NEW YORK – Researchers at the University of California, San Francisco hope to establish new prostate-specific antigen (PSA) cut-off values for prostate cancer screening in transgender women after a study published in JAMA Network in June showed that using current thresholds, providers could miss cancer in some patients.
Transgender women are less likely than cisgender men to receive regular prostate cancer screenings, and for those on gender-affirming hormone therapy, reference ranges for prostate-specific antigen may be too high to reliably detect cancer. Doctors usually recommend PSA screening beginning at age 50 for men who are at average risk of prostate cancer and at age 40 for men at high risk. For those with PSA levels under 2.5 ng/mL at their initial screen, repeat testing is recommended every two years, and men with levels above 2.5 ng/mL are recommended to receive annual screening.
However, there are no consensus PSA screening guidelines for transgender women. In the absence of specific guidelines, experts typically recommend cancer screening for transgender individuals that aligns with their gender assigned at birth.
Transwomen on hormone therapy between age 50 and 64 have around a twofold lower risk of being diagnosed with prostate cancer than cisgender men. That reduced cancer incidence may be due to the suppressive effects of estrogen on prostate cancer development for those on gender-affirming hormone therapy, but the data show that prostate cancer is not as uncommon in transgender women as previously thought.
When transwomen are diagnosed with prostate cancer, if they're receiving estrogen, they tend to have more aggressive disease, indicating delayed diagnosis or that estrogen treatment is driving resistance to androgen deprivation therapy. In a US Veterans Affairs (VA) study published in 2023, 35 percent of transgender women with prostate cancer receiving estrogen therapy had grade 4 or 5 biopsies, indicating more aggressive disease, compared to just 16 percent of cisgender male veterans.
A team led by Farnoosh Nik-Ahd, a urology resident at UCSF and lead author on the 2023 VA study, built on those findings in the newer study published in JAMA Network by investigating whether standard PSA screening cutoffs may be failing to catch prostate cancer in transgender women on estrogen. For both studies, she and her colleagues searched VA health records for adults with transgender identity using International Classification of Diseases (ICD) codes.
However, because there isn't a specific ICD code for transgender identity, the researchers searched for codes likely to be associated with a transgender person that are commonly used in medical records, such as codes for gender identity disorder. "Some of them have very outdated and problematic language … terms we don't really use anymore and are not necessarily at all specific for transgender identity," Nik-Ahd said. "They're not perfect, but we've previously studied their sensitivity and specificity."
They identified nearly 15,000 potential transgender patients in the VA system. Then, Nik-Ahd and her team conducted a detailed chart review of 1,000 randomly selected patients over 40 years of age to confirm transfeminine identity, no history of prostate cancer, and a record of PSA testing performed after at least six months of estrogen therapy.
Nik-Ahd said the reason they looked at patients who had been on estrogen for at least six months is that studies for a different class of medicines, dihydrotestosterone blockers, which are used to treat an enlarged prostate gland, show that after six months of treatment, PSA values are reduced. "We thought that we could extrapolate some of those findings" to estrogen therapy, Nik-Ahd said.
After reviewing those 1,000 charts, the researchers selected 210 transwomen who had received 852 PSA tests. Patients in this cohort had a median age of 60 years and had been on estrogen for a median of 4.7 years. The median PSA for that group was 0.02 ng/mL and 36 percent had undetectable PSA. Similarly aged cisgender men without known prostate cancer have a median PSA of 1 ng/mL.
"[0.02 ng/mL is] about fiftyfold lower compared to PSA values in similarly aged cisgender men," Nik-Ahd said. "It's clear that the upper limit of [4 ng/mL] that is often used as the cutoff for [additional evaluation] based on cisgender men is just way too high for transgender women who are on estrogen."
Sofia Merajver, a medical oncologist who sees many transwomen in the Breast and Ovarian Cancer Risk Evaluation Program at the University of Michigan's Rogel Cancer Center, said prostate cancer screening is often overlooked for transwomen. "We really need to make sure that transwomen are being screened for prostate cancer," she said, noting that stigma and discrimination "may be causing some reticence to bring up the prostate, because here is a person who embraces femininity and identifies as a woman."
Nik-Ahd agreed it's important to raise awareness among clinicians and transfeminine patients about prostate cancer risk. However, considering her study results, she said PSA values should be interpreted "very carefully," because a result that may seem normal is not necessarily normal.
In terms of next steps, Nik-Ahd said, "we are very interested in thinking about what should a [PSA] cutoff value be for a transgender woman who is on gender-affirming hormones, because what's clear from the study is that it's not [4 ng/mL], and we can't say based off this study what a proper cutoff should be."
Another future goal is to investigate the risks and benefits of screening transgender women for prostate cancer. "We don't know what the optimal way to screen transgender women is," Nik-Ahd said, "and even [whether] that screening should include PSA. Those are all things we hope to look at in the future."