Prevalence and clinical impact of PIK3CA and PTEN alterations from reflex genomic testing of newly diagnosed colorectal cancer: a population-based series

BACKGROUND: Results from the Adjuvant Low dose Aspirin in Colorectal Cancer (ALASCCA) clinical trial demonstrate a survival benefit associated with aspirin use in patients with non-metastatic colorectal cancer (CRC) harbouring phosphoinositide 3-kinase (PI3K) pathway alterations. Identification of patients in routine clinical care is required for implementation of this therapeutic approach. A real-world analysis of reflex diagnostic testing was performed to assess prevalence of PI3KCA and PTEN gene alterations and potential clinical impact.

METHODS: Next generation sequencing panel testing of all newly diagnosed CRC as part of a Lynch screening service began in the Northern Ireland Cancer Network in 2022. Profiling, using a capture hybridisation assay and custom Small Cancer Panel covers all coding regions of PTEN and PIK3CA with a limit of detection of 4% variant allele frequency (VAF).

RESULTS: 1516 CRC patients underwent genomic profiling at the point of diagnosis from January 2024-March 2025. Across all CRC stages, 170 patients (11.2%) had tumours harbouring PIK3CA mutations with the majority occurring in exon 9 and 20. A further 51 of 1516 tumours (3.4%) demonstrated PTEN mutations. Of 221 patients with PIK3CA/PTEN alterations, 174 (79%) had non-metastatic CRC, of whom 6 (3.4%) had an absolute contraindication to aspirin use. Overall, 168 (11.1%) of 1516 patients in this cohort were therefore identified by this reflex testing pathway as potentially eligible for treatment.

CONCLUSIONS: Prevalence of PIK3CA and PTEN alterations in this series (14.6%) was lower than in the ALASCCA trial (37%) but these results represent a real-world rather than a highly selected trial population. Regardless, our findings support implementing testing for use of a safe, inexpensive repurposed drug and underscore the importance of upfront testing for timely treatment decision-making and implementation of trial findings into routine practice.