LOS ANGELES — The defoliant known as Agent Orange has been linked to a wide range of malignancies since the conclusion of the Vietnam War, including prostate cancer. Veterans exposed to the toxic agent develop prostate cancer at a younger age and are diagnosed at a more advanced stage than those who were not.
Researchers at the VA Greater Los Angeles Healthcare System, the VA National Oncology Program and the Durham, NC, VAMC joined forces with others at the University of California-Los Angeles and the University of Pennsylvania to dig deeper into this correlation to determine whether exposed veterans developed different somatic mutations than their comrades.1
To do so, the team studied genomic alternations identified from tumor testing performed between 2019 and 2022 in a large population of veterans with metastatic prostate cancer. Primary prostate and metastatic carcinoma tissue specimens were also sent to Foundation Medicine for sequencing of the tumors.
Tumor-only genomic testing was done on samples from 2,673 veterans, of which 629 reported Agent Orange exposure. Cross-checks of service records confirmed 603 patients served during periods and in locations associated with Agent Orange exposure.
Univariate analysis found that TMPRSS2-ERG fusions occurred much more often in exposed veterans (35.5% vs 28.8%, p<0.01). In addition, the team found a correlation between Agent Orange exposure and higher rates of androgen receptor (AR) alterations (12.4% vs 9.5%, p<0.01) and noted that the frequency of FGFR1/2/3/4 alterations in exposed veterans was twice that in those not exposed to Agent Orange, 3.2% vs. 1.7% (p=0.02).
The researchers did not observe any correlation between exposure and mutations in TP53, CDK12, ERBB2, EGFR, BRCA, DNA damage response and repair, mismatch repair or PTEN/P13K/AKT pathways.
After adjustments for race, age at diagnosis, smoking status, secondary malignancies and environment, the only alteration that remained more common in exposed veterans was found in AR (OR 1.43, p=0.02). As previously noted, age at diagnosis and Black race decreased the likelihood of TMPRSS2-ERG alterations.
The researchers concluded that their findings could have implications for the prognosis of veterans exposed to Agent Orange and may provide an area of exploration for new therapies.
- Zhang JJH, Wadhwa A, Weiner AB, Kwan L, Kelley MJ, Chamie K, Maxwell KN, Garraway I. Genomic alterations and self-reported Agent Orange exposure in United States veterans with metastatic prostate cancer. 2023 ASCO annual meeting. June 2-6, 2023. J Clin Oncol 41, 2023 (suppl 16; abstr 5068).
