J Hamfjord1, T K Guren2, O Dajani3, J S Johansen4, B Glimelius5, H Sorbye6, P Pfeiffer7, O C Lingjærde8, K M Tveit9, E H Kure10, N Pallisgaard11, K-L G Spindler12. 1. Department of Oncology, Oslo University Hospital, Oslo; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo. 2. Department of Oncology, Oslo University Hospital, Oslo; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Electronic address: uxtour@ous-hf.no. 3. Department of Oncology, Oslo University Hospital, Oslo. 4. Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 5. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 6. Department of Oncology, Haukeland University Hospital, Bergen; Department of Clinical Science, University of Bergen, Bergen, Norway. 7. Department of Oncology, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark. 8. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo; Department of Computer Science, University of Oslo, Oslo. 9. Department of Oncology, Oslo University Hospital, Oslo; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. 10. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo; Faculty of Technology, Natural Sciences and Maritime Sciences, University of South-Eastern Norway, Bø in Telemark, Norway. 11. Department of Pathology, Zealand University Hospital, Roskilde. 12. Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Abstract
BACKGROUND: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00145314.
BACKGROUND:Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00145314.