Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents.

Anna Maria Rachiglio,Claudia Cardone,Erika Martinelli,Evaristo Maiello,Fortunato Ciardiello,Cristin Roma,Matilde Lambiase,Marianeve Carotenuto,Alessia Iannaccone,Francesca Fenizia,Antonella De Luca,Nicola Normanno,Daniela Frezzetti

doi:10.3390/cancers11060859

Abstract

Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the “Cetuximab After Progression in KRAS wild-type colorectal cancer patients” (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs.

Highlights

The median overall survival of patients affected by metastatic colorectal carcinomahas notably increased in the past 20 years, from 12 months using 5-fluorouracil-based chemotherapy to around 20–30 months with combination therapies including target-based agents [1]
We tested the tumor specimens with the Oncomine Comprehensive Panel that provides information on hotspot mutations of 73 oncogenes, copy number variations (CNVs) of 49 genes, full-length sequence of 26 tumor suppressor genes, and sequence of 22 driver gene fusions
The analysis revealed in all 21 patients the presence of at least 1 mutation and in 10/21 (47.6%)

Summary

Introduction

The median overall survival (mOS) of patients affected by metastatic colorectal carcinoma (mCRC)has notably increased in the past 20 years, from 12 months using 5-fluorouracil-based chemotherapy to around 20–30 months with combination therapies including target-based agents [1]. Cancers 2019, 11, 859 agents that block the epidermal growth factor receptor (EGFR), such as the anti-EGFR monoclonal antibodies (MoAbs) cetuximab or panitumumab, are an effective therapeutic option in combination with chemotherapy in mCRC patients [2,3]. Results from different clinical trials suggest that anti-EGFR MoAbs significantly improve survival only in patients with tumors in the left colon [6]. A number of genetic alterations might play a role in the de novo resistance to anti-EGFR agents in mCRC. Single nucleotide variants (SNVs), copy number variations (CNVs) and/or rearrangements in PIK3CA, PTEN, ERBB2, MAP2K1, NTRK1-3, RET, AKT1, ALK, and ROS1, have been claimed to be associated with resistance to anti-EGFR MoAbs [7,8,9,10,11]

Methods

Results

Conclusion