Mitsukuni Suenaga1, Marta Schirripa2, Shu Cao3, Wu Zhang4, Dongyun Yang3, Yan Ning4, Chiara Cremolini5, Carlotta Antoniotti5, Beatrice Borelli5, Tetsuo Mashima6, Satoshi Okazaki4, Martin D Berger4, Yuji Miyamoto4, Roel Gopez4, Afsaneh Barzi4, Sara Lonardi7, Toshiharu Yamaguchi8, Alfredo Falcone5, Fotios Loupakis7, Heinz-Josef Lenz9. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA; Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. 2. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA; Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy. 3. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. 4. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. 5. Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy. 6. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. 7. Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy. 8. Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. 9. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. Electronic address: lenz@med.usc.edu.
Abstract
BACKGROUND: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. PATIENTS AND METHODS: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. RESULTS: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). CONCLUSION: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy.
BACKGROUND: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. PATIENTS AND METHODS: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. RESULTS:CCL4rs1634517 and CCL3rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). CONCLUSION: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy.
Authors: Mitsukuni Suenaga; W U Zhang; Tetsuo Mashima; Marta Schirripa; Shu Cao; Satoshi Okazaki; Martin D Berger; Yuji Miyamoto; Afsaneh Barzi; Toshiharu Yamaguchi; Heinz-Josef Lenz Journal: Cancer Genomics Proteomics Date: 2021 May-Jun Impact factor: 4.069
Authors: Elena De Mattia; Erika Cecchin; Michela Guardascione; Luisa Foltran; Tania Di Raimo; Francesco Angelini; Mario D'Andrea; Giuseppe Toffoli Journal: World J Gastroenterol Date: 2019-08-07 Impact factor: 5.742