Clinical impact of circulating tumor RAS and BRAF mutation dynamics in patients with metastatic colorectal cancer treated with first-line chemotherapy plus anti–epidermal growth factor receptor therapy

Joan Maurel*, Vicente Alonso, Pilar Escudero, Carlos Fernández-Martos, Antonieta Salud, Miguel Méndez, Javier Gallego, Jose Ramon Rodriguez, Marta Martín-Richard, Julen Fernández-Plana, Hermini Manzano, José Carlos Méndez, Montserrat Zanui, Esther Falcó, Mireia Gil-Raga, Jorge Aparicio, Jaime Feliu, Xabier García-Albéniz, Ferràn Torres, Federico RojoBeatriz Bellosillo, Marta Mendiola, Veronica Fernández, Oscar Reig, Bart Claes, Geert Maertens, Erwin Sablon, Bart Jacobs, Clara Montagut

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

PURPOSE RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti–epidermal growth factor receptor therapy. METHODS RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease (P, .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD (P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations (P = .016). CONCLUSION Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti–epidermal growth factor receptor therapy.

Original languageAmerican English
JournalJCO Precision Oncology
Volume3
DOIs
Publication statusPublished - 2019

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