1. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer
- Author
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Adnan Nagrial, David Goldstein, Niall C. Tebbutt, Bert Vogelstein, Joshua D. Cohen, Lu Li, Andrew Haydon, Kenneth W. Kinzler, Koen Simons, Peter Gibbs, Jeanne Tie, Cristian Tomasetti, D W M Tai, Prasad Cooray, Nick Papadopoulos, C L Wolfgang, Matthew Burge, Lara Lipton, Belinda Lee, Mehrdad Nikfarjam, Ammar A. Javed, Marion Harris, Benjamin N. J. Thomson, A M Lennon, and B. Lawrence
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.disease_cause ,Deoxycytidine ,Disease-Free Survival ,Circulating Tumor DNA ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic tumor ,Pancreatic cancer ,Internal medicine ,Biomarkers, Tumor ,medicine ,Adjuvant therapy ,Humans ,Liquid biopsy ,Aged ,Aged, 80 and over ,business.industry ,Liquid Biopsy ,Cancer ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Gemcitabine ,Pancreatic Neoplasms ,030104 developmental biology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Mutation ,Female ,KRAS ,Sample collection ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
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.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.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.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.
- Published
- 2019
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