Undetectable <i>RAS</i>-Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients With <i>RAS</i>-Mutant Metastatic Colorectal Cancer.

Abstract

Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with <i>RAS</i> wild-type (<i>RAS</i>-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with <i>RAS</i> mutation (<i>RAS</i>-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was <i>RAS</i>-wt. The occurrence of Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (<i>BRAF</i>), and <i>PI3KCA</i> mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed <i>RAS</i>-mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with <i>RAS</i>-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with <i>RAS</i>-mt ctDNA were treated with the oncologist's choice of therapy. Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified <i>RAS</i>-mt in seven patients (44%) and <i>RAS</i>-wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with <i>RAS</i>-wt ctDNA and 17.9% for those with <i>RAS</i>-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively. Patients with <i>RAS</i>-mt mCRC whose plasma biopsies contained <i>RAS</i>-wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.