TY - JOUR
T1 - Circulating tumor dna analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer
AU - Tie, Jeanne
AU - Cohen, Joshua D.
AU - Wang, Yuxuan
AU - Christie, Michael
AU - Simons, Koen
AU - Lee, Margaret
AU - Wong, Rachel
AU - Kosmider, Suzanne
AU - Ananda, Sumitra
AU - McKendrick, Joseph
AU - Lee, Belinda
AU - Cho, Jin Hee
AU - Faragher, Ian
AU - Jones, Ian T.
AU - Ptak, Janine
AU - Schaeffer, Mary J.
AU - Silliman, Natalie
AU - Dobbyn, Lisa
AU - Li, Lu
AU - Tomasetti, Cristian
AU - Papadopoulos, Nicholas
AU - Kinzler, Kenneth W.
AU - Vogelstein, Bert
AU - Gibbs, Peter
N1 - Funding Information:
Funding/Support: This study was supported by Clinical Research Fellowship CRF14007 from the Victorian Cancer Agency (Dr Tie); grants P50-CA062924, CA06973, CA176828, and CA210170 from the NIH; the Virginia and D. K. Ludwig Fund for Cancer Research; and the John Templeton Foundation. Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
receiving grants from the Victorian Cancer Agency during the conduct of the study and serving on a steering committee for an early-stage colorectal cancer trial to explore novel therapy. Dr Tomasetti reported receiving grants from the John Templeton Foundation and the Marcus Foundation during the conduct of the study; personal fees from PapGene, Inc, outside the submitted work; and having a patent to C15049 CancerSEEK pending. Dr Papadopoulos reported receiving grants from Ludwig Cancer Research, the Marcus Foundation, Conrad N Hilton Foundation, The Commonwealth Fund, and the National Institutes of Health (NIH; CA152753, CA228991, CA230691, CA230400 ) during the conduct of the study; equity from Thrive Earlier Detection, Inc, Personal Genome Diagnostics, Inc, and NeoPhore outside the submitted work; personal fees from Thrive Earlier Detection, Inc outside the submitted work; having patents to SafeSeqS pending, issued, licensed, and with royalties paid and patents to Optimization of Methods for Detecting Rare Mutations in Clinical pending, issued, licensed, and with royalties paid; and being a founder of Personal Genome Diagnostics, Inc, and Thrive Earlier Detection, Inc, and an advisor of NeoPhore. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.Dr Kinzler reported receiving grants from Ludwig Cancer Research, the Marcus Foundation and the National Institutes of Health (NIH; CA152753) during the conduct of the study; equity from Thrive Earlier Detection, Inc, Personal Genome Diagnostics, Inc, NeoPhore, PhoreMost, and CAGE outside the submitted work; personal fees from Thrive Earlier Detection, Inc, Eisai-Morphotek and Sysmex-Inostics outside the submitted work; having patents to SafeSeqS pending, issued, licensed, and with royalties paid and patents to Optimization of Methods for Detecting Rare Mutations in Clinical pending, issued, licensed, and with royalties paid; and being a founder of Personal Genome Diagnostics, Inc, and Thrive Earlier Detection, Inc, and an advisor of Sysmex-Inostics, Eisai-Morphotek, CAGE, NeoPhore, and PhoreMost. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. Dr Vogelstein reported receiving grants from Ludwig Cancer Research and the Marcus Foundation during the conduct of the study; equity from Thrive Earlier Detection, Inc, Personal Genome Diagnostics, Inc, NeoPhore, PhoreMost, CAGE, and Nexus outside the submitted work; personal fees from Thrive Earlier Detection, Inc, Eisai-Morphotek and Sysmex-Inostics outside the submitted work; having patents to SafeSeqS pending, issued, licensed, and with royalties paid and patents to Optimization of Methods for Detecting Rare Mutations in Clinical pending, issued, licensed, and with royalties paid; and being a founder of Personal Genome Diagnostics, Inc, and Thrive Earlier Detection, Inc, and an advisor of Sysmex-Inostics, Eisai-Morphotek, CAGE, NeoPhore, PhoreMost, and Nexus. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. Dr Gibbs reported receiving grants from the National Health and Medical Research Council and the Victorian Cancer Agency during the conduct of the study. No other disclosures were reported.
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
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U2 - 10.1001/jamaoncol.2019.3616
DO - 10.1001/jamaoncol.2019.3616
M3 - Article
C2 - 31621801
AN - SCOPUS:85073773804
SN - 2374-2437
VL - 5
SP - 1710
EP - 1717
JO - JAMA Oncology
JF - JAMA Oncology
IS - 12
ER -