Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer

B. Lee, L. Lipton, J. Cohen, J. Tie, A. A. Javed, L. Li, D. Goldstein, M. Burge, P. Cooray, A. Nagrial, N. C. Tebbutt, B. Thomson, M. Nikfarjam, M. Harris, A. Haydon, B. Lawrence, D. W.M. Tai, K. Simons, A. M. Lennon, C. L. WolfgangC. Tomasetti, N. Papadopoulos, K. W. Kinzler, B. Vogelstein, P. Gibbs

Research output: Contribution to journalArticle

Abstract

Background: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Materials and methods: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. Results: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. Conclusion: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Original languageEnglish (US)
Pages (from-to)1472-1478
Number of pages7
JournalAnnals of Oncology
Volume30
Issue number9
DOIs
StatePublished - Sep 1 2019

Fingerprint

Adjuvant Chemotherapy
Pancreatic Neoplasms
DNA
Neoplasms
gemcitabine
Recurrence
Survival
Biomarkers
Mutation
Therapeutics
Standard of Care
Codon
Genetic Therapy

Keywords

  • adjuvant therapy
  • biomarkers
  • circulating tumor DNA
  • liquid biopsy
  • pancreatic cancer
  • pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. / Lee, B.; Lipton, L.; Cohen, J.; Tie, J.; Javed, A. A.; Li, L.; Goldstein, D.; Burge, M.; Cooray, P.; Nagrial, A.; Tebbutt, N. C.; Thomson, B.; Nikfarjam, M.; Harris, M.; Haydon, A.; Lawrence, B.; Tai, D. W.M.; Simons, K.; Lennon, A. M.; Wolfgang, C. L.; Tomasetti, C.; Papadopoulos, N.; Kinzler, K. W.; Vogelstein, B.; Gibbs, P.

In: Annals of Oncology, Vol. 30, No. 9, 01.09.2019, p. 1472-1478.

Research output: Contribution to journalArticle

Lee, B, Lipton, L, Cohen, J, Tie, J, Javed, AA, Li, L, Goldstein, D, Burge, M, Cooray, P, Nagrial, A, Tebbutt, NC, Thomson, B, Nikfarjam, M, Harris, M, Haydon, A, Lawrence, B, Tai, DWM, Simons, K, Lennon, AM, Wolfgang, CL, Tomasetti, C, Papadopoulos, N, Kinzler, KW, Vogelstein, B & Gibbs, P 2019, 'Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer', Annals of Oncology, vol. 30, no. 9, pp. 1472-1478. https://doi.org/10.1093/annonc/mdz200
Lee, B. ; Lipton, L. ; Cohen, J. ; Tie, J. ; Javed, A. A. ; Li, L. ; Goldstein, D. ; Burge, M. ; Cooray, P. ; Nagrial, A. ; Tebbutt, N. C. ; Thomson, B. ; Nikfarjam, M. ; Harris, M. ; Haydon, A. ; Lawrence, B. ; Tai, D. W.M. ; Simons, K. ; Lennon, A. M. ; Wolfgang, C. L. ; Tomasetti, C. ; Papadopoulos, N. ; Kinzler, K. W. ; Vogelstein, B. ; Gibbs, P. / Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. In: Annals of Oncology. 2019 ; Vol. 30, No. 9. pp. 1472-1478.
@article{9cf446e3f30547478962a631477e856e,
title = "Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer",
abstract = "Background: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Materials and methods: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. Results: Of 112 patients consented pre-operatively, 81 (72{\%}) underwent resection. KRAS mutations were identified in 91{\%} (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62{\%} (23/37) pre-operative and 37{\%} (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100{\%}) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. Conclusion: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.",
keywords = "adjuvant therapy, biomarkers, circulating tumor DNA, liquid biopsy, pancreatic cancer, pancreatic ductal adenocarcinoma",
author = "B. Lee and L. Lipton and J. Cohen and J. Tie and Javed, {A. A.} and L. Li and D. Goldstein and M. Burge and P. Cooray and A. Nagrial and Tebbutt, {N. C.} and B. Thomson and M. Nikfarjam and M. Harris and A. Haydon and B. Lawrence and Tai, {D. W.M.} and K. Simons and Lennon, {A. M.} and Wolfgang, {C. L.} and C. Tomasetti and N. Papadopoulos and Kinzler, {K. W.} and B. Vogelstein and P. Gibbs",
year = "2019",
month = "9",
day = "1",
doi = "10.1093/annonc/mdz200",
language = "English (US)",
volume = "30",
pages = "1472--1478",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer

AU - Lee, B.

AU - Lipton, L.

AU - Cohen, J.

AU - Tie, J.

AU - Javed, A. A.

AU - Li, L.

AU - Goldstein, D.

AU - Burge, M.

AU - Cooray, P.

AU - Nagrial, A.

AU - Tebbutt, N. C.

AU - Thomson, B.

AU - Nikfarjam, M.

AU - Harris, M.

AU - Haydon, A.

AU - Lawrence, B.

AU - Tai, D. W.M.

AU - Simons, K.

AU - Lennon, A. M.

AU - Wolfgang, C. L.

AU - Tomasetti, C.

AU - Papadopoulos, N.

AU - Kinzler, K. W.

AU - Vogelstein, B.

AU - Gibbs, P.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Background: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Materials and methods: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. Results: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. Conclusion: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

AB - Background: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Materials and methods: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. Results: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. Conclusion: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

KW - adjuvant therapy

KW - biomarkers

KW - circulating tumor DNA

KW - liquid biopsy

KW - pancreatic cancer

KW - pancreatic ductal adenocarcinoma

UR - http://www.scopus.com/inward/record.url?scp=85071383458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071383458&partnerID=8YFLogxK

U2 - 10.1093/annonc/mdz200

DO - 10.1093/annonc/mdz200

M3 - Article

C2 - 31250894

AN - SCOPUS:85071383458

VL - 30

SP - 1472

EP - 1478

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 9

ER -