Targeted agents for the treatment of hormone receptor–-positive, human epidermal growth factor receptor 2–negative metastatic breast cancer (HR+/HER2- MBC) with co-alterations in <i>ESR1</i> and <i>AKT</i> pathway: A retrospective analysis.

e13084 Background: HR+/HER2- MBC remains an incurable disease. In published series, the co-occurrence rate of ESR1 and PIK3CA mutations(m) is 10-15%. Tumors with an ESR1 m are targeted with elacestrant (E), and those with alterations in PIK3CA, AKT, or PTEN are candidates for capivasertib (C) or, if PIK3CA m, alpelisib (A). The efficacy of these approved targeted agents in pts with co-alterations remains unknown. Methods: Pts treated at Miami Cancer Institute between 2018-2025 with HR+/HER2- MBC who underwent ctDNA testing with Guardant360 and exhibited co-alterations in ESR1 and the AKT pathway (in the same sample) were included. Baseline demographics, comorbidities, tumor characteristics, and treatment history were collected. Median time on treatment (mTOT) on each targeted agent was analyzed by ANOVA. Median overall survival (mOS) from diagnosis of MBC was calculated by Kaplan-Meier analysis and Cox proportional model. P values were two-sided. Results: 81 pts with co-alterations were identified with baseline characteristics detailed in Table 1. mOS of the entire cohort was 76.6 months (mos). At any time point in their treatment history, 20 pts (24.7%) were treated with E, 34 pts (42%) were treated with A, 7 pts (8.6%) were treated with C, and 11 pts received both E and either A or C (E + A/C). mTOT with E was 98.5 days (d) (range 1-414). Median lines of therapy before E was 5 (range 1-12); 86.7% discontinued for progression. Median OS from time of diagnosis in those who received E was 143.6 mos vs 71.5 mos in those who did not ( p =0.007). mTOT with A was 135 d (range 4-601) with median 2 prior lines of therapy (range 1-9); 62.5% discontinued for progression. mOS for those who received A was 72.3 mos vs 81.6 mos in those who did not ( p =0.833). mTOT with C was 41.5 d (range 22-105) with 3 median prior lines of therapy (range 1-6); 66.7% discontinued for toxicity. mOS with C was 78.8 mos vs 72.3 mos without ( p =0.308). In the 11 pts (13.6%) who were treated with E + A/C in any order, mOS was 93.5 months. Mean TOT with E in these 11 pts was 146.8 d when received before A/C and 119.0 d with E after A/C ( p =0.667). Conclusions: In this real-world cohort, pts with HR+/HER2- MBC with co-alterations in ESR1 and AKT pathway, mTOT was longest with A, with the caveat that A treated pts received the fewest prior lines of therapy. mOS was significantly longer in those who received E vs those who did not. Analysis of pts receiving E+A/C was limited by small sample size and optimal sequencing should be studied in randomized prospective clinical trials. Pt Characteristics (n=81) N (%) or median (IQR) Age (yrs) 63 (53-69) Race White Black Other 71 (87.7)8 (9.9)2 (2.5) Ethnicity Non-Hispanic Hispanic 32 (39.5)49 (60.5) Diabetes Yes No 17 (21)64 (79) ESR1 Mutation D538 Y537 Other 27 (33.3)41 (50.6)13 (16.0) AKT alteration PIK3CA AKT PTEN 72 (88.9)5 (6.2)4 (4.9)