Miquel Porta1, José Pumarega2, André F S Amaral3, Jeanine M Genkinger4, Judit Camargo5, Lorelei Mucci6, Juan Alguacil7, Magda Gasull8, Xuehong Zhang6, Eva Morales9, Mar Iglesias5, Shuji Ogino6, Lawrence S Engel10. 1. School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. Electronic address: mporta@imim.es. 2. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. 3. National Heart and Lung Institute, Imperial College London, London, United Kingdom. 4. Department of Epidemiology, Columbia University, New York, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, USA. 5. School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. 6. Harvard Medical School, Harvard T. H. Chan School of Public Health, Brigham and Women's Hospital, Boston, USA. 7. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Universidad de Huelva, Huelva, Spain. 8. School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. 9. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIB-Arrixaca, Department of Public Health Sciences, University of Murcia. 10. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, USA.
Abstract
INTRODUCTION: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. OBJECTIVE: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. METHODS: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. RESULTS: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. CONCLUSIONS: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.
INTRODUCTION: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. OBJECTIVE: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. METHODS: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. RESULTS: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. CONCLUSIONS: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.
Authors: Anna Rosofsky; Patricia Janulewicz; Kristina A Thayer; Michael McClean; Lauren A Wise; Antonia M Calafat; Ellen M Mikkelsen; Kyla W Taylor; Elizabeth E Hatch Journal: Environ Res Date: 2016-12-29 Impact factor: 6.498
Authors: Humberto Parada; Mary S Wolff; Lawrence S Engel; Sybil M Eng; Nikhil K Khankari; Alfred I Neugut; Susan L Teitelbaum; Marilie D Gammon Journal: Eur J Cancer Date: 2016-01-19 Impact factor: 9.162
Authors: Lei Huang; Lina Jansen; Yesilda Balavarca; Esther Molina-Montes; Masoud Babaei; Lydia van der Geest; Valery Lemmens; Liesbet Van Eycken; Harlinde De Schutter; Tom B Johannesen; Claus W Fristrup; Michael B Mortensen; Maja Primic-Žakelj; Vesna Zadnik; Nikolaus Becker; Thilo Hackert; Margit Mägi; Tiziana Cassetti; Romano Sassatelli; Robert Grützmann; Susanne Merkel; Ana F Gonçalves; Maria J Bento; Péter Hegyi; Gábor Lakatos; Andrea Szentesi; Michel Moreau; Tony van de Velde; Annegien Broeks; Milena Sant; Pamela Minicozzi; Vincenzo Mazzaferro; Francisco X Real; Alfredo Carrato; Xavier Molero; Marc G Besselink; Núria Malats; Markus W Büchler; Petra Schrotz-King; Hermann Brenner Journal: Gut Date: 2017-11-20 Impact factor: 23.059
Authors: Daniel J Renouf; Jonathan M Loree; Jennifer J Knox; James T Topham; Petr Kavan; Derek Jonker; Stephen Welch; Felix Couture; Frederic Lemay; Mustapha Tehfe; Mohammed Harb; Nathalie Aucoin; Yoo-Joung Ko; Patricia A Tang; Ravi Ramjeesingh; Brandon M Meyers; Christina A Kim; Pan Du; Shidong Jia; David F Schaeffer; Sharlene Gill; Dongsheng Tu; Chris J O'Callaghan Journal: Nat Commun Date: 2022-08-26 Impact factor: 17.694