[Skip to Content]
[Skip to Content Landing]
Original Investigation
October 17, 2019

Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer

Author Affiliations
  • 1Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
  • 2Department of Medical Oncology, Western Health, Melbourne, Australia
  • 3Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
  • 4Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
  • 5Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 6Department of Pathology, Royal Melbourne Hospital, Melbourne, Australia
  • 7Western Centre for Health, Research and Education, Western Health, Melbourne, Australia
  • 8Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
  • 9Department of Medical Oncology, Eastern Health, Melbourne, Australia
  • 10Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
  • 11Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
  • 12Division of Biostatistics & Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 13Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
JAMA Oncol. 2019;5(12):1710-1717. doi:10.1001/jamaoncol.2019.3616
Key Points

Question  Can serial analysis of circulating tumor DNA levels provide a real-time indication of adjuvant chemotherapy efficacy in patients with stage III colon cancer?

Findings  In this multicenter cohort study of 96 patients with stage III colon cancer, a significant difference in 3-year recurrence-free interval was observed in patients with detectable vs undetectable levels of circulating tumor DNA after surgery (47% vs 76%) and after completion of chemotherapy (30% vs 77%).

Meaning  Postsurgical and postchemotherapy circulating tumor DNA analyses may identify patients at high risk of recurrence despite completing standard adjuvant treatment, presenting a unique opportunity to explore additional therapeutic approaches.

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.

Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    ×