RESUMO
PURPOSE: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy. EXPERIMENTAL DESIGN: Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome. RESULTS: One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with "early molecular response" (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with "early molecular progression" (increase in trunk and/or increase in resistant mutations). CONCLUSIONS: ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations. See related commentary by Eluri et al., p. 302.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Prospectivos , Resultado do Tratamento , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Biópsia Líquida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
JAK2V617F allele burden was prospectively measured in polycythemia vera (PV, n=52) and essential thrombocythemia (ET, n=39) patients receiving hydroxycarbamide (HC) and analyzed according to JAK2 46/1 haplotype and genotype of SLC14A1, SLC14A2 and ARG2 urea transporters. Molecular response (MR) was obtained in 68.7% and 38.9% of PV patients with GG and AA or GA genotype in SLC14A2, respectively (p=0.07). No significant differences were observed neither in PV nor in ET according to JAK2 46/1 haplotype, SLC14A1 and ARG2. In conclusion, JAK2 46/1 haplotype does not influence MR in HC treated patients and urea transporters polymorphisms display a minimal effect.