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

Jeanne Tie, Joshua D. Cohen, Yuxuan Wang, Michael Christie, Koen Simons, Margaret Lee, Rachel Wong, Suzanne Kosmider, Sumitra Ananda, Joseph McKendrick, Belinda Lee, Jin Hee Cho, Ian Faragher, Ian T. Jones, Janine Ptak, Mary J. Schaeffer, Natalie Silliman, Lisa Dobbyn, Lu Li, Cristian Tomasetti & 4 others Nicholas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs

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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.

Original languageEnglish
Pages (from-to)E1-E8
Number of pages8
JournalJAMA Oncology
DOIs
Publication statusAccepted/In press - 17 Oct 2019

Cite this

Tie, Jeanne ; Cohen, Joshua D. ; Wang, Yuxuan ; Christie, Michael ; Simons, Koen ; Lee, Margaret ; Wong, Rachel ; Kosmider, Suzanne ; Ananda, Sumitra ; McKendrick, Joseph ; Lee, Belinda ; Cho, Jin Hee ; Faragher, Ian ; Jones, Ian T. ; Ptak, Janine ; Schaeffer, Mary J. ; Silliman, Natalie ; Dobbyn, Lisa ; Li, Lu ; Tomasetti, Cristian ; Papadopoulos, Nicholas ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Gibbs, Peter. / Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. In: JAMA Oncology. 2019 ; pp. E1-E8.
@article{4566e8847b25447e9636275f5f0255ff,
title = "Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer",
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.",
author = "Jeanne Tie and Cohen, {Joshua D.} and Yuxuan Wang and Michael Christie and Koen Simons and Margaret Lee and Rachel Wong and Suzanne Kosmider and Sumitra Ananda and Joseph McKendrick and Belinda Lee and Cho, {Jin Hee} and Ian Faragher and Jones, {Ian T.} and Janine Ptak and Schaeffer, {Mary J.} and Natalie Silliman and Lisa Dobbyn and Lu Li and Cristian Tomasetti and Nicholas Papadopoulos and Kinzler, {Kenneth W.} and Bert Vogelstein and Peter Gibbs",
year = "2019",
month = "10",
day = "17",
doi = "10.1001/jamaoncol.2019.3616",
language = "English",
pages = "E1--E8",
journal = "JAMA Oncology",
issn = "2374-2437",
publisher = "American Medical Association (AMA)",

}

Tie, J, Cohen, JD, Wang, Y, Christie, M, Simons, K, Lee, M, Wong, R, Kosmider, S, Ananda, S, McKendrick, J, Lee, B, Cho, JH, Faragher, I, Jones, IT, Ptak, J, Schaeffer, MJ, Silliman, N, Dobbyn, L, Li, L, Tomasetti, C, Papadopoulos, N, Kinzler, KW, Vogelstein, B & Gibbs, P 2019, 'Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer', JAMA Oncology, pp. E1-E8. https://doi.org/10.1001/jamaoncol.2019.3616

Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. / Tie, Jeanne; Cohen, Joshua D.; Wang, Yuxuan; Christie, Michael; Simons, Koen; Lee, Margaret; Wong, Rachel; Kosmider, Suzanne; Ananda, Sumitra; McKendrick, Joseph; Lee, Belinda; Cho, Jin Hee; Faragher, Ian; Jones, Ian T.; Ptak, Janine; Schaeffer, Mary J.; Silliman, Natalie; Dobbyn, Lisa; Li, Lu; Tomasetti, Cristian; Papadopoulos, Nicholas; Kinzler, Kenneth W.; Vogelstein, Bert; Gibbs, Peter.

In: JAMA Oncology, 17.10.2019, p. E1-E8.

Research output: Contribution to journalArticleResearchpeer-review

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

PY - 2019/10/17

Y1 - 2019/10/17

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

SP - E1-E8

JO - JAMA Oncology

JF - JAMA Oncology

SN - 2374-2437

ER -