KRAS/BRAF Testing May Help Define Stage III Colon Cancer Prognosis

"In addition to perioperative immunotherapy, which has shown impressive results in patients with nonmetastatic MSI-H [disease] and is currently tested in phase 3 trials, our results support neoadjuvant and adjuvant trials testing for specific RAS- and BRAF-targeted agents, in an effort to overcome the poor prognosis associated with these mutations in patients with MSS [disease]," according to the study authors.

Testing for KRAS and BRAF V600E mutations may improve individual patient prognosis for those with stage III resected colon cancer and guide investigators in selecting patients for adjuvant clinical trials focusing on specific molecular subtypes with poor prognosis, according to findings from a pooled analysis study published in Annals of Oncology.

The median follow-up was 6.9 years (95% CI, 6.8-6.9) for patients with double-wild type (DWT) tumors, 6.9 years (95% CI, 6.9-7.0) for those with KRAS-mutated disease, and 7.0 years (95% CI, 6.9-7.1) for those with disease harboring BRAF V600E mutations. Both KRAS and BRAF V600E mutations conferred a shorter time to response (TTR), overall survival (OS), and survival after recurrence (SAR) based on multivariate analysis. An interaction test indicated that there was no significant relationship between mutational status and treatment with respect to TTR (P = .08) and OS (P =.42).

Among patients with microsatellite stable (MSS) tumors, TTR was reported to be shorter in those with KRAS mutations (HR, 1.31; 95% CI, 1.20-1.42; P <.0001) and BRAF V600E mutations (HR, 1.58; 95% CI, 1.36-1.83; P <.0001). Additionally, investigators highlighted shorter OS in patients with KRAS (HR, 1.35; 95% CI, 1.23-1.49; P <.0001) and BRAF mutations (HR, 2.06; 95% CI, 1.78-2.39; P <.0001). The median SAR was 2.7 years in patients with DWT tumors, 2.3 years in those with KRAS mutations (HR, 1.25; 95% CI, 1.12-1.39; P <.0001), and 0.9 years in those with BRAF mutations (HR, 2.87; 95% CI, 2.44-3.38; P <.0001).

With respect to patients with microsatellite instability–high (MSI-H) tumors, investigators reported no differences in TTR for those with KRAS (HR, 0.99; P = .97) and BRAF V600E mutations (HR, 0.98; P = .91) compared with those with DWT disease. KRAS mutations did not confer a significant effect on OS (HR, 1.18; P = .39), although those with BRAF V600E mutations experienced worse outcomes compared with the DWT population (HR, 1.36; P = .042). The median SAR was 1.9 years in the DWT group, 1.3 years in the KRAS mutation group (HR, 1.52; 95% CI, 0.97-2.37; P = .07), and 0.7 years in the BRAF V600E mutation group (HR, 1.99; 95% CI, 1.38-2.89; P <.001).

“We demonstrated the prognostic value of these mutated oncogenes on TTR, OS, and SAR in patients with MSS [disease], and on SAR alone for patients with MSI-H [disease],” the study authors wrote. “In addition to perioperative immunotherapy, which has shown impressive results in patients with nonmetastatic MSI-H [disease] and is currently tested in phase 3 trials, our results support neoadjuvant and adjuvant trials testing for specific RAS- and BRAF-targeted agents, in an effort to overcome the poor prognosis associated with these mutations in patients with MSS [disease].”

Investigators of this study assessed data from 8460 patients with resected stage III colon cancer who were enrolled on 7 clinical trials included in the ACCENT and IDEA databases. Patients across these trials were treated with regimens including fluoropyrimidine alone; fluorouracil plus leucovorin and oxaliplatin (FOLFOX); FOLFOX plus oxaliplatin and capecitabine; FOLFOX plus cetuximab (Erbitux); FOLFOX plus bevacizumab (Avastin); leucovorin calcium plus fluorouracil and irinotecan hydrochloride (FOLFIRI); and FOLFIRI plus cetuximab. Those with stage I, II, and IV colon cancer or lower-middle rectal cancer never treated with chemotherapy were not included in the study.

Investigators estimated TTR, OS, and SAR curves with the Kaplan-Meier method. A stratified Cox model adjusted for prognostic factors including age, sex, World Health Organization performance status, tumor stages, tumor grade, and tumor sidedness to control for potential confounding effects.

Of the overall study population, 52.4% had DWT tumors, 36.2% had a KRAS exon 2 mutation, and 11.4% had a BRAF V600E mutation. Additionally, 7492 patients had MSS disease, which included DWT tumors in 53.8%, KRAS mutations in 38.6%, and BRAF V600E mutations in 7.7%. Of 968 patients with MSI-H tumors, 41.3% were DWT, 18.1% harbored a KRAS mutation, and 40.6% were BRAF V600E mutant.

Of patients with KRAS-mutated, MSS tumors (n = 2889), most were p.G12D (32.4%), p.G12V (21.3%), p.G13D (20.8%), and p.G12C (9.3%). Additionally, most KRAS mutant MSI-H tumors (n = 175) were p.G13D (42.9%), p.G12D (36.0%), p.G12V (6.9%), and p.G12C (2.3%).

According to the investigators, codon 12 alterations, p.G13D mutations, and BRAF V600E mutations conferred worse TTR and OS for patients with MSS tumors. However, the differences in OS were not statistically significant for patients with p.G12V (P = .057). Additionally, p.G12C, p.G12D, p.G13D, and BRAF V600E mutations were related to worse SAR.

Reference

Taieb J, Sinicrope FA, Pederson L, et al. Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials. Published online August 22, 2023. doi:10.1016/j.annonc.2023.08.006