Increasing the Mutant Allele Fraction Cutoff in NGS Improved Mutation Detection in mCRC

Increasing the next-generation sequencing (NGS) mutant allele fraction (MAF) sensitivity cutoff to 1% increased the number of KRAS, NRAS, and BRAF mutations detected by 28% in previously untreated patients with metastatic colorectal cancer (mCRC), according to data presented at the 2018 ESMO World Congress on Gastrointestinal Cancer.¹

Optimal treatment of mCRC is best determined after extended RAS and BRAF analysis. The optimal threshold of RAS-mutated subclones has not been identified. The goal of this study was to determine the clinical relevance of using highly sensitive NGS for detecting point mutations in KRAS, NRAS, BRAF, and EGFR corresponding to the S492R variant in tumor tissue.

Tissue samples were collected from retrospective series and clinical trials of patients with untreated mCRC and 380 samples were analyzed by pyrosequencing with the NGS 454 GS Junior platform using both 1% and 5% MAF sensitivity thresholds.

With a MAF sensitivity cutoff of 5%, RAS/BRAF mutations were detected in 50% of patients, with KRAS mutations detected in 40%, NRAS in 7%, and BRAF in 3%. In contrast, with a sensitivity cutoff of 1%, KRAS mutations were detected in 52% of patients, NRAS in 19%, and BRAF in 6%.

Most KRAS mutations occurred within exon 2. NGS did not detect EGFR S492R mutations, regardless of the sensitivity cutoff.

Clinical analyses of outcomes associated with mutations is ongoing he authors concluded that increasing the sensitivity cutoff from 5% to 1% identified 28% more RAS/BRAF mutations.

Read more of Cancer Therapy Advisor‘s coverage of the ESMO World Congress on Gastrointestinal Cancer 2018 meeting by visiting the conference page.

Reference

1. Vidal J, Dalmeses A, Santos Vivas C, et al. Ultra-selection of metastatic colorectal cancer patients using next generation sequencing platform to improve clinical efficacy of anti-EGFR therapy. Ann Oncol. 2018;29 (suppl 5;abstr O-006):v102. doi: 10.1093/annonc/mdy149.005