The genomic landscape of patients with advanced colorectal adenocarcinoma with PIK3CA mutations using comprehensive cell free tumor DNA next generation sequencing.

Abstract

181 Background: PIK3CA mutations ( PIK3CAm) are highly prevalent in advanced CRC but the prognostic value is unclear. PIK3CAm are associated with advanced stage disease, tumor aggressiveness, resistance to therapy, and a poorer prognosis. In some cases, PIK3CAm co-occur with other genetic alterations leading to complex signaling networks. Understanding these genetics are crucial to devise effective treatments. In this study, evaluated the genomic landscape of PIK3CAm in advanced CRC using cell free tumor DNA (ctDNA) next generation sequencing. Methods: This analysis assessed advanced CRC samples between 2020-2022 from the Guardant360 database using plasma-based ctDNA (~15000 patients, ~17000 samples). PIK3CAm were assessed by patient demographics, MSI-H status, TMB score, and frequency of co-occurring alterations via cbioportal. A sub analysis was collected between 2021-2022 (~8000 samples) to examine the frequency of PIK3CA exon 9 vs. 20 mutations between BRAF V600E and non- V600E BRAF mutations, and separately between KRAS G12C and G13D. Comparisons were analyzed by two-sided Fisher’s exact test. Results: PIK3CAm were detected in ~21% (~3500) of mCRC samples. Of these samples, the median age was 63 years old and the sex distribution was 56% males. MSI-H was reported in 3.3% of samples. PIK3CAm included 25% E545 (Exon 9), 13% E542 (Exon 9), 5% Q546 (Exon 9), and 10% H1047 (Exon 20). PIK3CAm had increased median alterations per sample to PIK3CA not detected (8 vs. 5) and a significant increase in co-occurrence with most genes in the panel. Relevant clinical co-occurrences were APC (73.7% vs. 57.4%), BRAF (19.9% vs. 13.0%), EGFR (34.7% vs. 24.9%), ERBB2 (9.2% vs. 6.0%), and KRAS (62.9% vs. 41.2%). Additionally, PIK3CAm samples had higher median TMB scores (13.4 vs. 9.8 mut/Mb), with >25% of PIK3CAm reporting a TMB score above the 80th percentile (20.19 mut/Mb). In a sub analysis, there were significantly greater frequencies of PIK3CAm in exon 20 in BRAF V600E samples vs. non-V600E BRAFm samples (p=0.0003) with no significant differences in exon 9 or 20 mutations in KRAS G12C vs. G13D. Conclusions: Our study shows the frequency of PIK3CAm and distribution of exons 9 and 20 are similar to those found previously in the literature by Tan (Xie) et al., 2022. Our results demonstrate PIK3CA having a low frequency of MSI-H co-occurrence, higher TMB scores, and increased co-occurring alterations with notable increased in APC, BRAF, EGFR, ERBB2 and KRAS, which may suggest higher genomic instability. Our findings underscore the clinical significance of PIK3CAm in the context of CRC, emphasizing their role as key drivers of oncogenesis, and supports the development of tailored therapeutic strategies such as combining PIK3CAi with immunotherapy or other targeted therapies.