Abstract PS2-09-21: Real-world clinical outcomes and genomic insights for patients with PIK3CA-mutant metastatic breast cancer following progression on CDK4/6 inhibitor therapy

Abstract Background: PIK3CA mutations (PIK3CAmut) are detected in approximately 40% of hormone receptor-positive metastatic breast cancers (mBC) and are actionable therapeutically. The emergence of targeted therapies for mBC with PIK3CAmut, ESR1 mutations (ESR1mut), and those with dual mutant disease has made therapy decisions following progression on a CDK4/6 inhibitor (CDK4/6i) increasingly complex. Here we assessed treatment selection for patients (pts) with PIK3CAmut mBC post-CDK4/6i, examining clinical outcomes and associated genomic findings via circulating tumor DNA (ctDNA). Methods: Pts tested with Guardant360 (a ctDNA sequencing assay) since November 2023 (capivasertib approval date) were identified in Guardant INFORM, a real-world clinical-genomic dataset which combines de-identified genomic results with associated claims data. Eligible pts had mBC, were treated with a CDK4/6i after metastatic diagnosis, and had ctDNA-detected PIK3CAmut after CDK4/6i but prior to the start of the next line of therapy (LOT). The therapy selected following PIK3CAmut detection was assessed. Exposures of interest included treatment with capivasertib (CAPI), alpelisib (ALP), and elacestrant. Subgroup exposures included baseline and post-treatment genomic alterations detected on ctDNA, and dual PIK3CAmut/ESR1mut disease when alterations were identified on the same test. Outcomes analyzed included real-world time to treatment discontinuation (rwTTD), and overall survival (rwOS) in months using the Kaplan Meier method; log-rank tests compared time-to-event outcomes. Results: 460 pts met inclusion criteria of which 115 (25%) subsequently received CAPI, 22% a CDK4/6i regimen, 15% aromatase inhibitor (AI) monotherapy, 14% elacestrant, 12% chemo and 6% ALP. rwTTD was numerically longer for CAPI compared to ALP [6.0 vs. 5.5 months; HR: 0.82 (95% CI:0.46-1.44); p=0.48]; rwOS was not reached at this time. When assessing genomics, ctDNA testing post-CAPI (n=15), found several alterations with frequency >10% including TP53 single nucleotide variant (SNV) (53%), FGFR1 copy number variant (CNV) (20%), CCND1 CNV (20%), KRAS SNV (13%), and ESR1 SNV (13%). FGFR1 CNV, CCND1 CNV, and KRAS SNV frequencies increased substantially in post-treatment samples compared to baseline (FGFR1: 20% vs. 6%; CCND1: 20% vs. 10%; KRAS: 13% vs. 4%), suggesting post-progression enrichment and potential roles in CAPI resistance. For PIK3CAmut/ESR1mut tumors (n=165, 35%), 66 (40%) received elacestrant as next LOT, 28 (17%) received CAPI, 21 (13%) received AI only, 19 (12%) each received CDK4/6i or chemo, and 10 (6%) received ALP. In PIK3CAmut disease treated with CAPI, pts without ESR1mut had numerically longer rwTTD compared to those with ESR1mut (6.0 vs. 4.9 months; HR: 1.23 (95% CI: 0.63-2.39); p=0.54]. Outcomes need additional follow-up time for maturity and updated results will be presented at the meeting. Conclusions: In this real-world analysis, pts with PIK3CAmut mBC and CDK4/6i progression were most frequently treated with CAPI as subsequent therapy when no ESR1mut was identified; co-mutant disease received elacestrant most often. CAPI responses may differ based upon genomic alterations in baseline ctDNA, including the presence of ESR1mut, though these exploratory findings require additional follow up for data maturity. Higher frequencies of FGFR1, CCND1, and KRAS alterations at CAPI progression warrant further testing as potential acquired resistance mediators. Citation Format: M. R. Lloyd, L. Bucheit, D. Hintz, J. Liao, N. Vasan, K. Clifton, C. Ma, S. Wander. Real-world clinical outcomes and genomic insights for patients with PIK3CA-mutant metastatic breast cancer following progression on CDK4/6 inhibitor therapy [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 PS2-09-21.