Abstract
The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.
Highlights
Metastatic Colorectal Cancer is a major burden worldwide, with a 5-year survival rate of about 13% [1,2]
We identified 51 patients carrying actionable gene mutations, as4 ofdefined by Chakravarty et al
Depending on their RAS mutational status, and based on individual features and on the general algorithm described in [14], patients had been treated with first line conventional combination therapy, consisting of FOLFOX/CAPEOX (33 patients), FOLFIRI (22 patients) or FOLFOXIRI (10 patients), associated with monoclonal antibodies-mediated targeting of either EGFR (18 patients) or VEGF
Summary
Metastatic Colorectal Cancer (mCRC) is a major burden worldwide, with a 5-year survival rate of about 13% [1,2]. Standard chemotherapy includes oxaliplatin-based (FOLFOX) and irinotecan-based (FOLFIRI) regimens, which appear equivalent in efficacy and activity [3,4] allowing a median overall survival (OS) of about 18–20 months. A significant therapeutic improvement in the upfront treatment of mCRC can be achieved by a “triplet” approach consisting of 5-FU, platinum and irinotecan-based chemotherapy (FOLFOXIRI) [5]. The addition of targeted drugs, such as monoclonal antibodies directed against VEGF (Bevacizumab) or EGFR (Cetuximab and Panitumumab) have increased the median OS up to 30 months [6,7,8,9]. KRAS and NRAS (RAS) gene mutations confer innate resistance to anti-EGFR therapy [10,11]. Screening for RAS mutations is mandatory for first-line therapeutic decisions.
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