Impact of <i>RAS</i> and <i>BRAF</i> heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.

255 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS or BRAF mutations in their primary tumors but did have them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS or BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy. RAS, BRAF (V600E), and PIK3CA mutations were detected using digital PCR. Results: One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 12, 4, and 6 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations and one had both RAS and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with RAS or BRAF mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with RAS or BRAF mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS. Conclusions: Previously, we reported that the incidence of RAS and BRAF heterogeneity were 10% (1) and 4% (2). In the present study, RAS and BRAF heterogeneity were 12% and 4%, respectively. The heterogeneity of RAS and BRAF mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022. Clinical trial information: UMIN000031177 .