The following is a summary of “Acquired Genomic Alterations on First-Line Chemotherapy With Cetuximab in Advanced Colorectal Cancer: Circulating Tumor DNA Analysis of the CALGB/SWOG-80405 Trial (Alliance),” published in the January 2023 issue of Oncology by Raghav, et al.

In metastatic colorectal cancer (mCRC), acquired genomic alterations (Acq-GAs), including RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications, were identified as important causes of resistance to anti-EGFR-antibody treatment. However, there was a dearth of information surrounding the development of these Acq-GAs in response to the selective pressure of first-line anti-EGFR treatment. 

For a study, researchers used next-generation sequencing (Guardant360) to analyze circulating tumor DNA from matched plasma samples from the CALGB/SWOG-80405 study, which randomly allocated patients with metastatic colorectal cancer to receive bevacizumab (anti–VEGF-chemotherapy) or cetuximab (anti–EGFR-chemotherapy) as their first-line chemotherapy. The main goal was to quantify the prevalence of Acq-GAs associated with anti-EGFR chemotherapy and compare it to published prevalences for anti-VEGF chemotherapy on trial and pooled estimates (N = 292) associated with later-line anti-EGFR antibody treatment. 

In contrast to 10.1% (7) on anti-VEGF chemotherapy (odds ratio, 0.62; 95% CI, 0.20 to 2.11) and 62.0% on anti-EGFR-antibody treatment in later lines (odds ratio, 0.09; 95% CI, 0.03 to 0.23), only four (6.6%) of the 61 patients receiving anti-EGFR chemotherapy developed ≥1 Acq-GAs of interest. Acq-GAs, which are often linked to anti-EGFR antibody resistance in later lines (RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications), were uncommon, indicating distinct resistance mechanisms, when anti-EGFR treatment was used upfront. 

The results had significant translational implications for the timing and benefit of circulating tumor DNA-guided anti-EGFR rechallenge in mCRC patients, particularly in those who had already received anti-EGFR treatment.

Reference: ascopubs.org/doi/full/10.1200/JCO.22.00365