We conducted a biomarker study to identify significant genes to predict efficacy of cetuximab (cet) based treatment using tumor samples from mCRC patients (pts) enrolled in JACCRO CC-05/06AR (UMIN000010635) and FIRE-3 (NCT00433927), which evaluated 1st-line doublet plus cet therapy. There are no established predictive biomarkers beyond RAS mutations. We reported recently CDX2 gene expression levels as a promising biomarker for cet treatment in KRAS wild-type mCRC pts of the JACCRO trial (ASCO 2016, abst3592). Therefore, we performed the validation study using tumor samples from pts enrolled in the FIRE-3 trial.
We analyzed tissue samples of 77 pts of the JACCRO trial for discovery set and 250 pts of cet arm in the FIRE-3 trial for validation set. Gene expression levels were measured by HTG EdgeSeq Oncology Biomarker Panel, which is comprised of probes targeting 2560 genes implicated in numbers of pathways, using next generation sequencing for quantitative analysis of targeted RNAs. Univariate Cox regression analysis was conducted for all genes that passed QC filtering.
Seventy-one pts (male/female, 39/32; median age, 63 yrs) and 102 pts (male/female, 75/27; median age, 63 yrs) were successful for gene expression analysis in the JACCRO and FIRE-3 set, respectively. The Cox regression analysis identified 24 genes for overall survival (OS) and 8 genes for progression-free survival (PFS), which all were significant (p < 0.005) in the JACCRO set. Among those genes, LYZ and RNF43 genes were found to be significantly associated with OS (coefficients, 0.21; p = 0.013) and PFS (coefficients, -0.20; p = 0.037), respectively, in the FIRE-3 set. In the JACCRO set, high expression (log2>9.07) of CDX2 predicted a significantly longer PFS (p = 0.002). The same effect was found in the FIRE-3 set when applied the same cutoff value (median PFS 10.9 vs. 6.9 months, HR 0.39, 95%CI 0.22-0.72, p = 0.002).
Our biomarker study validated CDX2 as a novel predictor for clinical outcome of 1st-line cet based chemotherapy in mCRC. These data warrant further exploration of CDX2 as a biomarker or as a potential target for drug development.
Clinical trial identification
Legal entity responsible for the study
JACCRO, the National Cancer Institute (grant number P30CA014089), The Gloria Borges WunderGlo Foundation-The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, and Daniel Butler Research Fund.
We acknowledge Sachika Koyama and Yasushi Ohtake (JACCRO) for editorial assistance.
Y. Sunakawa: Honoraria for talks: Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Takeda, Merck Serono, Bayer Yakuhin, Sanofi. S. Stintzing: Consulting or advisory role, travel expenses, honoraria: Merck KGaA. A. Tsuji: Honoraria: Taiho Pharmaceutical, Merck Serono. T. Denda: Honoraria: Yakult Honsha, Taiho Pharmaceutical. K. Shimada: Corporate-sponsored research fee: Yakult Honsha, Taiho Pharmaceutical. M. Takeuchi: Consulting fees: Hisamitsu Pharmaceutical, Kowa, Shionogi Pharma, Abbvie, Astellas. W. Ichikawa: Consulting fees: Ono Pharmaceutical; Research funding: Takeda, Taiho Pharmaceutical, Eisai, Chugai Pharma, Merck Serono, Shionogi Pharma, Daiichi Sankyo; Honoraria: Merck Serono, Taiho Pharmaceutical, Chugai Pharma, Takeda, Ono Pharmaceutical, Lilly. V. Heinemann: Consulting or advisory role, travel expenses, honoraria, research funding: Merck. H-J. Lenz: Consulting or advisory role, travel expenses, honoraria, Merck Serono. All other authors have declared no conflicts of interest.