Abstract PS4-01-11: Exploration of racial differences in variants of uncertain significance (VUS), ESR1 and PIK3CA mutation frequency, matched therapy use, and outcomes in metastatic breast cancer (mBC)

Abstract Background: Black patients (pts) are more likely to be diagnosed with mBC and have higher mortality rates than White pts, in part due to social determinants of health, higher rates of de novo mBC, and possible genomic differences by race and ethnicity. Most variant classification efforts have focused on White populations, creating uncertainty about prevalence and significance of VUS in Black pts. It is also unclear if mutation frequency differences exist in genes with known targets, such as PIK3CA and ESR1. We examined a real-world (rw) database for racial differences in VUS, ESR1 and PIK3CA detected by circulating tumor DNA (ctDNA), matched therapy use, and outcomes by race for ESR1 and PIK3CA. Methods: Pts with mBC and ctDNA (Guardant360) results post-mBC diagnosis were identified from Guardant INFORM (n=46,286), which includes de-identified records with clinical genomic data, claims, and race when available. For Black and White pts (n=34,149), overall VUS rates were analyzed by race, as defined by OncoKB annotation. ESR1 and PIK3CA codons of interest ESR1 ligand binding domain (LBDmut); PIK3CA helical or kinase domains (HKmut), targeted therapy matching (elacestrant and alpelisib), and outcomes were evaluated by race. Outcomes were assessed using rw time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS) in months, stratified by race. Chi-squared tests compared proportions; log-rank tests compared time-to-event outcomes. Results: There were 12.5% Black (5,791/46,286) and 61.2% White (28,358/46,286) pts included. Mean VUS frequency was similar between groups (2.40 Black vs 2.47 White, p0.05). While White pts with ESR1 mutations more frequently had ESR1 LBDmut vs Black pts, there was no difference in matched therapy use with elacestrant by race for ESR1 LBDmut (Table 1). Black pts with ESR1 LBDmut and 2L elacestrant had significantly shorter rwTTD (3.5 vs 4.2, p=0.024) and shorter numeric rwTTNT (5.9 vs 8.9, p=0.32). White pts also had significantly more PIK3CA mutations, yet among PIK3CA HKmut, there was no difference in matched therapy use with alpelisib by race (Table 1). Black pts with PIK3CA HKmut treated with 2L alpelisib compared with white pts had numerically longer rwTTD (4.4 vs 3.7, p=0.48), rwTTNT (8.7 vs 6.6, p=0.33), and rwOS (33.9 vs 25.9, p=0.38); none reached statistical significance. Conclusion: In this large, rw analysis of a diverse patient population, differences in VUS rate, ESR1/PIK3CA matched therapy use, and outcomes were not observed between Black/White pts, suggesting the need for additional exploration of race-based differences on mBC outcomes. This study underscores the need for continued inclusion of diverse populations in genomic discovery and prospective studies to clarify known outcome disparities. Citation Format: A. A. Davis, L. S. Welch, J. Saha, L. Bucheit, M. D. Lipsyc-Sharf, A. Bardia, C. X. Ma, M. Cristofanilli, E. L. Podany. Exploration of racial differences in variants of uncertain significance (VUS), ESR1 and PIK3CA mutation frequency, matched therapy use, and outcomes in 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 PS4-01-11.