Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population

Prognostic Role of Androgen Receptor in Triple Negative Breast Cancer: A Multi-Institutional Study

Background: Androgen Receptor (AR) has emerged as a potential therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, conflicting reports regarding AR’s prognostic role in TNBC are putting its usefulness in question. Some studies conclude that AR positivity indicates a good prognosis in TNBC whereas others suggest the opposite, and some show that AR status has no significant bearing on the patients’ prognosis. Methods: We evaluated the prognostic value of AR in resected primary tumors from TNBC patients from six international cohorts {US (n=420), UK (n=239), Norway (n=104), Ireland (n=222), Nigeria (n=180), and India (n=242); total n=1407}. All TNBC samples were stained with the same anti-AR antibody using the same immunohistochemistry protocol, and samples with ≥1% of AR-positive nuclei were deemed AR-positive TNBCs. Results: AR status shows population-specific patterns of association with patients’ overall survival after controlling for age, grade, population, and chemotherapy. We found AR-positive status to be a marker of good prognosis in US and Nigerian cohorts, a marker of poor prognosis in Norway, Ireland and Indian cohorts, and neutral in UK cohort. Conclusion: AR status, on its own, is not a reliable prognostic marker. More research to investigate molecular subtype composition among the different cohorts is warranted

TBCRC 019: A phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer

Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation

Phase II Trial of Bicalutamide in Patients with Androgen Receptor-Positive, Estrogen Receptor-Negative Metastatic Breast Cancer

Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer

TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer

The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates

Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019

Circulating Tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether the EpCAM based capture system (CellSearch®) is effective in patients with triple negative (TN) MBC, and whether CTC-apoptosis and clustering enhances the prognostic role of CTC

Gonadotropin-releasing Hormone Agonists For Ovarian Function Preservation In Premenopausal Women Undergoing Chemotherapy For Early-stage Breast Cancer: A Systematic Review And Meta-analysis.

Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved. To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation. PubMed, SCOPUS, and Cochrane databases were searched for studies published between January 1975 and March 2015. The abstracts of the American Society of Clinical Oncology Annual Meeting between 1995 and 2014 and the San Antonio Breast Cancer Symposium between 2009 and 2014 were searched as well. Prospective, randomized, clinical trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected. Data extraction was performed independently by 2 authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals, and blinding process. Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as a surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model. Seven studies were included in this analysis, totaling 1047 randomized patients and 856 evaluable patients. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (odds ratio [OR], 2.41; 95% CI, 1.40-4.15; P = .002) and at least 12 months (OR, 1.85; 95% CI, 1.33-2.59; P < .001) following the last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02-3.36; P = .04), although this outcome was not uniformly reported and fertility or rate of pregnancy was not the primary outcome in any of the trials. Gonadotropin-releasing hormone agonists given with chemotherapy was associated with increased rates of recovery of regular menses in this meta-analysis. Evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility and needs further investigation.265-7