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Poster display session

2479 - Tumor sidedness and enriched gene groups for efficacy of 1st-line cetuximab (cet) treatment in metastatic colorectal cancer (mCRC)

Date

09 Sep 2017

Session

Poster display session

Presenters

Wataru Ichikawa

Citation

Annals of Oncology (2017) 28 (suppl_5): v158-v208. 10.1093/annonc/mdx393

Authors

W. Ichikawa1, K. Mogushi2, H. Lenz3, W. Zhang3, A. Tsuji4, T. Takahashi5, T. Denda6, K. Shimada7, M. Kochi8, M. Nakamura9, M. Kotaka10, Y. Segawa11, B. Lafleur12, J. Luecke12, D. Thompson12, M. Moran13, S.H. Astrow14, J. Hsiang13, M. Fujii8, Y. Sunakawa15

Author affiliations

  • 1 Department Of Medical Oncology, Showa University Fujigaoka Hospital, 227-8501 - Yokohama/JP
  • 2 Intractable Disease Research Center, Juntendo University School of Medicine, Tokyo/JP
  • 3 Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 4 Department Of Clinical Oncology, Kagawa University Faculty of Medicine, Miki/JP
  • 5 Department Of Medical Oncology, Showa University Hospital, Tokyo/JP
  • 6 Division Of Gastroenterology, Chiba Cancer Center, 260-8717 - Chiba/JP
  • 7 Department Of Medical Oncology, Showa University Koto Toyosu Hospital, Tokyo/JP
  • 8 Department Of Digestive Surgery, Nihon University School of Medicine, Tokyo/JP
  • 9 Aizawa Comprehensive Cancer Center, Aizawa Hospital, 390-8510 - Matsumoto/JP
  • 10 Gastrointestinal Cancer Center, Sano Hospital, Kobe/JP
  • 11 Department Of Medical Oncology, Saitama Medical University International Medical Center, Hidaka/JP
  • 12 Biostatistics And Bioinformatics, HTG Molecular Diagnostics, Inc., 85706 - Tucson/US
  • 13 Pharmaceutical Services, Cancer Genetics, Inc., 90033 - Los Angeles/US
  • 14 Vitro Diagnostics, Kite Pharma, Inc., 90404 - Santa Monica/US
  • 15 Medical Oncology, Showa University Northern Yokohama Hospital, 224-8503 - Yokohama/JP
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Resources

Abstract 2479

Background

Primary tumor location (PTL) has been shown to be not only a prognostic but also predictive factor for 1st-line cet treatment in mCRC. Molecular differences between PTLs may contribute the sidedness-specific response to cet. We investigated genes associated with efficacy of cet treatment depending on tumor sidedness.

Methods

We enrolled 77 patients (pts) (57% males, median 63-y old, and 15% right-colon cancer) with KRAS exon 2 wild-type tumors from the JACCRO CC-05 or CC-06 trial of 1st-line therapy with cet plus FOLFOX or SOX, respectively. All pts’ tissues were measured for expression levels of 2500 genes by HTG EdgeSeq Oncology Biomarker Panel using next generation sequencing for quantitative analysis of targeted RNAs. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted for all genes that passed QC filtering in each sidedness (left [L]/right [R]) to assess the association with clinical outcomes. Further univariate Cox regression analysis was performed to define an optimal cutoff point for significant genes. Also, we performed a gene set enrichment analysis (GSEA) to identify classes of genes associated with outcomes in each side. Tumors proximal or from L flexure to rectum were defined as R-sided or L-sided, respectively.

Results

Sixty-nine of 77 pts were assessable for gene expression data. NOTCH1 high-expression (log2(CPM) ≥ 7.5) predicted significant longer progression-free survival (PFS) (median 14.7 vs. 11.1 m, HR 0.43, 95%CI 0.22-0.81, P = 0.01) and overall survival (OS) (median 42.8 vs. 26.5 m, HR 0.35, 95%CI 0.15-0.79, P = 0.01) in pts with L-sided tumor (n = 60) but not in R-sided tumor (n = 9).The GSEA showed that gene set of inflammatory response correlated with better PFS in both sides. The regulation of DNA replication gene set was associated with favorable OS but no gene set correlated with bad OS in L-side. Several types of gene set were identified to predict better or worse outcomes in R-side.

Conclusions

Our data suggest that gene expression signatures may explain differences in cet efficacy dependent on tumor sidedness. NOTCH1 may potentially discriminate favorable responders to cet in pts with L-sided tumors.

Clinical trial identification

UMIN000024954, Nov/24/2016

Legal entity responsible for the study

Japan Clinical Cancer Research Organization: JACCRO

Funding

Japan Clinical Cancer Research Organization: JACCRO

Disclosure

W. Ichikawa: Consulting role from Daiichi Sankyo, Zeria Pharmaceutical, Ono Pharmaceutical. Honoraria from Merck Serono, Taiho Pharmaceutical, Chugai Pharma and Takeda. Research Funding from Takeda, Taiho, Eisai, Merck Serono, Ono, Chugai and Shionogi. H-J. Lenz: Advisory role from Merck Serono, Roche, Bayer, and Pfizer. Travel expenses from Merck Serono, Bayer, and Roche. Honoraria from Merck Serono, Roche, Bayer, and Boehringer-Ingelheim. A. Tsuji: Speakers\' Bureau from Chugai Pharma, Taiho Pharmaceutical, Takeda and Merck Serono. Honoraria from Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, Merck Serono, Takeda and Bristol-Myers Squibb Japan. M. Nakamura: Honoraria from Merck Serono, Taiho Pharmaceutical, Yakult Honsha. M. Kotaka: Honoraria from Chugai Pharma, Yakult Honsha, Daiichi Sankyo, and Merck Serono. Y. Segawa: Honoraria from Taiho Pharmaceutical, Eisai, Novartis and Mochida Pharmaceutical Co. Ltd. Research Funding from Taiho Pharmaceutical, Bayer Yakuhin, PAREXEL, GlaxoSmithKline K.K., Daiichi Sankyo and AstraZeneca Japan. Y. Sunakawa: Honoraria from Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Takeda, and Merck Serono. All other authors have declared no conflicts of interest.

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