Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: A prospective biomarker study

Jeanne Tie, Joshua D. Cohen, Yuxuan Wang, Lu Li, Michael Christie, Koen Simons, Hany Elsaleh, Suzanne Kosmider, Rachel Wong, Desmond Yip, Margaret Lee, Ben Tran, David Rangiah, Matthew Burge, David Goldstein, Madhu Singh, Iain Skinner, Ian Faragher, Matthew Croxford, Carolyn BamptonAndrew Haydon, Ian T. Jones, Christos S Karapetis, Timothy Price, Mary J. Schaefer, Jeanne Ptak, Lisa Dobbyn, Natallie Silliman, Isaac Kinde, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth Kinzler, Bert Volgestein, Peter Gibbs

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

Objective: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. Design: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. Results: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). Conclusion: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

Original languageEnglish
Pages (from-to)663-671
Number of pages9
JournalGut
Volume68
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019
Externally publishedYes

Keywords

  • chemotherapy
  • clinical decision making
  • colorectal cancer
  • molecular oncology
  • tumour markers

Cite this

Tie, Jeanne ; Cohen, Joshua D. ; Wang, Yuxuan ; Li, Lu ; Christie, Michael ; Simons, Koen ; Elsaleh, Hany ; Kosmider, Suzanne ; Wong, Rachel ; Yip, Desmond ; Lee, Margaret ; Tran, Ben ; Rangiah, David ; Burge, Matthew ; Goldstein, David ; Singh, Madhu ; Skinner, Iain ; Faragher, Ian ; Croxford, Matthew ; Bampton, Carolyn ; Haydon, Andrew ; Jones, Ian T. ; S Karapetis, Christos ; Price, Timothy ; Schaefer, Mary J. ; Ptak, Jeanne ; Dobbyn, Lisa ; Silliman, Natallie ; Kinde, Isaac ; Tomasetti, Cristian ; Papadopoulos, Nickolas ; Kinzler, Kenneth ; Volgestein, Bert ; Gibbs, Peter. / Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer : A prospective biomarker study. In: Gut. 2019 ; Vol. 68, No. 4. pp. 663-671.
@article{7e26b4667e7749ab8302160b51c16b0f,
title = "Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: A prospective biomarker study",
abstract = "Objective: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. Design: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. Results: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77{\%}, 8.3{\%} and 12{\%} of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33{\%} for the postoperative ctDNA-positive patients and 87{\%} for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). Conclusion: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.",
keywords = "chemotherapy, clinical decision making, colorectal cancer, molecular oncology, tumour markers",
author = "Jeanne Tie and Cohen, {Joshua D.} and Yuxuan Wang and Lu Li and Michael Christie and Koen Simons and Hany Elsaleh and Suzanne Kosmider and Rachel Wong and Desmond Yip and Margaret Lee and Ben Tran and David Rangiah and Matthew Burge and David Goldstein and Madhu Singh and Iain Skinner and Ian Faragher and Matthew Croxford and Carolyn Bampton and Andrew Haydon and Jones, {Ian T.} and {S Karapetis}, Christos and Timothy Price and Schaefer, {Mary J.} and Jeanne Ptak and Lisa Dobbyn and Natallie Silliman and Isaac Kinde and Cristian Tomasetti and Nickolas Papadopoulos and Kenneth Kinzler and Bert Volgestein and Peter Gibbs",
year = "2019",
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Tie, J, Cohen, JD, Wang, Y, Li, L, Christie, M, Simons, K, Elsaleh, H, Kosmider, S, Wong, R, Yip, D, Lee, M, Tran, B, Rangiah, D, Burge, M, Goldstein, D, Singh, M, Skinner, I, Faragher, I, Croxford, M, Bampton, C, Haydon, A, Jones, IT, S Karapetis, C, Price, T, Schaefer, MJ, Ptak, J, Dobbyn, L, Silliman, N, Kinde, I, Tomasetti, C, Papadopoulos, N, Kinzler, K, Volgestein, B & Gibbs, P 2019, 'Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: A prospective biomarker study', Gut, vol. 68, no. 4, pp. 663-671. https://doi.org/10.1136/gutjnl-2017-315852

Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer : A prospective biomarker study. / Tie, Jeanne; Cohen, Joshua D.; Wang, Yuxuan; Li, Lu; Christie, Michael; Simons, Koen; Elsaleh, Hany; Kosmider, Suzanne; Wong, Rachel; Yip, Desmond; Lee, Margaret; Tran, Ben; Rangiah, David; Burge, Matthew; Goldstein, David; Singh, Madhu; Skinner, Iain; Faragher, Ian; Croxford, Matthew; Bampton, Carolyn; Haydon, Andrew; Jones, Ian T.; S Karapetis, Christos; Price, Timothy; Schaefer, Mary J.; Ptak, Jeanne; Dobbyn, Lisa; Silliman, Natallie; Kinde, Isaac; Tomasetti, Cristian; Papadopoulos, Nickolas; Kinzler, Kenneth; Volgestein, Bert; Gibbs, Peter.

In: Gut, Vol. 68, No. 4, 01.04.2019, p. 663-671.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer

T2 - A prospective biomarker study

AU - Tie, Jeanne

AU - Cohen, Joshua D.

AU - Wang, Yuxuan

AU - Li, Lu

AU - Christie, Michael

AU - Simons, Koen

AU - Elsaleh, Hany

AU - Kosmider, Suzanne

AU - Wong, Rachel

AU - Yip, Desmond

AU - Lee, Margaret

AU - Tran, Ben

AU - Rangiah, David

AU - Burge, Matthew

AU - Goldstein, David

AU - Singh, Madhu

AU - Skinner, Iain

AU - Faragher, Ian

AU - Croxford, Matthew

AU - Bampton, Carolyn

AU - Haydon, Andrew

AU - Jones, Ian T.

AU - S Karapetis, Christos

AU - Price, Timothy

AU - Schaefer, Mary J.

AU - Ptak, Jeanne

AU - Dobbyn, Lisa

AU - Silliman, Natallie

AU - Kinde, Isaac

AU - Tomasetti, Cristian

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth

AU - Volgestein, Bert

AU - Gibbs, Peter

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Objective: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. Design: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. Results: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). Conclusion: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

AB - Objective: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. Design: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. Results: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). Conclusion: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

KW - chemotherapy

KW - clinical decision making

KW - colorectal cancer

KW - molecular oncology

KW - tumour markers

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