ABSTRACT
Currently, clinicopathologic characteristics of colon cancer tumors guide the selection of patients suitable for adjuvant therapy. Circulating tumor DNA (ctDNA) analysis after surgery has a strong correlation with prognosis, and positive ctDNA status defines a subset of patients with high risk of recurrence. Ongoing interventional adjuvant trials in colon cancer including ctDNA analyses will determine the predictive value of ctDNA in the adjuvant setting. For patients with stage III colon cancer, noninferiority of 3 months of adjuvant therapy compared with 6 months has not been demonstrated. However, for selected subgroups, the shorter duration of therapy may limit toxic effects without impairing clinical outcomes.
Subject(s)
Circulating Tumor DNA , Colonic Neoplasms , Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant , Circulating Tumor DNA/genetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/therapy , Humans , Neoplasm Recurrence, Local/pathologyABSTRACT
AIM: To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer. EXPERIMENTAL DESIGN: In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. RESULTS: Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044). CONCLUSION: Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.