B Lee1, L Lipton2, J Cohen3, J Tie4, A A Javed3, L Li5, D Goldstein6, M Burge7, P Cooray8, A Nagrial9, N C Tebbutt10, B Thomson11, M Nikfarjam12, M Harris13, A Haydon14, B Lawrence15, D W M Tai16, K Simons17, A M Lennon3, C L Wolfgang3, C Tomasetti18, N Papadopoulos3, K W Kinzler3, B Vogelstein3, P Gibbs4. 1. Division of Systems Biology and Personalised Medicine, Walter & Eliza Hall Institute (WEHI), Melbourne; Department of Medical Oncology, Royal Melbourne Hospital, Melbourne; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne. Electronic address: lee.b@wehi.edu.au. 2. Department of Medical Oncology, Royal Melbourne Hospital, Melbourne; Department of Medical Oncology, Western Health, Melbourne; Department of Medical Oncology, Cabrini Health, Malvern, Australia. 3. Ludwig Centre and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Centre, Baltimore. 4. Division of Systems Biology and Personalised Medicine, Walter & Eliza Hall Institute (WEHI), Melbourne; Department of Medical Oncology, Royal Melbourne Hospital, Melbourne; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne; Department of Medical Oncology, Western Health, Melbourne. 5. Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA. 6. Department of Medical Oncology, Prince of Wales Hospital, Randwick. 7. Department of Medical Oncology, Royal Brisbane Hospital, Brisbane. 8. Department of Medical Oncology, Eastern Health, Melbourne. 9. Department of Medical Oncology, Crown Princess Mary Cancer Centre Westmead, Westmead. 10. Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Melbourne. 11. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne; Department of Surgery, Royal Melbourne Hospital, Melbourne. 12. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne; Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Melbourne. 13. Department of Medical Oncology, Monash Medical Centre, Clayton. 14. Department of Medical Oncology, Alfred Hospital, Melbourne, Australia. 15. Department of Medical Oncology, Auckland City Hospital, Auckland, New Zealand. 16. Department of Medical Oncology, National Cancer Centre, Singapore. 17. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne; Centre for Epidemiology & Biostatistics, University of Melbourne, Melbourne, Australia. 18. Ludwig Centre and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Centre, Baltimore; Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA.
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.
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.
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