Genomic alterations (GA) in ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) patients (pts) with metastatic breast cancer (MBC): Co-occurrence and prevalence along treatment course.

1060 Background: The standard of care for HR(+) HER2(-) MBC is evolving with new biomarker-guided drugs, including novel selective estrogen receptor degraders (SERDs) for pts with ESR1 mutations (mut) and PIK3CA and AKT inhibitors for pts with alterations in the PI3K pathway (PIK3CA, AKT1, and PTEN). This study aimed to evaluate the co-occurrence and the prevalence of these GA in different metastatic lines of therapy in real-world practice for MBC. Methods: This study included pts with HR(+) HER2(-) MBC who underwent genomic testing using Foundation Medicine tissue or liquid comprehensive genomic profiling assays, with specimens collected within 60 days of therapy initiation. Clinical data were obtained by the nationwide (US-based) de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic breast cancer database (FH-FMI CGDB), originated from ~280 US cancer clinics (~800 sites of care) between 01/2011-06/2023. The prevalence of ESR1mut, PIK3CAmut, AKT1, PTENmut, and PTEN copy loss were calculated in tissue (TBx) and liquid biopsies (LBx) collected at time of 1st, 2nd, and 3rd lines of therapy. The co-occurrence of GA in TBx was evaluated. Results: Among patients with a TBx collected around therapy initiation (n=2,536), 81.5% (2,066) was collected at 1 st , 10.2% (258) at 2 nd , and 8.3% (212) at 3 rd line. Among patients with a LBx collected around therapy initiation (n=545), 47% (256) was collected at 1 st , 33.2% (181) at 2 nd , and 19.8% (108) at 3 rd line. In TBx, the prevalence of GA detected in 1 st , 2 nd , and 3 rd lines were 58.6% (1,210), 67.4% (174), and 71.2% (151), respectively. In LBx, the prevalence was 42.7% (121), 65.7% (119), and 60.1% (65), respectively. Among LBx with tumor fraction ³1%, the prevalence was 67.9% (74/109), 89.1% (81/91), and 84.3% (43/51). Among patients with a GA detected in TBx 1 st (n=1,210), 2 nd (n=174), and 3 rd (n=151) lines, both ESR1mut and a PIK3 pathway GA was detected in 7.4% (90), 12.1% (21), and 23.8% (36), respectively. Conclusions: In our dataset, 42-59% of patients with HR(+) HER2(-) MBC have at least one GA detected by TBx or LBx in 1 st line, with prevalence increasing in later lines of therapy to 60-71% due to acquisition of an ESR1mut. PTEN copy loss is detected at much higher rates in TBx than LBx, consistent with the known inherent limitations of ctDNA testing. Serial genomic testing with LBx with reflex TBx if alterations are not identified should strongly be considered with the recent approvals of several molecularly targeted agents for HR(+) HER2(-) MBC. Table: see text