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

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.

Characteristics of Differently Located Colorectal Cancers Support Proximal and Distal Classification: A Population-Based Study of 57,847 Patients

“…The predictive value of primary tumor location in survival among patients with metastatic CRC was confirmed in several latest studies[25–28]. Chen et al revealed that right-sided tumor site was an independent predictor of shorter PFS (HR = 1.32, P = 0.0072) and OS (HR = 1.45, P = 0.0003) among 969 patients with KRAS wild-type CRC receiving Cetuximab therapy treatment[26]. In agreement with it, Moretto et al’s study indicated that patients with right-sided RAS and BRAF wild-type metastatic CRC derived no benefit from single Cetuximab therapy (p<0.0001) [27].…”

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

“…The Role of Primary Tumor Sidedness: A growing body of data has shown that the location of the primary tumor can be both prognostic and predictive of response to EGFR inhibitors in metastatic CRC. [118][119][120][121][122][123][124][125] For example, outcomes of 75 patients with metastatic CRC treated with cetuximab, panitumumab, or cetuximab/irinotecan in first-line or subsequent lines of therapy at 3 Italian centers were analyzed based on sidedness of the primary tumor. 119 No responses were seen in the patients with rightsided primary tumors, compared with a response rate of 41% in those with left-sided primaries (P=.003).…”

“…118,119,121,122 The panel believes that primary tumor sidedness is a surrogate for the nonrandom distribution of molecular subtypes across the colon and that the ongoing analysis of tumor specimens from the study will enable a better understanding of the biologic explanation of the observed difference in response to EGFR inhibitors. Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease.…”

“…Until that time, only patients whose primary tumors originated on the left side of the colon (splenic flexure to rectum) should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease. Evidence also suggests that sidedness is predictive of response to EGFR inhibitors in subsequent lines of therapy, 118,119,122 but the panel awaits more definitive studies. Until such data are available, all patients with RAS wild-type tumors can be considered for panitumumab or cetuximab in subsequent lines of therapy if neither was previously given.…”

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

“…Hypermethylation of the promoter regions of the ligands in CMS1 subtypes of CRC is demonstrated to be associated with the downregulation of some other genes. For instance, overexpressed epidermal growth factor receptor (EGFR) and insulin receptor substrate 2 are also known to occur in distal carcinomas particularly the CMS2 phenotype (K. H. Chen et al, 2016). CMS1 subgroup of CRC tumors displays a diffused immune infiltrate, expression of Th1 cytokines which is associated with good prognosis in CRC.…”