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Clinicopathologic features stratified by treatment arm (RNA-seq analysis population).

Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P

Background: Chemotherapy remains the mainstay of treatment for early-stage triple negative breast cancer (TNBC), yet targetable drivers of interest are under investigation. A subset of TNBCs express the androgen receptor (AR) and exhibit androgen-dependent growth. The AR-antagonist enzalutamide (ENZA) has shown activity in patients with metastatic AR+ TNBC. In this study, the feasibility of adjuvant ENZA in early-stage, AR+ TNBC was assessed (NCT02750358). As reported previously, this study met its primary endpoint of feasibility (Traina et al., ASCO 2019). Here we report secondary survival endpoints. Methods: In this single-arm, open-label, multi-center trial, patients with stage I-III, AR≥1% TNBC (ER/PR Citation Format: Elaine M Walsh, Ayca Gucalp, Sujata Patil, Marcia Edelweiss, Dara S Ross, Pedram Razavi, Shanu Modi, Neil M Iyengar, Rachel Sanford, Tiffany Troso-Sandoval, Mila Gorsky, Jackie Bromberg, Pamela Drullinsky, Diana Lake, Serena Wong, Patricia DeFusco, Nicholas Lamparella, Ranja Gupta, Tasmila Tabassum, Leigh Ann Boyle, Artavazd Arumov, Tiffany A Traina. Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple negative breast cancer: A feasibility study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-14-03.

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 [ > 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 >20% 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 (David.page2@providence.org) Clinicaltrials.gov#: NCT03650894 Citation Format: David B Page, Krystle L Collins, Brie Chun, Zhaoyu Sun, William L Redmond, Maritza Martel, Yaping Wu, Nicole Moxon, Staci L Mellinger, Walter J Urba, Tiffany A Traina, Ayca Gucalp. 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) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-04.

Supplementary Figure S1. White adipose tissue inflammation. A. CLS-B positive breast WAT. H&E (upper panel) and anti-CD68 immunostaining (lower panel); 40x (left panel) and 400x (right panel). Arrow indicates CLS-B. B. CLS-B negative breast WAT. H&E (upper panel) and anti-CD68 immunostaining (lower panel); 40x (left panel) and 400x (right panel). WAT, white adipose tissue; CLS-B, crown-like structures of the breast.

Supplementary Figure 1 - PDF file 44K, Supplementary Figure 1A-D. Median hormone levels at baseline, C2 and EOS

Supplementary Table S1. Pharmacokinetic parameters for enzalutamide administered as a single oral dose administered on day 1 to women with breast cancer and and on day 49 to men with prostate cancer; Supplementary Table S2. Pharmacokinetic parameters for enzalutamide and its active metabolite in patients taking enzalutamide 160 mg once daily to steady state; Supplementary Table S3. Most common grade ≥3 adverse events in more than one patient in the safety population.

Relationships between aromatase inhibitor plasma exposures (AUCtau) and concentrations of (A, B) estradiol and (C, D) estrone in individual patients. Red lines indicate expected estrogen levels with anastrozole or exemestane use

Protocol 12 Supplement File

Supplementary Legend - PDF file 22K, Supplementary Legend

Supplementary figure legends

Purpose:To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer.Patients and Methods:In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis.Results:Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.Conclusions:Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

Supplementary Figure 2 - PDF file 275K, Supplementary Figure 2A-D. Changes in hormone levels over time per patient; responders (stable disease >6 months) highlighted in red

Plasma trough concentrations by week for (A) enzalutamide and (B) exemestane The labeled values denote mean (SD). The open circles denote trough concentration values of individual patients. Solid squares and vertical lines denote mean with error bars by one SD in both directions. Abbreviations: SD, standard deviation.

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046–54. ©2017 AACR.

Individual and mean plasma exposures (AUCtau or Cmin) to endocrine therapies alone or in combination with enzalutamide. Note: Box plots provide the mean (red line), median (black line), and 25%/75% quartiles with whiskers to the last point within 1.5-times interquartile range. Sample sizes are reported in Table 2 in the article.

Purpose: Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance.Experimental Design: WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) of the breast. Two independent groups were examined in cross-sectional (cohort 1) and retrospective (cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n = 10) or treatment (n = 90). Metabolic syndrome–associated circulating factors were compared by CLS-B status. The association between CLS of the breast and the metabolic syndrome was validated in cohort 2, which included 127 women who developed metastatic breast cancer. Distant recurrence-free survival (dRFS) was compared by CLS-B status.Results: In cohorts 1 and 2, breast WAT inflammation was detected in 52 of 100 (52%) and 52 of 127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and IL6 and lower high-density lipoprotein cholesterol and adiponectin (P < 0.05) in cohort 1. In cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P < 0.05). Compared with patients without breast WAT inflammation, the adjusted HR for dRFS was 1.83 (95% CI, 1.07–3.13) for patients with inflammation.Conclusions: WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis. Clin Cancer Res; 22(9); 2283–9. ©2015 AACR.

Supplementary Table 1 - PDF file 4K, Supplementary Table 1. Median hormone levels at baseline, start of cycle 2 (C2), and end of study (EOS) and the percent change in levels from baseline to C2 and C2 to EOS

AimsThe most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer.Methods and resultsUsing a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens—concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20–50 min at 55%–100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, −0.88 mL O2·kg−1·min−1; 95% confidence interval (CI): −3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg−1·min−1, P < 0.001).ConclusionThere was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

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.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.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.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.

Purpose: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer. Patients and Methods: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. Results: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Conclusions: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

BACKGROUND: A subset of TNBC expresses a luminal signature and demonstrates AR-dependence. Enzalutamide (ENZA), an AR-antagonist, has activity with metastatic AR+ TNBC, with a clinical benefit rate of 33% (Traina et al, JCO 2018). We recently demonstrated that one year (y) of adjuvant ENZA is feasible in early stage, AR+ TNBC, with no new safety signals observed (Traina ASCO 2019). Fatigue was the most common, treatment (tx)-related, adverse event of any grade according to investigator assessment (24%). Here we report per-protocol planned secondary analyses of PROs during one year of ENZA including quality of life (QoL), fatigue, and self-reported physical activity (NCT02750358). METHODS: Eligible patients have Stage I-III, ER/PR RESULTS: Between 5/2016 and 6/2018, 50 patients were enrolled. As of 6/27/19, 34 patients completed 1y of ENZA; 15 patients are off tx: recurrence (3), toxicity (5), nonadherence (4), and consent withdrawal (3). Patients evaluable for PRO (N): baseline (50), 12 weeks (43) and 52 weeks (34). Median scores on FACT-B and fatigue scales remained stable over the course of adjuvant ENZA in the 1st year of therapy (Table). Self-reported exercise increased during this period. Table. Median scores (range) for PROs during 1 year of adjuvant ENZATime PointBaselineWeek 12Week 52FACT-G88.0 (53.5-105.0)82.0 (36.4-105.0)89.5 (58.0-105.0)Breast Cancer Subscale28.5 (15.6-39.0)29.0 (9.0-40.0)29.0 (19.0-40.0)Total118.0 (77.0-141.0)111.0 (45.4-145.0)121.0 (83.0-145.0)FACT-B trial outcome index73.0 (43.0-92.0)73.0 (25.7-96.0)76.9 (51.0-96.0)FACIT43.0 (17.0-52.0)39.0 (10.0-52.0)43.0 (11.0-52.0)Total Exercise (min/week)120 (0-1260)152 (0-3120)180 (0-2580) CONCLUSIONS: Patient reported outcomes of health related QOL remain stable when ENZA is administered for 1 year in the adjuvant setting. Self-reported time spent engaged in physical exercise increased numerically during 1y of therapy. During presentation, additional analyses will be reported including QOL at additional time points, relationship of FACT-B score with FACIT fatigue score and exercise, and QOL changes in relation to relative dose intensity of ENZA, toxicity and off study reason. Citation Format: Tiffany A Traina, Lee W Jones, Victoria Blinder, Jessica Scott, Leigh Ann Boyle, Artavazd Arumov, Tina Alano, Sujata Patil, Patricia DeFusco, Nicholas Lamparella, Mark Robson, Ayca Gucalp. Patient-reported outcomes (PROs) during one year of adjuvant enzalutamide for the treatment of early stage androgen receptor positive (AR+) triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-09.

Background: Male breast cancer is rare, with approximately 2,600 cases diagnosed annually in the United States. Data are scant regarding the genomics and pathophysiology of male breast cancer, especially in the metastatic setting, requiring most treatment recommendations in male breast cancer to be made by inference from breast cancer in women. Methods: We performed prospective genomic profiling of primary and metastatic tumor samples from men with breast cancer treated at Memorial Sloan Kettering Cancer Center using the MSK-IMPACT targeted-DNA-sequencing panel for somatic mutations. Comprehensive demographic, clinical, and pathologic data were collected on all included patients. Statistics are descriptive. Results: Genomic sequencing was performed on 45 samples from 41 men (31 primary samples and 14 from metastatic sites). Median age at time of sample collection was 61 years, with a range of 27-92 years. Thirty-seven (90.2%) men had ER+/HER2- breast cancer, 3 (7.3%) had ER+/HER2+ breast cancer and 1 (2.4%) had triple negative disease. Thirty-nine (95.1%) had ductal carcinoma, and no cases of lobular carcinoma were identified. Forty patients underwent germline testing, and 12 (30%) were found to have pathogenic germline mutations (6 BRCA2 mutations, 2 BRCA1 mutations [one of whom had a concurrent CHEK2 mutation], and one mutation each in PALB2, MUTYH, and MSH6). Overall, the pattern of genomic alterations in male breast cancer was similar that in women. Twelve (29.3%) patients had PIK3CA mutations, 9 (22%) had GATA3 mutations, 3 (7.3%) had TP53 mutations, 3 (7.3%) had ARID1A mutations, 3 (7.3%) had KMT2C mutations, 2 (4.9%) had FOX1A mutations, 2 (4.9%) had RB1 mutations, and 2 (4.9%) had TERT promoter hotspot mutations. Eleven (26.8%) patients had CCND1 amplification, 8 (19.5%) had MYC amplification, 6 (14.6%) had FGFR1 amplification, and 5 (12.2%) had MDM2 amplification. All other findings were present in ≤ 1 patient. All included patients had normal mutational burden, and all samples were microsatellite stable. PIK3CA mutations occurred in 33% of primary samples vs. 15% of metastatic samples, CCND1 amplification occurred in 23% of primary samples vs. 38% of metastatic samples, and TERT hotspot promoter mutations were found only in metastatic samples. Of note, we observed a single ESR1 D538G mutation in the metastatic sample of a patient with significant prior exposure to aromatase inhibitors in the adjuvant and metastatic settings. We further found concurrent ERBB2 mutation and amplification in the post-treatment metastatic samples of an ER+/HER2- patient, who was treated with neratinib for 14 weeks with clinical response. Lastly, we report a heavily pretreated patient with metastatic secretory breast carcinoma who was found to have an ETV6-NTRK3 fusion gene. This patient was treated with a first-generation TRK inhibitor and continues to exhibit an ongoing clinical response at 8.6 months. Conclusions: Based on our data, the overall genomic landscape of male breast cancer appears comparable to that of breast cancer in women, as has been previously reported. However, despite the small number of metastatic cases examined, several previously unreported and treatment-informing signatures were discovered, especially in those patients with less common male breast cancer variants. Further study is warranted to confirm these findings in a larger cohort. Citation Format: Joshua Z Drago, Cristian Serna-Tamayo, Carlos H Dos Anjos, David N Brown, Shanu Modi, Komal Jhaveri, David B Solit, Tiffany A Traina, Sarat Chandarlapaty, Jorge S Reis-Filho, Mark E Robson, Ayca Gucalp, Pedram Razavi. Genomic profiling of primary and metastatic breast cancer in men [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-17-01.

BackgroundIt 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.2MethodsThis 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 [ > 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 >20% 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 RegistrationNCT03650894. The trial is open at Providence Cancer Institute (Portland, OR) and Memorial Sloan Kettering Cancer Center (New York, NY).ReferencesVelardi 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 ApprovalThis study was approved by the IRB department and Providence Portland Medical Center, Clinical Trials Department for study NCT03650894.ConsentWritten, informed consent is obtained from each participant.

Background The current study was conducted to evaluate the efficacy and safety of pembrolizumab-mediated programmed cell death protein 1 inhibition plus radiotherapy (RT) in patients with metastatic triple-negative breast cancer who were unselected for programmed death-ligand 1 expression. Methods The current study was a single-arm, Simon 2-stage, phase 2 clinical trial that enrolled a total of 17 patients with a median age of 52 years (range, 37-73 years). An RT dose of 3000 centigrays (cGy) was delivered in 5 daily fractions. Pembrolizumab was administered intravenously at a dose of 200 mg within 3 days of the first RT fraction, and then every 3 weeks ± 3 days until disease progression. The median follow-up was 34.5 weeks (range, 2.1-108.3 weeks). The primary endpoint of the current study was the overall response rate (ORR) at week 13 in patients with unirradiated lesions measured using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Secondary endpoints included safety and progression-free survival. Exploratory objectives were to identify biomarkers predictive of ORR and progression-free survival. Results The ORR for the entire cohort was 17.6% (3 of 17 patients; 95% CI, 4.7%-44.2%), with 3 complete responses (CRs), 1 case of stable disease, and 13 cases of progressive disease. Eight patients died prior to week 13 due to disease progression. Among the 9 women assessed using RECIST version 1.1 at week 13, 3 (33%) achieved a CR, with a 100% reduction in tumor volume outside of the irradiated portal. The CRs were durable for 18 weeks, 20 weeks, and 108 weeks, respectively. The most common grade 1 to 2 toxicity (assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) was dermatitis (29%). Four grade 3 adverse events were attributed to pembrolizumab: fatigue, lymphopenia, and infection. No were no grade 4 adverse events or treatment-related deaths reported. Conclusions The combination of pembrolizumab and RT was found to be safe and demonstrated encouraging activity in patients with poor-prognosis, metastatic, triple-negative breast cancer who were unselected for programmed death-ligand 1 expression. Larger clinical trials of checkpoint blockade plus RT with predictive biomarkers of response are needed.

Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P 0.00001). Notably, AR-V7 was detected in 2 primary BC and 7 metastatic/recurrent BC patients with no prior endocrine therapy. We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.

Purpose/Objective(s) We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. Materials/Methods We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. Results From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Conclusion Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation.

1023 Background: Metastatic triple negative breast cancer (mTNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi), approved to treat patients with HER2- breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation, have not shown efficacy in homologous recombination repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN-3694 sensitizes wild-type (WT) BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We previously reported results from the Ph 1b portion of the trial evaluating the combination of ZEN-3694 plus talazoparib, in TNBC patients without gBRCA1/2 mutations; here we present results from the completed Ph 1b/2 study. Methods: A Ph 1b dose finding portion (n = 15) was followed by a single arm Ph 2 Simon 2-stage portion (n = 17+20 (37)). The primary endpoint of the Ph 1b portion of the study was safety and recommended Ph 2 dose (RP2D). The secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = confirmed objective response rate (ORR) + stable disease > 16 weeks). Ph 2 measured CBR as the primary endpoint, ORR and duration of response (DOR) as key secondary endpoints. Eligibility criteria for Ph 1b included TNBC (ER/PR < 10%, HER2-), WT gBRCA1/2, and > 1 prior cytotoxic regimen for mTNBC, and in the Ph2 portion ER/PR < 1% and < 2 prior cytotoxic regimens for mTNBC. Patients were dosed daily in continuous 28 day cycles until disease progression or unacceptable toxicity. Adverse events, PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles. Results: RP2D was determined to be 48mg qd ZEN-3694 plus 0.75mg qd talazoparib. The most common AE for the Ph 1b/2 study was thrombocytopenia (TCP) (55% any grade, 34% G3/4), which was managed with dose holds and reductions. Dose intensity analysis showed average daily doses of ZEN-3694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 8 cycles. Robust target engagement was demonstrated using BET-dependent and HRR transcripts assessed in paired tumor biopsies. Ph 2 portion of the trial met its primary endpoint with a CBR of 30% (11/37). For the Ph 1b/2 trial, investgator assessed ORR was 22% (11/50), including 2 CR, CBR was 35% (18/51) and the median DOR was 24 weeks. For the subset of TNBC at diagnosis patients (no history of HR+ disease), ORR was 32% (11/34), and CBR was 44% (15/34). Conclusions: Combination of ZEN-3694 and talazoparib demonstrated anti-cancer activity in pretreated mTNBC WT gBRCA1/2 patients. All confirmed responses were observed in TNBC at diagnosis patients, whose tumors are expected to be more sensitive to the combination due to their basal-like properties. The trial is being expanded to Ph. 2b to accrue an additional 80 TNBC at diagnosis patients. Clinical trial information: NCT03901469.

12022 Background: Late alopecia is defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or from initiation of endocrine therapy. It has been reported in up to 25-30% of cancer survivors and is associated with decreased quality of life and reduced dose intensity of cancer therapies. Minoxidil is an aminopyridine potassium channel opener, resulting in vasodilation and premature entry of resting hair follicles into the anagen (growth) phase and increase in hair follicle size. This study aims to assess clinical outcomes and adverse events of oral minoxidil for the treatment of cancer therapy-related late alopecia. Methods: We retrospectively assessed all women with late alopecia treated with oral minoxidil (1.25 mg daily) evaluated at an oncodermatology referral program between 1/2018-5/2021. Outcomes were assessed by standardized photography (4 views) and trichoscopy (HairMetrix, Canfield Scientific, Inc.). Trichoscopy recorded hair density (hair count/cm2) and hair thickness (shaft diameter) at uniform frontal and occipital target areas (12 and 36 cm midline from the glabella, respectively). Adverse events were recorded and graded using CTCAE v5.0. Descriptive statistics were used to summarize the patient demographics and clinical characteristics. Changes in trichoscopy measurements from baseline to follow-up were estimated using paired t-tests. Results: Two hundred and sixteen patients (mean age 57.8±13.7) were included for analysis. Thirty-one (14%) received chemotherapy alone, 65 (30%) endocrine monotherapy, and 120 (56%) chemotherapy followed by endocrine therapy. The majority of patients (n = 170, 79.1%) had a history of breast cancer. Standardized photography assessments (n = 119) after a median of 105 days (IQR = 70) on oral minoxidil revealed clinical improvement in 88 (74%). Trichoscopy assessments (n = 42) after a median of 91 days (IQR = 126) demonstrated increased frontal hair density (124.2 vs 153.2 hairs/cm2, p = 0.008) and occipital hair density (100.3 vs 123.5 hairs/cm2, p = 0.004). There was no statistically significant difference in average frontal or occipital hair thickness (69.3 vs 67.3 μm, p = 0.22, and 70.3 vs 69.9 μm, p = 0.84, respectively). No patients reported discontinuation of oral minoxidil due to adverse effects. Conclusions: Oral minoxidil may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy. This regimen was well tolerated by patients. Prospective, controlled studies are needed to confirm these observations.

Male breast cancer (BC) is rare, representing approximately 1% of cancers that occur in men and approximately 1% of all BCs worldwide. Because male BC is rare, not much is known about the disease, and treatment recommendations are typically extrapolated from data available from clinical trials enrolling female BC patients. We review the epidemiology, risk factors, prognosis, and the varied molecular and clinicopathologic features that characterize male BC. In addition, we summarize the available data for the use of systemic therapy in the treatment of male BC and explore the ongoing development of targeted therapeutic agents for the treatment of this subgroup of BCs. There are important biological differences between male and female BC. Male BC is almost exclusively hormone receptor positive (+), including the androgen receptor (AR), and is associated with an increased prevalence of BRCA2 germline mutations, especially in men with increased risk for developing high-risk BC. Additional research is warranted to better characterize male BC. To accomplish this, a multi-national consortium approach, such as the International Male Breast Cancer Program, is needed in response to the scarcity of patients. This approach allows the pooling of information from a large number of men with BC and the creation of registries for future therapeutic-focused clinical trials. Given the unique biology of BC in men, promising new therapeutic targets are currently under investigation, including the use of poly-ADP-ribose polymerase inhibitors or AR-targeted agents either as monotherapy or in combination with other agents.

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

Background: The androgen-signaling pathway plays a role in breast cancer (BC) pathogenesis and emerging evidence suggests the androgen receptor (AR) is a therapeutic target. TBCRC011 established safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with androgen AR+/ER/PgR- metastatic BC (MBC). Treatment with B at 150 mg oral daily demonstrated a clinical benefit rate (CBR) of 19% in this population. The rationale for combining palbociclib (P) with AR blockade stems from prior work in ER+ MBC. P is an oral, selective inhibitor of CDK4/6 activity which significantly improved median progression-free survival (PFS) in combination with letrozole compared to letrozole monotherapy for the treatment of postmenopausal pts with ER+ MBC in the first-line setting. Consistent with preclinical data, P has been shown to reduce growth of AR+ ER/PgR- MDA-MB-453 breast cancer cells via reduced Rb phosphorylation. It has been shown that AR+ TNBC expresses a luminal profile and has intact Rb protein, the target of palbociclib activity. Therefore, we hypothesize that P will increase the efficacy of B in pts with metastatic AR+ TNBC. NCT02605486. Methods: Pts with AR+ (IHC ≥ 1%)/ER any/HER2(-) MBC on central review at MSK were eligible if met following criteria: ECOG ≤2, postmenopausal, no limit to prior regimens. Pts with ER+ BC must have had 1 prior endocrine therapy. Treatment: B orally daily and P orally daily 3 weeks on 1 week off. DLT period = 28 days. Pts are evaluated for toxicity every 2-4 weeks and for response every 8 weeks. Phase I standard 3+3 design with 3 dose escalations. The primary objective of the phase I portion of the study is to determine the recommended phase II dose of P in combination with B. Plasma for pharmacokinetics (PK) was collected throughout the study. Results: As of 5/11/17, 15 pts with AR+ MBC were enrolled to the phase I portion. Target accrual has been met for the phase I and has since closed. No DLTs were reported in any of the dose escalation cohorts. The maximum tolerated dose was determined to be B 150 mg daily and P 125 mg daily for 21 days in a 28 day cycle. Treatment has been well tolerated with no related Grade 4 or 5 adverse events (AEs). The most common grade 3 significant AEs were hematologic including neutropenia n =5, leukopenia n= 4, and lymphocytopenia n=3 and thought to be related to P. One Grade 4 hypercalcemia led to hospitalization and was deemed related to disease progression. Median time on study was 8 weeks (2-47 weeks). One patient from the phase I remains on study. PK analysis is ongoing and will be presented, including drug-drug interaction data. Conclusions: The combination of B+P has been well tolerated with no unexpected toxicity observed. Updated safety, response, and PK data will be presented. Enrollment on phase II is ongoing. Citation Format: Gucalp A, Edelweiss M, Patil S, Gounder MM, Feigin KN, Corben A, Arumov A, Traina TA. Phase I/II trial of palbociclib in combination with bicalutamide for the treatment of androgen receptor (AR)+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-04.

Background: Seviteronel (Sevi), an oral selective CYP17-lyase and AR inhibitor that blocks testosterone and estradiol production whilst competitively antagonizing the AR, is in Ph 2 clinical development for the treatment of advanced prostate and breast cancers (BC). Male BC is a high unmet need. Men with BC have a high rate of advanced disease at the time of diagnosis and disease-related deaths but no approved therapies. A majority of male BC tumors are AR+ (≥85%; Sas-Korczynska et al. Pol J Pathol. 2015; 66:347-52) suggesting a role for AR-directed therapies. The primary objective of this ongoing Ph 2 study (NCT02580448) is to estimate the activity of once daily Sevi in men with BC as measured by clinical benefit rate (CBR; proportion of pts with stable disease/partial response/complete response) at 16 weeks (wks). Methods: Male patients (pts) with ER+/HER2-normal locally advanced or metastatic BC following progression of at least 1 prior line of endocrine therapy were enrolled. Pts were ECOG 0 or 1 and undergoing gonadal suppression at the time of study entry. Evaluable (Eval) pts received at least 1 dose of Sevi, had 1 post-baseline scan, and were either discontinued or were on study at wk 16. Sevi was administered at 600 mg oral daily. Scans were performed every 8 wks. A Simon's 2-stage design was employed to determine activity (≥1 of 7 Eval pts with CBR16 allowed for accrual to Stage 2; total Ph 2 enrollment target of 18 Eval pts). Results: As of 01 June 2017, 7 men with BC were enrolled. Median age was 58y [53, 70] (median [range]) and 71% were ECOG = 1. 71% had visceral metastases; 14% with brain, 43% with liver and 57% with lung involvement. Median lines of prior therapies for BC in any setting was 9 [5, 22]. All pts enrolled had at least one line of prior therapy for advanced disease and 71% had ≥2 prior lines; these included hormonal therapy (14%), chemotherapy (14%) and hormonal + chemotherapy (43%). Median Sevi treatment duration was 58d [41, 185] and one pt is ongoing. One pt met CBR16, allowing for accrual to Stage 2. All discontinuations were for disease progression (n=6). The most common adverse events (≥2 pts) were fatigue (71%), back pain (29%), constipation (29%), decreased appetite (29%), dizziness (29%), hot flushes (29%), insomnia (29%) and nausea (29%); all Grade 1/2 except for one case of Grade 3 nausea. Updated duration of treatment and CBR data will be presented at the time of presentation. Conclusions: Seviteronel is active in male BC and was well tolerated with no discontinuations due to AEs. Stage 1 criteria for Sevi activity was met and full Ph 2 enrollment is ongoing for men with BC. In comparison to women with ER+ BC treated with Sevi in Ph 2 (Gucalp et al, ASCO 2017), men had more advanced disease (e.g., visceral disease and prior treatments for metastatic disease). Sevi may provide a novel treatment option for ER+ BC in heavily pre-treated men with high disease burden. Citation Format: Elias A, Gucalp A, Bardia A, Resaul A, Eisner J, Baskin-Bey E, Traina TA. Men with advanced breast cancer (BC): Initial phase (Ph) 2 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-23-04.

Background: The androgen receptor (AR) is expressed in >75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-07.

Background: Elevated body mass index (BMI) is associated with increased risk of hormone receptor (HR)-positive breast cancer in postmenopausal women and worsened outcomes after breast cancer diagnosis. These observations may be partly attributable to adipose inflammation, which is prevalent in the breasts of obese women and is associated with worsened breast cancer survival. In men, some studies have reported obesity to be a risk factor for breast cancer, however the biologic links are not well characterized. Whether adipose inflammation occurs in male breast tissue has not been previously reported. Here we examined the relationships among pre-diagnosis BMI, adipose inflammation, and breast cancer features in men. Methods: Males diagnosed with stage 0 – III breast cancer who underwent mastectomy at Memorial Sloan Kettering (MSK) between August 1991 – November 2011 were included in this retrospective cohort study. Pre-operative BMI was categorized as normal or underweight ( Results: A total of 141 men were included; median age 63 (range 23 – 96). By BMI category, 25 were normal or underweight, 65 overweight, and 51 obese – of which 19 were morbidly obese. Only 11 men had known BRCA1/2 mutations. Median age at diagnosis was 69 in normal/underweight men versus 63 in obese men and 51 in morbidly obese men (P≤0.05). Among those with invasive tumors, average tumor size was 1.50 cm (± 0.84) in normal/underweight men versus 2.04 (±0.81) in morbidly obese men (P≤0.05). Archived breast tissue was available from 92 (65%) men. Breast adipose inflammation was present in 55 (60%) men, and average BMI was 31 (±8) versus 28 (±5) in men with versus without inflammation, respectively (P=0.07). Conclusions: Obesity is associated with early onset breast cancer in men. Morbidly obese men were diagnosed with breast cancer at an even younger age and had larger tumors than normal weight individuals. These findings support further studies to investigate mechanisms, such as adipose inflammation, through which obesity may promote breast cancer in men. Citation Format: Williams S, Parrish JC, Zhou XK, Wang H, Dierickx A, Gucalp A, Dannenberg AJ, Iyengar NM. Obesity and adipose inflammation in men with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-04.

Obesity (body mass index (BMI)⩾30 kg m−2) is associated with an increased risk of estrogen-dependent breast cancer after menopause. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are elevated in breast tissue of obese women. Recently, the regulation of aromatase by the p53-hypoxia-inducible factor-1α (HIF1α)/pyruvate kinase M2 (PKM2) axis was characterized in adipose stromal cells (ASCs) of women with Li–Fraumeni Syndrome, a hereditary cancer syndrome that predisposes to estrogen-dependent breast cancer. The current study aimed to determine whether stimulation of aromatase by obesity-associated adipokine leptin involves the regulation of the p53-HIF1α/PKM2 axis. Human breast ASCs were used to characterize the p53-HIF1α/PKM2-aromatase axis in response to leptin. The effect of pharmacological or genetic modulation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), p53, Aha1, Hsp90, HIF1α and PKM2 on aromatase promoter activity, expression and enzyme activity was examined. Semiquantitative immunofluorescence and confocal imaging were used to assess ASC-specific protein expression in formalin-fixed paraffin-embedded tissue sections of breast of women and mammary tissue of mice following a low-fat (LF) or high-fat (HF) diet for 17 weeks. Leptin-mediated induction of aromatase was dependent on PKC/MAPK signaling and the suppression of p53. This, in turn, was associated with an increase in Aha1 protein expression, activation of Hsp90 and the stabilization of HIF1α and PKM2, known stimulators of aromatase expression. Consistent with these findings, ASC-specific immunoreactivity for p53 was inversely associated with BMI in breast tissue, while HIF1α, PKM2 and aromatase were positively correlated with BMI. In mice, HF feeding was associated with significantly lower p53 ASC-specific immunoreactivity compared with LF feeding, while immunoreactivity for HIF1α, PKM2 and aromatase were significantly higher. Overall, findings demonstrate a novel mechanism for the obesity-associated increase in aromatase in ASCs of the breast and support the study of lifestyle interventions, including weight management, which may reduce breast cancer risk via effects on this pathway.

Background Obesity, a cause of subclinical inflammation, is associated with increased risk of high grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown. Methods In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher’s exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics. Results Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004), and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P’s

Obesity is associated with breast white adipose tissue (WAT) inflammation, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that have been linked to the pathogenesis of breast cancer. Here, we determined whether metabolic obesity, including changes in breast biology and systemic effects, occurs in a subset of women with normal body mass index (BMI). Breast WAT and fasting blood were collected from 72 women with normal BMI ( See related article by Berger, p. 223–25.

Background: The combination of taxanes with trastuzumab (H) and pertuzumab (P) for first line treatment of HER2-positive metastatic breast cancer (MBC) is associated with improved progression-free survival (PFS) and overall survival (OS). Treatment per physician's choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is common, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of gemcitabine (G) with HP. Eligible patients had HER2-positive (IHC 3+ or FISH ≥ 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Patients received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. Using a Simon optimal 2-stage design, 21 patients were enrolled in stage 1. The successful 3-month PFS rate for stage 1 was set at 57% to allow accrual to stage 2 for a total of 45 patients. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of June 9, 2016, 28 patients are enrolled; 21 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 16/21 (76%) are progression free; 5 patients have progressed. The 3 month-PFS results for evaluable patients will be updated. There are no cardiac or febrile neutropenic events to date. Initially, 5 of 22 (23%) patients required G dose reduction (4 due to grade 3 neutropenia and 1 due to grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% (95% CI 55% to 89%) in evaluable patients, and updated data will be presented. These findings suggest clinical benefit when P is continued beyond progression. Citation Format: Iyengar NM, Smyth L, Lake D, Gucalp A, Singh JC, Traina TA, DeFusco P, Dickler MN, Fornier MN, Goldfarb S, Jhaveri K, Modi S, Troso-Sandoval T, Argolo D, Jack K, Ulaner G, Jochelson M, Baselga J, Norton L, Hudis CA, Dang CT. Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-Positive metastatic breast cancer after prior pertuzumab-based therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-34.

Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon's 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs > 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi's unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

This abstract was withdrawn by the authors.

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/1,000 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.

PURPOSE: IBM Watson for Oncology trained by Memorial Sloan Kettering (WFO) is a clinical decision support tool designed to assist physicians in choosing therapies for patients with cancer. Although substantial technical and clinical expertise has guided the development of WFO, patients’ perspectives of this technology have not been examined. To facilitate the optimal delivery and implementation of this tool, we solicited patients’ perceptions and preferences about WFO. METHODS: We conducted nine focus groups with 46 patients with breast, lung, or colorectal cancer with various treatment experiences: neoadjuvant/adjuvant chemotherapy, chemotherapy for metastatic disease, or systemic therapy through a clinical trial. In-depth qualitative and quantitative data were collected and analyzed to describe patients’ attitudes and perspectives concerning WFO and how it may be used in clinical care. RESULTS: Analysis of the qualitative data identified three main themes: patient acceptance of WFO, physician competence and the physician-patient relationship, and practical and logistic aspects of WFO. Overall, participant feedback suggested high levels of patient interest, perceived value, and acceptance of WFO, as long as it was used as a supplementary tool to inform their physicians’ decision making. Participants also described important concerns, including the need for strict processes to guarantee the integrity and completeness of the data presented and the possibility of physician overreliance on WFO. CONCLUSION: Participants generally reacted favorably to the prospect of WFO being integrated into the cancer treatment decision-making process, but with caveats regarding the comprehensiveness and accuracy of the data powering the system and the potential for giving WFO excessive emphasis in the decision-making process. Addressing patients’ perspectives will be critical to ensuring the smooth integration of WFO into cancer care.

Background: Metastatic triple-negative breast cancer (TNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi) are approved to treat breast cancer harboring germline BRCA1/2 (gBRCA1/2) mutations and have not shown efficacy in homologous recombination DNA repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN003694 sensitizes wild-type BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We report initial results from a Ph 1b/2 trial evaluating the combination of ZEN003694 and the PARPi, talazoparib, in TNBC patients without gBRCA1/2 mutations. Methods: A Ph 1b dose-finding segment will be followed by a single-arm Ph 2 Simon 2-stage segment. Ph 1b evaluated several dose combinations of ZEN003694 and talazoparib, with safety and recommended Ph 2 dose (RP2D) as primary endpoints and pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = Objective response rate (ORR) + stable disease > 4 months) as secondary endpoints. The Ph 2 segment has CBR as the primary endpoint and progression free survival (PFS) and duration of response as secondary endpoints. Eligibility criteria included TNBC (ER/PR < 10% and not a candidate for endocrine therapy), HER2-, wild-type gBRCA1/2, and > 1 prior chemotherapy regimen for metastatic disease. Patients were dosed daily in continuous 28-day cycles until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) period was one cycle. Adverse events (AE), PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles. Results: Findings of the Ph 1b are reported. 15 patients with a median 3 lines of prior therapy in the metastatic setting were enrolled in 3 dose-finding cohorts. RP2D was determined to be 48mg ZEN003694 plus 0.75mg talazoparib. Across the cohorts, the most common AE was thrombocytopenia (TCP) (73%) with 53% G3/4 (Table 1). G4 TCP was the DLT and 1 DLT patient required a platelet transfusion. TCP could be managed to G1/2 levels with intermittent dose holds and reductions. Other G1/2 AEs included fatigue, anorexia, neutropenia, nausea, dysgeusia, and photophobia. Dose intensity analysis showed average daily doses of ZEN003694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 4 cycles. Exposures of ZEN003694 and talazoparib were dose proportional with no drug-drug PK interactions. At RP2D, PD assessment by a whole blood mRNA assay for BET-dependent genes demonstrated robust down-regulation of CCR1, IL1RN, and IL8 to < 50% of baseline for > 8 h. Expression of HRR genes, RAD51 and BRCA1, in whole blood also decreased for > 8 h. Analysis of an on-treatment biopsy showed robust and durable BET target modulation assessed by comparing RNA sequence data with a reference BET dependent signature. Across the 3 cohorts, ORR by Investigator was 38% (5/13), including 1 CR and 4 PRs, and CBR was 57% (8/14). 6 of the 15 patients are ongoing as of data analysis date (2-9 cycles), with 1 patient responding for > 6 months. Conclusions: Combination of ZEN003694 and talazoparib demonstrated anti-cancer activity in pretreated metastatic TNBC patients without gBRCA1/2 mutations. TCP is frequent but manageable with dose adjustments. PK is predictable, and PD data show meaningful target engagement. The Ph 2 part of the trial is currently ongoing. Grade 3/4 Adverse EventsCohort 1(1mg talazoparib + 48mg ZEN003694)N=6Cohort 2(0.75 mg talazoparib + 48mg ZEN003694)N=6Cohort 3(1mg talazoparib + 36mg ZEN003694)N=3Thrombocytopenia3 (G3), 2 (G4, DLT)1 (G3), 1 (G4, DLT)1 (G3)Diarrhea1 (G3)00Neutropenia01 (G3)0 Citation Format: Philippe Aftimos, Mafalda Oliveira, Kevin Punie, Valentina Boni, Erika Hamilton, Ayca Gucalp, Payal Shah, Lida Mina, Priyanka Sharma, Lisa Bauman, Eric Campeau, Sarah Attwell, Margo Snyder, Karen Norek, Akos Czibere, Yanke Yu, Michael H Silverman, Sanjay Lakhotia, Susan Domchek, Jennifer Litton, Mark Robson. A Phase 1b/2 Study of the BET inhibitor ZEN003694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-10.

Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast cancer-related deaths each year. Owing to the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 expression, patients with triple-negative breast cancer do not benefit from generally well-tolerated and effective therapies targeting the estrogen and human epidermal growth factor receptor 2 signaling pathways and are faced with an increased risk of disease progression and poorer overall survival. The heterogeneity of triple-negative breast cancer has been increasingly recognized and this may lead to therapeutic opportunities because of newly defined oncogenic drivers and targets. A subset of triple-negative breast tumors expresses the androgen receptor (AR) and this may benefit from treatments that inhibit the AR-signaling pathway. The first proof-of-concept trial established activity of the AR antagonist, bicalutamide, in patients with advanced AR+ triple-negative breast cancer. Since that time, evidence further supports the activity of other next-generation AR-targeted agents such as enzalutamide. Not unlike in estrogen receptor-positive breast cancer, mechanisms of resistance are being investigated and rationale exists for thoughtful, well-designed combination regimens such as AR antagonism with CDK4/6 pathway inhibitors or PI3K inhibitors. Furthermore, novel agents developed for the treatment of prostate cancer, which reduce androgen production such as abiraterone acetate and seviteronel, are being tested as well. This review summarizes the underlying biology of AR signaling in breast cancer development and the available clinical trial data for the use of anti-androgen therapy in the treatment of AR+ triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) comprises about 15% of all breast cancer types, and has a particularly aggressive course. Following first-line therapy, the median PFS is 90% of TNBC, as measured by IHC, we conducted a trial to evaluate the safety and efficacy of a humanized anti-Trop-2 monoclonal antibody conjugated to a high concentration of SN-38, a camptothecin that is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan, with 2-3 logs higher potency than the prodrug. Methods: After establishing the optimal repeated dose in a Phase I trial (ClinicalTrials.gov, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC. Patients received 8 or 10 mg/kg IMMU-132 i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible. Results: As of May 10, 2015, 58 patients with TNBC, with a median of 4 prior therapies (range, 1-11), were treated with IMMU-132. Grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%). No patient developed antibodies to SN-38 or the antibody, and no patient discontinued therapy due to toxicity. Tumor responses were defined as ORR (CR+PR) in 31% of 49 evaluated patients, including 2 with CR, and a clinical benefit ratio (CR+PR+SD>6 mo) of 49% (63% with SD>4 mo; 23 patients continuing treatment after 1st assessment). The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient. Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining. Conclusions: The Trop-2-targeting IMMU-132, delivering cytotoxic doses of the topoisomerase I inhibitor, SN-38, shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This ADC appears to have a high therapeutic index in heavily pretreated patients. Citation Format: Bardia A, Diamond JR, Mayer IA, Starodub AN, Moroose RL, Isakoff SJ, Ocean AJ, Guarino MJ, Berlin JD, Messersmith WA, Thomas SS, O'Shaughnessy JA, Kalinsky K, Maurer M, Chang JC, Forero A, Traina T, Gucalp A, Wilhelm F, Wegener WA, Maliakal P, Sharkey RM, Goldenberg DM, Vahdat LT. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-06.

The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.

1017 Background: Genome-wide transcriptional analysis has identified a unique subset of androgen receptor (AR) +, estrogen receptor (ER)/progesterone receptor (PR)- breast cancer (BC). The functional role of AR was confirmed initially in preclinical models demonstrating that androgen-driven growth could be abrogated by antiandrogen therapy. TBCRC011 established the safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with AR+/ER/PR- metastatic BC (MBC) with a median progression free survival (PFS) of 12 weeks (wks) (95% CI, 11–22 wks). In preclinical data, palbociclib (P) has been shown to reduce growth of AR+/ER/PR- MDA-MB-453 BC cells. It has been shown that AR+ triple negative BC (TNBC) expresses a luminal profile and has intact Rb protein, the target of P activity. We conducted this Phase I/II trial of the AR inhibitor B in combination with the CDK4/6 inhibitor P in pts with AR+/ER/PR/HER2- BC (NCT02605486) to test the hypothesis that androgen blockade, paired with CDK4/6 inhibition would have increased efficacy in pts with androgen-dependent BC. Methods: Postmenopausal pts with AR+ TN MBC defined as IHC ≥ 1% nuclear staining (DAKO, Clone AR441 (5/2016-11/2016) then Ventana AR SP107 (11/2016-6/2018), ECOG ≤2, measurable/non-measurable disease were eligible for enrollment. Any number of prior regimens was permitted. Pts received B 150 mg daily and P 125 mg daily 3 wks on 1 wk off. Pts were evaluated for toxicity every 2-4 wks and for response every 8-12 wks. Primary endpoint: 6 month (mo) PFS. Secondary endpoints: clinical benefit rate, toxicity, correlative studies to better characterize AR+ TNBC. A Simon 2-stage minimax design that discriminates between 6 mo PFS rates of 20% and 40% was used. If ≥ 11/33 pts were PF at 6 mo then B+P would warrant further study. Results: As of 1.1.20 33 pts were enrolled on study with median (med) age 67 (42-79), performance status 0 (0-1). Number of pts with visceral metastases: 20, measurable disease: 22. AR% 1-9: 3, 10-50: 6; 51-100: 24. Med prior lines for MBC: 3 (0-9). Best response: (31 evaluable pts): 11 pts PF at 6mo: 10 SD > 6mo, 1 PR. Med wks on study: 14 (2-101). Toxicity > 10% grade >3 related: Number of pts with leukopenia: 21, neutropenia: 21, lymphocytopenia: 6, thrombocytopenia: 3. One pt with febrile neutropenia. One death due to disease progression within 30 days off study. Conclusions: In this selected subset of pts with AR+ TN MBC, this study met its prespecified endpoint with 11 pts PF at 6 mo on B 150 mg + P 125 mg. B+P has been well tolerated with no unexpected toxicity observed. Clinical trial information: NCT02605486 .