Abstract 1954P
Background
Breast carcinomas (BC) harboring double PIK3CA mutations exhibit elevated PIK3CA signaling and increased sensitivity to PI3Kα inhibitors (Vasan, et al. Science 2019). Here we examine the prevalence of double PIK3CA mutations in a large pan-cancer cohort.
Methods
Comprehensive genomic profiling was performed on 254,549 tumor samples for alterations in at least 324 genes (Foundation Medicine). Tumor mutational burden (TMB) was calculated on 0.8–1.1mb. Mutational signatures were determined based on Zehir et al., Nat Med 2017.
Results
Double PIK3CA mutations were found at an overall prevalence of 1.2%; 17 tumor types exhibited a prevalence of at least 1% including uterus/endometrial (6.4%), BC (4.5%), and cervix (4.4%). In uterus/endometrial, double mutations were highest in endometrioid (11%), with lower frequencies in clear cell (4.3%) and papillary serous (2.1%). In BC, the highest frequency was observed in invasive lobular carcinomas (10.6%) and ER+ disease (5.4%) with lower frequencies in TNBC (2.9%) and HER2+ disease (1.6%). Double mutations occur at similar frequencies in local and metastatic tumors. Pan-cancer, double PIK3CA mutations are mutually exclusive with many cancer drivers, including TP53, CDKN2A/B, and EGFR. In BC, double mutations are mutually exclusive with other PI3K-pathway alterations, including PTEN, AKT1, PIK3R1, and AKT2, and with ERBB2, BRCA1, and BRCA2. Second-site alterations were enriched at 10 codon sites, most frequently 726 and 453. Disease specific patterns of codon pairs were observed. Whereas 545:726 pairs and 545:1047 pairs are most common in BC, 542:545 pairs are observed at a 3.6-fold higher relative frequency in other tumor types. Higher TMB in double PIK3CA mutation samples led us to examine mutational signatures. Double mutations were enriched in TMB-H APOBEC-positive samples (12%) vs TMB-H APOBEC-negative samples (3.5%). Many of the enriched second-site mutations are C>T or C>A mutations in the TCA/TCT canonical APOBEC trinucleotide context, including E542K and E726K.
Conclusions
Double PIK3CA mutations are observed in a variety of tumor types. Since double PIK3CA mutant tumors have a higher TMB and often harbor an APOBEC signature, combination therapy approaches with immune checkpoint inhibitors and PI3K inhibitors appears feasible.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
NIH R21 CA223789, Susan G. Komen Career Catalyst Research Grant, Fund for Innovation in Cancer Informatics.
Disclosure
N. Vasan: Advisory/Consultancy: Novartis; Advisory/Consultancy: Petra Pharmaceuticals; Honoraria (institution): Volastra Therapeutics. S. Sivakumar, D. Jin, J.S. Ross, E.S. Sokol: Full/Part-time employment: Foundation Medicine. L.C. Cantley: Advisory/Consultancy, Leadership role, Officer/Board of Directors: Agios Pharmaceuticals; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Shareholder/Stockholder/Stock options, Officer/Board of Directors: Petra Pharmaceuticals. M. Scaltriti: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Officer/Board of Directors: Menarini Ricerche; Advisory/Consultancy, Officer/Board of Directors: Bioscience Institute; Research grant/Funding (self), Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (self), Research grant/Funding (institution): Daiichi-Sankio; Research grant/Funding (self), Research grant/Funding (institution): Targimmune; Research grant/Funding (self), Research grant/Funding (institution): Immunomedics; Leadership role: Medendi.org.