Agent orange exposure and prostate cancer risk in the million veteran program

Authors

  • Meghana S. Pagadala Research Service, VA San Diego Healthcare System, San Diego, CA, USA; Medical Scientist Training Program, University of California San Diego, La Jolla, CA, USA; Biomedical Science Program, University of California San Diego, La Jolla, CA, USA
  • Asona J. Lui Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA
  • Allison Y. Zhong Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA
  • Julie A. Lynch VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA
  • Roshan Karunamuni Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA
  • Kyung Min Lee VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA
  • Anna Plym Division of Urology, Brigham and Women’s Hospital, Boston, MA, USA; Epidemiology, TH Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • Brent S. Rose Research Service, VA San Diego Healthcare System, San Diego, CA, USA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA
  • Hannah K. Carter Department of Medicine, University of California San Diego, La Jolla, CA, USA
  • Adam S. Kibel Division of Urology, Brigham and Women’s Hospital, Boston, MA, USA
  • Scott L. DuVall VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA
  • J. Michael Gaziano Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
  • Matthew S. Panizzon Research Service, VA San Diego Healthcare System, San Diego, CA, USA; Center for Behavioral Genetics of Aging, University of California San Diego, La Jolla, CA, USA
  • Richard L. Hauger Research Service, VA San Diego Healthcare System, San Diego, CA, USA; Center for Behavioral Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA
  • Tyler M. Seibert Research Service, VA San Diego Healthcare System, San Diego, CA, USA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA; Department of Radiology, University of California San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

DOI:

https://doi.org/10.2340/1651-226X.2024.25053

Keywords:

Agent Orange, prostate cancer, MVP, race/ethnicity, health disparities

Abstract

Background: The US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk.

Patients and Methods: Participants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.

Results and Interpretation: On univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00–1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91–1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79–1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04–1.09, <10-6) but not with metastatic PCa (HR: 1.07, 95% CI: 0.98–1.15, p = 0.10) or PCa death (HR: 1.02, 95% CI: 0.83–1.23, p = 0.09). Similar results were found when accounting for genetic risk. Agent Orange exposure history may not improve modern PCa risk stratification.

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References

Kaur G, Kumar BVS, Singh B, Sethi RS. Exposures to 2,4-Dichlorophenoxyacetic acid with or without endotoxin upregulate small cell lung cancer pathway. J Occup Med Toxicol. 2021 Apr 17;16(1):14.

https://doi.org/10.1186/s12995-021-00304-4 DOI: https://doi.org/10.1186/s12995-021-00304-4

Coggon D, Ntan G, Harris EC, Jayakody N, Palmer KT. Soft tissue sarcoma, non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in workers exposed to phe-noxy herbicides: extended follow-up of a UK cohort. Occup Environ Med. 2015 Jun;72(6):435–41.

https://doi.org/10.1136/oemed-2014-102654 DOI: https://doi.org/10.1136/oemed-2014-102654

Goodman JE, Loftus CT, Zu K. 2,4-Dichlorophenoxyacetic acid and non-Hodgkin’s lym-phoma: results from the Agricultural Health Study and an updated meta-analysis. Ann Epidemiol. 2017 Apr;27(4):290.e5–2.e5.

https://doi.org/10.1016/j.annepidem.2017.01.008 DOI: https://doi.org/10.1016/j.annepidem.2017.01.008

Hoar SK, Blair A, Holmes FF, et al. Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma. JAMA. 1986 Sep 5;256(9):1141–7.

https://doi.org/10.1001/jama.256.9.1141 DOI: https://doi.org/10.1001/jama.256.9.1141

Burns C, Bodner K, Swaen G, Collins J, Beard K, Lee M. Cancer incidence of 2,4-D produc-tion workers. Int J Environ Res Public Health. 2011 Sep;8(9):3579–90.

https://doi.org/10.3390/ijerph8093579 DOI: https://doi.org/10.3390/ijerph8093579

CarloGL, Sund KG. Carcinogenicity of dioxin. Lancet. 1991 Nov 30;338(8779):1393.

https://doi.org/10.1016/0140-6736(91)92268-7 DOI: https://doi.org/10.1016/0140-6736(91)92268-7

Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet. 1991 Oct 19;338(8773):959–64.

https://doi.org/10.1016/0140-6736(91)91835-I DOI: https://doi.org/10.1016/0140-6736(91)91835-I

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, World Health Organization & International Agency for Research on Cancer. Polychlorina-ted Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. IARC Mono-graphs Evaluat. 1997:69:1–631.

Chang C, Benson M, Fam MM. A review of Agent Orange and its associated oncologic risk of genitourinary cancers. Urol Oncol. 2017 Nov;35(11):633–9.

https://doi.org/10.1016/j.urolonc.2017.08.029 DOI: https://doi.org/10.1016/j.urolonc.2017.08.029

Pavuk M, Michalek JE, Schecter A, Ketchum NS, Akhtar FZ, Fox KA. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in air force Vietnam ve-terans who did not spray agent orange? J Occup Environ Med. 2005 Apr;47(4):335–42.

https://doi.org/10.1097/01.jom.0000158739.56427.24 DOI: https://doi.org/10.1097/01.jom.0000158739.56427.24

Pavuk M, Michalek JE, Ketchum NS. Prostate cancer in US Air Force veterans of the Viet-nam war. J Expo Sci Environ Epidemiol. 2006 Mar;16(2):184–90.

https://doi.org/10.1038/sj.jea.7500448 DOI: https://doi.org/10.1038/sj.jea.7500448

Akhtar FZ, Garabrant DH, Ketchum NS, Michalek JE. Cancer in US Air Force veterans of the Vietnam War. J Occup Environ Med. 2004 Feb;46(2):123–36.

https://doi.org/10.1097/01.jom.0000111603.84316.0f DOI: https://doi.org/10.1097/01.jom.0000111603.84316.0f

Shah SR, Freedland SJ, Aronson WJ, et al. Exposure to Agent Orange is a significant pre-dictor of prostate-specific antigen (PSA)-based recurrence and a rapid PSA doubling time after radical prostatectomy. BJU Int. 2009 May;103(9):1168–72.

https://doi.org/10.1111/j.1464-410X.2009.08405.x DOI: https://doi.org/10.1111/j.1464-410X.2009.08405.x

Chamie K, DeVere White RW, Lee D, Ok J-H, Ellison LM. Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer. Cancer. 2008 Nov 1;113(9):2464–70.

https://doi.org/10.1002/cncr.23695 DOI: https://doi.org/10.1002/cncr.23695

Ansbaugh N, Shannon J, Mori M, Farris PE, Garzotto M. Agent Orange as a risk factor for high-grade prostate cancer. Cancer. 2013 Jul 1;119(13):2399–404.

https://doi.org/10.1002/cncr.27941 DOI: https://doi.org/10.1002/cncr.27941

Wilson EJ, Horsley KW, van der Hoek R. Australian Vietnam Veterans Mortality Study 2005. Canberra: Department of Veterans’ Affairs, 2005.

Gaziano JM, Concato J, Brophy M, et al. Million Veteran Program: a mega-biobank to study genetic influences on health and disease. J Clin Epidemiol. 2016 Feb:70:214–23.

https://doi.org/10.1016/j.jclinepi.2015.09.016 DOI: https://doi.org/10.1016/j.jclinepi.2015.09.016

Pagadala MS, Lynch J, Karunamuni R, et al. Polygenic risk of any, metastatic, and fatal pro-state cancer in the Million Veteran Program. J Natl Cancer Inst. 2023 Feb 8;115(2):190–9.

https://doi.org/10.1093/jnci/djac199 DOI: https://doi.org/10.1093/jnci/djac199

Huynh-Le MP, Karunamuni R, Fan CC, et al. Prostate cancer risk stratification improve-ment across multiple ancestries with new polygenic hazard score. Prostate Cancer Prostatic Dis. 2022 Apr;25(4):755–61.

https://doi.org/10.1038/s41391-022-00497-7 DOI: https://doi.org/10.1038/s41391-022-00497-7

Moses KA, Sprenkle PC, Bahler C, et al. NCCN Guidelines® Insights: prostate cancer early detection, Version 1.2023. J Natl Compr Canc Netw. 2023 Mar;21(3):236–46.

https://doi.org/10.6004/jnccn.2023.0014 DOI: https://doi.org/10.6004/jnccn.2023.0014

Conti DV, Darst BF, Moss LC, et al. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat Genet. 2021 Jan;53(1):65–75.

https://doi.org/10.1038/s41588-020-00748-0 DOI: https://doi.org/10.1038/s41588-020-00748-0

Hugosson J, Roobol MJ, Månsson M, et al. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. Eur Urol. 07 2019;76(1):43-51. doi:10.1016/j.eururo.2019.02.009 DOI: https://doi.org/10.1016/j.eururo.2019.02.009

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Published

2024-05-23

How to Cite

Pagadala, M. S., Lui, A. J., Zhong, A. Y., Lynch, J. A., Karunamuni, R., Lee, K. M., … Seibert, T. M. (2024). Agent orange exposure and prostate cancer risk in the million veteran program. Acta Oncologica, 63(1), 373–378. https://doi.org/10.2340/1651-226X.2024.25053

Issue

Vol. 63 (2024): Acta Oncologica

Section

Short report

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Copyright (c) 2023 Meghana S. Pagadala, Asona J. Lui, Allison Y. Zhong, Julie A. Lynch, Roshan Karunamuni, Kyung Min Lee, Anna Plym, Brent S. Rose, Hannah K. Carter, Adam S. Kibel, Scott L. DuVall, J. Michael Gaziano, Matthew S. Panizzon, Richard L. Hauger, Tyler M. Seibert

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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