Prostate cancer (PCa), the most common noncutaneous cancer in men, was projected to increase from 268,490 diagnoses in 2022 to 288,000 diagnoses in 2023. In 2022, the estimated prevalence of PCa in the US was over 3 million men.^1-4 Of all solid cancers, PCa has the highest incidence in US Air Force officers and all veterans.² In a study examining more than 34,000 fighter pilots and weapons systems officers compared to over 300,000 active duty Air Force ground officers between 1970 and 2004, aviators were 16% to 19% more likely to be diagnosed with PCa, and compared to nonflying officer peers, aviators have 23% greater odds.^2,4-6 PCa represents a large burden affecting veterans and the Veterans Health Administration, and thus identifying underlying risk factors is of utmost importance (Table).

Table. The Impact of Prostate Cancer on the US Veteran Population and the Veterans Health Administration System

Due to their occupational duties, military aviators are exposed to numerous carcinogens inside and outside the cockpit, as well as disruption of their circadian rhythm, induced by frequent nighttime flight schedules.^2,5,6 Occupational exposures at high altitudes are an important consideration for management of pilot health. A Pentagon investigation recently found that pilots and ground crews have higher cardiovascular and malignancy risk. Namely, in a study of 900,000 service members who worked or flew on military aircraft, they were found to have an 87% higher rate of melanoma, 39% higher rate of thyroid cancer, and a 16% higher rate of PCa. When looking at all cancer types, this population was found to suffer a 24% higher overall rate.²

The causative mechanisms for an increased incidence of PCa among fighter pilots remains unknown. Unique environmental exposures during extended flight times in the cockpit at high altitudes may pose unique mutational processes contributing to prostate oncogenesis. Sources of potential mutagens include ionizing and nonionizing radiation, electromagnetic fields generated by magnetrons for radar and electronic warfare jamming pods, radium-painted cockpit instruments, and exposure to depleted uranium (DU) ordinates.^2,4,5 Other unique exposures in the flight environment which could contribute to the initiation of genomic or epigenomic mutations include jet fuel (JP-8) combustion products, cadmium, and aircraft component cleaning solvents (toluene, benzene, trichloroethylene, etc), which are known carcinogens.^7,8 DU in military armaments does not have a clear causal link to PCa as of now, but the documented increase in birth defects in Iraqi children post-Gulf War highlights the mutational risks to which veterans may be exposed.⁸ DU is known to act as a chemical and radioactive poison, but also can have particulate effects in the respiratory system due to the fine dust, with possible deposition in lower airways and alveoli. Urine testing has confirmed the presence of DU in Gulf War veterans and civilians 8 years after exposure. For scale, the amount of DU that has been employed in the Iraq and Afghanistan conflicts is > 1000 tons, which equates to > 14,000 times more radiation than was detonated upon Hiroshima during World War II.⁸

Aviators and service members throughout the Iraq and Afghanistan theaters of operation were also exposed to burn-pit effluent, fumes, and smoke. In vitro studies have shown that gravitational loading has also been shown to potentially promote prostate carcinogenesis by altering extracellular matrix, focal adhesion, cellular growth, and apoptosis mechanisms.⁹ Known prostatic carcinogens that have a similar impact are dioxins/polychlorinated biphenyls (eg, Agent Orange/Blue). A similar increased risk of PCa was seen after exposure to dioxin (Agent Orange), which led to identifying multiple mechanisms for which dioxin may have contributed to PCa. Dioxin was found to promote metastasis and induce carcinoma-like patterns of prostate cells secondary to cholesterol ester accumulation and ACAT1 upregulation.^7,10 Cancers in veterans from these exposures entitle them to Veterans Health Administration care/compensation via the recently implemented PACT (Promise to Address Comprehensive Toxics) Act.

The higher rates of PCa in aviators underscore a potential difference in oncogenesis in this population compared to the general population, likely secondary to occupational factors. The aim of the Aviator Prostate Cancer Working Group, which is sponsored by the Prostate Cancer Foundation, is to understand the specific causes of this increased oncologic risk in a multifaceted manner. Our work will further elucidate the rate of PCa in military aviators and nonaviator subjects, and determine the transcriptional and metabolic footprint of aviator-associated PCa, as well as to look for patterns of DNA methylation which could establish a molecular signature of the exposures. Further investigations must be done to better understand these genomic, transcriptomic, metabolomic, and epigenomic alterations that occur in aircrew, which lead to the early-onset aggressive nature of PCa seen in military aviators.

The AUA Legislative Action Committee (LAC) Veterans Health Working Group (VHWG) has been a strong advocate for PCa research in veterans. The VHWG coordinated legislative efforts by the AUA LAC and Research Advocacy Committee which were pivotal in HR 4880/SR 2720 being signed into law as part of the 117th congressional omnibus bill, creating VPCTRA (the Veteran’s Prostate Cancer Treatment and Research Act). VPCTRA established the National Veterans Prostate Cancer Program, providing veterans with access to diagnostic testing and state-of-the-art PCa care, creation of the National Oncology Program clinical pathway, and research registries and initiatives that will focus on locoregional disease.

Earlier this year, VHWG member and US Navy flight surgeon Jeff “Indy” Jones (Figure 1) and fellow Tomcat pilots Mike “Bing” Crosby (Figure 2) and Chris “Kid” Provan (Figure 3) met with Texas Congressman Jake Ellzey (Figure 4), who worked with other members of the Mach 1 Caucus (Mike Garcia [California], Scott Franklin [Florida], August Pfluger [Texas; Figure 5]), a congressional cohort of former military fighter pilots, to propose specialized research on PCa in military pilots. Figure 6 shows various types of aircraft flown. AUA president Randall Meacham, supported by the AUA LAC, signed a letter endorsing the legislation, and this advocacy along with pressure from military medicine resulted in Congressman August Pfluger’s introduced HR 4886–Aviation Cancer Examination Study (ACES) Act language being included in the National Defense Authorization Act for fiscal year 2023, which has since been sent to the US Senate for further deliberation. In broad terms, the ACES Act would direct the study of the incidence and mortality of cancer among individuals who served in the Navy, Air Force, or Marine Corps as aviators or aircrew members. While the ACES Act will support causation research for PCa in aviation personnel, additional work will need to include identifying chemicals, compounds, agents, and other phenomena that cause elevated cancer incidence and mortality risk among the cohort.

In summary, due to the exposures required of their profession, PCa in veterans represents a unique challenge, as reflected in the higher rate and earlier onset in aviators, and more aggressive cancers in the dioxin exposed, thus requiring a sophisticated and comprehensive research program with inclusion of multiomic and focused epigenetic studies. The AUA, via the LAC, Research Advocacy Committee, and the VHWG, is proud to advocate for this important research in the defenders of our skies.