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The absence of effective therapeutic targets and aggressive nature of triple-negative breast cancer (TNBC) renders this disease subset difficult to treat. Although estrogen receptor beta (ERβ) is expressed in TNBC, studies on its functional role have yielded inconsistent results. However, recently, our preclinical studies, along with other observations, have shown the potential therapeutic utility of ERβ in the context of mutant p53 expression. The current case study examines the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutant TNBC with brain metastases. Significant increase in ERβ protein expression and anti-proliferative interaction between mutant p53 and ERβ were observed after cessation of tamoxifen therapy, with significant regression of brain metastases. This case study provides supporting evidence for the use of tamoxifen in p53-mutant, ERβ+TNBC, especially in the setting of brain metastasis.

Background: CDK 4/6 inhibitors have demonstrated substantial efficacy in treating ER+/HER2- metastatic breast cancer. Therefore, there is great interest in exploring their ability to reduce recurrence risk in early breast cancer. However, conflicting results were observed in the large adjuvant phase 3 clinical trials investigating combination of endocrine therapy and CDK 4/6 inhibitor (PALLAS, MONARCH-E). While these adjuvant clinical trials evaluated upfront use of CDK 4/6 inhibitor, the optimal timing of adding CDK 4/6 inhibitor for HR+/HER2- breast cancer remains unknown. We conducted a prospective phase II clinical trial to evaluate the addition of a CDK 4/6 inhibitor, ribociclib, in patients who were already on adjuvant endocrine therapy. Methods: In part 1 of the clinical trial, eligibility included patients with localized stage I-III ER+ (≥ 10%), HER2- breast cancer; completed surgery; and were on adjuvant endocrine therapy (any number of years) with at least one year or more of treatment remaining. Patients were randomized to two different ribociclib schedules: continuous (400 mg daily of 28-day cycle; arm 1) or intermittent (600 mg daily on days 1-21 of 28-day cycle; arm 2) for one year. Patients were concurrently treated with an aromatase inhibitor (plus GnRH agonist if premenopausal). Tolerance was evaluated via CTCAE version 4.03 and proportion of subjects who discontinued CDK 4/6 treatment early. Stratification factors for statistical analysis included: disease stage (III vs lower), duration of prior endocrine therapy (within 2 years; 2-5 years vs > 5 years), and whether the patient received prior chemotherapy or not. Baseline characteristics and risk factors for recurrence and for early discontinuation were compared between the arms of the study using Pearson's chi-squared test. Actuarial analysis of time to recurrence was done using the Kaplan-Meier estimator. The primary objective of part 1 was to estimate adherence to ribociclib treatment in the adjuvant setting. Results: In total, 81 patients were enrolled between February 2018 and September 2019, and 25 (31%) discontinued ribociclib treatment early, with no significant difference between study arms. The most common grade 3 or greater adverse events (AEs) leading to study discontinuation were neutropenia (44%), alanine aminotransferase increase (28%), and aspartate aminotransferase increase (16%). Among patients who discontinued early, neutropenia was more frequent in the 600 mg arm, 9 of 12 patients (75%), versus 2 of 13 patients (15%) in the 400 mg arm. No patients discontinued early due to prolonged QTc. Ribociclib was dose reduced for 22 patients (27%), with no significant difference between study arms (p = 0.12). After a median follow-up of 20 months, two patients have experienced disease recurrence with recurrence-free survival of 100% at 1 year and 97% (95% CI 88-99%) at 2 years. Biomarker (ctDNA) results will be reported at the meeting. Conclusions: Results demonstrate that while serious AEs with one year of adjuvant ribociclib are low, a substantial number of patients discontinued adjuvant CDK 4/6 inhibitor within 1 year. Overall, with limited follow-up, only two patients had recurrent disease since completion of ribociclib treatment. Tolerability and identifying patient subsets who will most benefit need to be carefully considered with CDK 4/6 inhibitors in the adjuvant setting. Citation Format: Laura M Spring, Lauren Scarpetti, Andrzej Niemierko, Steven J Isakoff, Beverly Moy, Seth A Wander, Elisabeth Smith, Elizabeth Abraham, Jennifer Shin, Jaymin M Patel, Amy Comander, Therese Mulvey, Aditya Bardia. Phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor, ribociclib, for localized ER+/HER2- breast cancer (LEADER, part 1) [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 P1-14-02.

ObjectiveThe National Comprehensive Cancer Network recommends that all women diagnosed with epithelial ovarian cancer undergo genetic testing, as the diagnosis of pathogenic variants may inform cancer survival and impact treatment options. The objective of this study was to assess factors associated with referral to genetic counseling in women with epithelial ovarian cancer.MethodsA retrospective cohort study identified women with epithelial ovarian cancer from 2012 to 2017 at Massachusetts General Hospital and North Shore Medical Center, a community hospital affiliated with Massachusetts General Hospital. Multivariate logistic regression evaluated how race, age, stage, year of diagnosis, insurance status, family history of breast or ovarian cancer, and language relates to the receipt of genetic counseling.ResultsOf the total 276 women included, 73.9% were referred for genetic screening, of which 90.7% attended a genetic counseling visit. Older women were less likely to undergo genetic counseling (age ≥70 years: OR 0.26, 95% CI 0.07–0.94, p=0.04). Women who died within 365 days of initial oncology consult rarely reached a genetic counselor (OR 0.05, 95% CI 0.01–0.24, pConclusionOlder women with epithelial ovarian cancer and those who died within 1 year of initiation of care were less likely to undergo recommended genetic counseling. Race, insurance status, and language were not identified as predictive factors, although we were limited in this assessment by small sample size.

Background: The cyclin-dependent 4/6 inhibitors (CDK4/6i), in combination with an anti-estrogen, have emerged as the standard of care for patients with HR+/HER2- MBC. While only limited insight exists into the molecular factors that drive progression, emerging evidence suggests that activation of AKT1 may provoke resistance in a subset of patients. Overexpression of AKT1 also conveys resistance in HR+/HER2- breast cancer cells in vitro. AKT1 plays a well-established role in promoting tumor progression and metastasis. Targeting AKT1 following progression on CDK4/6i may provide durable clinical benefit in HR+/HER2- MBC. Trial Design: This is an open-label phase Ib trial with three arms - Arm A includes fulvestrant + ipatasertib and Arm B includes an aromatase inhibitor (AI) + ipatasertib. Arm C includes fulvestrant + ipatasertib + palbociclib. Arm A and B are dose-expansion cohorts while Arm C is a dose-escalation (standard 3+3 design) followed by subsequent dose-expansion. Eligibility Criteria: Key inclusion criteria include the presence of locally advanced/unresectable and metastatic HR+/HER2- breast cancer; postmenopausal status or pre/peri-menopausal status s/p oophrectomy or GNRH agonist; at least one prior therapy for MBC including any CDK4/6i; adequate performance status (ECOG 0-2); and adequate bone marrow and hepatic function. Stable CNS metastatic disease and up to two prior lines of chemotherapy for MBC are allowed (no limit on number of prior lines of endocrine therapy). Key exclusion criteria include prior use of fulvestrant (for Arm A); any prior intolerable toxicity with CDK4/6i (for Arm C); prior exposure to an AKT inhibitor in any setting; active CNS disease; concurrent use of specific CYP3A4 inhibitors or inducers; poorly controlled intercurrent illness; and pregnancy or active child-bearing potential. Specific Aims: The primary objective of this study is to evaluate the safety and tolerability of ipatasertib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) with or without CDK4/6i in patients with HR+/HER2- MBC who have received prior CDK 4/6i. Secondary objectives include assessment of objective response rate (ORR), clinical benefit rate (CBR), and progression free survival (PFS). Exploratory objectives include next generation sequencing of solid tumor biopsies and cfDNA along with immunohistochemical analysis of tumor biopsies to identify genomic and protein-based predictors of response and resistance. Statistical Methods: Arms A and B constitute dose-expansion cohorts to confirm the safety/tolerability of ipatasertib use with anti-estrogens and evaluate preliminary efficacy. A dose-limiting toxicity (DLT) rate of Present and Target Accrual: Anticipated accrual for Arms A+B will be n=15 (each). Arm C enrollment will be n=15-30 pending establishment of RP2D/MTD prior to dose expansion. Current enrollment n=4, since study activation in May 2019. Citation Format: Seth A. Wander, Dejan Juric, Laura M. Spring, Neelima Vidula, Maureen Beeler, Karleen Habin, Elene Viscosi, Lauren Scarpetti, Elizabeth Tripp, Rachel Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Aditya Bardia. A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC) [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 OT2-08-01.

1066 Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .