Satoshi Tani

Prognostic Impact of Primary Tumor Location on Clinical Outcomes of Metastatic Colorectal Cancer Treated With Cetuximab Plus Oxaliplatin-Based Chemotherapy: A Subgroup Analysis of the JACCRO CC-05/06 Trials

Introduction: Primary tumor location is a critical prognostic factor in metastatic colorectal cancer (mCRC); however, it remains unclear whether tumor location is a predictor of the response to cetuximab treatment. It is also uncertain if BRAF mutation contributes to the impact of tumor location on survival. We assessed the prognostic impact of tumor location on clinical outcomes in mCRC patients treated with first‐line cetuximab chemotherapy. Patients and Methods: The associations of tumor location with overall survival and progression‐free survival were evaluated in mCRC patients with KRAS exon 2 wild‐type tumors who were enrolled onto 2 clinical trials: JACCRO CC‐05 of cetuximab plus FOLFOX (n = 57, UMIN000004197) and CC‐06 of cetuximab plus SOX (n = 61, UMIN000007022). Tumors proximal or from splenic flexure to rectum were defined as right‐sided or left‐sided, respectively. In addition, exploratory RAS and BRAF mutation analyses were performed. Results: A total of 110 patients were assessable for tumor location; 90 had left‐sided tumors. Left‐sided tumors were significantly associated with longer overall survival (36.2 vs. 12.6 months, hazard ratio = 0.28, P < .0001) and progression‐free survival (11.1 vs. 5.6 months, hazard ratio = 0.47, P = .0041) than right‐sided tumors; similar results were obtained in multivariate analysis. A subanalysis showed that the association was evident in the FOLFOX group and that tumor location was an independent prognostic factor irrespective of BRAF status in RAS wild‐type patients. Conclusion: Primary tumor location might be a predictor of survival independent of BRAF status in mCRC patients who receive first‐line cetuximab combined with oxaliplatin‐based chemotherapy. &NA; Primary tumor location is a prognostic factor in metastatic colorectal cancer (mCRC). We assessed the prognostic impact of tumor location on survival and the association between BRAF mutation and tumor sidedness in mCRC patients treated with cetuximab. Tumor location is a prognostic marker for first‐line cetuximab plus oxaliplatin‐based chemotherapy, irrespective of BRAF status.

Immune-related Genes to Dominate Neutrophil-lymphocyte Ratio (NLR) Associated With Survival of Cetuximab Treatment in Metastatic Colorectal Cancer

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. Micro‐Abstract Our study, using data of prospective trials, demonstrated that the neutrophil‐lymphocyte ratio (NLR) was associated with survival time in patients with KRAS wild‐type metastatic colorectal cancer treated with first‐line chemotherapy with cetuximab. The expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR‐low and NLR‐high groups. Genes encoding for activities on macrophages may affect the NLR.