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

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

Mammographic screening in male patients at high risk for breast cancer: is it worth it?

PURPOSE: To investigate the utility of mammography for breast cancer screening in a population of males at increased risk for breast cancer. METHODS: In this HIPAA-compliant institutional review board-approved single-institution study, mammography records and clinical data of 827 male patients who underwent digital mammography from September 2011-July 2018 were analyzed via the electronic medical record. 664 of these men presented with masses, pain, or nipple discharge and were excluded from this study. The remaining 163 asymptomatic men with familial and/or personal history of breast cancer, or with a known germline mutation in BRCA, underwent screening mammography and were included in this analysis. RESULTS: 163 asymptomatic men (age: mean 63 years, range 24-87 years) underwent 806 screening mammograms. 125/163 (77%) had a personal history of breast cancer and 72/163 (44%) had a family history of breast cancer. 24/163 (15%) were known mutation carriers: 4/24 (17%) BRCA1 and 20/24 (83%) BRCA2. 792/806 (98%) of the screening mammograms were negative (BI-RADS 1 or 2); 10/806 (1.2%) were classified as BI-RADS 3, all of which were eventually downgraded to BI-RADS 2 on follow-up. 4/806 (0.4%) mammograms were abnormal (BI-RADS 4/5): all were malignant. The cancer detection rate in this cohort was 4.9 cancers/1000 examinations. CONCLUSIONS: In our cohort, screening mammography yielded a cancer detection rate of 4.9 cancers/1000 examinations which is like the detection rate of screening mammography in a population of women at average risk, indicating that screening mammography is of value in male patients at high risk for breast cancer

OT1-18-04. A phase II study of dual immune checkpoint blockade (ICB) plus bicalutamide to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC)

Background: The addition of anti-programmed death 1 / ligand 1 (anti-PD-1/L1) improves progression-free survival when combined with chemotherapy in PD-L1-positive triple-negative MBC. However, novel combination therapies are needed to improve efficacy in hormone receptor positive (HR+) MBC, or in patients with PD-L1-negative disease. Dual ICB with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) has not been studied in depth in MBC despite its success in other solid tumors. Furthermore, MBCs often express the androgen receptor (AR), which can be targeted therapeutically. AR blockade agents have been shown to stimulate thymic production of naïve T-cell clones. It is proposed that ICB in conjunction with AR blockade may facilitate thymopoeisis and subsequent activation of novel, tumor-reactive T-cell clones. Trial design: This is a phase II, open-label trial investigating the combination of ICB (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) and AR blockade (bicalutamide, 150mg PO daily) in MBC. Two cohorts will be studied: AR-positive TNBC [ \u3e 1% by IHC, constituting ~50% of TNBCs]; and HR+ MBC (of which the great majority are AR-positive). Eligibility: Patients must have RECIST1.1 measurable disease, ECOG performance score 0-1, and adequate hematological and hepatic function. Subjects may have received no more than 1 prior non-curative chemotherapy. Specific aims: Subjects will be assessed for clinical benefit by iRECIST criteria and safety by CTCAE v4.0, with clinical efficacy defined as \u3e20% improvement in week 24 clinical benefit rate, over historical control (30% per EMBRACE clinical trial). Statistical analysis will be performed by a Simon 2-stage design to minimize futility (n = 46/cohort, stage I: n = 15). As exploratory aims, thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay), TcR excision circles (TRECs), and flow cytometry using markers of recent thymic emigration. Present accrual: As of 7/8/2021, n=19 subjects are enrolled (4 TNBC, 15 HR+). The trial is open at Providence Cancer Institute (Portland, OR) and Memorial Sloan Kettering Cancer Center (New York, NY). Target accrual: stage I: n=15 per arm; a maximum of 138 patients (46 per cohort) may be enrolled in expansion cohorts. Contact: Dr. David Page ([email protected]) Clinicaltrials.gov#: NCT0365089

399 A phase II study of nivolumab, ipilimumab, plus androgen receptor blockade with bicalutamide to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer

Background It has previously been shown that immune checkpoint blockade (ICB) with anti-programmed death 1/ligand 1 (anti-PD-1/L1) improves survival when combined with chemotherapy in PD-L1-positive first-line triple-negative metastatic breast cancer (MBC). Given the lower efficacy of ICB in hormone receptor positive (HR+) or PD-L1-negative disease, and in later lines of therapy, novel combinations are necessary. Dual ICB with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) has shown success in other solid tumors but has not been extensively studied in MBC. Furthermore, MBCs often express the androgen receptor (AR), which can be targeted to modulate immune response. AR blockade may stimulate thymic production of naïve T-cell clones by modulating the Notch pathway,1 whereas ICB can amplify the immune activity of recent thymic emigrants by blocking PD-1-mediated peripheral tolerance.2 Methods This is an open-label, Simon 2-stage phase II trial investigating the dual ICB (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) and AR blockade (bicalutamide, 150mg PO daily) in MBC. Two cohorts will be studied: AR-positive TNBC [ \u3e 1% by IHC, constituting ~50% of TNBCs]; and HR+ MBC (of which the great majority are AR-positive). Eligible patients must have RECIST1.1 measurable disease, Eastern Cooperative Oncology Group performance score 0 or 1, adequate hematological/hepatic function, and received no more than 1 prior course of non-curative chemotherapy. Target accrual is n=15 per arm (stage I), with a maximum of 46 patients per cohort. Current cohort accrual n=15 HR+ and n=5 TNBC. The primary endpoint is week 24 clinical benefit by iRECIST criteria, with success defined as \u3e20% improvement over historical control (30% per EMBRACE clinical trial).3 Safety will be evaluated by CTCAE v4.0. Biomarkers of recent thymic activation will be evaluated via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay), TcR excision circles (TRECs), and flow cytometry using markers for recent thymic emigration (CD3+CD45RA+CD45RO-CD31+) Trial Registration NCT03650894. The trial is open at Providence Cancer Institute (Portland, OR) and Memorial Sloan Kettering Cancer Center (New York, NY). References Velardi E, Tsai JJ, Holland AM, et al. Sex steroid blockade enhances thympoesis modulating notch signaling. J Exp Med 2014;211(12):2341–49. Thangavelu G, Parkman JC, Ewen CL, et al. Programmed death-1 is required for systemic self-tolerance in newlygenerated T cells during the establishment of immune homeostasis. Journal of autoimmunity 2011;36(3–4):301–12. Kaufman PA, Awada A, Twevles C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2015;33(6):594–601. Ethics Approval This study was approved by the IRB department and Providence Portland Medical Center, Clinical Trials Department for study NCT03650894. Consent Written, informed consent is obtained from each participant. http://dx.doi.org/10.1136/jitc-2021-SITC2021.39