Abstract PO1-19-09: Integrating gene signatures to guide HR+ MBC therapy in a diverse cohort (INSIGHT)

Abstract Background: Black women with breast cancer (BC) have a 40% higher mortality rate compared to Non-Hispanic White (NHW) women. Among women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) BC, Black women have worse outcomes than NHW despite comparable systemic therapies. Gene expression profiling assays have been used in early-stage BC to provide prognostic and sometimes predictive information beyond standard immunohistochemical classifications. The 80-gene molecular subtype signature (BluePrint) with the 70-gene risk of distant recurrence signature (MammaPrint®) (Agendia, Irvine, CA) further classify HR+/HER2- BC into luminal A-type, luminal B-type, HER2-type, and basal-type tumors. Luminal B, HER2, and basal-type tumors (non-luminal A) are more aggressive with worse survival outcomes and are overrepresented among Black women. In the metastatic setting, the role of molecular subtype signatures in guiding therapeutic decisions has not yet been determined. We hypothesize that patients with metastatic HR+/HER2- non-luminal A-type BC post-progression on endocrine therapy +/- CKD4/6 inhibition will derive more benefit from chemotherapy than standard-of-care endocrine therapy in the second line setting. We also hypothesize that the impact of the intervention will be more pronounced in Black women compared to NHW women. Methods: This is a randomized phase II study that will evaluate the anti-tumor effect of capecitabine compared to physician’s choice endocrine therapy as second line therapy for adult ( 18 years) patients with non-Luminal A HR+/HER2- metastatic or unresectable locoregional invasive carcinoma (NCT 05693766). The study plans to enroll up to 62 patients. This trial enriches for racial/ethnic minority patients through collaborations with the University of Texas Southwestern and the University of Alabama at Birmingham, two health systems that serve a large minority population. Eligible patients who have received prior endocrine therapy with a CDK4/6 inhibitor will have their tumor tissue analyzed using the MammaPrint® and BluePrint assays. Patients with Luminal A tumors will receive standard of care and will be followed for survival only. Patients with non-Luminal A tumors will be randomized (1:1) to receive physician’s choice endocrine therapy versus capecitabine (dosed at 2000mg twice daily for 7 days on, 7 days off) with stratifications by molecular subtype and race. Patients will be evaluated for response every three cycles using the Response Evaluation Criteria in Solid Tumors. Therapy will be continued until evidence of disease progression or unacceptable major toxicity. The primary endpoint is progression free survival; secondary endpoints are overall response rate, clinical benefit rate, overall survival, and patient reported outcomes. The study will have 80% power to detect a minimal hazard ratio of 0.5 at one-sided significance level of 0.05. Cell-free DNA will be collected at baseline and at three times post-baseline to investigate potential genetic markers of disease response and resistance. Enrollment opened on June 1, 2023. We anticipate opening the trial at the external sites before the end of 2023. Citation Format: Moriah Forster, Jennifer Whisenant, Ben Park, Erica Stringer-Reasor, William Audeh, Andrea Menicucci, Fei Ye, Heather McArthur, Sonya Reid. Integrating gene signatures to guide HR+ MBC therapy in a diverse cohort (INSIGHT) abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-09.