Abstract P5-13-13: PIK3CA mutations co-occurring with copy number gain identify patients with adverse outcome and potentially different treatment sensitivity among hormone receptor positive and HER2 negative metastatic breast cancer
Authors: Migliaccio Ilenia , Paoli Marta , Risi Emanuela , Biagioni Chiara , Biganzoli Laura , Benelli Matteo , Malorni Luca 
Published: March 2022

Abstract
INTRODUCTION: Somatic mutations of the PIK3CA gene, encoding for the class IA PI3K p110α subunit, are the most common activating mutations in breast cancer (BC), occurring in 30-50% of early and in 28% of metastatic ER+/HER2- disease. We have previously demonstrated that PIK3CA mutations co-occurring with copy number (CN) gain (PIK3CA-mut/gain) are associated with worse outcome in patients with early hormone receptor positive and HER2 negative (HR+/HER2-) BC, including those receiving endocrine therapy (ET). Here we aim to evaluate the prognostic role of PIK3CA-mut/gain in patients with metastatic HR+/HER2- BC treated with chemotherapy, ET alone or in combination with targeted therapies (CDK4/6 inhibitors or everolimus) included in a publicly available dataset of BC. PATIENTS AND METHODS: We accessed genomic, clinical, treatment and outcome data from 1365 patients with HR+/HER2- BC included in the MSK-2018 dataset. Patients treated for distant metastases were selected. PIK3CA status, considering both protein-affecting mutations and CN alterations, was derived from pre-treatment biopsies data. Tumors were classified as: PIK3CA wt and CN neutral (-wt/neut), PIK3CA wt with CN gain (-wt/gain), PIK3CA mutant and CN neutral (-mut/neut), and PIK3CA mutant with CN gain (-mut/gain). Tumors with PIK3CA loss were excluded from the analyses. For each patient and treatment type, only progression free survival (PFS) from the first available line of treatment was analyzed, thus excluding data concerning possible retreatments with the same drug in subsequent lines. Multivariate Cox proportional hazard models were used to assess the association between PIK3CA status and PFS including treatment line and the four categories of PIK3CA as co-variates. RESULTS: The proportion of PIK3CA-mut/gain was 15.4% in the chemotherapy group (n=454), 17.3% in the ET alone group (n= 352), 13.4% in the ET plus CDK4/6 inhibitors group (n= 268) and 10.5% in the ET plus everolimus group (n= 143). As expected, in all groups treatment line was significantly and independently associated with PFS. In the ET alone group, patients whose tumors had gain in PIK3CA CN, with or without co-occurring mutations, were at significantly higher risk of progression compared with PIK3CA-wt/neut (HR 2.2 [1.53-3.2] p&lt;0.001 for PIK3CA -mut/gain; HR 1.5 [1.03-2.2] p= 0.034 for PIK3CA-wt/gain), while PIK3CA-mut/neut status was not significantly associated with progression (HR 1.2 [0.87 − 1.6] p= 0.289). Similar observations, without reaching statistical significance, were also made in the CDK4/6 inhibitors group (HR 1.6 [0.92-2.6] p= 0.099 for PIK3CA-mut/gain; HR 1.6 [0.97-2.5] p= 0.068 for PIK3CA-wt/gain) and in the chemotherapy group (HR 1.4 [0.98-2] p= 0.063 for PIK3CA-mut/gain; 1.2 [0.89-1.6] p= 0.223 for PIK3CA-wt/gain). On the other hand, in patients treated with ET plus everolimus, while there was a borderline significant increased risk of progression for patients with PIK3CA-wt/gain tumors (HR 1.8 [1.00 − 3.3] p= 0.051) and for those with PIK3CA-mut/neut (HR 1.6 [0.98-2.5) p= 0.06), this was not observed in patients with PIK3CA-mut/gain tumors (HR 1.1 [0.5-2.2] p=0.89), potentially suggesting a treatment benefit. CONCLUSIONS: Our data suggest that patients with metastatic HR+/HER2- BC with tumors with PIK3CA-mut/gain have poor outcome. These data are in line with our previous report in patients with early BC. Further studies are warranted to understand if patients with PIK3CA-mut/gain tumors might benefit from the combination of ET and everolimus.
Citation Format: Ilenia Migliaccio, Marta Paoli, Emanuela Risi, Chiara Biagioni, Laura Biganzoli, Matteo Benelli, Luca Malorni. PIK3CA mutations co-occurring with copy number gain identify patients with adverse outcome and potentially different treatment sensitivity among hormone receptor positive and HER2 negative metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-13.