Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone. (ClinicalTrials.gov number, NCT00028990 [ClinicalTrials.gov].).

We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.

Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.

Purpose The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2− metastatic breast cancer (MBC). Experimental Design MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2− MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS) and overall survival (OS). Results Patients (n=132) had a median of 3 (range 1–8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12 month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI: 13.3, 27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). Conclusion In this poor-prognosis, heavily pre-treated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single agent abemaciciclib was well tolerated and exhibited promising clinical activity.

Purpose To develop recommendations about endocrine therapy for women with hormone receptor (HR) –positive metastatic breast cancer (MBC). Methods The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. Recommendations Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2–positive MBC, human epidermal growth factor receptor 2–targeted therapy plus an AI can be effective for those who are not chemotherapy candidates.

The underlying mechanism behind age-induced wastage of the human ovarian follicle reserve is unknown. In this study, we identify impaired ATM (ataxia-telengiectasia mutated)-mediated DNA double strand break (DSB) repair as a cause of aging in mouse and human oocytes. We show that DSBs accumulate in primordial follicles with age. In parallel, expression of key DNA DSB repair genes BRCA1, MRE11, Rad51, and ATM, but not BRCA2, decline in single mouse and human oocytes. In BRCA1-deficient mice, reproductive capacity was impaired, primordial follicle counts were lower, and DSBs were increased in remaining follicles with age relative to wild-type mice. Furthermore, oocyte-specific knockdown of BRCA1, MRE11, Rad51 and ATM expression increased DSBs and reduced survival while BRCA1 overexpression enhanced both parameters. Likewise, ovarian reserve was impaired in young women with germline BRCA1 mutations compared to controls as determined by serum concentrations of anti-mullerian hormone. These data implicate DNA DSB repair efficiency as an important determinant of oocyte aging in women.

A B S T R A C T PurposeNo biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. Patients and MethodsDNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. ResultsThe VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio ϭ 0.58; 95% CI, 0.36 to 0.93; P ϭ .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio ϭ 0.62; 95% CI, 0.46 to 0.83; P ϭ .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P ϭ .005 and P ϭ .022, respectively). ConclusionOur data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.

IMPORTANCE Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention.OBJECTIVE To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines.