Standard guidelines recommend mutation testing for KRAS, NRAS and BRAF in MCRC. POG at BC Cancer is an investigational project that performs WGTA to identify potential hypothetical actionable biomarkers. We aimed to determine its clinical significance compared to standard sequencing panels by analyzing the prevalence of actionable variants and their impact on treatment decisions.
We analyzed 69 POG MCRC patients (pts) and summarized their WGTA results to identify germline and somatic coding variants, copy number alterations, structural alterations and gene expression outliers. Actionable items were defined as variants that could direct therapy with an investigational or approved agent, and were classified as either standard (found in local sequencing panel- BC Oncopanel) or expanded (not in Oncopanel).
74% of pts received 2 or more prior lines of chemotherapy. 1 pt died before biopsy was made available and 1 pt had an unsuccessful biopsy. Remaining analysis of 67 pts revealed 49 (73%) pts with actionable alterations, of which 43% consisted of mutation changes, 40% expression changes, 14% copy number variants, and 3% high mutational burden or HRD. Most common standard alterations (54%) were mutations in TP53, KRAS, BRAF, PIK3CA and most common expanded items (46%) were high expression of FGFR1/3, FLT1/3, and VEGFA/B. Among these, 13 (27%) pts had alterations that led to standard chemotherapy or anti-EGFR based treatment, and 7 (14%) pts had a variant that resulted in non-standard therapies. Of those, only irbesartan, targeting the FOS-JUN pathway, resulted in a meaningful response duration of 28 months, while the remaining had an average PFS of 1.7 month. 29 (59%) pts did not receive therapy outlined in POG analysis due to lack of access for the target drug (n = 15), poor performance status (n = 7), and patient or physician preference (n = 7).
WGTA in MCRC provided additional understanding of tumor biology, with high rates of expression changes not otherwise captured in standard sequencing panel. However, at the present time, there is limited additional clinical therapeutic benefit in comparison. Future development is needed and ongoing.
Clinical trial identification
Legal entity responsible for the study
BC Cancer Foundation.
All authors have declared no conflicts of interest.