Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer

Abstract

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log 2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cutoff point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assess-able for gene expression data. Overexpression of BECN1 [log 2 (CPM) ! 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log 2 (CPM) ! 7.5] predicted significantly longer progressionfree survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P ¼ 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P ¼ 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors. Mol Cancer Ther; 17(12); 2788-95. Ó2018 AACR.

Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment

“…(25) Although the reasons for the different outcomes according to PTL remain unclear, different molecular profiles related to sensitivity or resistance to anti-EGFR antibodies could be responsible. (26,27) In the CORRELATE and our study, most patients with RAS wild-type had already been treated with anti-EGFR therapy. A possible explanation for the difference in the prognostic value of PTL among studies is whether the anti-EGFR therapy-naive and RAS wild-type/leftsided patients, who would benefit more from anti-EGFR therapy, were included or not.…”