Clinical Features and Outcomes of Patients with Colorectal Cancers Harboring NRAS Mutations

Abstract

Purpose NRAS mutations are now routinely included in RAS testing prior to EGFR (epidermal growth factor receptor) inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS mutant mCRC. Experimental Design We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008–2015. Comparison groups consisted of RAS wild-type and KRAS mutant mCRC consecutive cases genotyped from 2008–2012. Results Three percent (87/2764) of mCRC patients had NRAS mutant tumors (45% exon 2, 55% exon 3), including three cases with concurrent NRAS and KRAS mutations. Left-sided primary site and African-American self-reported race were associated with NRAS mutation (p<0.01). Resection rate at 12 months was lower for NRAS mutant mCRC than for RAS wild-type or KRAS mutant mCRC. Median survival from time of first known metastasis was 33 months for NRAS mutant, 47 months for KRAS mutant, and 78 months for RAS wild-type cases (p<0.001). Multivariate analysis assigned a hazard ratio for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (p<0.01). Conclusions NRAS defines a molecular subset with distinct clinical characteristics from KRAS mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans. Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS mutant or wild-type mCRC.

Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies

“…Furthermore, among different codon or other alterations, KRAS G12V, KRAS G13D and KRAS amplification correlated with poor OS when compared to patients with RAS wild‐type (HR: 1.64, 95% CI: 1.18–2.30, p = 0.004, HR: 2.07, 95% CI: 1.27–3.38, p = 0.004 and HR: 1.88, 95% CI: 1.09–3.24, p = 0.02, respectively [multivariate]; Table ). Our findings are consistent with previous reports indicating that varied RAS alterations do not all have the same impact . Distinct clinical outcomes may be attributable to dissimilar degrees of GTP‐binding ability among RAS anomalies, thus leading to a differential impact on downstream signaling and effectors .…”

“…Clinically, evaluation of RAS alteration status is routinely done for patients with metastatic colorectal cancer since their presence predicts lack of response to anti‐EGFR therapies (cetuximab and panitumumab). The presence of RAS alterations has also been associated with significantly worse overall survival (OS) among lung, colorectal and pancreatic cancers when compared to patients with wild‐type RAS …”

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy

“…The study by Cercek et al. described NRAS mutations enriched in left‐sided primary tumors and among African Americans conferring a poor survival and worse outcomes than either KRAS‐mutant or wild‐type mCRC . Interestingly in our study, all NRAS mutations were accompanied by other co‐mutations (Table ).…”

“…Interestingly in our study, all NRAS mutations were accompanied by other co‐mutations (Table ). In contrast with these results, in our series, three of the cases with NRAS mutations were found in patients with CRC diagnosed in the right colon and only one in the left side …”

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

“…Colorectal cancer is one of the most extreme cases, with mutations in KRAS being detected in 35-50% of the cases 13 , including even distribution across all tumorigenic stages 14 . In contrast, mutations in NRAS are only identified in 3-5% of mCRC patients and predominantly in malignant CRCs [13][14][15] , while HRAS mutations are virtual absent 12 . Moreover, the relative mutation frequency at hotspot locations differs between RAS isoforms, with G12 and G13 mutations most often detected in KRAS (combined 90%) and Q61 mutations frequently found in NRAS (57%) 16 .…”