PharmStatus.com
Oncology Intelligence

Breast Cancer

The intent of these pages is to provide a broad overview of current BC treatment, focusing on therapeutics that are new or in development and are intended for general education. The views expressed are the author’s, unless explicitly referenced. If you are a cancer patient, you may want to start by reading the American Cancer Society pages or other patient advocacy groups you will find referenced at the end of this page, particularly to orient yourself in terms of resources and more traditional treatment options.

BC, like all cancers begins with a series of genetic errors, resulting in colonies of cells with a set of characteristics that allow these cells to grow, propagate, and thrive in environments foreign and hostile to their ancestor cells. These characteristics are called the Hallmarks of Cancer.(1) The goal of all cancer treatments is to remove or kill more of these rogue cells than the health cells that support the life and functions of the patient. In some cases, enough of these cells can be removed so that the body’s natural defenses can scavenge any that remain. If this cannot be done quickly enough, cancer continues to evolve, to acquire new characteristics that enable it to evade future therapies, resulting in treatment specific resistance.

There are a number of different diseases that are loosely called BC and that differ from one another in the characteristics of the cells, their genetic mutations, the progression of the disease, and the prognosis for the patient. The most common types of BC are ductal carcinoma in situ, invasive ductal carcinoma, and invasive lobular carcinoma: all characterized by glandular tissue epithelial cell abnormalities.(2) Most BCs are invasive having escaped their point of origin and invaded the surrounding breast tissue. Invasive ductal carcinoma (IDC) starts in a milk duct, whereas lobular carcinoma (ILC) begins in the milk glands. Inflammatory BC, Paget disease of the nipple, Phyllodes tumors, and angiosarcomas are rare invasive BCs.(2) Carcinoma in situ are clusters of abnormal epithelial cells that have not invaded nearby tissues, but have similar characteristics as invasive carcinoma cells. Not all patients with carcinoma in situ will develop invasive cancer.(3-5) Ductal carcinoma in situ (DCIS) is the most common type of carcinoma in situ, accounting for 83% of in situ cases diagnosed from 2008-2012. Lobular carcinoma in situ (LCIS) is less common than DCIS, accounting for about 13% of female in situ BCs diagnosed during 2008-2012, and indicated increased risk of developing cancer rather than a precursor of invasive cancer.(2, 4, 6, 7) Other in situ BCs have characteristics of both ductal and lobular carcinomas or have unknown origins.(8-10)

Epidemiology

In 2015, approximately 232 thousand new cases of invasive BC and 60 thousand carcinoma in situ were diagnosed in US women and less than 3 thousand cases in men.(4, 11) In the 1970s, the lifetime risk of being diagnosed with BC was 9.1%. Today, that risk is a 12.3%. This increase in risk over the past 4 decades is due to longer life expectancy, changes in reproductive patterns, menopausal hormone use, increased obesity, and increased detection through screening.(8) The BC incidence rate decreased almost 7% among white women from 2002 to 2003, attributed to reductions in the use of menopausal hormone therapy (MHT).(4, 12) From 2007 to 2011, BC incidence rates were stable in white women and increased by 0.3% per year in black women, while DCIS incidence rate increased to 0.8% per year over all populations.(4, 13, 14) While BC incidence and death rates generally increase with age, a decrease occurs in women 80 and older. During 2008-2012, the median age at the time of BC diagnosis was 61.(13)

For all stages combined, the 5-, 10-, and 15-year relative survival rates for BC are 89%, 83%, and 78%, respectively. Sixty-one percent of BCs are diagnosed at a localized stage, for which the 5-year relative survival rate is 99%.(4, 13) Survival is lower among women with a more advanced stage or larger tumor size at diagnosis.(8, 15) At the end of the 20th century, available chemotherapy regimens provided an OS that rarely exceeded 20 months.(16) Newer chemotherapeutic agents pushed survival to above 20 months.(17) Though recent years have seen a number of new classic cytotoxic agents with positive results, and targeted therapy.(18, 19)

About 41 thousand BC deaths occurred in 2015. Death rates for BC have steadily decreased in women since 1989. The decrease in BC death rates represents improvements in early detection and treatment.(4, 8, 20) Overall BC death rates decreased 36% from 1989 to 2012.(13) Black women are more likely to die from BC.(8, 13) As treatment for BCs has improved, the racial disparity has widened; by 2012, BC death rates were 42% higher in black than white women.(8) Poverty and a lack of health insurance are associated with lower BC survival.(21) BC patients who reside in lower-income areas have lower 5-year survival rates than those in higher-income areas at every stage of diagnosis.(8, 22)

Risk Factors

Increased risk of getting BC include family history, early menarche, increased age, and a personal history of BC.(23, 24) Risk factors that patients have some ability to control include obesity, use of MHT, physical inactivity, alcohol consumption, high-dose radiation to the chest at an early age, and long-term, heavy smoking.(24-27) Factors that patients have no ability to control include high breast tissue density, high bone mineral density, type 2 diabetes, certain benign breast conditions, and carcinoma in situ.(28) Reproductive factors that increase risk include a long menstrual history, never having children, and having one’s first child after age 30. Recent use of oral contraceptives (combined estrogen and progesterone) is associated with a an increase in BC risk, particularly among women who begin use before 20 years of age or before first pregnancy.(8, 29) Factors associated with a decreased risk of BC include breastfeeding for at least one year, regular moderate or vigorous physical activity, and maintaining a healthy body weight.(4, 30-32) Soy intake was inversely associated with BC risk in Asian but not Western populations.(33) High levels of fruit and vegetable consumption may reduce the risk of HR- BC, possibly due to high levels of carotenoids found in these foods.(8, 34, 35)

Inherited mutations in BRCA1 and BRCA2 account for 5-10% of all BCs.(36, 37) Compared to women in the general population, who have a 7% risk of developing BC by age 70, the average risk for BRCA1 and BRCA2 mutation carriers is 40-85%.(23, 38) However these mutations are very rare (much less than 1%) in the general population.(39) Rare mutations in PALB2 confer risk similar to BRCA2 mutations.(40) Other inherited conditions associated with increased BC risk include the Li-Fraumeni and Cowden syndromes.(41) Interestingly, most of the observed occurrence of BC clustered in families results from the interaction between lifestyle factors and multiple low-risk genetic variations, rather than specific high risk mutations like BRCA.(8, 42)

BC Subtypes

BC is distinguished by histological and molecular subtypes.(43, 44) Advances in translational research have increased scientific understanding of the molecular mechanisms of metastatic breast cancer (mBC), including the development of therapeutic targets and understanding of the mechanisms of resistance to treatment.(19, 45, 46) Most notable of the molecular markers, or biomarkers, for BC are the hormonal receptors (HR): ER and PR, and the growth receptor HER2.  Whether these are expressed or amplified or mutated is the primary way almost all BCs are subtyped.

Luminal A (HR+/HER2-)

74% of BCs express ER and/or PR but not HER2. These cancers tend to be slow- growing and less aggressive than other subtypes. Luminal A tumors are associated with the most favorable prognosis, particularly in the short term, in part because expression of HRs is predictive of a favorable response to hormonal therapy.(8, 47) Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all BCs; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA, andMAP3K1 with the Luminal A subtype.(43)

Triple Negative (TNBC)

About 12% of BCs are triple negative (ER-, PR-, and HER2-), though TNBCs is twice as common in black women compared to white women in the US. TNBC has fewer molecular targets and therefore treatment relies more on systemic chemotherapy and has a poorer short-term prognosis than other BCs.(8, 47)  TNBC is seen more often in patients with germline BRCA1 mutations, from specific ethnic groups, and in younger women.(43, 48, 49)  About 75% of TNBCs are the basal-like subtype. Basal-like tumors showed a high frequency of TP53 mutations and loss of function. Other genes reported to be mutated or amplified in basal-like tumor samples include RB1, PIK3CA, PTEN, INPP4B, KRAS, BRAF, EGFR, FGFR1, FGFR2, IGFR1, c-KIT, MET, and PDGFRA, and HIF1a/ARNT pathway.(43, 50)

Luminal B (HR+/HER2+)

Like luminal A BCs, luminal B BCs are ER+ and/or PR+ and are further defined by being highly positive for Ki67 or HER2. About 10% of BCs are ER+ and/or PR+ and HER2+. Luminal B BCs tend to be higher grade and more aggressive than luminal A BCs.(8, 51) Luminal/ER+ BCs displays high expression of ESR1, GATA3, FOXA1, XBP1, and cMYB. The TP53 pathway was differentially inactivated in Luminal/ER+ BCs, with a low TP53 mutation frequency in Luminal A (12%) and a higher frequency in Luminal B (29%). RB1 was detectable in most Luminal cancers with highest levels within Luminal A. A common oncogenic event was Cyclin D1 amplification and high expression, which preferentially occurred within Luminal tumors, and more specifically within Luminal B. The presumed tumor suppressor p18/CDKN2C was at its lowest levels in Luminal A. Luminal A tumors, which have the best prognosis, are the most likely to retain activity of the major tumor suppressors RB1 and TP53. In Luminal/ER+ cancers, the high frequency of PIK3CA mutations suggests that inhibitors of this activated kinase or its signaling pathway may be beneficial. Other potential candidates include AKT1 inhibitors and PARP inhibitors for BRCA1/2 mutations, as well as Cyclin D1/CDK4/CDK6.(43)

HER2-enriched (HR-/HER2+)

About 4% of BCs produce excess HER2 and do not express hormone receptors. These cancers tend to grow and spread more aggressively than other BCs and are associated with poorer short-term prognosis compared to ER+ BCs.(47) However, the recent widespread use of targeted therapies for HER2+ cancers has reversed much of the adverse prognostic impact of HER2 overexpression.(8)

Mutational Signatures

Biomarkers are used to identify specific mutations in patients that help to identify the subgroup of their BC and direct the best individual course of treatment.  Biomarkers can be prog­nostic (who to treat) or predictive (how to treat).(52-55)  Biomarkers have been identified using a number of big data databases to ascertain mutation patterns in large numbers of cancer tissues.  Among the larger of these databases are The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Surveillance, Epidemiology and End Results (SEER), and Embase.(56, 57)  Biomarkers signaling the development of resistance to trastuzumab and/or tamoxifen, including pSTS3, KLK10, HER2A16, were uncovered in this way.(58, 59)  Genes that signal BC when overexpressed were likewise revealed using Embase: Survivin, miR-21, miR-155.(60, 61) Similarly a number of biomarkers were noted to be correlated with metastatic disease: U79277, AK024118, BC040204, Ak000974, miR-105, mi-R126, eIF4E, ER, PR, HER2, MMP-9, and SK1.(62-68)  Other markers were found to be correlated with BRCA and/or p53 expression, such as miR-10b, miR-26a, miR-146a, miR-153, and EZH2.(69, 70)  And PD-L1 was shown in TCGA to be a marker indicative of antitumor adaptive immune response.(71, 72) Other mechanisms or biomarkers in development include AFF2, AKT1, CBFB, CCND3, CDH1, CDKN1B, GATA3, MLL3, MAP3K1, NF1, PIK3CA, PIK3R1, PTEN, PTPN22, PTPRD, RB1, RUNX1, SF3B1, TBX3, and TP53.(8, 43, 45, 73-76) Gene panels, such as Oncotype DX, PAM 50 ROR, and MammaPrint are used to assess the risk of recurrence and to identify those who would likely benefit from various therapeutics.(8)

 

Hallmarks of BC

The major BC molecular subtypes are defined by hormonal and growth receptors belonging to the sustaining proliferative signaling hallmark of cancer. Of three hormonal receptors (ER, PR, and AR) and the growth receptor (HER2), ER plays the dominant role in proliferation of BC. ER+ tumors comprise up to 75% of all BC patients, are well-differentiated and less aggressive than ER- tumors.(77, 78) PR+ tumors comprise 65-75% of BCs.(79)  ER+PR- tumors are less responsive to endocrine treatment than ER+PR+ tumors.(80) AR is expressed in 90% ER+ and 55% ER- tumors.(81) Lakes et al. have classified ER-PR- tumors into ER-PR-AR+ (molecular apocrine, abbreviated as MAC) and HR- carcinomas (ER-PR-AR-). MAC accounts for 13% of BC cases, is often characterized by KI67+, and has a favorable outcome comparable with ER+ and/or PR+ tumors when treated with taxane.(72, 82) HER2 amplification is associated with poor prognosis, but respond to systemic chemotherapy treatment.(83, 84) HER2+ BC is more resistance to endocrine therapies than HER2- BC, though such resistance does not apply to AIs.(85) Topoisomerase II alpha (TOP2A) expression is correlated with KI67 expression and is found in 30%-90% of HER2+ BCs. It has been suggested as a potential biomarker with aberrations being associated with increased responsiveness to anthracycline-based chemotherapy.(86)

Basal, EMT, or stem cell markers are members of the activating invasion and metastasis hallmark of cancer and are more likely to be enriched in TNBC. The basal subtype is ER-PR-HER2- generally with CK5/6+ and EGFR+.(87-89) Markers of Epithelial to mesenchymal transition (EMT) include VIM, SNAI1, SNAI2, TWIST1, TWIST2, ZEB1, ZEB2, CDH1, CLDN3, CLDN4, CLDN7, while stem cell markers include CD44, CD24, EpCAM, CD10, CD49, CD29, MUC1, THY1 and ALDH1A1.(90) Two ER-PR-HER2- BC groups can be defined from these markers: claudin-low and metaplastic BC (MBC). MBC are distinct from claudin-low tumors by harboring PIK3CA (47% vs 0%), AKT, or KRAS mutations.(91) Claudin-low tumors are ER-PR-HER2- tumors that account for 7-14% of BC, and result poor overall survival (OS).(72, 92)

The interferon-rich subtype is recently identified from ER-PR-HER2- tumors, account for 10% of BCs, and express STAT1 and SP110.(72, 93)

BCL2 is a suppressor of apoptosis and its expression is shown to be inversely correlated with TP53, and its function could be substituted by TP53 mutation. BCL2 is a prognostic marker for all types of early-stage BC, and its strong correlation with HR might contribute to the superior survival observed for BCL2+ BCs.(94) The predictive value of BCL2 is reported for ER-PR-HER2- BCs, with ER-PR-HER2-BCL2- patients found beneficial from anthracycline-based regimen.(95) These indicate that 'resisting cell death' is not a determinant factor for breast tumors to be aggressive but is important for TNSBCs to develop anthracycline resistance.(72)

Elevated prolonged ROS generation, overactive PI3K-AKT-mTOR signaling, and/or favoring of glycolytic flux over OXPHOS may set the conditions for a metabolic switch towards tumorigenesis. This may include germline BRCA1 deficiency, TP53 mutations, and PTEN loss. TP53-PR- tumors are found associated with the worst prognosis among all BCs. It has been shown that p53 mutation adversely affects BC response to tamoxifen.(72, 96) Activation of proto-oncogenes (e.g. RAS, NFKB1, TGFB1) as well as loss of tumor-suppressor genes (e.g. BRCA1) in cancer cells have been shown to be sufficient to induce metabolic reprogramming of the fibroblast compartment via ROS generation.(97) There is a close relationship between tumor suppressor genes and Warburg-like metabolism. For instance, mutations in genetic components of the PI3K-AKT-mTOR-PTEN pathway usually result in strong basal activation of mTOR signaling, which is one of the most characteristic features of the CAF phenotype. Up to 44 % of all BC subtypes bear PI3K pathway aberrations such as PIK3CA, PIK3R1, AKT1, and PTEN mutations, in particular luminal A and HER2+ subtypes, although much less common in the basal-like subtype. TP53 mutations can be found in about 37% of all BCs and in up to 80 % of basal-like and HER2+ tumors, have also been demonstrated to cause the metabolic switch towards glycolysis in a Warburg-like manner.(43, 98) Higher level of circulating vitamin D metabolites is shown to be associated with decreased BC risk, and the statues of vitamin D receptor (VRD), AR and ER are known to be correlated with tumor differentiation state.(99) Santagata et al. have proposed BCs could be quantitatively classified into 4 categories, i.e., HR3 (ER+AR+VDR+), HR2 (ER+AR+, AR+VDR+, ER+VDR+), HR1 (ER+, VDR+, AR+), and HR0 (ER-AR-VDR-). HR3 tumors being associated with the best survival and HR1 and HR0 tumors the most aggressive. An intriguing implication of this novel classification is targeting VDR and AR in conjunction with ER for patients receiving hormone therapy, which is potentially a more efficient therapeutic strategy.(72, 100)

BRCA1-associated BC is often TNBC.(101) Although mainly known for its role in homologous recombination DNA repair, BRCA1 has a role in cellular energy metabolism and in the regulation of oxidative stress.(102) A BRCA1-mutated BC cell line transfected with wild-type BRCA1 has displayed the reversal of Warburg-like metabolic features, including an activation of OXPHOS and an impairment of glycolytic flux via the inhibition of the expression of genes that all play major roles in glycolysis (e.g. SLC2A1, HK1, HK2, PFKFB3, and LDHA).(102) BRCA1 also interacts with HIFla, AKT1, MYC, and TP53, which have well-established roles in the regulation of glycolysis. Another interesting relationship exists between BRCA1 and NAD+: BRCA1 knockdown results in elevated NAD+ levels, whereas BRCA1 mRNA levels conversely increase with available NAD+.(103) As PARP enzymes also use NAD+ as a substrate for their functioning in base excision repair, and as PARP inhibitors raise the pool of available NAD+. Aromatase expression is inhibited by BRCA1 in a manner similar to TP53, therefore limiting estradiol (E2) production.(104) BRCA1 reduces expression levels of IGF1R and IGF1. Consequently, the PI3K- AKT-mTOR pathway is stressed in multiple ways in BRCA1 -deficient cells: E2 directly activates PI3K and AKT1, IGF1 activates the pathway by binding to IGF1R, and ERa provokes the phosphorylation of AKT1, while the inhibition of the latter by BRCA1 is hampered. Finally, BRCA1 has been identified as an important player in autophagy, in the sense that BRCA1 deficiency promotes Beclin 1-dependent autophagic pathways in response to metabolic stresses. BRCA1 impairment can be expected to result in Warburg-like metabolism, activation of PI3K signaling, elevated ROS signaling, impaired antioxidant response, and enhanced autophagy - the very features of the CAF phenotype. As silencing of BRCA1 expression by means of promoter hypermethylation has also been suggested as an important event in the pathogenesis of sporadic BC disease, particularly so in TNBC, these findings may have broad implications beyond hereditary BC pathogenesis.(98)

A summary of mutations defining or found in BC subtypes are presented in the table below:

Dominant genomic, clinical, and proteomic features of BC subtypes: Percentages are based on 466 tumor overlap list (43)

 

Luminal A

Luminal B

Basal-like

HER2E

% ER+/HER2-

87%

82%

10%

20%

% HER2+

7%

15%

2%

68%

% TNBC

2%

1%

80%

9%

p53 Pathway

TP53 mut (12%)

Gain of MDM2 (14%)

TP53 mut (32%)

Gain of MDM2 (31%)

TP53 mut (84%)

Gain of MDM2 (14%)

TP53 mut (75%)

Gain of MDM2 (30%)

PIK3CA/PTEN Pathway

PIK3CA mut (49%) PTEN mut/loss (13%) INPP4B loss (9%)

PIK3CA mut (32%) PTEN mut/loss (24%) INPP4B loss (16%)

PIK3CA mut (7%) PTEN mut/loss (35%) INPP4B loss (30%)

PIK3CA mut (42%) PTEN mut/loss (19%) INPP4B loss (30%)

RB1 Pathway

Cyclin D1 amp (29%) CDK4 gain (14%)

Low expression of CDKN2C

High expression of RB1

Cyclin D1 amp (58%) CDK4 gain (25%)

RB1 mut/loss (20%)

Cyclin E1 amp (9%)

High expression of CDKN2A Low expression of RB1

Cyclin D1 amp (38%) CDK4 gain (24%)

DNA Mutations

PIK3CA (49%) TP53 (12%) GATA3 (14%) MAP3K1 (14%)

TP53 (32%) PIK3CA (32%) MAP3K1 (5%)

TP53 (84%) PIK3CA (7%)

TP53 (75%) PIK3CA (42%) PIK3R1 (8%)

Prognosis and staging

Prognosis and selection of therapy are determined by the age and menopausal status of the patient, the stage of the disease, the histologic and nuclear grade of the primary tumor, the ER, PR, and HER2 status of the tumor, and proliferative capacity of the tumor (e.g., Ki67).(105) Some of forms of invasive BC may have a better prognosis than IDC, including adenocystic, adenosquamous, medullary, mucinous, papillary, and tubular carcinomas. Other invasive BCs have the same or maybe worse prognoses than IDC, including metaplastic, micropapillary, and mixed carcinomas.(2)

The prognosis of invasive BC is strongly influenced by the stage of the disease. There are two main staging systems for cancer. The TNM classification of tumors uses information on tumor size and how far it has spread within the breast and to adjacent tissues (T), the extent of spread to the nearby lymph nodes (N), and the presence or absence of distant metastases (M).(106) Once the T, N, and M are determined, a stage of 0, I, II, III, or IV is assigned, with stage 0 being in situ, stage I being early stage invasive cancer, and stage IV being the most advanced disease. The Surveillance, Epidemiology, and End Results (SEER) Summary Stage system is more simplified and is commonly used in reporting cancer registry data.(107) According to the SEER Summary Stage system, local stage refers to cancers that are confined to the breast (stage I and some stage II in the TNM staging system), regional stage refers to tumors that have spread to surrounding tissue or nearby lymph nodes (stage II or III, depending on size and lymph node involvement), and distant stage refers to cancers that have metastasized to distant organs or lymph nodes above the collarbone (stage IIIc and all stage IV).(8)

Treatment

BC is commonly treated by surgery, radiation therapy, chemotherapy, hormone therapy, and/or targeted therapy.(105) Most women with early stage BC will have some type of surgery, which is often combined with other treatments to reduce the risk of recurrence. Patients with metastatic disease are primarily treated with systemic therapies.(8)  Below is a table of current treatment options by BC subtype and biomarker availability.

Current treatment options, biomarkers, and future developments.(19)

Subtype

Current treatment options

Predictive biomarkers

In Development

ER+

Tamoxifen

ER status

New PI3k inhibitors (ex: buparlisib)

Fulvestrant ± Palbociclib

AIs ± Palbociclib or Everolimus or Trastuzumab (if ER+/HER2+)

Next generation estrogen degraders (ex: Rad1901)

HER2+

Trastuzumab + Chemotherapy

HER2 status

 

Pertuzumab + Trastuzumab + Docetaxel

TDM-1

Lapatinib + Capecitabine or Trastuzumab

TNBC

Cytotoxic chemotherapy (monotherapy or doublet)

No biomarkers

PARP inhibitors

BRCA expression biomarker

Bevacizumab + paclitaxel (where approved)

Immunotherapy

VEGFA as biomarker of response

 

Surgery and/or Radiation

Treatment usually involves either breast-conserving surgery (BCS) or mastectomy. Numerous studies have shown that for early BC, long-term survival is similar for women treated with BCS plus radiation therapy as those treated with mastectomy.(4) BCS is almost always followed by radiation therapy because it has been shown to reduce the risk of BC recurrence by about 50% and the relative risk of BC death by about 20% in most patients.(108) Radiation therapy is recommended for most women who have BCS: an analysis of 4 clinical trials showed that 18% of women who had BCS alone experienced recurrence, compared to 8% of women who had BCS plus radiation therapy 5 years after treatment.(4, 109) Mastectomy rates among DCIS patients decreased from 46% in 1991 to 25% in 2005.(4, 110) Although there is a higher risk of local recurrence with BCS than with mastectomy, clinical trials with more than 20 years of follow-up data have confirmed that a woman who chooses BCS and radiation will have the same expected long-term survival as if she had chosen mastectomy.(111) However, now patients eligible for BCS are tending to elect mastectomy. Reasons include reluctance to undergo radiation therapy after BCS and fear of recurrence.(8, 51) Women at very high risk of BC (e.g. BRCA mutations), particularly younger women, may also elect prophylactic mastectomy.(4) Removing both breasts before cancer is diagnosed reduces the risk of BC by 90% or more.(8, 112, 113)

Systemic therapy

Systemic therapies approved for BC include chemotherapies, hormonal therapies, and targeted therapies. Systemic therapy is the main treatment option for women with metastatic breast cancer (mBC). Systemic treatment given to patients before surgery is called neoadjuvant therapy, whereas systemic treatment given after surgery is adjuvant therapy.(8, 114)

Chemotherapy drugs generally work by attacking cells that grow quickly, such as cancer cells.(8) TNBC and HER2+ BCs tend to be more sensitive to chemotherapy, while ER+/PR+ tumors are generally less responsive. Combinations of drugs can be more effective than one drug alone for treatment of early stage BC.(8, 115) Chemotherapies approved by the FDA include capecitabine, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, paclitaxel, and nab-paclitaxel.(116) A combined analysis of three trials emphasized the superiority of anthracycline containing adjuvant chemotherapy regimens compared with docetaxel/cyclophosphamide.(117-119)

Hormonal therapy (HT)

Hormonotherapy (HT) is the oldest form of targeted therapy. Tamoxifen, a selective ER modulator (sERm), was the first compound that showed dramatic responses and a relatively good safety profile in patients with mBC.(120) Agents that directly or indirectly target ER by different mechanisms, such as aromatase inhibitors (AI), luteinizing hormone releasing hormones (LHRH) agonists, and the ER receptor degrader fulvestrant were also found to be effective in ER+ BC.(121) HT works by either blocking or lowering the levels of natural hormones, which act to promote cancer growth in HR+ BC.(8) Women with early stage HR+ BC benefit from treatment with HT for at least 5 years. Tamoxifen blocks estrogen in ER+ BC, is used to treat both premenopausal and postmenopausal cancers, reduces the rate of recurrence by approximately 40%-50% for 10 years, and reduces mortality by a third for 15 years.(122, 123) Potentially reversible ovarian ablation is achieved with a class of drugs called luteinizing hormone-releasing hormone (LHRH) analogs (e.g., goserelin or leuprolide). Adding ovarian suppression to tamoxifen has been shown to improve survival in mHR+ BC when compared to tamoxifen alone.(124)  Ovarian suppression includes aromatase inhibitors (AIs) in premenopausal women. For postmenopausal women, treatment with an aromatase inhibitor (AI; e.g., letrozole, anastrozole, or exemestane) provides a small survival advantage when used instead of or in addition to tamoxifen.(4, 8, 125) The MA17.R trial evaluated the prolongation of adjuvant AI therapy and demonstrated that while increased disease-free survival was observed, a higher fracture rate was found.(117, 126, 127) The combination of LHRH analog and AIs has been used for some time in the treatment of metastatic disease. This combination reduces the risk of recurrence more than either tamoxifen alone or tamoxifen with ovarian suppression in women with earlier stage disease.(8, 128) Fulvestrant is an anti-estrogen treatment reduces ERs and blocks estrogen binding in mBC.(8) FDA approved hormonal therapies include anastrozole, tamoxifen, goserelin, leuprolide, letrozole, exemestane, fulvestrant, ixabepilone, megestrol, methotrexate, pamidronate, and toremifene.(116) Three trials evaluating AI (anastrozole) and fulvestrant versus anastrozole alone as first line treatment showed conflicting results: SWOG 226 trial showed OS gain of 6.4 months (HR = 0.81, p = 0.049) both the SOFEA and FACT trials did not show any advantage to the dual combination.(129-131) Tamoxifen naive patients without any development of acquired resistance may benefit from dual therapy at first line. Therefore, dual anastrozole and fulvestrant is currently not indicated and sequential treatment remains the standard. Regarding the first line anti-HT of choice, in hormono­therapy naive patients, the FIRST trial showed an advantage in terms of OS for the fulvestrant group over the anastrozole group (median OS, 54.1 versus 48.4 months, p = 0.04).(19, 132) HR+HER2- tumors have the best prognosis and response to HT.(72)

The use of drugs to reduce the risk of disease is called chemoprevention. Clinical trials of chemoprevention agents for women at high risk of BC have found decreased incidence of DCIS among women receiving tamoxifen or raloxifene, another sERm.(4, 133) Tamoxifen can be used by both premenopausal and postmenopausal women, but raloxifene is only approved for use in postmenopausal women. A recent meta-analysis found that taking a sERm reduced BC risk by 38% over 10 years.(4, 134, 135) Clinical trials are also examining AIs as chemopreventives: early clinical trial results show that BC risk was reduced by more than half in high-risk women taking anastrozole or exemestane compared to placebo.(8, 136)

HT resistance

Patients can acquire a resistance to HT that makes it less effective.  Different paths lead to endocrine resistance, including: (1) loss of the ER receptor; (2) mutations in the ER receptor; (3) up regulation of alternative signal transduction pathways, including  EGFR/HER2, PIK3CA/mTOR.(19) Additionally, a small subset of ER+ BCs with a lower Allred score, higher KI67 in­dex, and a more aggressive natural evolution (Luminal B), are primarily resistant to HT from the beginning of treatment.(137)  In these tumors, the dysregulation of CDK is an often exploited proliferation pathway. Indeed several clinical trials are currently evaluating selective CDK 4-6 inhibitors (ribociclib, abemaciclib, palbociclib) with HT.(138) The results of the PALOMA-1 trial, which tested palbociclib in combination with letrozole versus letrozole alone as first-line treatment of ER+ HER2- mBC demonstrated significantly improved progression free survival (PFS; 20.2 versus 10.2 months).(139) The results of PALOMA 1 were recently confirmed in the phase 3 PALOMA 2 trial, with a median PFS was 24.8 versus 14.5 months. The PALOMA-3 study that compared palbociclib and fulvestrant to fulvestrant alone in patients who had pro­gressed during HT or relapsed after adjuvant treatment showed a PFS advantage of 5.4 months.(19, 140) Another attempt to overcome ER resistance by blocking EGFR/HER was performed in a trial that combined gefitinib (EGFR tyrosine kinase inhibitor) and tamoxifen.(141) Unfortunately, the combina­tion was not found to be superior to tamoxifen although some positive signal was seen in HT naive and HER2+ patients. The usefulness of targeting PI3K/AKT/mTOR pathway was tested in the BOLERO-2 study: the mTOR inhibitor everolimus and exemestane were compared to exemestane alone in patients with MBC who had failed previous AI. While PFS was superior for the combi­nation arm, no differences were seen in overall survival (OS).(142) Women with two or more alterations in CCND1, PIK3CA, FGFR1/2 or PTEN, did not benefit from everolimus treatment. More recently, in the BELLE-2 trial of buparlisib, a pan-PI3K inhibitor in association with fulvestrant versus fulvestrant, the association was marginally supe­rior in terms of PFS (6.9 versus 5). Interestingly, the presence of PI3K mutant circulating tumor DNA (ctDNA) predicted an enhanced benefit.(19, 143)

Targeted therapy

Targeted drugs are newer and work by blocking specific molecules in or on cells that may be more common or active in cancer cells, often those molecules are also biomarkers.(8) FDA approved targeted therapies for BC include HER2-targeting ado-trastuzumab, trastuzumab, lapatinib, and pertuzumab, mTOR-targeting everolimus, and CDK4/CDK6-targetting palbociclib.(116)

HER2 targeted therapy

For the 14% of women whose cancer overexpresses HER2, several targeted therapies are available.(4, 8) Trastuzumab is a monoclonal antibody (mAb) that directly targets HER2 and is a part of the standard of care for advance HER2+ BC.(144) The combined results of two large trials indicate that adding trastuzumab to standard chemotherapy for early stage HER2+ BC reduces the risk of recurrence and death by 52% and 33%, respectively, compared to chemotherapy alone.(145).

HER2-targeted treatment resistance

Different pathways to HER2-targeted therapy resistance can arise: (1) reduced binding between trastuzumab and HER2; (2) alter­native activating mechanisms at receptor level or down­stream; (3) crosstalk; and (4) failure to trigger immune-mediated mechanisms to destroy tumor cells.(19, 146)

Lapatinib bypasses resistance by targeting the intracellular domain of the HER2 receptor and has been in clinical use for many years. Lapatinib is effective in delaying disease progression in women with HER2+ BCs that have become resistant to trastuzumab.(8, 147) Its relevance in clinical practice has been diminished by newer agents.

Pertuzumab an anti-­heterodimerization (HER2/HER3) mAb is a more recently approved that attaches to a different location on HER2 than trastuzumab. This drug can be used in combination with trastuzumab and chemotherapy to treat HER2+ BC in either the metastatic or neoadjuvant setting, where it has been shown to improve OS by 15 months compared to docetaxel and trastuzumab alone.(148) CLEOPATRA is a phase 3 study that evaluated adding pertuzumab to trastuzumab + docetaxel in first-line MBC. Both PFS and OS were in favor of the pertuzumab group (OS 56.5 versus 40.8 months).(19, 146, 149) Biomarker evaluation of the CLEOPATRA trial showed that while pertuzumab consistently showed a PFS benefit, PI3K wild-type patients had twice the PFS of PI3K mutated patients.(19, 150)

Ado-trastuzumab (T-DM1) is a mAb attached to the chemotherapy drug DM-1, is used to treat HER2+ mBC, and has been shown to shrink tumors and extend survival.(151) The EMILIA trial showed that TDM1 significantly prolonged PFS and OS for all subgroups compared to lapatinib + capecitabine in HER2+ mBC previously treated with trastuzumab and a taxane. Several biomarkers were evaluated from this trial which showed PI3K mutations were associated with shorter PFS and OS for the lapatinib + capecitabine arm.(152)  The THERESA trial compared TDM1 to physician choice in previously treated patients, and results showed TDM1 superiority for both PFS (6.2 versus 3.3 months) and OS (22.7 versus 15.8 months in the physician choice arm).(153, 154) In the neoadjuvant treatment of HER2+ BC, the KRISTINE trial compared T-DM1 + pertuzumab with docetaxel, carboplatin, trastuzumab, + pertuzumab (TCPH). Results indicated that T-DM1 has considerable activity that cannot be further improved by the combination of pertuzumab.(117)  In the front line setting, the MARIANNE trial of HER2+ BC showed similar PFS for TDM1 versus TDM1 + pertuzumab versus trastuzumab + taxane. The LUX-breast 1 trial added the pan-HER blocker afatinib to vinorelbine or trastuzumab and vinorelbine in patients who had previously received trastuzumab as adjuvant or first line metastatic treatment, but was closed due to toxicity in the afatinib arm.(19, 155) For first line therapy or trastuzumab naive patients the current recom­mendation is pertuzumab + trastuzumab and docetaxel, and for second line and trastuzumab exposed patients, TDM1 is preferred.(19)

mTOR targeted therapy

Blocking the mTOR pathway is one way that has been attempted to overcome HER2-targeted therapy resistance. Everolimus blocks mTOR and improves the effectiveness of HT. Everolimus is approved in combination with exemestane to treat advanced, HR+/HER2- BC in postmenopausal women. It is indicated in women whose cancers have grown while they were being treated with either letrozole or anastrozole.(156) While the BOLERO-3 trial of everolimus + trastuzumab + vinorelbine in the second-line setting demonstrated PFS advantage of 7 versus 5.8 months with the addition of everolimus, particularly for ER- or PTEN loss patients, BOLERO-1 did not confirm the benefit adding everolimus to trastuzumab + paclitaxel in the first-line setting.(157) Since there are better treatment alternatives, for both first line (pertuzumab) and second line (TDM1), the results of the BOLERO 1 and 3 trials have not changed clinical practice.(19)

CDK4/6 Targeted therapy

Palbociclib targets CDK4/CDK6 and is used in combination with HT to treat mBC, as it prolongs time to progression when added to letrozole or fulvestrant.(140) In the PALOMA-2 trial, the addition of palbociclib to letrozole prolonged PFS from 14.5 to 24.8 months in mBC in the first-line setting. In premenopausal patients from the PALOMA-3 trial, ovarian function suppression plus fulvestrant + palbociclib yielded results comparable to the post­menopausal population. The PALOMA-2 trial HR+/HER2- BCs were treated with letrozole + palbociclib or letrozole. In contrast to PALOMA-2, pretreated women were included in the PALOMA-3 trial and randomized to fulvestrant +/- palbociclib.(117)

Targeting angiogenesis in TNBC

Angiogenesis is a hallmark of cancer, particularly in TNBC. When bevacizumab, a VEGF targeting mAb anti-angiogenesis therapeutic, was added to neoadjuvant chemotherapy in the ARTemis trial there was no improvement over chemotherapy alone in terms of DFS and OS first-line chemotherapy for HER2- mBC.(117)  The RIBBON-2 trial which evaluated bevacizumab with investigator choice of chemo­therapy in previously treated MBC showed again improved PFS for the bevacizumab with suggested stronger effect for TNBC patients and for patients who received bevacizumab with taxanes.(158) The TANIA trial evaluated bevacizumab + chemotherapy versus chemotherapy alone in second-line treatment cancer after first-line treatment with bevacizumab + chemotherapy in HER2- population. The PFS was 6.3 versus 4.2 months in favor of the bevacizumab arm.(159) In toto, bevacizumab plays a modest role in the first and second line of ER- mBC. Ramucirumab, another antiangiogenic, failed to show benefit in a large phase 3 trial with 22% of TNBC subpopulation.(19, 160)

 

Pivotal clinical trials supportive of the role of bevacizumab in TNBC.(19)

Trial title (and name)

Trial identifier NCT number

Major findings

First-line bevacizumab in combination with chemotherapy for HER2-negative mBC: pooled and subgroup analyses of data from 2447 patients

N/A

In this pooled analysis the subgroup of patients with TNBC, had PFS HR = 0.63 (95% CI 0.52—0.76, p < 0.0001) and one-year survival rates were 71% with bevacizumab-containing therapy versus 65% with chemotherapy alone.

RIBBON-2: a randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second- line treatment of human epidermal growth factor receptor 2­negative mBC

NCT00281697

The combination of bevacizumab with commonly used chemotherapies improved PFS in the second- line treatment of patients with HER2-negative mBC especially in the TNBC group: HR = 0.49.

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or mBC after first-line treatment with bevacizumab plus chemotherapy (TANIA)

NCT01250379

The PFS was 6.3 versus 4.2 months (HR = 0.75, p = 0.0068) in favor of the bevacizumab arm.

Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative mBC (IMELDA)

NCT00929240

PFS was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (11.9 months vs 4.3 months p < 0-0001).

 

Targeting DNA repair in TNBC

Patients with certain BRCA1 and 2 mutations are more sensitive to PARP inhibitors.(161) Currently the OlymipiAD and BRAVO trials recruit BRCA+, TNBC (or HER2-) patients to randomized phase 3 trials that compare olaparib or niraparib, respectively, to physician's choice.(19)

Immunotherapy

PD-L1 targeting therapy

TNBCs lack of targetable receptors, and while prognosis of ER+ and HER2+ cancers improved during the last decade, that of TNBC remains poor, with chemotherapy as largely its only treatment option. Limited results have been demonstrated with angio­genesis and DNA repair directed therapies. Immunotherapy may in the coming years yield positive results in TNBC, as 20% of these tumors express PDL1, with the ongoing Keynote 012 phase 1 trial showing promising results.(19, 162, 163) In a phase Ib study, patients with metastatic TNBC received a combination of nab-paclitaxel + atezolizumab, a mAb targeting PD-L1. Activity was promising with high response rates across all treatment lines independently of PD-L1 expression. Owing to these favorable outcomes, a corresponding phase III trial (IMPASSION; NCT02425891) is currently ongoing.(117)

References

1.                    Hanahan D, Weinberg RA. The hallmarks of cancer. cell. 2000;100(1):57-70.

2.                    types-of-breast-cancer. Available from: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/types-of-breast-cancer.html.

3.                    Rohan TE HD, Franco EL, Albores-Saavedra. Cancer Precursors. Schottenfeld D FJ, Jr., editor. New York: Oxford University Press; 2006.

4.                    Society AC. Cancer Facts & Figures 20152015. Available from: http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf.

5.                    Benevolenskaya EV, Islam AB, Ahsan H, Kibriya MG, Jasmine F, Wolff B, Al-Alem U, Wiley E, Kajdacsy-Balla A, Macias V. DNA methylation and hormone receptor status in breast cancer. Clinical epigenetics. 2016;8(1):17.

6.                    Sun J, Chen X, Wang Z, Guo M, Shi H, Wang X, Cheng L, Zhou M. A potential prognostic long non-coding RNA signature to predict metastasis-free survival of breast cancer patients. Scientific reports. 2015;5:16553.

7.                    Zhang Y, Yang P, Sun T, Li D, Xu X, Rui Y, Li C, Chong M, Ibrahim T, Mercatali L. miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nature cell biology. 2013;15(3):284-94.

8.                    Society. AC. Breast Cancer Facts & Figures 2015-2016. . Atlanta: 2016.

9.                    Sonnenblick A, Brohée S, Fumagalli D, Vincent D, Venet D, Ignatiadis M, Salgado R, Eynden G, Rothé F, Desmedt C. Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer. BMC medicine. 2015;13(1):177.

10.                 Yuen HF, Chan YK, Grills C, McCrudden CM, Gunasekharan V, Shi Z, Wong ASY, Lappin TR, Chan KW, Fennell DA. Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail‐induced epithelial–mesenchymal transition. The Journal of pathology. 2011;224(1):78-89.

11.                 Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152(5):1173-83.

12.                 Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The decrease in breast-cancer incidence in 2003 in the United States. New England Journal of Medicine. 2007;356(16):1670-4.

13.                 Howlader N NA, Krapcho M, et al. . SEER Cancer Statistics Review, 1975-2012. . Bethesda, MD: National Cancer Institute, 2015.

14.                 Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. Journal of the National Cancer Institute. 2010;102(3):170-8.

15.                 SEER*Stat Database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2014 Sub (1973-2012 varying) - Linked To County Attributes - Total U.S., 1969-2013 Counties, National Cancer Institute, DCCPS [Internet]2015. Available from: www.seer.cancer.gov.

16.                 Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V, Tinazzi A, Liberati A. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. Journal of Clinical Oncology. 1998;16(10):3439-60.

17.                 Dear RF, McGeechan K, Jenkins MC, Barratt A, Tattersall MH, Wilcken N. Combination versus sequential single agent chemotherapy for metastatic breast cancer. The Cochrane Library. 2013.

18.                 Mendes D, Alves C, Afonso N, Cardoso F, Passos-Coelho JL, Costa L, Andrade S, Batel-Marques F. The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer–a systematic review. Breast Cancer Research. 2015;17(1):140.

19.                 Sonnenblick A, Pondé N, Piccart M. Metastatic breast cancer: The Odyssey of personalization. Molecular Oncology. 2016;10(8):1147-59.

20.                 Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JDF, Feuer EJ. Effect of screening and adjuvant therapy on mortality from breast cancer. New England Journal of Medicine. 2005;353(17):1784-92.

21.                 Shi R, Taylor H, McLarty J, Liu L, Mills G, Burton G. Effects of payer status on breast cancer survival: a retrospective study. BMC cancer. 2015;15(1):211.

22.                 Harper S, Lynch J, Meersman SC, Breen N, Davis WW, Reichman MC. Trends in area-socioeconomic and race-ethnic disparities in breast cancer incidence, stage at diagnosis, screening, mortality, and survival among women ages 50 years and over (1987-2005). Cancer Epidemiology and Prevention Biomarkers. 2009;18(1):121-31.

23.                 Kar G, Gursoy A, Keskin O. Human cancer protein-protein interaction network: a structural perspective. PLoS Comput Biol. 2009;5(12):e1000601.

24.                 Liu Y, Nguyen N, Colditz GA. Links between alcohol consumption and breast cancer: a look at the evidence. Women’s Health. 2015;11(1):65-77.

25.                 Fuhrman BJ, Schairer C, Gail MH, Boyd-Morin J, Xu X, Sue LY, Buys SS, Isaacs C, Keefer LK, Veenstra TD. Estrogen metabolism and risk of breast cancer in postmenopausal women. Journal of the National Cancer Institute. 2012;104(4):326-39.

26.                 Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. Jama. 2013;310(13):1353-68.

27.                 Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. Jama. 2011;306(17):1884-90.

28.                 De Bruijn K, Arends L, Hansen B, Leeflang S, Ruiter R, van Eijck C. Systematic review and meta‐analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. British Journal of Surgery. 2013;100(11):1421-9.

29.                 Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Annals of epidemiology. 2015;25(3):193-200.

30.                 Li CI, Beaber EF, Tang M-TC, Porter PL, Daling JR, Malone KE. Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20–44 years of age. Breast cancer research and treatment. 2013;137(2):579-87.

31.                 La Vecchia C, Giordano SH, Hortobagyi GN, Chabner B. Overweight, obesity, diabetes, and risk of breast cancer: interlocking pieces of the puzzle. The oncologist. 2011;16(6):726-9.

32.                 Wu Y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast cancer research and treatment. 2013;137(3):869-82.

33.                 Dong J-Y, Qin L-Q. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast cancer research and treatment. 2011;125(2):315-23.

34.                 Jung S, Spiegelman D, Baglietto L, Bernstein L, Boggs DA, Van Den Brandt PA, Buring JE, Cerhan JR, Gaudet MM, Giles GG. Fruit and vegetable intake and risk of breast cancer by hormone receptor status. Journal of the National Cancer Institute. 2013:djs635.

35.                 Eliassen AH, Liao X, Rosner B, Tamimi RM, Tworoger SS, Hankinson SE. Plasma carotenoids and risk of breast cancer over 20 y of follow-up. The American journal of clinical nutrition. 2015:ajcn105080.

36.                 Blackwood MA, Weber BL. BRCA1 and BRCA2: from molecular genetics to clinical medicine. Journal of clinical oncology. 1998;16(5):1969-77.

37.                 Schwartz GF, Hughes KS, Lynch HT, Fabian CJ, Fentiman IS, Robson ME, Domchek SM, Hartmann LC, Holland R, Winchester DJ. Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007. Cancer. 2008;113(10):2627-37.

38.                 Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, Evans DG, Izatt L, Eeles RA, Adlard J. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. Journal of the National Cancer Institute. 2013;105(11):812-22.

39.                 Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, Beeri R, Gal M, Grinshpun-Cohen J, Djemal K. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proceedings of the National Academy of Sciences. 2014;111(39):14205-10.

40.                 Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F. Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine. 2014;371(6):497-506.

41.                 Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet. 2008;9:321-45.

42.                 Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. New England journal of medicine. 2000;343(2):78-85.

43.                 Network CGA. Comprehensive molecular portraits of human breast tumors. Nature. 2012;490(7418):61.

44.                 Barnard ME, Boeke CE, Tamimi RM. Established breast cancer risk factors and risk of intrinsic tumor subtypes. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2015;1856(1):73-85.

45.                 Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-52.

46.                 Wang Y-C, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers-role of estrogen receptor and HER2 reactivation. Breast Cancer Research. 2011;13(6):R121.

47.                 Blows FM, Driver KE, Schmidt MK, Broeks A, Van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7(5):e1000279.

48.                 Perou CM. Molecular stratification of triple-negative breast cancers. The oncologist. 2011;16(Supplement 1):61-70.

49.                 Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Jama. 2006;295(21):2492-502.

50.                 Fedele CG, Ooms LM, Ho M, Vieusseux J, O'Toole SA, Millar EK, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proceedings of the National Academy of Sciences. 2010;107(51):22231-6.

51.                 Parise CA, Caggiano V. Breast cancer survival defined by the ER/PR/HER2 subtypes and a surrogate classification according to tumor grade and immunohistochemical biomarkers. Journal of cancer epidemiology. 2014;2014.

52.                 Simon R. Sensitivity, specificity, PPV, and NPV for predictive biomarkers. Journal of the National Cancer Institute. 2015;107(8):djv153.

53.                 Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. Journal of Clinical Oncology. 2009;27(24):4027-34.

54.                 Fine JP, Pencina MJ. On the quantitative assessment of predictive biomarkers. Oxford University Press; 2015.

55.                 Miquel-Cases A, Schouten PC, Steuten LM, Retèl VP, Linn SC, van Harten WH. (Very) Early technology assessment and translation of predictive biomarkers in breast cancer. Cancer Treatment Reviews. 2017;52:117-27.

56.                 Luo L, McGarvey P, Madhavan S, Kumar R, Gusev Y, Upadhyay G. Distinct lymphocyte antigens 6 (Ly6) family members Ly6D, Ly6E, Ly6K and Ly6H drive tumorigenesis and clinical outcome. Oncotarget. 2016;7(10):11165.

57.                 Lee E, Moon A. Identification of Biomarkers for Breast Cancer Using Databases. Journal of Cancer Prevention. 2016;21(4):235.

58.                 Huynh FC, Jones FE. MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2Δ16 mediated breast tumorigenesis and reverse trastuzumab resistance. PLoS One. 2014;9(12):e114419.

59.                 Wang Z, Ruan B, Jin Y, Zhang Y, Li J, Zhu L, Xu W, Feng L, Jin H, Wang X. Identification of KLK10 as a therapeutic target to reverse trastuzumab resistance in breast cancer. Oncotarget. 2016.

60.                 Song J, Su H, Zhou Y-y, Guo L-l. Prognostic value of survivin expression in breast cancer patients: a meta-analysis. Tumor Biology. 2013;34(4):2053-62.

61.                 Girotra S, Yeghiazaryan K, Golubnitschaja O. Potential biomarker panels in overall breast cancer management: advancements by multilevel diagnostics. Personalized Medicine. 2016;13(5):469-84.

62.                 Meng J, Li P, Zhang Q, Yang Z, Fu S. A four-long non-coding RNA signature in predicting breast cancer survival. Journal of Experimental & Clinical Cancer Research. 2014;33(1):84.

63.                 Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor STF, Chin AR. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer cell. 2014;25(4):501-15.

64.                 Saltzman BS, Malone KE, McDougall JA, Daling JR, Li CI. Estrogen receptor, progesterone receptor, and HER2-neu expression in first primary breast cancers and risk of second primary contralateral breast cancer. Breast cancer research and treatment. 2012;135(3):849-55.

65.                 Yin X, Kim RH, Sun G, Miller JK, Li BD. Overexpression of eukaryotic initiation factor 4E is correlated with increased risk for systemic dissemination in node-positive breast cancer patients. Journal of the American College of Surgeons. 2014;218(4):663-71.

66.                 Wu J, Qiu K, Zhu J, Li J, Lin Y, He Z, Li G. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with breast cancer treated with HER2 blockade. The Breast. 2015;24(6):699-704.

67.                 Song J, Su H, Zhou Y-Y, Guo L-L. Prognostic value of matrix metalloproteinase 9 expression in breast cancer patients: a meta-analysis. Asian Pacific Journal of Cancer Prevention. 2013;14(3):1615-21.

68.                 Zhang Y, Wang Y, Wan Z, Liu S, Cao Y, Zeng Z. Sphingosine kinase 1 and cancer: a systematic review and meta-analysis. PloS one. 2014;9(2):e90362.

69.                 M’hamed IF, Privat M, Trimeche M, Penault-Llorca F, Bignon Y-J, Kenani A. miR-10b, miR-26a, miR-146a And miR-153 Expression in Triple Negative Vs Non Triple Negative Breast Cancer: Potential Biomarkers. Pathology & Oncology Research. 2017:1-13.

70.                 Jiang T, Wang Y, Zhou F, Gao G, Ren S, Zhou C. Prognostic value of high EZH2 expression in patients with different types of cancer: a systematic review with meta-analysis. Oncotarget. 2016;7(4):4584.

71.                 Mittendorf E, Philips A, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Harrington S, Su X, Wang Y, Gonzalez-Angulo A. et-al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2014; 2: 361-70; PMID: 24764583.

72.                 Dai X, Xiang L, Li T, Bai Z. Cancer Hallmarks, Biomarkers and Breast Cancer Molecular Subtypes. Journal of Cancer. 2016;7(10):1281.

73.                 Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, Travaglino E, Groves MJ, Godfrey AL, Ambaglio I. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011;118(24):6239-46.

74.                 Higgins MJ, Baselga J. Targeted therapies for breast cancer. The Journal of clinical investigation. 2011;121(10):3797.

75.                 Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences. 2001;98(19):10869-74.

76.                 Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA: the journal of the American Medical Association. 2006;295(21):2492-502.

77.                 Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast cancer research and treatment. 2002;76(1):27-36.

78.                 Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Research. 2007;9(1):R6.

79.                 Regan MM, Viale G, Mastropasqua MG, Maiorano E, Golouh R, Carbone A, Brown B, Suurküla M, Langman G, Mazzucchelli L. Re-evaluating adjuvant breast cancer trials: assessing hormone receptor status by immunohistochemical versus extraction assays. Journal of the national cancer Institute. 2006;98(21):1571-81.

80.                 Rakha EA, El-Sayed ME, Green AR, Paish EC, Powe DG, Gee J, Nicholson RI, Lee AH, Robertson JF, Ellis IO. Biologic and clinical characteristics of breast cancer with single hormone receptor–positive phenotype. Journal of Clinical Oncology. 2007;25(30):4772-8.

81.                 Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA, Tamimi RM. Androgen receptor expression and breast cancer survival in postmenopausal women. Clinical cancer research. 2011;17(7):1867-74.

82.                 Lakis S, Kotoula V, Eleftheraki AG, Batistatou A, Bobos M, Koletsa T, Timotheadou E, Chrisafi S, Pentheroudakis G, Koutras A. The androgen receptor as a surrogate marker for molecular apocrine breast cancer subtyping. The Breast. 2014;23(3):234-43.

83.                 Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. Journal of Clinical Oncology. 2008;26(35):5697-704.

84.                 Gianni L, Norton L, Wolmark N, Suter TM, Bonadonna G, Hortobagyi GN. Role of anthracyclines in the treatment of early breast cancer. Journal of Clinical Oncology. 2009;27(28):4798-808.

85.                 Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. The lancet oncology. 2008;9(1):23-8.

86.                 Mueller RE, Parkes RK, Andrulis I, O'Malley FP. Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. Genes, Chromosomes and Cancer. 2004;39(4):288-97.

87.                 Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clinical Cancer Research. 2008;14(5):1368-76.

88.                 Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, El-Sayed ME, Benhasouna A, Brunet J-S, Akslen LA. Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clinical Cancer Research. 2009;15(7):2302-10.

89.                 Matos I, Dufloth R, Alvarenga M, Zeferino LC, Schmitt F. p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Archiv. 2005;447(4):688-94.

90.                 Palmer C, Diehn M, Alizadeh AA, Brown PO. Cell-type specific gene expression profiles of leukocytes in human peripheral blood. BMC genomics. 2006;7(1):115.

91.                 Hennessy BT, Gonzalez-Angulo A-M, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee J-S, Fridlyand J, Sahin A, Agarwal R, Joy C. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer research. 2009;69(10):4116-24.

92.                 Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast cancer research. 2010;12(5):R68.

93.                 Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome biology. 2007;8(8):R157.

94.                 Hwang KT, Woo JW, Shin HC, Kim HS, Ahn SK, Moon HG, Han W, Park I, Noh DY. Prognostic influence of BCL2 expression in breast cancer. International journal of cancer. 2012;131(7):E1109-E19.

95.                 Abdel-Fatah T, Perry C, Dickinson P, Ball G, Moseley P, Madhusudan S, Ellis I, Chan S. Bcl2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings. Annals of oncology. 2013;24(11):2801-7.

96.                 Olivier M, Langer A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bi I. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clinical cancer research. 2006;12(4):1157-67.

97.                 Martinez-Outschoorn UE, Balliet R, Lin Z, Whitaker-Menezes D, Birbe RC, Bombonati A, Pavlides S, Lamb R, Sneddon S, Howell A. BRCA1 mutations drive oxidative stress and glycolysis in the tumor microenvironment: implications for breast cancer prevention with antioxidant therapies. Cell Cycle. 2012;11(23):4402-13.

98.                 Penkert J, Ripperger T, Schieck M, Schlegelberger B, Steinemann D, Illig T. On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer. Oncotarget. 2016;7(41):67626-49.

99.                 Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, Flesch-Janys D, Chang-Claude J. Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer—results of a large case–control study. Carcinogenesis. 2008;29(1):93-9.

100.              Santagata S, Thakkar A, Ergonul A, Wang B, Woo T, Hu R, Harrell JC, McNamara G, Schwede M, Culhane AC. Taxonomy of breast cancer based on normal cell phenotype predicts outcome. The Journal of clinical investigation. 2014;124(2):859-70.

101.              Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. New England journal of medicine. 2010;363(20):1938-48.

102.              Privat M, Radosevic-Robin N, Aubel C, Cayre A, Penault-Llorca F, Marceau G, Sapin V, Bignon Y-J, Morvan D. BRCA1 induces major energetic metabolism reprogramming in breast cancer cells. PloS one. 2014;9(7):e102438.

103.              Li D, Chen N-N, Cao J-M, Sun W-P, Zhou Y-M, Li C-Y, Wang X-X. BRCA1 as a nicotinamide adenine dinucleotide (NAD)-dependent metabolic switch in ovarian cancer. Cell cycle. 2014;13(16):2564-71.

104.              Kim J, Johnson L, Skrzynia C, Buchanan A, Gracia C, Mersereau JE. Prospective multicenter cohort study of estrogen and insulin-like growth factor system in BRCA mutation carriers. Cancer Causes & Control. 2015;26(8):1087-92.

105.              Simpson JF, Gray R, Dressler LG, Cobau CD, Falkson CI, Gilchrist KW, Pandya KJ, Page DL, Robert NJ. Prognostic Value of Histologic Grade and Proliferative Activity in Axillary Node–Positive Breast Cancer: Results From the Eastern Cooperative Oncology Group Companion Study, EST 4189. Journal of clinical oncology. 2000;18(10):2059-69.

106.              Edge S, Byrd D, Compton C, Fritz A, Greene F. Trotti A, editors: AJCC cancer staging manual. New York: Springer. 2010.

107.              Fritz AG, RHIT C, Hurlbut AA, RHIT C, Young Jr J, Roffers S, Ries L, Fritz A, Hurlbut A. SEER Summary Staging Manual-2000 Codes and Coding Instructions2001.

108.              Group EBCTC. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. The Lancet. 2011;378(9804):1707-16.

109.              Correa C, McGale P, Taylor C, Wang Y, Clarke M, Davies C, Peto R, Bijker N, Solin L, Darby S. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. Journal of the National Cancer Institute Monographs. 2009;2010(41):162-77.

110.              Zujewski JA, Harlan LC, Morrell DM, Stevens JL. Ductal carcinoma in situ: trends in treatment over time in the US. Breast cancer research and treatment. 2011;127(1):251-7.

111.              Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, Aguilar M, Marubini E. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New England Journal of Medicine. 2002;347(16):1227-32.

112.              Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. Jama. 2010;304(9):967-75.

113.              Tuttle TM, Jarosek S, Habermann EB, Arrington A, Abraham A, Morris TJ, Virnig BA. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. Journal of clinical Oncology. 2009;27(9):1362-7.

114.              Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. Journal of the National Cancer Institute. 2005;97(3):188-94.

115.              Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal a breast cancer? Journal of Clinical Oncology. 2012;30(12):1260-3.

116.              Lee J-S, Smith E, Shilatifard A. The language of histone crosstalk. Cell. 2010;142(5):682-5.

117.              Bartsch R, Bergen E. ASCO 2016: highlights in breast cancer. memo-Magazine of European Medical Oncology. 2016:1-4.

118.              Blum JL FP, Yothers G, et al. . Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophos¬phamide (TC) vanthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2- negative breast cancer. . J Clin Oncol 2016. 2016;34(suppl):ASCO abstr 1000.

119.              Bergh JC FT, von Minckwitz G, et al. . PANTHER: Prospective randomized phase III trial of tailored and dose- dense versus standard tri-weekly adjuvant chemotherapy for high-risk breast cancer in the modern era of endocrine and anti-HER2 therapy. . J Clin Oncol 2016. 2016;34(suppl):abstr 1002.

120.              Ward H. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J. 1973;1(5844):13-4.

121.              Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute. 2006;98(18):1285-91.

122.              Group EBCTC. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. The lancet. 2011;378(9793):771-84.

123.              Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. Journal of Clinical Oncology. 2014;32(21):2255-69.

124.              Klijn J, Blamey R, Boccardo F, Tominaga T, Duchateau L, Sylvester R. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. Journal of Clinical Oncology. 2001;19(2):343-53.

125.              Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. Journal of Clinical Oncology. 2009;28(3):509-18.

126.              Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S. Extending aromatase-inhibitor adjuvant therapy to 10 years. New England Journal of Medicine. 2016;375(3):209-19.

127.              Hongchao P GR, Davies C, et al. . Predictors of recurrence during years 5-14 in 46,138 women with ER+ breast cancer allocated 5 years only of endocrine therapy (ET). J Clin Oncol 2016;34(suppl):abstr505.

128.              Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ. Adjuvant ovarian suppression in premenopausal breast cancer. New England Journal of Medicine. 2015;372(5):436-46.

129.              Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB. Combination anastrozole and fulvestrant in metastatic breast cancer. New England Journal of Medicine. 2012;367(5):435-44.

130.              Bergh J, Jönsson P-E, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. Journal of Clinical Oncology. 2012;30(16):1919-25.

131.              Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, Im Y-H, Braybrooke JP, Brunt AM, Cheung K-L. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. The Lancet Oncology. 2013;14(10):989-98.

132.              Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Emerson L, Dean A, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’study. Breast cancer research and treatment. 2012;136(2):503-11.

133.              Vogel VG, Costantino JP, Wickerham DL, McCaskill-Stevens W, Clarfeld RB, Grant MD, Wolmark N. Carcinoma in situ outcomes in National Surgical Adjuvant Breast and Bowel Project Breast Cancer Chemoprevention Trials. Journal of the National Cancer Institute Monographs. 2009;2010(41):181-6.

134.              Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. The Lancet. 2013;381(9880):1827-34.

135.              Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, Mamounas EP, Julian TB, Geyer CE, Costantino JP. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor–positive ductal carcinoma in situ: A study based on NSABP Protocol B-24. Journal of Clinical Oncology. 2012:JCO. 2010.34. 0141.

136.              Cuzick J, Sestak I, Forbes JF, Dowsett M, Knox J, Cawthorn S, Saunders C, Roche N, Mansel RE, Von Minckwitz G. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. The Lancet. 2014;383(9922):1041-8.

137.              Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, De Azambuja E, Viale G, Sotiriou C, Piccart M. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. Journal of Clinical Oncology. 2014;32(25):2794-803.

138.              Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Research. 2016;18(1):17.

139.              Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The lancet oncology. 2015;16(1):25-35.

140.              Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K. Palbociclib in hormone-receptor–positive advanced breast cancer. New England Journal of Medicine. 2015;373(3):209-19.

141.              Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, Schiff R, Gutierrez C, Migliaccio I, Anagnostou VK. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor–positive metastatic breast cancer: a randomized phase II study. Clinical Cancer Research. 2011;17(5):1147-59.

142.              Piccart M, Hortobagyi GN, Campone M, Pritchard K, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo H, Deleu I. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Annals of oncology. 2014:mdu456.

143.              Baselga J, Im, S-A., Iwata, H., Clemons, M., Ito, Y., Awada, A., et al. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2- advanced BC (BC): first results from the randomized, phase III BELLE-2 trial. .  Abstract SABACS 2015.

144.              Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Journal of clinical oncology. 2013;31(31):3997-4013.

145.              Romond EH, Perez EA, Bryant J, Suman VJ, Geyer Jr CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. New England Journal of Medicine. 2005;353(16):1673-84.

146.              Advani P, Cornell L, Chumsri S, Moreno-Aspitia A. Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer. Breast Cancer: Targets and Therapy. 2015;7:321.

147.              Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: final survival analysis of a phase III randomized trial. The oncologist. 2010;15(9):924-34.

148.              Swain SM, Baselga J, Kim S-B, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero J-M, Schneeweiss A, Heeson S. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. New England Journal of Medicine. 2015;372(8):724-34.

149.              Swain SM, Kim S-B, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero J-M, Schneeweiss A, Knott A. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. The lancet oncology. 2013;14(6):461-71.

150.              Baselga J, Cortés J, Im S-A, Clark E, Ross G, Kiermaier A, Swain SM. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2–positive, first-line metastatic breast cancer. Journal of clinical oncology. 2014;32(33):3753-61.

151.              Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh D-Y, Diéras V, Guardino E. Trastuzumab emtansine for HER2-positive advanced breast cancer. New England Journal of Medicine. 2012;367(19):1783-91.

152.              Baselga J, Phillips GDL, Verma S, Ro J, Huober J, Guardino E, Samant M, Olsen S, de Haas S, Pegram MD. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clinical Cancer Research. 2016:clincanres. 2499.015.

153.              Krop IE, Kim S-B, González-Martín A, LoRusso PM, Ferrero J-M, Smitt M, Yu R, Leung AC, Wildiers H. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. The lancet oncology. 2014;15(7):689-99.

154.              Wildiers H, Kim S, Gonzalez-Martin A, LoRusso P, Ferrero J, Yu R, Smitt M, Krop I. Abstract S5-05: Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. AACR; 2016.

155.              Harbeck N, Huang C-S, Hurvitz S, Yeh D-C, Shao Z, Im S-A, Jung KH, Shen K, Ro J, Jassem J. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. The Lancet Oncology. 2016;17(3):357-66.

156.              Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero J-M, Freyer G, Abadie-Lacourtoisie S, Eymard J-C, Debled M, Spaëth D. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. Journal of Clinical Oncology. 2012;30(22):2718-24.

157.              André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. The lancet oncology. 2014;15(6):580-91.

158.              Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: A randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. Journal of clinical oncology. 2011;29(32):4286-93.

159.              von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. The lancet oncology. 2014;15(11):1269-78.

160.              Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, Manikhas A, Gelmon KA, Konecny GE, Webster M. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. Journal of Clinical Oncology. 2014;33(2):141-8.

161.              Sonnenblick A, De Azambuja E, Azim Jr HA, Piccart M. An update on PARP inhibitors [mdash] moving to the adjuvant setting. Nature reviews Clinical oncology. 2015;12(1):27-41.

162.              Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A. PD-L1 expression in triple-negative breast cancer. Cancer immunology research. 2014;2(4):361-70.

163.              Pusztai L, Karn, T., Safonov, A., Abu-Khalaf, M.M., Bianchini, G. New strategies in BC: immunotherapy. . Clin Cancer Res Off J Am Assoc Cancer Res [Internet]. 2016. Available from: http://dx.doi.org/10.1158/1078-0432.CCR-15-1315.

 

Historic & ongoing breast clinical trials


News