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Transgender Patients With Hereditary Cancer Risk Variants Benefit From Individualized Approach

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Doctor with a stethoscope wearing a rainbow badge

NEW YORK – Some healthcare providers are taking an individualized approach to cancer screening and surveillance for transgender and gender-diverse people with pathogenic variants in hereditary cancer risk genes such as BRCA1/2, not just using the limited evidence and guidelines in this area but also factoring in patients' preferences, treatment goals, and negative experiences in the healthcare system.

Transgender carriers of hereditary cancer risk variants may have a different level of risk for certain cancers than cisgender individuals with these variants, since the former may use gender-affirming hormone therapy or surgical procedures. Transgender individuals may also experience gender dysphoria or have negative encounters with the healthcare system that make them reluctant to undergo genetic testing, routine screening, or surveillance for cancer recurrence.

One study published in 2022 in the American Journal of Clinical Oncology found that transgender people are less likely than cisgender people to undergo breast and cervical cancer screening. Another study published in 2023 in BMJ Evidence-Based Medicine concluded that transgender and gender-diverse individuals did not receive cervical and mammography screening at recommended frequencies. Transgender patients also receive fewer prostate cancer screenings than their cisgender counterparts, as noted in a 2024 publication in JAMA Network Open.

Until recently, there was little guidance specifically on cancer prevention strategies for transgender patients with hereditary cancer risk variants, but that's beginning to change. This year, the National Comprehensive Cancer Network issued cancer risk reduction guidelines for transgender, nonbinary, and gender-diverse people with hereditary cancer syndromes based on genetic factors and their familial cancer history. The guidelines are part of a 2020 NCCN initiative that directs committees to develop recommendations that fully address the needs of all sexual orientations and gender identities of patients.

Certain hereditary risk variants are of particular concern when treating transgender and gender-diverse patients. Patients with pathogenic germline variants in BRCA1, BRCA2, ATM, BRIP2, PALB2, RAD51C, and RAD51D and those with Lynch syndrome are at heightened risk for ovarian cancer. BRCA1, PTEN, and Lynch syndrome are associated with uterine cancer. Prostate cancer risk can be affected by pathogenic variants in BRCA1, BRCA2, and ATM. And patients with BRCA1, BRCA2, ATM, CHEK2, and other pathogenic alterations are at increased risk for breast cancer.

The NCCN guidelines flag these risks and offer suggestions for screening, surveillance, and risk reduction, as well as advice to minimize gender dysphoria for transgender, nonbinary, and gender-diverse patients. Many of the recommendations match what would be advised for the person's gender assigned at birth.

For example, Sofia Merajver, a medical oncologist at the University of Michigan and a member of the committee that wrote the new NCCN guidelines, noted that a transfeminine individual with reduced testosterone exposure but who carries a pathogenic variant in a hereditary cancer risk gene like BRCA1 or BRCA2 is likely at lower risk of prostate cancer than a cisgender male carrying such variants. However, because there is no data confirming that, the transgender patient would default to the same regular screening as a cisgender male.

For individuals assigned male at birth, the lifetime risk of breast cancer is about 6 percent, Merajver said, and even if those men are carriers of BRCA1 or BRCA2 pathogenic alterations, they would still be at lower risk for breast cancer than the lowest-risk cisgender female. "[Transwomen] can definitely have a mammogram every year," Merajver said. "However, if they were [cis] females, they would not be recommended to be screened at 6 percent [risk] beyond just starting at the usual age of 40."

Despite the NCCN now recommending that transgender individuals can undergo screening similar to cisgender individuals in many cases, guidelines still have significant gaps when it comes to addressing the effects of gender-affirming hormone therapy, and there are uncertainties about how to manage the intersection of gender-affirming surgery and risk-reducing surgery. Decisions about hormones, surgery, and other choices related to transition are largely left to doctors and patients. In the absence of research clarifying risks and best practices, many providers are advocating for an individualized approach, taking into account the patient's goals and quality of life in addition to cancer risk calculations that are often largely theoretical.

Uncertainties around gender-affirming hormone therapy

Transgender and gender-diverse patients with hereditary cancer risk variants may be on or considering gender-affirming hormone therapy. Hormone therapy for transfeminine individuals can include androgen blockers to reduce testosterone levels and estrogen and progesterone to achieve goals such as breast growth, body fat redistribution, and reduced body hair. Transmasculine patients on gender-affirming hormone therapy primarily receive testosterone, which causes the voice to deepen, increases facial and body hair, builds muscle mass, and suppresses ovarian function.

Theoretically, both types of hormone therapy could drive the growth of hormone-sensitive cancers. For example, increased levels of estrogen in the body can drive the growth of estrogen-sensitive breast cancer, and testosterone can be converted to a form of estrogen in the body, potentially leading to the same effect. However, the science underlying those speculative risks is largely based on data from cisgender individuals. Very few studies have examined the effects of gender-affirming hormones in transgender patients, and even less is known about their use in transgender people with hereditary cancer risk variants.

Ole-Petter Hamnvik, an endocrinologist at Brigham and Women's Hospital in Boston who specializes in care for cancer patients with endocrine concerns, said the lack of research is largely due to the rarity of the two overlapping patient categories. Transgender people represent approximately 0.6 percent of the US population ages 13 and older, according to a 2022 report by the Williams Institute at the UCLA School of Law. Meanwhile, only a small percentage of the population carry hereditary cancer risk variants.

For example, in a population-based case control study published in 2021 in the New England Journal of Medicine, just 1.63 percent of patients in a group of more than 32,000 patients without breast cancer had pathogenic variants in a dozen cancer-associated genes, including BRCA1 and BRCA2.

Hamnvik compared studying hereditary cancer risk variants in transgender people to attempting to study people with two uncommon comorbidities. He offered the example of breast cancer patients with rheumatoid arthritis. There isn't any data on whether doctors should modify the treatment for this subset of patients, "and we don't tend to get overly concerned about it. … We go ahead and treat the cancer."

Tailoring treatment to patients' goals

While Hamnvik would love to use data from big studies when making decisions about cancer screening for transgender people with cancer risk variants, smaller studies have shown that breast and prostate cancers are less common among transgender individuals on gender-affirming hormone therapy than their cisgender counterparts. In Hamnvik's view, given the lack of studies clarifying the risks, doctors can navigate decisions with patients.

"It becomes even more important, then, to have a conversation with the patient about the potential, theoretical risks that we have no data on," Hamnvik said, adding that there might be benefits with options such as gender-affirming therapy that are more of a priority to the patient than minimizing cancer risk as much as possible.

Hamnvik said hereditary cancer risk concerns for a transgender individual arise about once a month in his practice, which necessitates a referral for genetic testing. Only a portion of those patients test positive for a pathogenic variant associated with hereditary cancer risk, and they are the only ones for whom decisions must be made about gender-affirming hormone therapy.

"As an endocrinologist, I'm very comfortable with hormones," Hamnvik said. "Medical oncologists are typically more on the cautious side … because they hear hormone-responsive cancers, and the gut reaction is to be afraid of the hormones."

Hamnvik said that the prevailing cultural prejudice against transgender individuals can sometimes make providers resistant to gender-affirming hormone therapy, and within any care team, he sees his role as that of an educator. He recalled an experience with a transmasculine patient whose ovarian cancer had recurred but after treatment, the patient had no evidence of disease. Still, the oncologist told this patient that he remained at high risk of cancer recurrence and expressed concerns that the patient's gender-affirming testosterone therapy could increase that risk as some testosterone is converted to estrogen in the body.

This patient had been off testosterone therapy for a year after the first recurrence and had been miserable due to loss of the masculine features that he had developed previously with hormone treatment. The patient preferred to go back on hormone therapy, knowing it could increase the risk of another cancer recurrence.

"The oncologists are appropriately focused on reducing the risk of cancer," Hamnvik said. "Just like I wouldn't make cancer treatment decisions on behalf of the oncologist, decisions about gender-affirming hormones probably should not be made by the medical oncologist on behalf of the endocrinologist."

Hamnvik said his approach to gender-affirming hormone therapy where there is hereditary cancer risk is to evaluate whether the standard of care in that situation for a cisgender patient would be to remove the ovaries or testes or use medications to suppress all hormone production.

For example, the standard-of-care for a cis woman with a BRCA1/2 mutation with a family history of cancer is to remove the breasts and ovaries by age 35. Since the resulting loss of estrogen can lead to uncomfortable vasomotor symptoms and bone loss, Hamnvik will typically offer estrogen replacement therapy after a discussion of risks and benefits.

Applying the same logic to transfeminine individuals, Hamnvik would not consider a known BRCA1/2 mutation to be an absolute contraindication to estrogen therapy in such patients, but will offer it after a discussion of risks and benefits. Similarly, testosterone therapy could also be offered to transmasculine patients after risk-reducing surgeries as there is no recommendation to institute androgen deprivation in cisgender individuals with known BRCA1/2 mutations. 

"Very rarely is the patient in a situation where you would render them hypogonadal, or without hormones, because of cancer risk," Hamnvik said, noting also that there's no evidence exogenous hormones increase cancer risk more than those produced by the human body. "If I'm not concerned about allowing a cisgender person to continue to have their hormones, there's no reason I should be worried about providing a trans person with hormones."

While a gender transition involving hormone therapy may lead to a somewhat increased risk for certain kinds of hormone-sensitive cancers, based on the limited studies available, Merajver believes that the individual's risk will remain close to that of their gender assigned at birth. Other factors such as alcohol use, diet and exercise habits, and obesity impact the risk of breast cancer much more than a gender transition, she reflected. For example, transwomen on estrogen therapy have a lower risk of prostate cancer than their cis male counterparts. Merajver noted that the changes in cancer risk involved in a gender transition journey are much less significant than those associated with lifestyle factors, which are difficult, or often impossible, to calculate for an individual patient.

After considering what is known and unknown about cancer risk, the patient's own goals can't be ignored, in Hamnvik's view. For some patients, achieving an overall male or female phenotype is more important than minimizing cancer risk. In others, transgender patients with hereditary cancer risk variants may prefer to forgo hormones and meet their embodiment goals in other ways. For instance, Hamnvik said if the patient carries a pathogenic variant in BRCA1 or BRCA2 and the main goal is to develop breast tissue, skipping hormones in favor of breast augmentation may be a better choice.

Another accommodation that could be made for patients with elevated risk for hormone-sensitive cancers would be to adjust or reduce the hormone dose, according to Hamnvik. That might particularly be an appropriate option for patients over 60 years old, whose cancer risk and overall medical risk is higher, but for whom hormone therapy is also a priority.

Hamnvik recalled an experience navigating a cancer risk concern for a patient, who was assigned male at birth and requested gender-affirming estrogen therapy while undergoing gender transition. However, her family health history revealed that her mother had breast cancer in her 40s.

"This was a scenario where obviously there was a concern for a hereditary breast cancer syndrome," Hamnvik said. He referred the mother for genetic counseling and testing for hereditary cancer risk variants. In the meantime, the patient had been contemplating her transition for some time and was eager to begin gender-affirming hormone therapy. Hamnvik reasoned that for a cisgender woman in the patient's position, he would not recommend removal of the ovaries immediately, and therefore, estrogen therapy comparable to what would be produced by the ovaries would be safe enough while they waited for more information. As it turned out, the patient's mother was a carrier of a CHEK2 pathogenic variant, but the patient herself tested negative for the same variant.

Balancing risks and benefits of surgery

Transgender patients may seek surgery to alleviate gender dysphoria and align their physical characteristics with their gender identity. These surgeries fall broadly into two categories known colloquially as top and bottom surgeries. A top surgery alters the chest or breasts. For example, a transmasculine individual may seek surgery to remove the breasts to create a more masculine chest, while for a transgender woman, top surgery could involve breast augmentation. Similarly, transgender people may undergo procedures, such as a vaginoplasty or a phalloplasty, to modify the genitals or undergo surgeries to remove the ovaries or testicles.

However, a gender-affirming mastectomy and a mastectomy performed to reduce breast cancer risk are different in that the former leaves behind some breast tissue and the latter doesn't. This necessitates a nuanced decision-making process between the patient and physician about how much tissue to leave behind depending on the patient's goals and tolerance for cancer risk.

Hamnvik recalled a transgender male patient who opted for a more extensive mastectomy than usual due to a family history of breast cancer. However, the patient requested that the surgeon not remove the nipples, because that was aesthetically important to him.

If a transgender person has a known cancer risk variant, it can also affect decisions around bottom surgery. Rachel Hodan, a genetic counselor at Stanford University, specializes in hereditary gastrointestinal conditions, including Lynch syndrome. She and collaborators published recommendations for cancer surveillance for transgender and gender-diverse patients with Lynch syndrome in Familial Cancer last year. Those recommendations include avoiding the use of the sigmoid colon — the portion of the large intestine that links the colon to the rectum — to construct a neovagina during bottom surgery for patients with hereditary cancer syndromes predisposing them to colon cancer, such as Lynch syndrome.

Hodan said the use of colon tissue in constructing a neovagina is a much less common practice today than it once was, but still cautioned that for patients with Lynch syndrome, reconstructed tissue would be associated with an increased risk for colon cancer and make it harder for providers to surveil for cancer. "The tissue is just not as accessible as it would be in the sigmoid [colon] where you could potentially remove a polyp during a colonoscopy," she said. For patients with Lynch syndrome who have already had gender-affirming vaginoplasty using sigmoid colon tissue, Hodan and her collaborators recommend adding a pelvic exam with colposcopy to the surveillance schedule at the same one-year to three-year interval recommended for colonoscopy.

Countering discrimination and dysphoria

For many transgender and gender-diverse patients with elevated hereditary cancer risk, gender dysphoria and negative experiences in the healthcare system are nearly as distressing as a potential cancer diagnosis. Patients often must be seen in clinics that cater to a specific gender and undergo procedures that remind them of the gender that they hoped to leave behind.

An attorney in the Boston area, who goes by the singular name Morgan, was diagnosed with breast cancer while in therapy for gender dysphoria and tested positive for a pathogenic BRCA2 variant. They underwent aggressive treatment for the cancer, including mastectomy, ovary removal, radiation, and chemotherapy.

"During this whole time, I'm grappling with gender identity stuff. I came out of it with this attitude that life is really [expletive] short," Morgan said. "I went on [testosterone] fairly soon after I finished up cancer treatment."

Entering cancer surveillance as a trans man and a BRCA2 carrier, Morgan was thrown into a highly gendered breast clinic environment. "Everything had pink ribbons on it. It was super lady focused," Morgan said. "That did not feel like a welcoming space for me."

"Gendering of institutional milieus shapes how trans patients feel when they enter the building and navigate care," said Sarah Roth, a genetic counselor and graduate student in the department of anthropology at Johns Hopkins University, who also identifies as genderqueer and carries a BRCA1 pathogenic variant. "From pink ribbon campaigns to the spaces themselves, the overt gendering of oncology creates an atmosphere of discomfort for LGBTQI+ folks."

In Genetic Counseling last year, Roth and other colleagues published on how transgender and gender-diverse patients experience risk assessment and counseling for hereditary cancer syndromes in the medical system. Patients they spoke to described dealing with a range of complex interactions, from microaggressions to overt discrimination.

"Unfortunately, transgender and gender-diverse patients encounter discrimination relatively frequently, especially in regions with policies in place that are hostile to trans folks," said Roth. "In our study, most participants described experiences of discrimination or insensitive care in the context of their cancer treatment or prevention." Those experiences included misgendering, risk assessment based purely on norms for cisgender patients, and refusal of care.

In one interview, a nonbinary patient, Zoe, recounted how they asked a plastic surgeon about having a risk-reducing mastectomy without reconstruction. The surgeon responded that they "don't serve trans people," leaving Zoe feeling unsupported and mistaken for a trans man when they were actually nonbinary.

Morgan recounted an encounter with a surgeon who tried to talk them out of continuing gender-affirming hormone therapy due to the unknown effects of testosterone on breast cancer risk.

Roth and her coauthors said that demonstrations of allyship and mindful use of language among providers could mitigate feelings of gender dysphoria brought up during cancer screening and surveillance. "Being mindful means going beyond a checklist and treating an encounter as an intersubjective dynamic that calls for awareness and compassion, for the patient and for oneself," she said.

Providers can also help transgender patients with pathogenic variants in hereditary cancer risk genes by anticipating additional challenges they may have. For example, Hodan, the genetic counselor from Stanford University, noted that many trans individuals are not in contact with their families and are unable to gather family history information or recommend genetic testing to their families.

"Transgender and gender-diverse patients [often] don't have access to their biological family because of trauma and discrimination or rejection from their nuclear family," Hodan said.

That consideration might inspire ideas such as offering sedation during pelvic exams, wearing a rainbow lanyard to show allyship, or simply apologizing after accidentally misgendering a patient. Hamnvik recalled a situation, in which a transmasculine patient with breast cancer was uncomfortable in the clinic waiting room. His breast oncologist arranged for him to see him in the lung cancer clinic upstairs, which does not specifically cater to women, and it was a much more comfortable environment for him.

Although the NCCN guidelines and efforts to study trans patients' experiences in the healthcare system are helping doctors manage transgender patients with cancer risk variants, providers are still working amid large knowledge gaps. "When we get together for conferences, to be honest, there is a tremendous amount of uncertainty," Merajver said. 

Hodan emphasized that more studies are needed to clarify the most effective care for this population of patients. "A lot of medical providers feel unprepared for the encounter [with a transgender patient]," she said. Although it helps to have practical guidance to prepare for these conversations, additional data clarifying the risks would go a long way to relieving anxiety for patients and providers.

In the 2024 NCCN guidelines for genetic and familial high-risk assessment for breast, ovarian, and pancreatic cancer, the authors highlight a need for research regarding the impact of gender-affirming hormones and puberty-blocking agents and their interactions with hereditary cancer risk to optimize prevention strategies for transgender patients. They also call for a national registry on health outcomes for transgender, nonbinary, and gender-diverse populations to facilitate study of those risks, with the caveat that patient privacy must be protected.

Until more data is available, doctors can help by providing sensitive, individualized care that balances cancer risk reduction with the patient's individual gender transition goals. "Quality of life impacts length of life," Merajver said. "Having a stable, embraced, accepted trajectory is a very important part of your quality of life."