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

Purpose: Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with wild-type (-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with mutation (-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was -wt.

Materials And Methods: The occurrence of Kirsten rat sarcoma viral oncogene homolog (), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (), and mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed -mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with -wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with -mt ctDNA were treated with the oncologist's choice of therapy.

Results: 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 -mt in seven patients (44%) and -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 -wt ctDNA and 17.9% for those with -mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.

Conclusion: Patients with -mt mCRC whose plasma biopsies contained -wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.