Abstract LB372: Real-world evidence from AACR Project Genie: Overall survival with combination chemotherapy plus endocrine and targeted therapy in HER2-negative, ER-positive metastatic breast cancer

Abstract Introduction: In HER2-negative (HER2-), estrogen receptor-positive (ER+), stage III/IV metastatic breast cancer (mBC), overall survival (OS) and time to progression depend on treatment response as well as patient factors, molecular profiles, and prior therapy. We questioned whether combination chemotherapy + fulvestrant + aromatase inhibitor (AI) + targeted therapy improves OS and delays progression versus chemotherapy + endocrine therapy excluding fulvestrant and AI ± targeted therapy. Methods: Using AACR Project Genie, we compared OS (median, 12-, 24-, 36-, 48-, 60-, 72-month landmark) between women treated with chemotherapy + fulvestrant + AI + combination cyclin-dependent kinase 4/6 (CDK 4/6), mammalian target of rapamycin (mTOR), or AKT inhibitor (Group A) versus chemotherapy + combination endocrine therapy excluding fulvestrant + AI with or without targeted therapy with AKT, CDK 4/6, or mTOR inhibitor (Group B). Adjusting for confounding, we used inverse propensity score weighting and Cox proportional hazards to estimate hazard ratios (HRs) with Kaplan-Meier (KM) methods in R v4.4.1. We also compared between-group ages at initial and metastatic diagnosis as time-to-event (TTE) end points. Results: Among 111 patients, adjusted weighted median OS was 89.87 (67.43-not estimable [NE]) months for Group A versus 52.53 (43.06-NE) months for Group B (HR 0.42, 95% CI 0.24-0.75; P<.001). A numeric OS advantage emerged at 24 months in Group A, reached significance at 48 months, and remained at 72 months. Mean TTE was 3 years in Group A versus 1.6 years in Group B (HR 0.60, 95% CI 0.42-0.87; P=.005). Discussion: In HER2-, ER+, late-stage mBC, we found statistically significantly delayed TTE and a mean 58% OS advantage with chemotherapy plus fulvestrant + AI + targeted therapy over chemotherapy plus endocrine-based regimens excluding fulvestrant and AI. As neither OS nor progression can be attributed to treatment alone, future studies should evaluate these regimens long-term in the context of contributing factors and explore the potential for more personalized care. Citation Format: Alexandrina Balanean, Samuel Baird, Brooke Leon, Parisa Asgarisabet, Camryn Craig, Yolaine Smith, Harlen Hays, Bruce Feinberg, Shahnjayla Connors. Real-world evidence from AACR Project Genie: Overall survival with combination chemotherapy plus endocrine and targeted therapy in HER2-negative, ER-positive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB372.