B. Median PFS and OS were 3.9 and 6.5 months in Arm A and 4.5 and 5.4 months in Arm B. Conclusions: Docetaxel/irinotecan combination is associated with considerable toxicity. Objective responses were infrequent and addition of cetuximab in an unselected population was not beneficial, but PFS and OS were comparable with those achieved with other regimens. Docetaxel/irinotecan therapy is active in metastatic pancreatic cancer.
Sunday, July 31, 2016 10:05 PM|Mittal, D., Sinha, D., Barkauskas, D., Young, A., Kalimutho, M., Stannard, K., Caramia, F., Haibe-Kains, B., Stagg, J., Khanna, K. K., Loi, S., Smyth, M. J.|Cancer Research recent issues|Labels: EGFR, breast cancer
Adenosine plays an important role in inflammation and tumor development, progression, and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony-forming ability, while transiently delaying cell-cycle arrest in vitro. The prometastatic activity of adenosine is partly tumor A2BR dependent and independent of host A2BR expression. In humans, TNBC cell lines express higher A2BR than luminal and Her2+ breast cancer cell lines, and high expression of A2BR is associated with worse prognosis in TNBC. Collectively, high A2BR on mouse and human tumors promotes cancer metastasis and is an ideal candidate for therapeutic intervention. Cancer Res; 76(15); 4372–82. ©2016 AACR.
Sunday, July 31, 2016 10:05 PM|Zigler, M., Shir, A., Joubran, S., Sagalov, A., Klein, S., Edinger, N., Lau, J., Yu, S.-F., Mizraji, G., Globerson Levin, A., Sliwkowski, M. X., Levitzki, A.|Cancer Immunology Research recent issues|Labels: EGFR, breast cancer

The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688–97. ©2016 AACR.

Thursday, July 28, 2016 7:56 AM|Marusyk, A., Tabassum, D., Guerriero, J., Place, A., Rozhok, A., Letai, A., Polyak, K.|Cancer Research recent issues|Labels: EGFR, breast cancer
Tumors represent abnormal organs comprised not only of neoplastic cells, but also of normal cells and extracellular matrix (ECM). Therefore, clinical progression as well as response to therapies depends not only on properties of neoplastic cells, but also on the interactions between different types of cells within tumors. Cancer-associated fibroblasts (CAFs) are the major non-nenoplastic cell component of tumors and major the producers of ECM. Despite extensive research, mechanisms and consequences of interactions between breast carcinoma cells and CAFs remain insufficiently understood.Using organotypic 3d co-cultures between breast carcinoma cell lines representing different sub-types of the disease and CAFs, we interrogated changes in gene expression and metabolism that result from the interaction. We found that while contact with fibroblats induces robust changes in expression and metabolism, the majority of changes are subtype and cell line specific. Furthermore, we found that fibroblasts can provide a dramatic protection against dual EGFR/HER2 inhibitor lapatinib. Protective effect requires close contact between the two cell types in context of 3d culture, and is mediated by both reduced accumulation of the drug within carcinoma cells and elevated apoptotic threshold. Using synthetic lethality screens, we have identified several signaling pathways whose inhibition enhances cytotoxic effects of lapatinib. Interrogation of functional relevance of ECM has revealed that the stromal protection can be reversed by targeting hyaluronan, a major ECM component produced by fibroblasts. Rather than simply enhancing cytotoxic activity of lapatinib against carcinoma cells, hyaluronidase treatment sensitized CAFs to lapatinib, thereby removing the protective niche. Our studies shed light on molecular changes induced by the interaction with CAFs and offer novel approaches for overcoming microenvironmental protection by therapeutically targeting CAFs.Citation Format: Andriy Marusyk, Doris Tabassum, Jennifer Guerriero, Andrew Place, Andrii Rozhok, Antony Letai, Kornelia Polyak. Targeting hyaluronan sensitizes breast cancer-associated fibroblasts to lapatinib and overcomes stromal resistance. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B24.
Thursday, July 28, 2016 7:56 AM|Chiang, C.-T., Chiu, C.-L., Arnesano, C., Fraser, S. E., Agus, D. B., Ruderman, D. L., Mumenthaler, S. M.|Cancer Research recent issues|Labels: EGFR, lung cancer
Tyrosine kinase inhibitors (TKIs) that target the EGFR are the standard of care for patients with EGFR mutant non-small lung cancer (NSCLC). However, TKIs are not curative; most patients with EGFR-mutant NSCLC treated with EGFR TKIs develop resistance within 9 to 14 months. The tumor microenvironment is thought to influence the fitness of cancer cells and drive the evolution of a tumor, but the effect of altered environmental conditions on oncogenic signaling and therapeutic response is not well understood. In the present study, we used the Operetta® High Content Imaging System to track cell dynamics over time and found that microenvironmental stress, specifically nutrient starvation, had a differential effect on growth rates of TKIs sensitive and resistant cells. Furthermore, we discovered that TKIs sensitive and resistant cells have differential metabolic signaling in response to this microenvironmental stress. To further interrogate cellular metabolism in TKIs sensitive and resistant cells, we utilized fluorescence lifetime imaging microscopy (FLIM), a state-of-the-art live-cell imaging technique to measure the autofluorescence lifetime of metabolic coenzyme NADH, the principle electron acceptor in glycolysis and electron donor in oxidative phosphorylation. Taken together, our data suggest that TKIs sensitive and resistant cells have adopted different metabolic strategies to cope with stressful environmental conditions, and interrogating tumor metabolic adaptations would inform the design of new therapeutic strategies to delay or prevent the outgrowth of resistant clones during treatment of EGFR mutant NSCLC.Citation Format: Chun-Te Chiang, Chi-Li Chiu, Cosimo Arnesano, Scott E. Fraser, David B. Agus, Dan L. Ruderman, Shannon M. Mumenthaler. Interrogating cellular metabolism to improve therapy for EGFR mutant NSCLC. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B36.
Thursday, July 28, 2016 7:56 AM|Veneziale, B., Huang, L., Li, X., Zhao, Q., Zhao, C., Osgood, R., Cowell, J., Rosengren, S., Parise, J., Wei, G., Phan, K., Connor, R., Rowe, S., Keller, G., Frost, G., Maneval, D., Thompson, C., Shepard, M., Thanos, C.|Cancer Research recent issues|Labels: BRAF, EGFR, RAS
The epidermal growth factor (EGF) signaling pathway relies on recognition by its receptor, EGFR, and subsequent downstream signaling by the KRAS and BRAF proteins to relay proper proliferative, migratory, and angiogenic functions. Cancers with activating KRAS or BRAF mutations are resistant to EGFR targeting agents and correspond to a significant unmet medical need. We hypothesized that an anti-EGFR antibody-drug conjugate (ADC) could be active against KRAS or BRAF mutated tumors, due to the cytotoxic mechanism of the ADC warhead. In an effort to eliminate the known dermal toxicity associated with anti-EGFR therapy, and to mitigate potential toxicities associated with treatment by an anti-EGFR ADC, we wished to engineer an antibody with enhanced specificity towards EGFR in the tumor microenvironment (TME) and attenuated binding to EGFR in normal tissue. This was achieved by screening a library of antibody variants (based on cetuximab) in a spatially addressed manner for binding to a recombinant version of the EGFR extracellular domain (EGFRECD) in two separate ELISA reaction conditions. High affinity binding to the EGFRECD was desired in the first condition, which approximated the physicochemical properties of the TME (acidic pH, high lactic acid concentration, 25% human serum). In the second assay condition, which approximated mAb binding to EGFRECD in normal tissue (neutral pH, low lactic acid concentration, 25% human serum), attenuated binding affinity was desired. We identified a lead mAb variant, cMab-1501, which possessed several fold reduced binding to EGFRECD in the neutral pH, low lactic acid condition, when compared to EGFRECD binding in the low-pH, high lactic acid, assay condition. To evaluate enhanced specificity for binding to EGFR in vivo, cMab-1501 was compared to cetuximab for binding to both human donor foreskin xenografts and human A431 tumor xenografts, using a DyLight 755 conjugated version of each antibody, and subsequent fluorescence detection with a Caliper IVIS system. cMab-1501 and cetuximab demonstrated relatively comparable binding towards human A431 tumor xenografts in vivo. In addition, cetuximab bound relatively equally between human tumor xenografts and human skin grafts. However, no binding to EGFR in the human skin graft was detected for cMab-1501 over all days measured; suggesting that cMab-1501 was highly specific for binding to EGFR in the TME. We next generated an cMab-1501 based ADC (antibody-drug conjugate), via maleimide chemistry carrying a protease cleavable valine-citrulline-p-aminobenzyloxycarbonyl monomethylauristatin E (vcPAB-MMAE) cytotoxic moiety, forming a cMab-1501-vcPAB-MMAE conjugate. Both the conjugated and un-conjugated versions of cMab-1501 were rapidly internalized by EGFR positive MDA-MB-231M tumor cells over several hours. In tumor xenograft models, the TME-specific anti-EGFR ADC demonstrated complete tumor regressions against two human EGFR overexpressing tumor types, MDA-MB-231M (TNBC, KRAS G13D) and HT-29 (CRC, BRAF V600E). In both in vivo models, tumors were resistant to treatment by cetuximab. These data suggest that it is possible to engineer a monoclonal antibody with enhanced specificity for its target within the TME and that an ADC-based approach could be utilized as potential treatment of EGFR overexpressing tumors with KRAS or BRAF mutations.Citation Format: Bob Veneziale, Lei Huang, Xiaoming Li, Qiping Zhao, Chunmei Zhao, Ryan Osgood, Jessica Cowell, Sanna Rosengren, Jason Parise, Ge Wei, Kim Phan, Robert Connor, Steve Rowe, Gilbert Keller, Gregory Frost, Dan Maneval, Curtis Thompson, Michael Shepard, Christopher Thanos. A tumor microenvironment specific EGFR targeting antibody-drug conjugate promotes regression in KRAS or BRAF mutant tumors. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B32.
Thursday, July 28, 2016 7:56 AM|Johnson, K. E., Machlus, K. R., Forward, J. A., Tippy, M. D., El-Husayni, S. A., Italiano, J. E., Battinelli, E. M.|Cancer Research recent issues|Labels: EGFR, breast cancer, IL
Platelets, primarily known for their role in hemostasis, are now recognized to play an integral role in cancer progression and metastasis. Recent evidence has established that platelets are activated by tumor cells, including breast cancer cells, leading to the release of hundreds of growth factors, cytokines, chemokines and angiogenesis mediators that could influence tumor growth and metastasis. Indeed, work from our group has demonstrated that factors released from activated platelets promote both metastasis and angiogenesis. However, little is known about the specific factors and signaling pathways that mediate this critical platelet-tumor cell crosstalk. To address this question, we performed an angiogenesis array (Ray Biotech) to identify specific pro-angiogenic and pro-metastatic factors released by tumor cells during platelet-tumor cell interactions. We identified several factors that were secreted by MCF-7 breast tumor cells in response to activated platelet releasate, including high levels of interleukin 8 (IL-8, CXCL8). IL-8 is a cytokine known to play a critical role in metastasis and angiogenesis and is elevated in the serum and tumor tissue of breast cancer patients. We confirmed that exposure to platelets strongly induced the production of IL-8 in several human breast cancer cell lines (MDA-MB-231, BT-20, SKBR-3 and MCF-7) by ELISA and found that platelets themselves do not contain detectable levels of IL-8. Furthermore, IL-8 production was highest in the more aggressive, triple negative MDA-MB-231 and BT-20 lines, suggesting a link between platelet-induced IL-8 and tumor subtype. Next we sought to determine the role of platelet-induced IL-8 in metastasis. We performed standard invasion assays using MDA-MB-231 cells transfected with IL-8shRNA or control cells. Platelets were able to increase the invasion of control MDA-MD-231 cells by 5 fold, while IL-8 knockdown reduced the effect by 50%. Furthermore, the ability of platelets to promote tumor cell migration across an endothelialized membrane was reduced 87% in IL-8 knockdown MDA-MB-231s compared to controls in standard transendothelial migration assays. These results suggest that platelets promote metastasis, in part, by driving tumor cell IL-8. To identify the specific component or components of platelet releasate responsible for driving tumor cell IL-8, we first characterized the contents of activated platelet releasate by array (Ray Biotech) and found an abundance of both chemokine (C-C motif) ligand 5 (CCL5, RANTES) and epidermal growth factor (EGF). Next, we treated breast tumor cell lines directly with recombinant CCL5 or EGF and observed an increase in IL-8 production; however, sensitivity to CCL5, EGF or the combination varied among the cell lines tested. We found that cell lines MCF-7 and MDA-MB-231, which express the CCL5 receptor CCR5, produced IL-8 in response to CCL5 while BT-20 and SKBR-3 cells produce IL-8 in response to EGF and express high levels of EGFR. To determine if platelet-derived CCL5 drives tumor cell IL-8 in MDA-MD-231 and MCF-7 cells, tumor cells were pretreated with the CCR5 blocker maraviroc and then exposed to platelets. CCR5 blockade abrogated the induction of IL-8 in response to platelets and decreased platelet-induced invasion. Similarly EGFR blockage with AG-1478 reduced IL-8 production in platelet-treated BT-20 and SKBR-3 tumor cells. Furthermore, pre-treatment of platelets with aspirin, an irreversible platelet inhibitor, diminished their ability to drive tumor cell IL-8 and to enhance invasion. Taken together, these results suggest that platelets, through release of soluble factors, drive tumor cells to produce IL-8 and that blocking this communication can disrupt the pro-metastatic potential of platelets. Ultimately, these studies support targeting specific platelet-tumor cell interactions as a novel means of limiting disease progression in breast cancer.Citation Format: Kelly E. Johnson, Kellie R. Machlus, Jodi A. Forward, Mason D. Tippy, Saleh A. El-Husayni, Joseph E. Italiano, Jr., Elisabeth M. Battinelli. Platelets promote breast cancer metastasis by reprogramming tumor cells to produce IL-8. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C12.
Thursday, July 28, 2016 7:56 AM|Kidambi, S.|Cancer Research recent issues|Labels: EGFR, Src, breast cancer
The development of resistance to trastuzumab is a major obstacle for lasting effective treatment of patients with ErbB2-overexpressing tumors. Here, we demonstrate that the physical contact of breast cancer cells with mesenchymal stem cells (MSCs) is a potential modulator of trastuzumab response by activation of nonreceptor tyrosine kinase c-SRC (Src) and down regulation of phosphatase and tensin homolog (PTEN). In this study we demonstrate a method for controlling breast cancer cells adhesion on polyelectrolyte multilayer (PEM) films without the aid of adhesive proteins/ligands to study the role of tumor and stromal cell interaction on cancer biology. Numerous studies have explored engineering co-culture of tumor and stromal cells predominantly using transwell co-culture of stromal cells cultured onto cover slips that were subsequently added to tumor cell cultures. However, these systems imposed an artificial boundary that precluded cell-cell interactions. To our knowledge this is the first demonstration of patterned co-culture of tumor cells and stromal cells that captures the temporal changes in the miRNA signature as the breast tumor develops through various stages. In this study we utilized cancer cells derived from two different tumor stages and two different stromal cells to effectively model heterogeneous tumor microenvironment and emulate various tumor stages. The co-culture model mimics the proliferative index (Ki67 expression) and tumor aggressiveness (HER-2 expression) akin to those observed in clinical tumor samples. We also demonstrated that our patterned co-culture model captures the temporal changes in the miRNA-21 and miRNA-34 signature as the breast tumor develops through various stages. Using our patterned breast cancer/MSC co-culture model, we find that the presence of MSCs results in Src activation that is missing in cancer cells monoculture, transwell co-culture, and cells treated with MSCs conditioned media. Interestingly, the co-culture model also results in PTEN loss and activation of PI3K/AKT pathway that has been demonstrated as fundamental proliferative and survival pathways in clinical settings. In addition, breast cancer cells in co-culture with MSCs conferred trastuzumab resistance in vitro as observed in the lack of inhibition of proliferative and migrative properties of the cancer cells. Our findings show that MSCs are potent mediators of resistance to trastuzumab and might reveal targets to enhance trastuzumab efficacy in patients. The engineered co-culture platform lays groundwork towards precision medicine wherein patient-derived tumor cells can be incorporated within our in vitro models to identify potential pathways and drug treatment regimens for individual patients.Citation Format: Srivatsan Kidambi. Physical intimacy of breast cancer cells with mesenchymal stem cells elicits trastuzumab resistance through Src activation. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A33.
Thursday, July 28, 2016 7:56 AM|Gruosso, T., Gigoux, M., Bertos, N., Saleh, S., Omeroglu, A., Zuo, D., Zhao, H., Souleimanova, M., Weaver, V., Meterissian, S., Hallett, M., Park, M.|Cancer Research recent issues|Labels: EGFR, breast cancer
Triple negative breast cancer (TNBC), defined as tumors lacking expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), are especially difficult to treat effectively. While ER+ and HER2+ breast cancer subtypes can be treated with Tamoxifen and Herceptin, respectively, there are no targeted therapies for TNBC patients. Furthermore, while only 20-30% of TNBC patients respond to chemotherapy in the neoadjuvant setting, overall outcome remains poor for non-responding patients. However, mounting evidence suggests that immune-checkpoint inhibitor immunotherapies may be especially promising for TNBC patients. We and others have shown that the presence of CD8+ T cells, a crucial component of the cytotoxic arm of the adaptive immune response, is a sign of good clinical outcome in TNBC patients. However, good outcome only correlates with CD8+ T cell invasion of the tumor parenchyma. Here we show that some patients have an accumulation of CD8+ T cells in the surrounding tumor-associated stroma, but not the tumor epithelium, and these patients responded as poorly as patients with no CD8+ T cells at all. Yet how cancer associated fibroblasts (CAFs), a dominant cell type of the tumor-associated stroma, affects CD8+ T cell invasion into the tumor epithelium is still poorly understood.To identify potential stroma-dependent mechanisms that potentiate or inhibit CD8+ T cells invasion into the tumor epithelium, we performed gene expression profiling of laser-capture microdissected tumor-associated stroma (and matched epithelium) from 56 TNBC cases. Here we identify several key stromal features that may explain the accumulation of CD8+ T cells outside of the tumor epithelium. Preliminary data by immunohistochemistry and immunofluorescence validate some key stromal features and decipher the implication of other immune cell types in CD8+ T cells lack of tumor epithelium infiltration. These key stromal features that impair CD8+ T cell infiltration into the tumor in some patients might explain the relative low efficiency of immunotherapies in TNBC patients (20% of patients respond). One could speculate that targeting these key stromal features would allow a significant CD8+ T cell infiltration into the tumor and thus sensitize patients to immunotherapies.Citation Format: Tina Gruosso, Mathieu Gigoux, Nicholas Bertos, Sadiq Saleh, Atilla Omeroglu, Dongmei Zuo, Hong Zhao, Margarita Souleimanova, Valerie Weaver, Sarkis Meterissian, Michael Hallett, Morag Park. Mechanisms of CD8+ T cell immunosuppression in triple negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A15.
Wednesday, July 27, 2016 11:11 AM|PLOQUIN, A., ZERIMECH, F., ESCANDE, F., ADENIS, A., GIRAUD, C., GASNAULT, L., BOURGEOIS, V., DESAUW, C., HEBBAR, M.|Anticancer Research recent issues|Labels: EGFR, RAS, CRC

Background/Aim: We previously identified three clinical predictive factors of efficacy of cetuximab-irinotecan. Here, we analyzed the clinical characteristics of patients with metastatic colorectal cancer (CRC) in order to detect potent correlations with KRAS mutations. Patients and Methods: We conducted a retrospective, multicenter study between 2008 and 2012. We included patients with metastatic colorectal adenocarcinomas, previously treated by irinotecan, and with an available KRAS mutation test. Results: We included 299 patients. The median age was 60 years; the median number of metastatic sites was 2. One hundred and eight patients (36.1%) had a previous objective response to irinotecan. The median interval between diagnosis and irinotecan discontinuation was 1.94 years. A KRAS mutation was detected in 133 patients (44.5%). In univariate and multivariate analyses, none of the assessed factors was associated with the presence of a KRAS mutation. Conclusion: No easily clinically assessable parameter was significantly associated with KRAS mutations in patients with colorectal cancer.

Sunday, July 24, 2016 6:00 PM|Bahriye Aktas, Sabine Kasimir-Bauer, Volkmar Müller, Wolfgang Janni, Tanja Fehm, Diethelm Wallwiener, Klaus Pantel and Mitra Tewes|Articles: Heinrich Heine Universität Düsseldorf|Labels: EGFR, breast cancer
The expression of HER2, estrogen (ER) and progesterone (PR) receptor can change during the course of the disease in breast cancer (BC). Therefore, reassessment of these markers at the time of disease progressi...
Friday, July 22, 2016 8:03 AM|Clavarezza, M., Puntoni, M., Gennari, A., Paleari, L., Provinciali, N., DAmico, M., DeCensi, A.|Clinical Cancer Research Online First Articles|Labels: EGFR, breast cancer

Purpose: (Neo)adjuvant treatment with chemotherapy plus trastuzumab reduces recurrence and death risk in HER2-positive (HER2+) breast cancer. Randomized trials assessed HER2 dual block by adding lapatinib to trastuzumab and chemotherapy in the neoadjuvant setting using pathologic complete response (pCR) as the outcome measure. We conducted a meta-analysis of randomized trials testing neoadjuvant dual block with lapatinib and trastuzumab versus trastuzumab alone in HER2+ breast cancer.

Experimental Design: Trials were identified by Medline (PubMed), ISI Web of Science (Science Citation Index Expanded), Embase, Cochrane library, and reference lists of published studies, review articles, editorials, and by hand-searched reports from major cancer meeting reports.

Results: Six randomized trials including 1,155 patients were identified, of whom 483 (41.8%) were hormone receptor–negative, 672 (58.2%) hormone receptor–positive, 534 (46.2%) received taxanes alone, and 621 (53.8%) anthracyclines plus taxanes or the docetaxel–carboplatin regimen. Overall, the dual block was associated with a significant 13% absolute improvement in pCR rate compared with single-agent trastuzumab (summary risk difference, SRD 0.13; 95% CI, 0.08–0.19). The activity was greater in hormone receptor–negative patients who received chemotherapy with taxanes alone (SRD 0.25; 95% CI, 0.13–0.37), compared to hormone receptor–positive or hormone receptor–negative disease treated with anthracyclines plus taxanes or the docetaxel–carboplatin regimen (SRD 0.09; 95% CI, 0.02–0.15; Pinteraction = 0.05).

Conclusions: On the basis of pCR data, the dual block with trastuzumab and lapatinib plus chemotherapy is a very active treatment only in HER2+ and hormone receptor–negative breast cancer treated with taxane monochemotherapy. Clin Cancer Res; 1–10. ©2016 AACR.

Thursday, July 14, 2016 10:05 PM|Gao, S., Ye, H., Gerrin, S., Wang, H., Sharma, A., Chen, S., Patnaik, A., Sowalsky, A. G., Voznesensky, O., Han, W., Yu, Z., Mostaghel, E. A., Nelson, P. S., Taplin, M.-E., Balk, S. P., Cai, C.|Clinical Cancer Research recent issues|Labels: AR, EGFR, prostate cancer

Purpose: ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors.

Experimental Design: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model.

Results: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression.

Conclusions: ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. Clin Cancer Res; 22(14); 3672–82. ©2016 AACR.

Tuesday, July 12, 2016 9:13 AM|Walker, A. J., Wedam, S., Amiri-Kordestani, L., Bloomquist, E., Tang, S., Sridhara, R., Chen, W., Palmby, T. R., Fourie Zirkelbach, J., Fu, W., Liu, Q., Tilley, A., Kim, G., Kluetz, P. G., McKee, A. E., Pazdur, R.|Clinical Cancer Research Online First Articles|Labels: CDK, EGFR, breast cancer, regulatory

On February 19th, 2016, the U.S. Food and Drug Administration (FDA) approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n=347) or placebo plus fulvestrant (n=174). The primary endpoint was investigator assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% CI: 0.36-0.59; p<0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine based therapy.

Thursday, June 30, 2016 10:05 PM|Varadan, V., Gilmore, H., Miskimen, K. L. S., Tuck, D., Parsai, S., Awadallah, A., Krop, I. E., Winer, E. P., Bossuyt, V., Somlo, G., Abu-Khalaf, M. M., Fenton, M. A., Sikov, W., Harris, L. N.|Clinical Cancer Research recent issues|Labels: EGFR, PD-1/PD-L1, breast cancer

Purpose: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer.

Experimental Design: In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response.

Results: The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4+ follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035).

Conclusions: Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2+ breast cancers. Clin Cancer Res; 22(13); 3249–59. ©2016 AACR.

Thursday, June 30, 2016 10:05 PM|Matsusaka, S., Hanna, D. L., Cao, S., Zhang, W., Yang, D., Ning, Y., Sunakawa, Y., Okazaki, S., Berger, M. D., Miyamato, Y., Parekh, A., Stintzing, S., Loupakis, F., Lenz, H.-J.|Clinical Cancer Research recent issues|Labels: EGFR, VEGF, CRC, clinical trial, IL

Purpose: The IL6/STAT3 axis promotes inflammation, angiogenesis, and cancer. The effect of genetic variants within this pathway on benefit from antiangiogenic cancer therapy is unknown. We tested whether SNPs in genes involved in IL6/STAT3 signaling can predict efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer (mCRC) patients.

Experimental Design: Associations between potentially functional IL6 (rs2069837 and rs1800795) and STAT3 (rs744166 and rs4796793) SNPs and clinical outcomes [progression-free survival (PFS), overall survival, and tumor response rate] were evaluated in mCRC patients receiving first-line FOLFIRI plus bevacizumab in two randomized phase III trials: TRIBE (n = 223, training cohort) and FIRE-3 (n = 288, validation cohort). Patients receiving FOLFIRI plus cetuximab in FIRE-3 (n = 264) served as a control cohort. The interaction between genotype and primary tumor location with clinical outcomes was examined. Genomic DNA isolated from whole blood or tumor tissue was analyzed by PCR-based direct sequencing.

Results: Patients with an IL6 rs2069837 G allele treated with FOLFIRI plus bevacizumab had an inferior PFS than those with the A/A genotype in TRIBE [9.4 vs. 11.1 months; HR = 1.53; 95% confidence interval (CI), 1.12–2.10; P = 0.004] and FIRE-3 (8.8 vs. 10.9 months; HR = 1.40; 95% CI, 1.06–1.85; P = 0.015). These associations were confirmed in multivariable analyses and were not seen in the control cohort. In subgroup analysis, the effect of IL6 rs2069837 on PFS was present only in patients with left-sided cancers, but the test for interaction was not significant.

Conclusions: IL6 rs2069837 genotype is a clinically relevant prognostic factor in mCRC patients treated with first-line bevacizumab-based chemotherapy. Clin Cancer Res; 22(13); 3218–26. ©2016 AACR.

Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: EGFR, CRC

According to data from a phase II study, the anti-HER2 combination of trastuzumab and lapatinib is active in patients with KRAS–wild-type, HER2-positive metastatic colorectal cancer. None of the study participants responded to previous, standard treatment with the EGFR inhibitors cetuximab or panitumumab, but 30% achieved an objective response to dual HER2 blockade.

Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: EGFR, breast cancer, clinical trial

Preliminary data from the phase III Heritage trial suggest that a biosimilar to trastuzumab, MYL-14010, is just as safe and effective as its brand-name equivalent for women with HER2-positive advanced breast cancer. The findings, presented during the annual meeting of the American Society of Clinical Oncology in June, may pave the way for the first FDA-approved biosimilar for cancer.

Thursday, June 30, 2016 10:05 PM|Miller, L. D., Chou, J. A., Black, M. A., Print, C., Chifman, J., Alistar, A., Putti, T., Zhou, X., Bedognetti, D., Hendrickx, W., Pullikuth, A., Rennhack, J., Andrechek, E. R., Demaria, S., Wang, E., Marincola, F. M.|Cancer Immunology Research recent issues|Labels: EGFR, breast cancer

The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis-free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biologic attributes that influence this association and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell–specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2-enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not in IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of TNFα/IFN signaling pathways in IBE tumors and the activation of the transforming growth factor-β pathway in IBD tumors. This prediction supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation. Cancer Immunol Res; 4(7); 600–10. ©2016 AACR.

Monday, June 27, 2016 10:52 AM|SHIRAIWA, S., KINUGASA, T., KAWAHARA, A., MIZOBE, T., OHCHI, T., YUGE, K., FUJINO, S., KATAGIRI, M., SHIMOMURA, S., TAJIRI, K., SUDO, T., KAGE, M., KUWANO, M., AKAGI, Y.|Anticancer Research recent issues|Labels: EGFR, CRC

Background/aim: Y-Box-binding protein-1 (YB-1), a DNA/RNA-binding protein, is an important oncogenic transcription and translation factor. We aimed to evaluate the relationships between nuclear YB-1 expression, epidermal growth factor receptor (EGFR) status, and poor clinical outcomes in patients with colorectal cancer (CRC). Materials and Methods: Nuclear YB-1 expression was immunohistochemically analyzed in CRC tissues obtained from 124 patients who underwent curative resection between 2005 and 2008. Correlations between nuclear YB-1 expression, various clinicopathological characteristics, EGFR status, and prognostic factors were evaluated. Results: High-grade nuclear YB-1 expression was detected in 62.9% of cases and was found to be an independent predictor of poorer overall survival (p<0.001) and relapse-free survival (p<0.001). A trend was also observed towards a positive correlation between nuclear YB-1 expression and EGFR status (p=0.051). Conclusion: Nuclear YB-1 expression is a useful prognostic biomarker that correlates with EGFR status in patients with CRC.

Monday, June 27, 2016 10:52 AM|NAM, S. O., YOTSUMOTO, F., MIYATA, K., FUKAGAWA, S., ODAWARA, T., MANABE, S., ISHIKAWA, T., KUROKI, M., YASUNAGA, S., MIYAMOTO, S.|Anticancer Research recent issues|Labels: EGFR, breast cancer

Background/Aim: Heparin-binding epidermal growth factor-like growth factor (HB-EGF), which belongs to the epidermal growth factor family, is a rational therapeutic target for triple-negative breast cancer (TNBC). This study aimed to assess the anti-tumor efficacy of intravenous (i.v.) HB-EGF-specific inhibitor (CRM197) for TNBC. Materials and Methods: NOD/SCID mice were subcutaneously injected withTNBC cells, MDA-MB-231, and, then, treated with i.v. CRM197 in either dose- or frequency-dependent manners, using an advanced cancer model and an adjuvant therapy model. Tumor volume and mouse body weight were calculated weekly. Statistical significance was assessed by the Mann-Whitney U-test. Results: Mice that received i.v. CRM197 showed a significant anti-tumor effect in dose- and frequency-dependent manners in both models. However, their body weight did not differ significantly among groups. Conclusion: These results suggest that i.v. CRM197 is an effective treatment for TNBC.

Monday, June 27, 2016 10:52 AM|YAMAGUCHI, T., IWASA, S., NAGASHIMA, K., IKEZAWA, N., HAMAGUCHI, T., SHOJI, H., HONMA, Y., TAKASHIMA, A., OKITA, N., KATO, K., YAMADA, Y., SHIMADA, Y.|Anticancer Research recent issues|Labels: EGFR, RAS, CRC

Background/Aim: Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan. Patients and Methods: Data, from 139 patients who received panitumumab or cetuximab, in combination with irinotecan, for KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan were analyzed. The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan. Results: Baseline characteristics of the panitumumab plus irinotecan (n=42) and cetuximab plus irinotecan (n=97) groups were similar. Among patients with measurable lesions, the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group. Median progression-free survival (PFS) was 4.3 and 5.7 months in the panitumumab and cetuximab groups, respectively. Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab. Conclusion: Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan.

Friday, June 17, 2016 2:47 AM|William D. Figg|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: EGFR, breast cancer, biomarker diagnostic

Precision Oncology Medicine: The Clinical Relevance of Patient Specific Biomarkers Used to Optimize Cancer Treatment
Keith T. Schmidt Cindy H. Chau, Douglas K. Price, William D. Figg
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Precision medicine in oncology is the result of an increasing awareness of patient specific clinical features coupled with the development of genomic‐based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug‐target pairs were the first to widely utilize clinically applicable tumor biomarkers (e.g. HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to a FDA approved targeted therapy (e.g. trastuzumab, erlotinib). Clinically relevant germline mutations in drug metabolizing enzymes and transporters (e.g. TPMT, DPYD) have been shown to impact drug response, providing rationale for individualized dosing to optimize treatment. The use of multigene expression‐based assays to analyze an array of prognostic biomarkers have been shown to help direct treatment decisions, especially in breast cancer (e.g. Oncotype DX). More recently, the use of Next‐Generation Sequencing to detect many potential “actionable” cancer molecular alterations is further shifting the one gene‐one drug paradigm towards a more comprehensive, multi‐gene approach. Currently, many clinical trials (e.g. NCI‐MATCH, NCI‐MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics, while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials like the NCI‐MATCH will help determine the clinical utility and future development of the precision‐medicine approach. This article is protected by copyright. All rights reserved

CONCLUSIONSBoth drugs are effective and well tolerated as NET in postmenopausal women with HR‐positive/HER2‐negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
CONCLUSIONSBoth HAT and HA‐HAT have promising activity in patients with HER2‐positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
CONCLUSIONSWithin this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard‐of‐care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti‐HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Monday, June 6, 2016 4:58 AM|YAMADA, K., AZUMA, K., TAKESHITA, M., UCHINO, J., NISHIDA, C., SUETSUGU, T., KONDO, A., HARADA, T., EIDA, H., KISHIMOTO, J., ERIGUCHI, G., TAKAYAMA, K., NAKANISHI, Y., SUGIO, K.|Anticancer Research recent issues|Labels: EGFR, lung cancer, clinical trial

Background: As the incidence of lung cancer in the elderly is increasing worldwide, there exists a need to develop a clinically effective, less toxic therapy for this patient population. Although erlotinib has shown proven effectiveness against non-small cell lung cancer (NSCLC), few studies have prospectively investigated its application to elderly patients. Patients and Methods: Patients aged ≥75 years with advanced or recurrent NSCLC including wild-type EGFR who had previously received one or two chemotherapy regimens were enrolled in this trial. Erlotinib was initially administered at a dose of 150 mg/day orally until disease progression or unacceptable toxicities occurred. The primary endpoint was the objective response rate. Results: Forty patients were enrolled between May 2009 and January 2014. An objective response was observed in 8 patients (20%, 95%CI=9.1-35.7%), and the disease control rate reached 62.5% (95%CI=45.8-77.3%). After a median follow-up period of 12.2 months (range=1.4-47.2 months), the median progression-free survival period was 5.0 months (95%CI=2.3-7.6 months), and the median survival period was 12.2 months (95%CI=6.1-24.7 months). Major toxicities were skin disorders, fatigue, and anorexia. Most adverse events were grade 2 or less, but 13 patients (32.5%) required a dose reduction. Two patients developed interstitial lung disease, that was nevertheless reversible, and there were no treatment-related deaths. Conclusion: Although the percentage of patients requiring dose reduction seemed relatively higher than that in previous studies, erlotinib is a potentially useful therapeutic option for unselected elderly patients with previously treated advanced or recurrent NSCLC, as has been also shown for younger patients.

Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: EGFR, bladder cancer

HER2 or ERBB3 alterations are predictive of afatinib response in refractory urothelial carcinomas.

Thursday, June 2, 2016 8:00 AM|Lung Cancer News From Medical News Today|Labels: EGFR, lung cancer, biomarker diagnostic
The U.S. Food and Drug Administration has approved the cobas EGFR Mutation Test v2, a blood-based companion diagnostic for the cancer drug Tarceva (erlotinib).
Tuesday, May 31, 2016 10:05 AM|Lyle, L. T., Lockman, P. R., Adkins, C. E., Mohammad, A. S., Sechrest, E., Hua, E., Palmieri, D., Liewehr, D. J., Steinberg, S. M., Kloc, W., Izycka-Swieszewska, E., Duchnowska, R., Nayyar, N., Brastianos, P. K., Steeg, P. S., Gril, B.|Clinical Cancer Research Online First Articles|Labels: EGFR, breast cancer

Purpose: The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (a) quantified the permeability of experimental brain metastases; (b) determined the composition of the BTB; (c) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability. Experimental Design: A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA-231-BR6, HER2+ JIMT-1-BR3) were serially sectioned; low and high permeability lesions were identified with systemic 3kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test. Results: When uninvolved brain was compared to any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low- and high permeability were compared, increased expression of a desmin+ subpopulation of pericytes was associated with higher permeability (231-BR6 p=0.0002; JIMT-1-BR3 p=0.004; SUM190-BR3 p=0.008); desmin+ pericytes were also identified in human craniotomy specimens. Trends of reduced CD13+ pericytes (231-BR6 p=0.014; JIMT-1-BR3 p=0.002, SUM190-BR3, NS) and laminin α2 (231-BR6 p=0.001; JIMT-1-BR3 p=0.049; SUM190-BR3 p=0.023) were also observed with increased permeability. Conclusions: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin+ pericytes and laminin α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy.

Tuesday, May 17, 2016 9:25 AM|Ingold Heppner, B., Untch, M., Denkert, C., Pfitzner, B. M., Lederer, B., Schmitt, W. D., Eidtmann, H., Fasching, P. A., Tesch, H., Solbach, C., Rezai, M., Zahm, D. M., Holms, F., Glados, M., Krabisch, P., Heck, E., Ober, A., Lorenz, P., Diebold, K., Habeck, J.-O., Loibl, S.|Clinical Cancer Research Online First Articles|Labels: EGFR, breast cancer, biomarker diagnostic

Purpose: We elucidated the value of tumor-infiltrating lymphocytes (TILs) as an independent predictor for pathological complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. Experimental Design: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; {greater than or equal to} 60% TILs), and correlated with pCR rate and DFS. Results: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared to non LPBC-types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, p=0.002; LPBC: OR 2.02, p=0.002) and multivariate analyses (10% TILs: OR 1.1, p=0.014; LPBC: OR 1.87, p=0.009). This effect was also detectable in the trastuzumab treated (10%TILs: OR 1.12, p=0.018; LPBC: OR 2.08, p=0.013) but not in the lapatinib treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple positive breast cancer, TILs are of more prognostic relevance than pCR. Conclusions: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR-rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions.

Friday, May 13, 2016 4:00 AM|News-Medical.Net Cetuximab News Feed|Comments|Labels: EGFR, CRC
Cancer researchers have identified a marker that shows up in a blood test that determines which patients with colorectal cancer that has spread would benefit from receiving the drug cetuximab.
Thursday, April 28, 2016 9:59 AM|OGAWA, M., ANAN, T., SUZUKI, T., OKUMA, M., ICHIHARA, K., HASEGAWA, T., YOSHIDA, K., YANAGA, K.|Anticancer Research recent issues|Labels: EGFR, RAS, CRC, clinical trial

Aim: This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX (S-1 and oxaliplatin)+cetuximab as first-line chemotherapy for wild-type K-RAS metastatic colorectal cancer. Patients and Methods: We studied patients with previously untreated, unresectable, advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013. Their performance status (PS) was 0 to 1. Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab). S-1 was given orally at a dose of 40 mg/m2 (40-60 mg, calculated according to body surface area) twice daily after meals for 2 weeks, followed by a 2-week rest (course 1). Oxaliplatin (85 mg/m2) was given on days 1 and 15 of each course. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2) and 15 (500 mg/m2) of course 1, followed by every 2 weeks (500 mg/m2) thereafter. Results: The study group comprised of 18 patients. The mean age was 61 (range=32-72) years, the male:female ratio was 10:8 and the PS was 0 in 12 patients and 1 in 6 patients. The median number of administered courses was 6 (range=2-12). The treatment response was complete response (CR) in 2 and partial response (PR) in 10 (response rate=67% (12/18 patients)). The minimum number of treatment courses until a PR was 2, indicating an early response. Liver resection was performed in 4 patients (22.2%). The incidence of any adverse events (Grade 3/4) was 28% (5/18), including skin disorder (16.7%) as dry skin, cutaneous pruritus, contusion and paronychia, as well as peripheral sensory neuropathy (11.1%). The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients. These events were controllable by preventive skin care and by withdrawal and dose reduction, respectively. Death due to adverse events was not observed. Adverse events did not require the withdrawal of this regimen. Conclusion: Based on the 18 patients studied, combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment, as required. These regimens seem to be promising for conversion therapy (4 out of 18 patients) because of good outcomes and an early response.

Thursday, April 28, 2016 9:59 AM|TONISSI, F., LATTANZIO, L., ASTESANA, V., CAVICCHIOLI, F., GHIGLIA, A., MONTEVERDE, M., VIVENZA, D., GIANELLO, L., RUSSI, E., MERLANO, M., LO NIGRO, C.|Anticancer Research recent issues|Labels: EGFR, HNN, clinical trial

Background/Aim: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation. This work aimed to analyze the reoxygenation effect on proliferation in response to radiation in HNC cells. Materials and Methods: HNC cell lines CAL33 and CAL166 were subjected to an 8-Gy radiation dose in hypoxia and/or after reoxygenation. Cell proliferation and molecular factors involved in response to treatments were studied. Results: Cytotoxicity test confirmed radioresistance in hypoxia and highlighted that reoxygenation before RT restores sensitivity in both cell lines. Our results showed a similar proliferation inhibition effect and EGFR modulation but a different cell death mechanism in the two cell lines after treatment. Conclusion: Reoxygenation before RT rescued radiosensitivity in HNC cells.

Thursday, April 28, 2016 9:59 AM|LAKIS, S., DIMOUDIS, S., KOTOULA, V., ALEXOPOULOU, Z., KOSTOPOULOS, I., KOLETSA, T., BOBOS, M., TIMOTHEADOU, E., PAPASPIROU, I., EFSTRATIOU, I., ARAVANTINOS, G., KARAVASILIS, V., ZAGOURI, F., GOGAS, H., RAZIS, E., PENTHEROUDAKIS, G., CHRISTODOULOU, C., PECTASIDES, D., FOUNTZILAS, G.|Anticancer Research recent issues|Labels: EGFR, breast cancer

Wnt and epidermal growth factor receptor (EGFR) pathway abnormalities and de-stabilization of cell adhesion are all important aspects of the pathogenesis of triple-negative breast cancer (TNBC). Herein we investigated how the expression of related protein markers may affect the outcome of patients bearing TNBC treated in the adjuvant setting. Immunohistochemistry for beta-catenin, Myc (Wnt pathway), E-cadherin, P-cadherin (cell-adhesion), EGFR and cytokeratin 5 (CK5) (identification of basal-like tumors) was carried out in 364 centrally confirmed TNBCs. Survival analysis was performed with Cox-regression models according to dichotomized continuous protein expression data and marker interactions. In 352 evaluable tumors, 81.5% were basal-like TNBC. E-cadherin and P-cadherin were positively associated, with co-expression being present in 68% of tumors. Individual markers did not affect patient outcome. However, a statistically significant interaction was shown such that low expression of beta-catenin in the cell membrane, defined as expression below the median of the H-score distribution, was associated with unfavourable disease-free survival among tumors that expressed EGFR, but not in the absence of EGFR expression (interaction p=0.0085). The interaction persisted after correcting for clinicopathological variables. A considerable number of TNBC co-expresses E-cadherin and P-cadherin, while membranous localization of beta-catenin may predict patient outcome in an EGFR-dependent manner. This novel interaction seems worthy for validating with regards to its biological and clinical relevance.

Friday, April 22, 2016 10:24 AM|Lung Cancer|Labels: EGFR, lung cancer, regulatory
The US Food and Drug Administration has approved Gilotrif (afatinib) to treat squamous cell lung cancer.
Monday, March 28, 2016 5:30 AM|Current Cancer Therapy Reviews|MedWorm: Cancer Therapy|Comments|Labels: EGFR, breast cancer
Trastuzumab has been clearly demonstrated to improve overall survival for both early and metastatic HER2 positive breast cancer. However, despite the improved clinical outcomes seen with the addition of HER2 targeted therapy to conventional cytotoxic agents, the response rates remain between 30-55% and the majority of patients with advanced breast cancer experience disease progression within 1 year. In this review article, we provide a summary of the key mechanisms of resistance to trastuzumab, including the truncated form of HER2 (p95HER2), compensatory up-regulation of receptor cross-talk, genetic mutations and aberrancies in molecular pathways that allow tumor cells to evade cell cycle regulations. In recent years, treatment options for patients with trastuzumab-resistant disease have b...
Friday, March 25, 2016 10:33 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, mTOR, lung cancer
Authors: Wang CI, Chen YY, Wang CL, Yu JS, Chang YS, Yu CJ Abstract Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specif...
Wednesday, March 23, 2016 4:00 PM|Thoracic Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, HSP
ConclusionsThe novel therapy of gefitinib combined with radiofrequency hyperthermia is safe and effective for advanced NSCLC patients. Whether an improvement in therapeutic efficacy is associated with the elevation of serum HSP70 concentration requires further study. (Source: Thoracic Cancer)
Monday, March 21, 2016 10:38 PM|Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer
Conclusions: The Q787Q EGFR polymorphism allows stratifying lung squamous cell carcinoma patients and could be an independent prognostic marker, particularly among those in stages I and II.Oncology (Source: Oncology)
CONCLUSIONS: This study explores the role of TKIs in EGFR non-mutated NSCLC patients. OS analysis highlights a trend to a benefit in patients who received TKI in third-line, even if this result is statistically non-significant. Further analysis are needed to find an explanation for this observation. PMID: 26993607 [PubMed - as supplied by publisher] (Source: Oncotarget)
Sunday, March 20, 2016 4:00 PM|Mini Reviews in Medicinal Chemistry|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR
REVIEW ON EGFR INHIBITORS: CRITICAL UPDATES. Mini Rev Med Chem. 2016 Mar 21; Authors: Singh D, Attri BK, Gill RK, Bariwal J Abstract Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein that constitutes one of the four members of ErbB family of tyrosine kinase receptors. Activation of EGFR leads to autophosphorylation of receptor tyrosine kinase that initiates a cascade of downstream signaling pathways involved in regulating cellular proliferation, differentiation, and survival. EGFR is abnormally activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with the development of variety of human cancers. EGFR inhibition is one of the key targets for c...
Saturday, March 19, 2016 10:51 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer
Authors: Lu Y, Wang Y, Zhang M, Liu L, Li F, Zhang J, Ye M, Zhao H, Zhao J, Yan B, Yang A, Zhang R, Li X, Ren X Abstract Overexpression of human epidermal growth factor receptor type2 (HER2) is closely associated with aggressive progression and poor prognosis in non-small cell lung cancer (NSCLC). Here, we generated an EGFR-scFv-arginine nonamer peptide fusion protein (scFv-9R) as a cargo to deliver HER2 specific siRNA into HER2-positive NSCLC cells both in vitro and in vivo. HER2-siRNAs delivered by scFv-9R effeciently silenced HER2 expression in EGFR-positive NSCLC cells, and consequently resulted in G1 arrest and cell growth inhibition. Importantly, intravenous injection of scFv-9R/HER2-siRNA complex markedly suppressed growth of EGFR-positive NSCLC xenograft in nude mice, resul...

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Friday, March 18, 2016 5:00 PM|Annals of Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, RAS, lung cancer
Conclusions This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies. (Source: Annals of Oncology)
Wednesday, March 16, 2016 4:00 PM|Biochemical and Biophysical Research communications|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer
Authors: Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A, Yagishita S, Tajima K, Hidayat M, Shimada N, Suina K, Yoshioka Y, Sasaki S, Moriyama M, Moriyama H, Takahashi K Abstract Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC c...
ConclusionsIn advanced NSCLC patients, an exon 19 deleton may provide superior ORR, PFS, and OS after EGFR‐TKI treatment compared with an exon 21 L858R mutation. (Source: Thoracic Cancer)

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CONCLUSIONSThe B‐DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B‐DOC. Docetaxel‐based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, March 9, 2016 4:00 PM|Current Treatment Options in Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, PD-1/PD-L1, lung cancer
The objective response rate and progression-free survival observed with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with metastatic epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) are modest. The adverse events associated with EGFR TKIs are manageable but they must be considered in the context of the limited efficacy. The development of anti-PD-1 immunotherapy as second-line therapy has reduced the role of EGFR TKIs in EGFR wild-type NSCLC. Recently, there has been increased recognition of the benefit of the earlier integration of palliative care and symptom management, and this is reasonable alternative to treatment with an EGFR TKI for many patients. My practice pattern for patients with EGFR wild-type NSCLC is ...
Monday, March 7, 2016 11:40 AM|PharmaManufacturing.com|MedWorm: Vaccines|Comments|Labels: EGFR, brain cancer, clinical trial
The vaccine, Rintega, belongs to an emerging class of drugs that spur the immune system to recognize and attack cancer. (Source: PharmaManufacturing.com)

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Sunday, February 28, 2016 4:00 PM|Clinical Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, clinical trial
CONCLUSIONS: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. PMID: 26927662 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

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Sunday, February 28, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Carcinoma in Situ|Comments|Labels: EGFR, WNT, breast cancer
Conclusion: BCL9 is a molecular driver of DCIS invasive progression. The molecular mechanism for BCL9's role in breast cancer progression is through the enhancement in the canonical Wnt and EGFR signaling.Citation Format: Hanan Elsarraj, Hong Yan, Jennifer Knapp, Anna Tsimelzon, Shixia Huang, Andrew Godwin, Sue Hilsenbeck, Dean Edwards, Fariba Behbod. B cell lymphoma 9 mediates a cross talk between the canonical Wnt and EGFR signaling in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B01. (Source: Molecular Cancer Research)
Sunday, February 28, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, breast cancer, clinical trial
Purpose: HER2+ and triple-negative (TN) breast cancers (BC) are associated with an aggressive course and poor prognosis, with currently available treatments yielding low response rates and decreased progression-free survival (PFS) due to a high relapse rate, rapid disease progression, and development of resistance. Hence, novel agents with efficacy and a tolerable safety profile are needed for this challenging patient (pt) population. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase (BTK), which is a crucial signaling molecule in the B-cell receptor pathway. It has demonstrated robust clinical activity in B-cell malignancies. In preclinical studies, ibrutinib inhibited tyrosine phosphorylation of ErbB and ErbB2 in HER2- positive BC cell lines, thereby suppressing A...
Saturday, February 27, 2016 4:00 PM|Annals of Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, clinical trial
Conclusion Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy. Trial registration number NCT01085136 (clinicaltrials.gov). (Source: Annals of Oncology)

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Saturday, February 27, 2016 2:24 PM|Zoran Gatalica et al.|Department of Pathology, Anatomy and Cell Biology Faculty Papers|Labels: EGFR, breast cancer, biomarker diagnostic

Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

Thursday, February 25, 2016 5:00 PM|Ricardo Hitt|Cancers|Labels: EGFR, HNN
Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing.
Wednesday, February 24, 2016 12:12 AM|International Journal of Radiation Oncology * Biology * Physics|MedWorm: Nonmelanoma Skin Cancer|Comments|Labels: EGFR, HNN
The objective of this study was to investigate the safety, tolerability, and preliminary efficacy of radiation therapy (RT) plus cetuximab in high-risk CSCC patients. (Source: International Journal of Radiation Oncology * Biology * Physics)
Wednesday, February 17, 2016 4:00 PM|Cancer Research|MedWorm: Carcinoma in Situ|Comments|Labels: EGFR, breast cancer
ConclusionPLCIS is an uncommon in situ carcinoma presenting via mammographic and also in the symptomatic setting. Unlike classical LCIS, PLCIS is a disease of postmenopausal women. It is multifocal in approximately one fifth of the cases.PLCIS is commonly associated with classical LCIS and both ILC and IPLC. When identified in core biopsy, the upgrade rate in this series was 30.4% which increased to 50% if the lesion co-existed with DCIS. The associated cancers are often ER positive, HER2 negative. These findings support managing those lesions surgically as per DCIS.Citation Format: Shaaban AM, Smith S, Bradley S, McMahon M, Sharma N. Pleomorphic lobular carcinoma in situ (PLCIS)-presentation, associated lesions and outcome. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR...
Wednesday, February 17, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: EGFR, breast cancer, clinical trial
Background: Biologically relevant epithelial to mesenchymal transformation (EMT) associated proteins, a subpopulation of tumor cells with stem like properties, have been identified and are responsible for tumor initiation, metastasis formation and resistance to cancer therapies involved in breast cancer (BC) initiation. It is hypothesized that the acquisition of stem cell properties is driven by EMT induction and that BC stem cells express EMT-associated proteins. A vaccine which would educate the immune system to recognize and eliminate cells that have up-regulated proteins associated with BC stem cells/EMT could eradicate BC at the time of initiation or relapse. We have identified 5 stem cell/EMT proteins that are immunogenic in BC patients and created a vaccine, STEMVAC, composed of ext...
Eribulin mesylate, a mitotic inhibitor, is indicated for the treatment of patients (pts) with metastatic breast cancer (MBC) who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease, including an anthracycline and a taxane. The recommended dose is 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on d1 and 8 of a 21d cycle. A modified biweekly dose regimen—which may improve safety profile without compromising efficacy—is also being explored.This presentation describes an ongoing phase 2, open-label, single-arm, multicenter study of eribulin (1.4 mg/m2) administered intravenously (IV) biweekly (d1 and 15) in 28d cycles for the treatment of pts with human epidermal growth factor receptor (HER)2-negative MBC previously ...
Eribulin mesylate, a mitotic inhibitor, is indicated for the treatment of patients (pts) with metastatic breast cancer (MBC) who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease, including an anthracycline and a taxane. The recommended dose is 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on d1 and 8 of a 21d cycle. A modified biweekly dose regimen—which may improve safety profile without compromising efficacy—is also being explored.This presentation describes an ongoing phase 2, open-label, single-arm, multicenter study of eribulin (1.4 mg/m2) administered intravenously (IV) biweekly (d1 and 15) in 28d cycles for the treatment of pts with human epidermal growth factor receptor (HER)2-negative MBC previously ...
Wednesday, February 17, 2016 4:00 PM|Cancer Research|MedWorm: Carcinoma in Situ|Comments|Labels: EGFR, breast cancer, clinical trial
Conclusions:HER2 overexpression is associated with increased risk of DCIS-IBE but not of I-IBE. HER2 status is predictive of radiotherapy response with larger reductions in both I-IBE and DCIS-IBE seen in HER2 positive DCIS.Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-02. (Source: Cancer Research)
Conclusion: The RP2D of ganetespib is 150mg/m2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting.Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D,...

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Conclusion: Concordance in risk prediction between RS and MP was greater using RS defined by TRx compared to GH, and RS using TRx increases those categorized as intermediate risk. There appeared to be no correlation between CP features and decisions to use chemotherapy across risk groups. Interestingly, in those with intermediate risk RS (GH or TRx), there was a non-significant trend toward use of chemotherapy in those with high risk by MP. Although gene expression tests are used frequently to aid in treatment decisions in ESBC, considerable variation exists in their application in clinical practice.Citation Format: Jiang H, Denduluri N, Majure M, Favret A, Rugo HS. Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patie...
Monday, February 15, 2016 4:00 PM|BMB Reports|MedWorm: Cancer Therapy|Comments|Labels: EGFR, CRC, clinical trial
Authors: Joo D, Woo JS, Cho KH, Han SH, Min TS, Yang DC, Yun CH Abstract Type-specific features of cancer cells may strongly influence the effectiveness of therapeutic interventions. Here, we show that the spontaneous reactivation of extracellular signal-regulated kinase (ERK), distinct from conventional ERK activation, represents a potent mechanism for cancer cell survival. We studied ERK1/2 activation in vitro in SW480 colorectal cancer cells. Although ERK signaling tends to be only transiently activated, we observed the delayed reactivation of ERK1/2 in EGF-stimulated SW480 cells. This effect was observed even after EGF withdrawal. While phosphorylated ERK1/2 translocated into the nucleus following its primary activation, it remained in the cytoplasm during late-phase activation...
Thursday, February 4, 2016 3:21 PM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: EGFR, breast cancer, ovarian cancer
Authors: Palanca-Wessels MC, Booth GC, Convertine AJ, Lundy BB, Berguig GY, Press MF, Stayton PS, Press OW Abstract The therapeutic potential of RNA interference (RNAi) has been limited by inefficient delivery of short interfering RNA (siRNA). Tumor-specific recognition can be effectively achieved by antibodies directed against highly expressed cancer cell surface receptors. We investigated the utility of linking an internalizing streptavidin-conjugated HER2 antibody to an endosome-disruptive biotinylated polymeric nanocarrier to improve the functional cytoplasmic delivery of siRNA in breast and ovarian cancer cells in vitro and in an intraperitoneal ovarian cancer xenograft model in vivo, yielding an 80% reduction of target mRNA and protein levels with sustained repression for at ...

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• Results of global Phase IIb LUX-Lung 7 trial demonstrate afatinib superior in reducing the risk of lung cancer progression and the risk of treatment failure both by 27% compared to gefitinib1 • More patients on afatinib were free of cancer growth 18 and 24 months after the start of treatment (27% vs 15% and 18% vs 8%, respectively)1 • The overall frequency of patients experiencing serious adverse events and discontinuing treatment due to adverse events was similar in both arms1 (Source: Boehringer Ingelheim Corporate News)

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Sunday, January 24, 2016 1:59 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, MapK, lung cancer
This study determined the signaling pathway that contributes to PTX resistance. We first established PTX resistant cell lines (H460/R and 226B/R) using a dose-escalating maintenance of PTX. We found that p38 MAPK and epidermal growth factor receptor (EGFR) were constitutively activated in these cell lines. The inhibition of p38 MAPK activity by SB203580 treatment or the transfection of dominant-negative p38 MAPK sensitized both cell lines to PTX treatment. Erlotinib, an EGFR inhibitor, also increased PTX-induced apoptosis in PTX resistant cells, which suggests a role for p38 MAPK and EGFR in the development of PTX resistance. We demonstrated that p38 MAPK enhanced EGFR expression via the induction of the rapid degradation of mouse double-minute 2 homolog (MDM2) and the consequent stabiliza...
Sunday, January 24, 2016 1:59 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, RAS, lung cancer
CONCLUSIONS: MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance. PMID: 26799287 [PubMed - as supplied by publisher] (Source: Oncotarget)
Thursday, January 21, 2016 10:49 AM|Oncology Letters|MedWorm: Carcinoma in Situ|Comments|Labels: EGFR, VEGF, esophageal cancer
Authors: Niyaz M, Anwer J, Liu H, Zhang L, Shayhedin I, Awut I Abstract The present study aimed to understand the expression characteristics of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) in individuals of Uygur, Han and Kazak ethnicity with esophageal carcinoma in Xinjiang (China) and their interrelation analysis, and to investigate the expression differences in these genes between esophageal carcinoma and pericarcinoma tissue samples, and between the three ethnic groups. The expression levels of EGFR and VEGFR-2 from 119 pairs of esophageal carcinoma tissue and corresponding pericarcinoma tissue from Uygur, Han and Kazak patients with esophageal carcinoma were detected by immunohistochemistry following surgical resection, an...
Tuesday, January 12, 2016 4:00 PM|Medical Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer
Abstract Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti-proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiam...
Thursday, January 7, 2016 4:00 PM|Clinical Cancer Research|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, clinical trial
CONCLUSIONS: These findings suggest the cobas® and BEAMing plasma tests can be useful tools for non-invasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. PMID: 26747242 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: EGFR, RAS, breast cancer
Tumor microenvironment (TME) plays a critical role in tumor growth, invasion and metastasis. In TME, epidermal growth factor receptor (EGFR) family members, including HER1, HER2, HER3 and HER4, are involved in determining aggressive growth of breast cancer due to their ability to transduce the growth promoting functions of growth factors. This activity is potentiated by the over-expression of these receptor molecules in cancer cells. To reduce the activity of EGFR molecules, various inhibitors have been developed. EGFR/HER1 tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show antitumor activity but these drugs have not meet their primary goal of improved survival in the overall patient population. A similar TKI, lapatinib, has shown some limited success in breast cancer. While ...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, mTOR
Conclusions: CB-839 has been well tolerated when administered BID with food at and above doses that produced robust inhibition of GLS in platelets and in tumors. Evidence of prolonged SD in pts receiving single agent CB-839, together with strong preclinical data in combination with SOC agents including paclitaxel, everolimus and erlotinib, provides a clear rationale for continued evaluation of CB-839 in several tumor types, as a single agent and in combination with SOC therapies.Citation Format: Funda Meric-Bernstam, Angela DeMichele, Melinda L. Telli, Pamela Munster, Keith W. Orford, George D. Demitri, Gary K. Schwartz, Othon Iliopoulos, James W. Mier, Taofeek K. Owonikoko, Mark K. Bennett, Manish R. Patel, Jeffery R. Infante, James J. Harding. Phase 1 study of CB-839, a first-in-class, o...
Tarloxotinib bromide (T) is a prodrug that releases an irreversible EGFR/HER2 inhibitor (T-TKI) under hypoxic conditions. NSCLC is known to be a hypoxic disease and wild type (WT) EGFR is upregulated by multiple hypoxia-driven mechanisms (Curr Pharm Des, 19:907). Mutant EGFR NSCLC is commonly heterozygous and may result in maintenance of WT EGFR signalling (Can Sci, 103:1946; PloS One 8:e54170). Clinical studies indicate NSCLC patients harbouring WT/mut heterozygous EGFR have significantly poorer ORR, PFS and OS on treatment with EGFR-TKI (Can Sci, 99:929). Other mechanisms of resistance to EGFR-TKI include 50-60% with T790M EGFR mutation, 8-13% with HER2 amplification, while 15-20% lack identifiable mutation/amplification events (Nat Rev Clin Onc, 11:473). The combination of cetuximab/afa...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR
Conclusions:These findings suggest that TAS-121 could specifically modulate the immune system including T cells, leading to the anti-tumor immune responses. Therefore, TAS-121 has a unique profile among the 3rd generation EGFR-TKI. Considering this immune-modulating profile, combination with immune checkpoint blockade agent such as anti-PD1 monoclonal antibody might be beneficial for NSCLC patients harboring mutant EGFR.Citation Format: Satoshi Fukaya, Yoshimi Aoyagi, Masanori Katoh, Kimihiro Itoh, Toshihiro Shibutani, Nozomu Tanaka, Tomonori Haruma, Akihiro Hashimoto, Kazutaka Miyadera, Kenichi Matsuo, Yoshikazu Iwasawa, Teruhiro Utsugi, Kazuhiko Yonekura. TAS-121, a highly potent and mutant-specific EGFR inhibitor, modulates the immune system, resulting in anti-tumor immune responses. [a...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, biomarker diagnostic
In conclusion, we have developed three highly sensitive blood-based assays to identify sensitizing and resistance mutations for EGFR (L858R and exon 19 deletion E746 - A750, and T790M, respectively) in circulating DNA in plasma from patients previously diagnosed with NSCLC. These results indicate that plasma cfDNA is a reliable source for EGFR mutation analysis in clinical practice, especially for those patients unable to provide tissue-based samples. The results can be delivered to physicians within 72 hours from sample shipment and may facilitate more immediate patient management.Citation Format: Trudi Foreman, Kristina Koch, Amanda Weaver, Nicholas Dupuis, Steven Arrivo, Ubaradka Sathyanarayana, Hestia Mellert, Gary Pestano. Development of a rapid blood-based test for EGFR sensitizing a...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer
Conclusion: These results suggest that overexpression of AXL confers resistance to EGFR-TKIs in NSCLC cells and ASP8273 may show antitumor activity against EGFR-TKIs-resistant NSCLC patients with AXL expression.Citation Format: Naoki Kaneko, Hiroaki Tanaka, Satoshi Konagai, Hiroko Yamamoto, Hideki Sakagami, Tomohiro Eguchi, Takahiro Matsuya, Masamichi Mori, Hiroyuki Koshio, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu, Masahiro Takeuchi. Preclinical antitumor activity of ASP8273, a mutant-selective irreversible EGFR inhibitor in an AXL-overexpressing NSCLC model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B188. (...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, clinical trial
Conclusions: The analysis of ctDNA from urine identified a similar proportion of T790M+ patients as tissue-based testing with highest PPA amongst patients with urine volumes ≥90 mL. Discordant samples between urine and tissue that were not identified by the tumor test may be explained by tumor heterogeneity and/or inadequate biopsy. EGFR mutation detection from urine increases with urine volume and DNA yields and should be considered as a viable approach, particularly when tumor tissue is not available. Lastly, monitoring urine ctDNA T790M mutations longitudinally with baseline and post-therapy sampling could be clinically useful to determine benefit from therapy.Citation Format: Shirish Gadgeel, Chris Karlovich, Vlada Melnikova, Lecia V. Sequist, D. Ross Camidge, Heather Wakelee, Mauri...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, clinical trial
Conclusions: The recommended dose of Trem in phased combination with Gef in EGFR-mut pts with NSCLC was identified as 3mg/kg. The safety profile was consistent with the previously defined AE profile. An expansion cohort is enrolling pts at RP2D.Citation Format: David Planchard, Fabrice Barlesi, Carlos Gomez-Roca, Julien Mazieres, Andrea Varga, Laurent Greillier, Nathalie Chaput-Gras, Emilie Lanoy, Cedric Parlavecchio, Katty Malekzadeh, Maud Ngocamus, Sarah ZAHI, Benjamin Besse, Audrey Poterie, Jean-Charles Soria. Phase I, safety, tolerability and preliminary efficacy study of Tremelimumab (Trem) in combination with Gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics;...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, lung cancer, clinical trial
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7.Citation Format: Giorgio V. Scagliotti, Sergey Orlov, Joachim von Pawel, Frances A. Shepherd, Wallace Akerley, Jeffrey S. Ross, Dale Shuster, Qiang Wang, Brian Schwartz, Reinhard von Roemeling. Tivantinib in combination with erlotinib vs erlotinib alone for EGFR mutant NSCLC: Subgroup results from the phase 3 MARQUEE study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(1...