Background: ALP was approved by the FDA for treatment of HR+/HER2- advanced BC with activating PIK3CAm based on the phase 3 SOLAR-1 trial. Enrollment used 11 PIK3CAm (SOLAR1m) in PIK3CA exons 7, 9 and 20. We report the prevalence of SOLAR1m and other predicted activating mutations elsewhere in the PIK3CA gene (OTHERm) in pts with BC, as well as rw clinical outcomes of ALP treatment in these pts. Methods: Comprehensive genomic profiling (CGP) results from 31,765 tissue and 4,147 liquid biopsies from pts with BC were analyzed. Clinical characteristics and treatment history were available for 1,579 pts with PIK3CAm in a de-identified Flatiron Health-Foundation Medicine clinico-genomic database (data obtained from ̃800 US sites, 1/2011 - 9/2020, via technology-enabled abstraction of clinician notes and radiology/pathology reports). 3 cohorts were considered. Cohort A: HR+/HER2- pts receiving fulvestrant (FUL) alone (n = 124) or ALP/FUL (n = 111) in treatment line ≥2L were considered in survival analysis. Rw progression-free survival (rwPFS) from start of treatment was estimated with Kaplan-Meier analysis and hazard ratios from Cox proportional hazards models adjusted for survival bias. Cohort B: 627 HR+/HER2- pts who received a clinical report with ALP listed (report date after 5/2019) Cohort C: 36 pts with OTHERm only, any receptor subtype, treated with ALP in any combination. Results: Among 31,765 BC tissue biopsies, 10,869 (34%) had PIK3CAm. 8,750 (28%) had SOLAR1m, and of these 1,146 had ≥1 additional OTHERm. 2,119 pts (6.7%) had ≥1 OTHERm without any SOLAR1m. OTHERm more common in the presence of a SOLAR1m were: E726K, E418K, E365K, E453Q, and H1048R (p < 0.0001). OTHERm more common in absence of a SOLAR1m were: N345K, G1049R, Q546K, and indels disrupting PIK3R1 binding (p < 0.0001). Among 4,147 liquid biopsies, detection rates were comparable to tissue: 1,391 (34%) had PIK3CAm and 1159 (28%) had SOLAR1m. In Cohort A, median rwPFS was 4.1 mo on FUL [95%CI: 3-6.2] versus 6.5 mo on ALP/FUL [95%CI: 4.8-9.5] (p = 0.027). In Cohort B, 202/524 (39%) pts with a SOLAR1m were treated with ALP, compared to 28/103 (27%) pts who had OTHERm only. Pts with SOLAR1m received ALP treatment earlier: median [interquartile range] 4L [3-6] versus 5.5L [4-8]. In Cohort C, rwPFS > 6 months was observed in 5 pts bearing: N345K, Q75E, R38C, G106_108del, and N345K/N1044K. Conclusions: This study validates the activity of ALP among a diverse real world population, showing pts with PIK3CA mutations have longer rwPFS on ALP/FUL than FUL alone. Pts with SOLAR1m were more likely to be treated with ALP- and tended to be treated in earlier line setting- than pts with OTHERm. No consistent effect in a small subset of pts with OTHERm treated with ALP was observed, but there is evidence that OTHERm may differ in their degree of PI3K activation, oncogenicity, and ALP sensitivity. Liquid biopsy CGP detected PIK3CAm at similar rates to tissue biopsy.