Jeanne Tie1,2,3,4, Joshua D Cohen5, Yuxuan Wang5, Michael Christie1,6, Koen Simons7,8, Margaret Lee1,2,9, Rachel Wong1,9,10, Suzanne Kosmider2, Sumitra Ananda1,2,3,4, Joseph McKendrick9, Belinda Lee1,3, Jin Hee Cho2, Ian Faragher2, Ian T Jones11, Janine Ptak5, Mary J Schaeffer5, Natalie Silliman5, Lisa Dobbyn5, Lu Li12, Cristian Tomasetti12,13, Nicholas Papadopoulos5, Kenneth W Kinzler5, Bert Vogelstein5, Peter Gibbs1,2,4. 1. Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. 2. Department of Medical Oncology, Western Health, Melbourne, Australia. 3. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. 4. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia. 5. Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Department of Pathology, Royal Melbourne Hospital, Melbourne, Australia. 7. Western Centre for Health, Research and Education, Western Health, Melbourne, Australia. 8. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia. 9. Department of Medical Oncology, Eastern Health, Melbourne, Australia. 10. Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia. 11. Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia. 12. Division of Biostatistics & Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. 13. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Abstract
Importance: Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective: To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants: This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures: Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures: Detection of ctDNA and recurrence-free interval (RFI). Results: After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance: Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.
Importance: Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective: To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants: This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures: Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures: Detection of ctDNA and recurrence-free interval (RFI). Results: After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance: Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.
Authors: Preeti Narayan; Soma Ghosh; Reena Philip; J Carl Barrett; Robert T McCormack; Justin I Odegaard; Geoffrey R Oxnard; Laurel J Pracht; P Mickey Williams; Gary J Kelloff; Julia A Beaver Journal: Oncologist Date: 2020-06-29
Authors: Joshua D Cohen; Brenda Diergaarde; Nickolas Papadopoulos; Kenneth W Kinzler; Robert E Schoen Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-10-08 Impact factor: 4.254
Authors: Jeanne Tie; Joshua D Cohen; Serigne N Lo; Yuxuan Wang; Lu Li; Michael Christie; Margaret Lee; Rachel Wong; Suzanne Kosmider; Iain Skinner; Hui Li Wong; Belinda Lee; Matthew E Burge; Desmond Yip; Christos S Karapetis; Timothy J Price; Niall C Tebbutt; Andrew M Haydon; Janine Ptak; Mary J Schaeffer; Natalie Silliman; Lisa Dobbyn; Maria Popoli; Cristian Tomasetti; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Peter Gibbs Journal: Int J Cancer Date: 2020-10-06 Impact factor: 7.396