KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy

Abstract

Mutations in RAS occur in 30–50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS , NRAS , HRAS , BRAF and PIK3CA . Molecular testing was performed on 1,286 consecutive mCRC from 1,271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS , NRAS and HRAS for 15, 5 and 2 cases, respectively (6 to 21 gene copies). Patients with a KRAS -amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology and MMR proficiency (p ≤ 0.017). Four patients with a KRAS -amplified mCRC and no concomitant RAS / BRAF / PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS -amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS -amplified mCRCs is limited, our data suggests the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

“…Another retrospective study by Favazza et al (11) reported that all eight patients with KRASamplified mCRC showed disease progression at the time of anti-EGFR therapy, and they concluded that KRAS amplification is responsible for the primary resistance to EGFR inhibitors. Meanwhile, RAS amplifications (involving KRAS, NRAS, and HRAS) were correlated with a younger median patient age at initial diagnosis and a history of inflammatory bowel disease (11). In the present case, KRAS amplification was present before chemotherapy, resulting in resistance to cetuximab.…”

“…KRAS amplification in CRC is a rare event, with an overall prevalence of 0.67–2% ( 11 , 12 ). Previous studies have identified somatic mutations in KRAS as biomarkers for inherent resistance to EGFR-targeted drugs in patients with CRC ( 13 ), with a positive tissue mutation rate of 32–52.1% ( 7 ).…”

Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology

“…KRAS is part of the RAS/MAPK pathway, a signalling pathway that plays a prominent role in cell proliferation and differentiation. This oncogene has long been found to be mutated, and more recently, amplified, in various types of human cancers, such as colorectal and lung cancer [35][36][37][38][39][40]. Even though RAS mutations are rare in human HCC, RAS activation occurs despite the absence of its mutation [41].…”

Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma

“…The mutual exclusivity of EGFR amplification and KRAS mutations has been described in lung adenocarcinoma and colorectal carcinoma (CRC) and co-expression caused cytotoxic effect on cells 39 , 40 . Even though the incidence of KRAS amplification compared to its mutation is low, such as less than10% of patients with gastric cancer or CRC and 17% in EAC, clinical features of patients with KRAS amplification are distinct, and the amplification is usually associated with poor prognosis in these patients 41 – 44 . The oncogenic effect of wild type KRAS amplification is mediated through the increased receptor tyrosine kinase-dependent activation of the Ras pathway in CRC 45 .…”

“…Like in gastric cancer, EAC, and CRC patients, KRAS amplification is associated with worse survival in ESCC patients 38 . Similar to mutant KRAS , wild type KRAS amplification confers EGFR inhibitor resistance 41 . Therefore, ESCC patients may benefit from detailed EGFR profiling and determination of tumor KRAS amplification status before targeted therapies.…”