Abstract PS1-11-30: Implications of PIK3CA/HER2 Status and Age/Comorbidities on Clinical Investigators’ (CIs) Selection of First-Line Systemic Therapy for Hormone Receptor-Positive (HR+) Metastatic Breast Cancer (mBC)

Abstract BACKGROUND: The 2023 and 2024 San Antonio Breast Cancer Symposium presentations of the Phase III INAVO120 and PATINA trials, respectively, have added important considerations in the decision of first-line therapy for select patients with HR+, PIK3CA-mutant or HER2-overexpressing mBC. In addition, the lack of direct comparison among the 3 approved CDK4/6 inhibitors (CDKis) has made choosing treatment a challenge in many clinical situations. This initiative attempted to identify how various factors influence CIs’ chioce of first-line therapy for HR+ mBC. METHODS: In April 2025, 20 US-based and international CIs completed a case-based survey on their choice of initial systemic therapy for HR+ mBC. For each case, a number of clinical factors (PIK3CA and HER2 status, age, performance status, comorbidities, site/extent of metastases, and prior adjuvant therapy) were varied. A modest honorarium was offered. RESULTS: Ribociclib (R) was the most common CDKi recommended for PIK3CA-wildtype, HER2-negative tumors, including patients with symptomatic visceral and asymptomatic bone metastases (Table). For patients with PIK3CA-mutated tumors with disease relapse 2 years into adjuvant endocrine therapy (ET), respondents most commonly recommended inavolisib (I)/palbociclib (P)/ET, and of great interest, 7 of 20 CIs would recommend this triplet for a patient with de novo disease. For patients with HR+, HER2-positive tumors, P/ET in addition to trastuzumab/pertuzumab was the most common recommendation for postchemotherapy/anti-HER2 maintenance treatment. However, for patients with multiple comorbidities and polypharmacy or for those who are frail and age 80 and older, respondents often did not recommend a CDKi. When one was used, it was commonly P. CONCLUSION: The clinical practice trend of selecting R as the preferred initial CDKi because of its consistent overall survival benefit has been modified by data from INAVO120 and PATINA, in which the perceived better tolerability of P led to its combination with targeted therapies that significantly improved outcomes. New questions revolve around the role of the I/P/ET combination for patients without endocrine resistance (de novo) and the use of a CDKi (P) in the HER2 maintenance setting for patients treated with trastuzumab deruxtecan based on recent data from the DESTINY-Breast09 study. Finally, the documentation that many investigators withhold a CDKi for older patients with poor performance status and comorbidities raises the issue of how to optimally identify patients for whom the risk/benefit ratio of these life-prolonging and generally tolerable agents does not weigh in their favor. These issues will be addressed in future surveys. Citation Format: K. H. Pang, J. O’Shaughnessy, V. Kaklamani, G. Kelly, T. Wallace, T. Cruse, K. Miller, K. A. Ziel, D. Paley, N. Love. Implications of PIK3CA/HER2 Status and Age/Comorbidities on Clinical Investigators’ (CIs) Selection of First-Line Systemic Therapy for Hormone Receptor-Positive (HR+) Metastatic Breast Cancer (mBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-11-30.