Abstract PO1-26-03: Activity of alpelisib in a panel of breast XPDX models harboring hotspot and uncommon PIK3CA mutations

Abstract

Abstract Background: Therapies targeting mutated phosphoinositide 3-kinase (PI3K) p110α catalytic subunit (PIK3CA) cancers remain an active field of research. Alpelisib was approved in combination with fulvestrant in ER+/HER2- breast cancer patients harboring PIK3CA mutations on hotspot amino acids E542, E545 Q546 or H1047. While mutation at these sites have been widely studied, they only comprise ~25% of identified variants in this protein. Recent studies have reported other mutations, including those at the c-terminus, which can lead to constitutive activation of PIK3CA; however, whether these variants are sensitive to agents like alpelisib is unclear. To better understand these variants and their role in PIK3CA-mediated breast cancer, we established a panel of PIK3CA-mutated ER+ and ER- breast XPDX models and evaluated each in vivo with single agent alpelisib. Methods: Ninety previously developed XPDX models representing PIK3CA-mutated ER+ and ER- breast cancer were evaluated in this study. Models were grown subcutaneously in female athymic nude mice supplemented with estradiol in drinking water when necessary and ER expression confirmed at multiple passes; PIK3A variants were determined by WES and RNAseq. For in vivo studies, alpelisib was administered once daily by oral gavage at 35 mg/kg through study completion. Endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C< 0%) versus Day 0 tumor volume was also reported. Results: 60% of PIK3CA-mutated models were found ER+ with 40% also HER2+ while 20% of ER- PIK3CA-mutated models were also HER2+. H1047X mutations accounted for 40% of all PIK3CA variants, 75% of which were single or dual PIK3CAH1047R. Several hotspot-mutated models were sensitive to alpelisib some with regressions including ST986 (E542K), ST1097 (E454K) and STF040 (H1047R), as well as ST1245C (R88Q/N1044H), ST2076 (102-103ins/R357Q) and ST4176 (E726K/H1047R). HER2+ models were less sensitive to alpelisib although STM148D (H1047L) reported tumor regressions. Interestingly, ST1799/PBR (E542K/H1065L), a palbociclib resistant clone of the ER+ parent ST1799 model was resistant to alpelisib while the parent was found sensitive. Conclusion: We have benchmarked a panel of PIK3CA-mutated breast XPDX models with alpelisib and compared activity of models harboring hotspot versus uncommon PIK3CA mutations with ER and HER2 expression. This data is a valuable tool in further developing PIK3CA inhibitors and identifying new variant targets in breast cancer. Citation Format: Mercedes Castaneda, Alyssa Simonson, Johnnie Flores, Maci DeBoer, Jim Lund, Tahmi Rouzbahan, Kyriakos P. Papadopoulos, Amy Lang, Gladys Rodriguez, Maryam Elmi, Arthur Rosenthal, Drew Rasco, Victor Moreno, Amita Patnaik, Tatiana Hernandez, Emiliano Calvo, Lon Smith, Manish Sharma, Muralidhar Beeram, Michael Wick. Activity of alpelisib in a panel of breast XPDX models harboring hotspot and uncommon PIK3CA mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-26-03.