Abstract P5-02-32: Differential Gene Mutation Landscape in Patients With PIK3CA-altered and Non-altered Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer in the SOLAR-1 Clinical Study
Authors: Juric Dejan , Rugo Hope , Reising Albert , Ma Chong , Ciruelos Eva , Loibl Sibylle , Singer Christian F. , Sohn Joo Hyuk , Campone Mario , Conte PierFranco , Iwata Hiroji , Ghaznawi Farhat , Miller Michelle , Taran Tetiana , Su Faye , Andre Fabrice 
Published: March 2023

Abstract
Introduction: The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) is found mutated (mut) in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC); some of these alterations can lead to PI3K pathway hyperactivation and are associated with endocrine resistance and poor prognosis in advanced disease. Alpelisib (ALP), an α-selective PI3K inhibitor and degrader, demonstrated clinical benefit in combination with fulvestrant (FUL) in the SOLAR-1 study in pts with PIK3CA-mut HR+, HER2− ABC. SOLAR-1 (NCT02437318) was a double-blind, placebo (PBO)-controlled, stratified, randomized (per PIK3CA-alt status as determined by QIAGEN PIK3CA RGQ PCR test), Phase III study of ALP in combination with FUL in pts with HR+, HER2− ABC who progressed on/after aromatase inhibitor therapy. Here, we compare the gene alteration landscape in pts with altered (alt) and non-alt PIK3CA and the efficacy of ALP + FUL in pts whose tumors have alterations in both selected genes or cell signaling pathways as well as PIK3CA-alt or non-alt status as determined by next-generation sequencing (NGS).
Methods: In this analysis, retrospective NGS analysis using the FoundationOne CDx 324-gene panel was performed on available FFPE tissue samples. In all, 398 pts were categorized into 2 cohorts based on NGS-tested PIK3CA status. The PIK3CA-alt cohort comprised 237 patients (ALP, n=120; PBO, n=117); the PIK3CA-non-alt cohort 161 patients (ALP, n=81; PBO, n=80). Selected genes altered in &gt;20 SOLAR-1 pts were investigated further. Clinical benefit was assessed by progression-free survival (PFS) based on gene alt status in the PIK3CA-alt and -non-alt cohorts. Hazard ratios (HR) for PFS were estimated using a multivariate Cox PH model by adjusting multiple clinical covariates including age, ECOG performance status, bone lesion, prior CDK4/6 inhibitor treatment, and lung/liver metastasis.
Results: PIK3CA-alt and -non-alt cohorts had differential genomic landscapes; differential PFS benefit was observed among the genes analyzed, including ARID1A, EMSY, FGFR2, MAP3K1, MYC, RAD21, RAD51C, TP53, and a gene set associated with the MAPK pathway. In most pts with analyzed gene alterations, numerically longer PFS was observed with ALP vs PBO in the PIK3CA-alt cohort than the -non-alt cohort, particularly pts with alterations in ARID1A (median [m] PFS for ALP vs PBO in PIK3CA-alt cohort: 22.11 vs 12.42 mo, HR 0.48; vs mPFS in PIK3CA-non-alt cohort: 6.21 vs 22.31 mo, HR 1.33) and MAP3K1 (PIK3CA-alt cohort: 17.25 vs 7.70 mo, HR 0.50; vs PIK3CA-non-alt cohort: 9.17 vs 5.26 mo, HR 1.32). Full results are found in the Table. Results should be interpreted with caution, as analyses used small sample sizes and were not adjusted for multiple testing.
Conclusions: A differential genomic landscape was observed in PIK3CA-alt and PIK3CA-non-alt populations. Clinical benefit of ALP vs PBO was observed in pts with PIK3CA-alt disease who also had alterations in analyzed genes and/or genes associated with the MAPK pathway. The data from this analysis suggest that, of the genes analyzed, only PIK3CA mutations can predict pt sensitivity to ALP.
Table. PFS in PIK3CA-altered PIK3CA-non-altered populations by gene alteration
Citation Format: Dejan Juric, Hope Rugo, Albert Reising, Chong Ma, Eva Ciruelos, Sibylle Loibl, Christian F. Singer, Joo Hyuk Sohn, Mario Campone, PierFranco Conte, Hiroji Iwata, Farhat Ghaznawi, Michelle Miller, Tetiana Taran, Faye Su, Fabrice Andre. Differential Gene Mutation Landscape in Patients With PIK3CA-altered and Non-altered Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer in the SOLAR-1 Clinical Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-32.