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

被引：167

作者：

Lee, B. ^{[1
,2
,3
]}

Lipton, L. ^{[2
,4
,5
]}

Cohen, J. ^{[6
,7
]}

Tie, J. ^{[1
,2
,3
,4
]}

Javed, A. A. ^{[6
,7
]}

Li, L. ^{[8
]}

Goldstein, D. ^{[9
]}

Burge, M. ^{[10
]}

Cooray, P. ^{[11
]}

Nagrial, A. ^{[12
]}

Tebbutt, N. C. ^{[13
]}

Thomson, B. ^{[3
,14
]}

Nikfarjam, M. ^{[3
,13
]}

Harris, M. ^{[15
]}

Haydon, A. ^{[16
]}

Lawrence, B. ^{[17
]}

Tai, D. W. M. ^{[18
]}

Simons, K. ^{[3
,19
]}

Lennon, A. M. ^{[6
,7
]}

Wolfgang, C. L. ^{[6
,7
]}

Tomasetti, C. ^{[6
,7
,8
]}

Papadopoulos, N. ^{[6
,7
]}

Kinzler, K. W. ^{[6
,7
]}

Vogelstein, B. ^{[6
,7
]}

Gibbs, P. ^{[1
,2
,3
,4
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Div Syst Biol & Personalised Med, Melbourne, Vic, Australia

[2] Royal Melbourne Hosp, Dept Med Oncol, Melbourne, Vic, Australia

[3] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne, Vic, Australia

[4] Western Hlth, Dept Med Oncol, Melbourne, Vic, Australia

[5] Cabrini Hlth, Dept Med Oncol, Malvern, Australia

[6] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr, Baltimore, MD USA

[7] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA

[8] Johns Hopkins Univ, Sch Med, Dept Oncol, Div Biostat & Bioinformat, Baltimore, MD 21205 USA

[9] Prince Wales Hosp, Dept Med Oncol, Randwick, NSW, Australia

[10] Royal Brisbane Hosp, Dept Med Oncol, Brisbane, Qld, Australia

[11] Eastern Hlth, Dept Med Oncol, Melbourne, Vic, Australia

[12] Crown Princess Mary Canc Ctr Westmead, Dept Med Oncol, Westmead, NSW, Australia

[13] Olivia Newton John Canc & Wellness Ctr, Dept Med Oncol, Melbourne, Vic, Australia

[14] Royal Melbourne Hosp, Dept Surg, Melbourne, Vic, Australia

[15] Monash Med Ctr, Dept Med Oncol, Clayton, Vic, Australia

[16] Alfred Hosp, Dept Med Oncol, Melbourne, Vic, Australia

[17] Auckland City Hosp, Dept Med Oncol, Auckland, New Zealand

[18] Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore

[19] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia

来源：

ANNALS OF ONCOLOGY | 2019年 / 30卷 / 09期

基金：

美国国家卫生研究院;

关键词：

circulating tumor DNA; pancreatic ductal adenocarcinoma; pancreatic cancer; liquid biopsy; biomarkers; adjuvant therapy; PLASMA DNA; MUTATIONS; QUANTIFICATION; GEMCITABINE;

D O I：

10.1093/annonc/mdz200

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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) preoperative 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.

引用

页码：1472 / 1478

页数：7

共 20 条

[1]

AIHW (Australian Institute of Health and Welfare), AUSTR CANC INC MORT

[2] MOST HUMAN CARCINOMAS OF THE EXOCRINE PANCREAS CONTAIN MUTANT C-K-RAS GENES [J].

ALMOGUERA, C ;

SHIBATA, D ;

FORRESTER, K ;

MARTIN, J ;

ARNHEIM, N ;

PERUCHO, M .

CELL, 1988, 53 (04) :549-554

[3]

[Anonymous], 2019, UPDATE ON ABRAXANE C

[4] Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer [J].

Bernard, Vincent ;

Kim, Dong U. ;

San Lucas, F. Anthony ;

Castillo, Jonathan ;

Allenson, Kelvin ;

Mulu, Feven C. ;

Stephens, Bret M. ;

Huang, Jonathan ;

Semaan, Alexander ;

Guerrero, Paola A. ;

Kamyabi, Nabiollah ;

Zhao, Jun ;

Hurd, Mark W. ;

Koay, Eugene J. ;

Taniguchi, Cullen M. ;

Herman, Joseph M. ;

Javle, Milind ;

Wolff, Robert ;

Katz, Matthew ;

Varadhachary, Gauri ;

Maitra, Anirban ;

Alvarez, Hector A. .

GASTROENTEROLOGY, 2019, 156 (01) :108-+

[5] Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies [J].

Bettegowda, Chetan ;

Sausen, Mark ;

Leary, Rebecca J. ;

Kinde, Isaac ;

Wang, Yuxuan ;

Agrawal, Nishant ;

Bartlett, Bjarne R. ;

Wang, Hao ;

Luber, Brandon ;

Alani, Rhoda M. ;

Antonarakis, Emmanuel S. ;

Azad, Nilofer S. ;

Bardelli, Alberto ;

Brem, Henry ;

Cameron, John L. ;

Lee, Clarence C. ;

Fecher, Leslie A. ;

Gallia, Gary L. ;

Gibbs, Peter ;

Le, Dung ;

Giuntoli, Robert L. ;

Goggins, Michael ;

Hogarty, Michael D. ;

Holdhoff, Matthias ;

Hong, Seung-Mo ;

Jiao, Yuchen ;

Juhl, Hartmut H. ;

Kim, Jenny J. ;

Siravegna, Giulia ;

Laheru, Daniel A. ;

Lauricella, Calogero ;

Lim, Michael ;

Lipson, Evan J. ;

Marie, Suely Kazue Nagahashi ;

Netto, George J. ;

Oliner, Kelly S. ;

Olivi, Alessandro ;

Olsson, Louise ;

Riggins, Gregory J. ;

Sartore-Bianchi, Andrea ;

Schmidt, Kerstin ;

Shih, Ie-Ming ;

Oba-Shinjo, Sueli Mieko ;

Siena, Salvatore ;

Theodorescu, Dan ;

Tie, Jeanne ;

Harkins, Timothy T. ;

Veronese, Silvio ;

Wang, Tian-Li ;

Weingart, Jon D. .

SCIENCE TRANSLATIONAL MEDICINE, 2014, 6 (224)

[6] FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer [J].

Conroy, T. ;

Hammel, P. ;

Hebbar, M. ;

Ben Abdelghani, M. ;

Wei, A. C. ;

Raoul, J. -L. ;

Chone, L. ;

Francois, E. ;

Artru, P. ;

Biagi, J. J. ;

Lecomte, T. ;

Assenat, E. ;

Faroux, R. ;

Ychou, M. ;

Volet, J. ;

Sauvanet, A. ;

Breysacher, G. ;

Di Fiore, F. ;

Cripps, C. ;

Kavan, P. ;

Texereau, P. ;

Bouhier-Leporrier, K. ;

Khemissa-Akouz, F. ;

Legoux, J. -L. ;

Juzyna, B. ;

Gourgou, S. ;

O'Callaghan, C. J. ;

Jouffroy-Zeller, C. ;

Rat, P. ;

Malka, D. ;

Castan, F. ;

Bachet, J. -B. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 379 (25) :2395-2406

[7] Detection and quantification of mutations in the plasma of patients with colorectal tumors [J].

Diehl, F ;

Li, M ;

Dressman, D ;

He, YP ;

Shen, D ;

Szabo, S ;

Diaz, LA ;

Goodman, SN ;

David, KA ;

Juhl, H ;

Kinzler, KW ;

Vogelstein, B .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (45) :16368-16373

[8] Circulating mutant DNA to assess tumor dynamics [J].

Diehl, Frank ;

Schmidt, Kerstin ;

Choti, Michael A. ;

Romans, Katharine ;

Goodman, Steven ;

Li, Meng ;

Thornton, Katherine ;

Agrawal, Nishant ;

Sokoll, Lori ;

Szabo, Steve A. ;

Kinzler, Kenneth W. ;

Vogelstein, Bert ;

Diaz, Luis A., Jr. .

NATURE MEDICINE, 2008, 14 (09) :985-990

[9] Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer [J].

Hadano, Naoto ;

Murakami, Yoshiaki ;

Uemura, Kenichiro ;

Hashimoto, Yasusi ;

Kondo, Naru ;

Nakagawa, Naoya ;

Sueda, Taijiro ;

Hiyama, Eiso .

BRITISH JOURNAL OF CANCER, 2016, 115 (01) :59-65

[10] Detection and quantification of rare mutations with massively parallel sequencing [J].

Kinde, Isaac ;

Wu, Jian ;

Papadopoulos, Nick ;

Kinzler, Kenneth W. ;

Vogelstein, Bert .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (23) :9530-9535

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