Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study.

Kuo-Hsing Chen,Kun-Huei Yeh,Zhong-Zhe Lin,Ho-Min Chen,Yu-Lin Lin,Ann-Lii Cheng,Yu-Yun Shao,Mei-Shu Lai

doi:10.1186/s12885-016-2358-2

Kuo-Hsing Chen, Kun-Huei Yeh + Show 6 more

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https://doi.org/10.1186/s12885-016-2358-2

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Abstract

BackgroundPrevious studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC).MethodsThis study enrolled a cohort of patients, who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type (exon 2 nonmutant) metastatic CRC, from the databases of Taiwan Cancer Registry (2004–2010) and National Health Insurance (2004–2011). Survival data were obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after the start of cetuximab treatment were compared between patients with LCRC (splenic flexure to rectum) and RCRC (cecum to hepatic flexure).ResultsA total of 969 CRC patients were enrolled. Among them, 765 (78.9 %) and 136 (14.0 %) patients had LCRC and RCRC, respectively. Patients with LCRC, compared to patients with RCRC, had longer TTD (median, 4.59 vs. 2.75 months, P = .0005) and OS (median, 12.62 vs. 8.07 months, P < .0001) after the start of cetuximab treatment. Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD (adjusted hazard ratio [HR] = 1.32, using the LCRC group as a reference, 95 % confidence interval: 1.08–1.61, P = .0072) and OS (adjusted HR = 1.45, 95 % CI: 1.18–1.78, P = .0003).ConclusionOur findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 nonmutant) metastatic CRC.

Highlights

Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features
A total of 58 736 patients with a newly diagnosed CRC were identified from the Taiwan Cancer Registry (TCR) database; among them, 969 patients met the inclusion criteria and were enrolled in this study (Fig. 1)
Patients with a primary site of cancer at the transverse colon or an unspecified site were excluded from survival analysis

Summary

Introduction

Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC). Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), either used alone, or a combination with cytotoxic agents have been demonstrated to prolong survival in patients with metastatic colorectal cancer (CRC) harboring KRAS wild-type or expanded RAS [1,2,3,4,5,6]. Not all patients experienced clinical benefits of the anti-EGFR antibody treatment These studies have emphasized the importance of additional predictive biomarkers for anti-EGFR antibody treatment. Some predictive biomarkers, such as the gene expression of EGFR ligands, have been reported to correlate with patient responses after the anti-EGFR antibody treatment [7, 8]. The negative predictive roles of expanded RAS [KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4)] have been well established, but other biomarkers, including BRAFV600E mutation, amplification of KRAS, MET, and ERBB2, and cross-talk with PI3K/Akt/PETN,, still remain to be investigational [5, 6, 9,10,11,12,13,14,15,16,17]

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