Cancer Medicine
Open Access
ORIGINAL RESEARCH
Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy Kjetil Boye1,2, Havjin Jacob3, Kari-Anne M. Frikstad1, Jahn M. Nesland4,5, Gunhild M. Mælandsmo1,6, Olav Dahl3,7, Arild Nesbakken5,8,9,10 & Kjersti Flatmark1,5,11 1Department
of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 3Section for Oncology, Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway 4Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 5Medical Faculty, University of Oslo, Oslo, Norway 6Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway 7Department of Oncology and Radiophysics, Haukeland University Hospital, Bergen, Norway 8K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway 9Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway 10Department of Gastroenterological Surgery, Ullevål Hospital, Oslo University Hospital, Oslo, Norway 11Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 2Department
Keywords 5-fluorouracil, adjuvant chemotherapy, colorectal cancer, prognostic factor, S100A4 Correspondence Kjetil Boye, Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953 Nydalen, NO-0424 Oslo, Norway. Tel: +4722781852; Fax: +4722781895; E-mail: [email protected] Funding Information This work was supported by the Legacy for Cancer Research, the Henrik Homan Memorial Legacy, the Western Norway Regional Health Authority, and the Norwegian Cancer Society. Received: 18 January 2016; Revised: 6 April 2016; Accepted: 8 April 2016 Cancer Medicine 2016; 5(8):1840–1849 doi: 10.1002/cam4.766
Abstract Current clinical algorithms are unable to precisely predict which colorectal cancer patients would benefit from adjuvant chemotherapy, and there is a need for novel biomarkers to improve the selection of patients. The metastasis-promoting protein S100A4 predicts poor outcome in colorectal cancer, but whether it could be used to guide clinical decision making remains to be resolved. S100A4 expression was analyzed by immunohistochemistry in primary colorectal carcinomas from a consecutively collected, population-representative cohort and a randomized phase III study on adjuvant 5-fluorouracil/levamisole. Sensitivity to treatment with 5-fluorouracil in S100A4 knockdown cells was investigated using 2D and 3D cell culture assays. Strong nuclear expression of S100A4 was detected in 19% and 23% of the tumors in the two study cohorts, respectively. In both cohorts, nuclear immunoreactivity was associated with reduced relapse- free (P 66%) strongly positive. For study cohort 2, immunoreactivity was scored as negative, moderate, and strong according to the criteria defined through analysis of cohort 1, and dichotomized as negative/moderate and strong for all analyses. Evaluation was performed by two independent observers (H. J. and J. M. N.). 1841
S100A4 Expression in Colorectal Cancer
Statistical analysis Associations between S100A4 staining and clinicopathological variables were tested using Fisher’s exact test, linear-by-linear association chi-square test, or independent samples t test as appropriate. Univariate survival analysis was performed according to the Kaplan–Meier method, and survival was compared using the log rank test. Multivariate analysis was conducted using the Cox proportional hazards regression model with backward, stepwise elimination of variables. The time from surgery (cohort 1) or randomization (cohort 2) to diagnosis of distant or local recurrence was recorded as relapse-free survival. Patients were censored at death of any cause or when lost to follow-up. Overall survival was defined as the time from surgery or randomization to death of any cause. Median follow- up for overall survival for patients still alive was 9.7 years for cohort 1 (range 5.2–17.3) and 7.6 years (range 4.9–11.0) for cohort 2. Data analysis was performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). All P values are two-tailed and considered significant when P
Open Access
ORIGINAL RESEARCH
Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy Kjetil Boye1,2, Havjin Jacob3, Kari-Anne M. Frikstad1, Jahn M. Nesland4,5, Gunhild M. Mælandsmo1,6, Olav Dahl3,7, Arild Nesbakken5,8,9,10 & Kjersti Flatmark1,5,11 1Department
of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 3Section for Oncology, Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway 4Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 5Medical Faculty, University of Oslo, Oslo, Norway 6Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway 7Department of Oncology and Radiophysics, Haukeland University Hospital, Bergen, Norway 8K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway 9Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway 10Department of Gastroenterological Surgery, Ullevål Hospital, Oslo University Hospital, Oslo, Norway 11Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 2Department
Keywords 5-fluorouracil, adjuvant chemotherapy, colorectal cancer, prognostic factor, S100A4 Correspondence Kjetil Boye, Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953 Nydalen, NO-0424 Oslo, Norway. Tel: +4722781852; Fax: +4722781895; E-mail: [email protected] Funding Information This work was supported by the Legacy for Cancer Research, the Henrik Homan Memorial Legacy, the Western Norway Regional Health Authority, and the Norwegian Cancer Society. Received: 18 January 2016; Revised: 6 April 2016; Accepted: 8 April 2016 Cancer Medicine 2016; 5(8):1840–1849 doi: 10.1002/cam4.766
Abstract Current clinical algorithms are unable to precisely predict which colorectal cancer patients would benefit from adjuvant chemotherapy, and there is a need for novel biomarkers to improve the selection of patients. The metastasis-promoting protein S100A4 predicts poor outcome in colorectal cancer, but whether it could be used to guide clinical decision making remains to be resolved. S100A4 expression was analyzed by immunohistochemistry in primary colorectal carcinomas from a consecutively collected, population-representative cohort and a randomized phase III study on adjuvant 5-fluorouracil/levamisole. Sensitivity to treatment with 5-fluorouracil in S100A4 knockdown cells was investigated using 2D and 3D cell culture assays. Strong nuclear expression of S100A4 was detected in 19% and 23% of the tumors in the two study cohorts, respectively. In both cohorts, nuclear immunoreactivity was associated with reduced relapse- free (P 66%) strongly positive. For study cohort 2, immunoreactivity was scored as negative, moderate, and strong according to the criteria defined through analysis of cohort 1, and dichotomized as negative/moderate and strong for all analyses. Evaluation was performed by two independent observers (H. J. and J. M. N.). 1841
S100A4 Expression in Colorectal Cancer
Statistical analysis Associations between S100A4 staining and clinicopathological variables were tested using Fisher’s exact test, linear-by-linear association chi-square test, or independent samples t test as appropriate. Univariate survival analysis was performed according to the Kaplan–Meier method, and survival was compared using the log rank test. Multivariate analysis was conducted using the Cox proportional hazards regression model with backward, stepwise elimination of variables. The time from surgery (cohort 1) or randomization (cohort 2) to diagnosis of distant or local recurrence was recorded as relapse-free survival. Patients were censored at death of any cause or when lost to follow-up. Overall survival was defined as the time from surgery or randomization to death of any cause. Median follow- up for overall survival for patients still alive was 9.7 years for cohort 1 (range 5.2–17.3) and 7.6 years (range 4.9–11.0) for cohort 2. Data analysis was performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). All P values are two-tailed and considered significant when P
