PMID- 32791343 OWN - NLM STAT- MEDLINE DCOM- 20201211 LR - 20220531 IS - 1096-0953 (Electronic) IS - 0013-9351 (Print) IS - 0013-9351 (Linking) VI - 190 DP - 2020 Nov TI - Influence of KRAS mutations, persistent organic pollutants, and trace elements on survival from pancreatic ductal adenocarcinoma. PG - 109781 LID - S0013-9351(20)30674-5 [pii] LID - 10.1016/j.envres.2020.109781 [doi] AB - 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. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Porta, Miquel AU - Porta M AD - School of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain; CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. Electronic address: mporta@imim.es. FAU - Pumarega, Jose AU - Pumarega J AD - CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. FAU - Amaral, Andre F S AU - Amaral AFS AD - National Heart and Lung Institute, Imperial College London, London, United Kingdom. FAU - Genkinger, Jeanine M AU - Genkinger JM AD - Department of Epidemiology, Columbia University, New York, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, USA. FAU - Camargo, Judit AU - Camargo J AD - School of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. FAU - Mucci, Lorelei AU - Mucci L AD - Harvard Medical School, Harvard T. H. Chan School of Public Health, Brigham and Women's Hospital, Boston, USA. FAU - Alguacil, Juan AU - Alguacil J AD - CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain; Universidad de Huelva, Huelva, Spain. FAU - Gasull, Magda AU - Gasull M AD - School of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain; CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. FAU - Zhang, Xuehong AU - Zhang X AD - Harvard Medical School, Harvard T. H. Chan School of Public Health, Brigham and Women's Hospital, Boston, USA. FAU - Morales, Eva AU - Morales E AD - CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain; IMIB-Arrixaca, Department of Public Health Sciences, University of Murcia. FAU - Iglesias, Mar AU - Iglesias M AD - School of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain; Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain. FAU - Ogino, Shuji AU - Ogino S AD - Harvard Medical School, Harvard T. H. Chan School of Public Health, Brigham and Women's Hospital, Boston, USA. FAU - Engel, Lawrence S AU - Engel LS AD - Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, USA. CN - PANKRAS II Study Group LA - eng GR - P42 ES007373/ES/NIEHS NIH HHS/United States GR - R35 CA197735/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200611 PL - Netherlands TA - Environ Res JT - Environmental research JID - 0147621 RN - 0 (KRAS protein, human) RN - 0 (Trace Elements) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - *Adenocarcinoma/genetics MH - Gas Chromatography-Mass Spectrometry MH - Humans MH - Mutation MH - *Pancreatic Neoplasms/genetics MH - Persistent Organic Pollutants MH - Proto-Oncogene Proteins p21(ras)/genetics MH - Spain MH - *Trace Elements PMC - PMC7689512 MID - NIHMS1640476 OTO - NOTNLM OT - KRAS oncogene OT - metals OT - pancreatic cancer OT - pancreatic ductal adenocarcinoma (PDAC) OT - persistent organic pollutants (POPs) OT - survival OT - trace elements COIS- The authors have no conflicts of interest in connection with the paper, and declare no competing financial interests. Conflicts of interest: The authors declare no potential conflicts of interest. EDAT- 2020/08/14 06:00 MHDA- 2020/12/15 06:00 PMCR- 2021/11/01 CRDT- 2020/08/14 06:00 PHST- 2020/01/28 00:00 [received] PHST- 2020/05/02 00:00 [revised] PHST- 2020/06/02 00:00 [accepted] PHST- 2020/08/14 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/08/14 06:00 [entrez] PHST- 2021/11/01 00:00 [pmc-release] AID - S0013-9351(20)30674-5 [pii] AID - 10.1016/j.envres.2020.109781 [doi] PST - ppublish SO - Environ Res. 2020 Nov;190:109781. doi: 10.1016/j.envres.2020.109781. Epub 2020 Jun 11.