Molecular characteristics of advanced colorectal cancer and multi-hit PIK3CA mutations

Introduction: Approximately 20% of patients living with colorectal cancer (CRC) have activating mutations in their tumors in the PIK3CA oncogene. Two or more activating mutations (multi-hit) for the PIK3CA allele increase PI3KA signaling compared to single-point mutations, resulting in exceptional response to PI3KA inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in metastatic CRC to identify patients who may benefit from PI3K inhibitors. Methods: The Foundation Medicine database (Boston, MA, USA) was analyzed for patients with CRC who underwent genomic profiling on tumor DNA isolated during routine clinical care from 2013 to 2021. Molecular and clinical variables were abstracted for patients with PIK3CA mutations. Results: We identified 49 051 patients with CRC who underwent Foundation Medicine testing. 710/41154 (1.7%) patients had multi-hit PIK3CA mutations, of which 53% were male (n = 448) with a median age of 60. Microsatellite status was available for 697 patients with multi-hit PIK3CA and 17.6% (123/697) were microsatellite instability-high. Clinically relevant mutations in KRAS and BRAFV600E were seen in 459/710 (64.7%) and 65/710 (9.1%), respectively. The 4 most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%), and R88Q (7.1%). The most common variant pair was E542K-E545K (4.7%). Conclusions: Multi-hit mutations in PIK3CA are seen in 1.7% of advanced CRC, a meaningful prevalence given the high burden of CRC worldwide, and may represent a subset of patients that have enhanced sensitivity to PI3K inhibition. Future investigation regarding the clinical utility of PI3K inhibitors is warranted in multi-hit PIK3CA CRC.