Yu Sunakawa1, Dongyun Yang2, Shu Cao2, Wu Zhang3, Miriana Moran4, Stephanie H Astrow5, Jack Hsiang4, Craig Stephens4, Akihito Tsuji6, Takehiro Takahashi7, Hiroaki Tanioka8, Yuji Negoro9, Akinori Takagane10, Satoshi Tani11, Tatsuro Yamaguchi12, Tetsuya Eto13, Masashi Fujii14, Wataru Ichikawa7, Heinz-Josef Lenz3. 1. Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. Electronic address: y.suna0825@gmail.com. 2. Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA. 3. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA. 4. R&D and Pharmaceutical Services, Cancer Genetics, Inc, Los Angeles, CA. 5. Kite, a Gilead Company, Santa Monica, CA. 6. Department of Clinical Oncology, Kagawa University Faculty of Medicine Cancer Center, Kagawa University Hospital, Kita-gun, Kagawa, Japan. 7. Division of Medical Oncology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan. 8. Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan. 9. Department of Oncological Medicine, Kochi Health Sciences Center, Kochi, Kochi, Japan. 10. Department of Surgery, Hakodate Goryoukaku Hospital, Hakodate, Hokkaido, Japan. 11. Department of Internal Medicine, Konan Hospital, Kobe, Hyogo, Japan. 12. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. 13. Division of Gastroenterology, Tsuchiura Kyodo General Hospital, Tsuchiura, Ibaraki, Japan. 14. Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
Abstract
BACKGROUND: Few clinical studies have investigated the association between neutrophil-lymphocyte ratio (NLR) and treatment with cetuximab-based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune-related genes affect the NLR remain unclear. PATIENTS AND METHODS: In 77 patients with KRAS exon2 wild-type mCRC from prospective trials of first-line chemotherapy with cetuximab, expression levels of 354 immune-related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2-sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR-low and NLR-high groups among all measured genes. RESULTS: NLR data were available for 71 patients. The NLR was associated with progression-free survival and overall survival (r = -0.24; P = .040 and r = -0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan-Meier curve of NLR-low versus NLR-high differed significantly for both progression-free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2-sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR-low and NLR-high groups (t test P-value < .005; false discovery rate P-value < .15). CONCLUSION: NLR is significantly associated with survival in patients with mCRC treated with first-line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR.
BACKGROUND: Few clinical studies have investigated the association between neutrophil-lymphocyte ratio (NLR) and treatment with cetuximab-based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune-related genes affect the NLR remain unclear. PATIENTS AND METHODS: In 77 patients with KRAS exon2 wild-type mCRC from prospective trials of first-line chemotherapy with cetuximab, expression levels of 354 immune-related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2-sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR-low and NLR-high groups among all measured genes. RESULTS: NLR data were available for 71 patients. The NLR was associated with progression-free survival and overall survival (r = -0.24; P = .040 and r = -0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan-Meier curve of NLR-low versus NLR-high differed significantly for both progression-free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2-sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR-low and NLR-high groups (t test P-value < .005; false discovery rate P-value < .15). CONCLUSION: NLR is significantly associated with survival in patients with mCRC treated with first-line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR.
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