The emergence of RAS mutations in patients with RAS wild-type mCRC receiving cetuximab as first-line treatment: a noninterventional, uncontrolled multicenter study
Menée à partir d'échantillons plasmatiques et d'échantillons tumoraux prélevés sur 108 patients atteints d'un cancer colorectal métastatique avec gène RAS non muté, cette étude analyse la survenue de mutations au niveau du gène RAS durant un traitement de première ligne par cétuximab et examine la corrélation entre le statut de RAS au niveau de l'ADN tumoral circulant et la réponse thérapeutique ainsi que la survie des patients
Background : Patients treated with anti-epidermal growth factor receptor (anti-EGFR) will ultimately develop acquired resistance promoted by clonal selection, mainly the emergence of mutations in the MAPK pathway (mostly RAS mutations). Baseline assessment of RAS mutations in the blood of patients correlates well with RAS tumour tissue testing and is currently an alternative option in routine clinical practice to guide first-line therapy. The aim of this study was the prevalence of acquired genomic alterations detected in the auxiliary tool of ctDNA testing and investigated the role of RAS ctDNA status for detecting tumour response and predicting benefit to anti-EGFR therapy.
Methods : Only patients with concordant wild-type formalin-fixed, paraffin-embedded (FFPE) tumour tissue and baseline ctDNA RAS wild-type were included. RAS mutations in plasma were evaluated using MassARRAY platform. Blood samples were collected at baseline, every 3 months during first-line treatment, and at disease progression. The primary endpoint was the detection rate of RAS mutations during cetuximab treatment. The correlation between response and survival outcomes and the emergence of circulating RAS mutations was also analysed.
Results : The detection rate of RAS mutations during treatment was 9.3% (10/108). RAS mutations detection occurred a median of 3 months prior to radiologic documentation. The subgroup of patients with RAS mutations exhibited significantly inferior progression-free survival and overall survival (P = 0.002 and 0.027, respectively) but the baseline characteristics, response rates, disease control rates, and metastatectomy were not significant (all P > 0.05).
Conclusions : We demonstrated that RAS ctDNA status might be a valuable biomarker for detecting early tumour response and predicting benefit to anti-EGFR therapy.
British Journal of Cancer , article en libre accès, 2023