Time to start testing KRAS and BRAF V600E mutations in stage III colon cancer? Not in routine care, yet in clinical trials

Major advances in the systemic therapy of metastatic colon cancer (CC) have significantly improved patients’ prognosis. Given their predictive value for targeted agents and immunotherapies, guidelines currently recommend routine testing of all CC for microsatellite instability (MSI) and the mutational status of the tumor for KRAS, NRAS and BRAF genes. 1 Cervantes A. Adam R. Roselló S. et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar On the other hand, the recurrence rate after surgical treatment of stage III colon cancer remains high, even with the use of optimal adjuvant chemotherapy, and only modest advances have been made in recent decades. 2 Argilés G. Tabernero J. Labianca R. et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020; 31: 1291-1305 Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar The selection of patients who presumably derive larger benefit from adjuvant chemotherapy is based on traditional prognostic clinicopathologic factors, which offer an inaccurate risk stratification, and therefore, are associated with both overtreatment and undertreatment. Taïeb and colleagues must be congratulated for the huge effort of aggregating data from 7 clinical trials to perform a pooled analysis of the prognostic value of KRAS and BRAF mutations adjusted for MSI status in stage III CC. 3 Taïeb J. Sinicrope F.A. Pederson L. et al. Different prognostic values of KRAS exon 2 sub-mutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of 7 trials. Ann Oncol. 2023; 34: 1025-1034 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar In patients with microsatellite stable (MSS) tumors, risk of recurrence or death at 5 years was 38% if BRAF V600E mutated, 34% if KRAS exon 2 mutated, and 27% if double KRAS and BRAF wild type. In the MSI population, risk of recurrence or death at 5 years was close to 25% in all mutation subgroups. The study confirmed the prognostic value of these genomic markers in multivariable models, independently of clinicopathologic factors, opening the door for clinical application. Indeed, the authors concluded: “Our results suggest that KRAS and BRAF V600E mutations have to be tested and included as stratification variables in future adjuvant clinical trials dedicated to stage III CC patients”. In my opinion, the results do not change clinical practice and the ESMO guidelines for localized CC management are still valid: “Besides MSI status, other genetic markers, e.g. RAS and BRAF mutations are not recommended for the routine assessment of risk of recurrence in non-metastatic patients, based on their lack of utility in the adjuvant decision-making process”. 2 Argilés G. Tabernero J. Labianca R. et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020; 31: 1291-1305 Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar The reasons for a conservative interpretation of the study results are discussed next and summarized in Figure 1. 1.When a prognostic marker should be assessed in routine care of early-stage cancers?