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

Mohamed Bouchahda; Raphael Saffroy; Abdoulaye Karaboué; Jocelyne Hamelin; Pasquale Innominato; Faouzi Saliba; Francis Lévi; Nelly Bosselut; Antoinette Lemoine

doi:10.1200/PO.19.00400

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

JCO Precis Oncol. 2020 Sep 16:4:PO.19.00400. doi: 10.1200/PO.19.00400. eCollection 2020.

Authors

Mohamed Bouchahda^{1

2}, Raphael Saffroy³, Abdoulaye Karaboué^{4

5}, Jocelyne Hamelin³, Pasquale Innominato^{4

6

7}, Faouzi Saliba⁸, Francis Lévi^{1

4

7}, Nelly Bosselut³, Antoinette Lemoine³

Affiliations

¹ Medical Oncology Department, Paul Brousse Hospital, Villejuif, France.
² Medical Oncology Unit, Clinique du Mousseau, Evry, France.
³ Oncogenetics Department, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Université Paris-Saclay, Villejuif, France.
⁴ French National Institute for Health and Medical Research (INSERM), Unit 935, Villejuif, France.
⁵ Medical Oncology Unit, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France.
⁶ North Wales Cancer Centre, Ysbyty Gwynedd, Betsi Cadwaladr University Health Board, Bangor, United Kingdom.
⁷ Cancer Chronotherapy Team, Cancer Research Centre, Division of Biomedical Sciences, Warwick Medical School, Coventry, United Kingdom.
⁸ Centre Hépato Biliaire, Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France.

Abstract

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

Materials and methods: The occurrence of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (BRAF), and PI3KCA mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed RAS-mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with RAS-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with RAS-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 RAS-mt in seven patients (44%) and RAS-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 RAS-wt ctDNA and 17.9% for those with RAS-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.

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