Abstract
Mutations in KRAS (codon 12/13), NRAS, BRAF V600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4, RNF43, and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs.
Highlights
Colorectal cancer (CRC) is one of the most common causes of cancerrelated deaths worldwide [1]
This case report indicates the potential of increased KRAS gene copy numbers (GCN) in primary resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) in patients with CRC
We present a patient with an early onset CRC with an initial diagnosis of moderate-to-poorly differentiated locally advanced rectal adenocarcinoma
Summary
Colorectal cancer (CRC) is one of the most common causes of cancerrelated deaths worldwide [1]. We present a patient with an initial diagnosis of KRASamplified locally advanced rectal adenocarcinoma who demonstrated no clinical response to anti-EGFR MoAb and chemotherapy, and the disease progressed rapidly. This case report indicates the potential of increased KRAS gene copy numbers (GCN) in primary resistance to anti-EGFR MoAb in patients with CRC. The mutation abundance of the three mutant genes was observed using blood-based circulating tumor DNA (ctDNA) analysis: SMAD4 increased from 38.69 to 58.0%, RNF43 increased from 41.25 to 48.03%, and PREX2 increased from 39.22 to 52.99%, after the failure of second-line treatment. The TMB detected in ctDNA was reported as medium level (11.82 mutations/MB) after the failure of second-line therapy
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