Breast Cancer and Gender-Affirming Hormone Therapy for Transgender and Gender-Diverse (TGD) Individuals

Abstract

Transgender and gender-diverse (TGD) individuals are at risk for breast cancer, but are less likely to undergo screening mammograms and appear to suffer poorer cancer-related outcomes than cisgender women. Gender-affirming hormone therapy (GAHT) may be lifesaving for TGD individuals from the perspective of affirming their core identities; however, the effects of GAHT on cancer development, progression, and outcomes are poorly understood.

Introduction

Transgender and gender-diverse (TGD) people identify with a different gender from that assigned at birth. This diverse community is inclusive of people who identify as transgender men, transgender women, and as non-binary whose identities lie outside the traditional, cisnormative binary. There are also gender-diverse individuals who find other terms to be more affirming of their gender identity. TGD individuals experience numerous breast cancer-related disparities, but many issues facing TGD individuals with breast cancer remain understudied. This review includes discussions of what is currently known about these breast cancer-related disparities, associations between gender-affirming hormone therapy (GAHT) and breast cancer risks, interactions between GAHT and breast cancer-directed therapies, and survivorship/symptom control issues facing TGD individuals.

Methods

We searched PubMed using the keywords transgender or “gender identity” and related, yet outdated (and non-affirming) terms for people identifying as transgender (including “transsexual,” “female-to-male,” “male-to-female”) and breast cancer. While initially, the search was limited to clinical trials, meta-analysis, randomized controlled trials, and systematic reviews, this only yielded 17 results. Therefore, the search was broadened to all article types over all years, which identified 239 peer-reviewed publications. This search strategy was supplemented by a search of the references of key articles. We achieved inclusion of identified articles by assessing a study’s impact and its methods, with preference given to higher quality studies, such as randomized controlled trials.

Breast Cancer-Related Disparities Facing Transgender and Gender-Diverse People

The number of TGD people who have come out in the United States is growing exponentially, primarily driven by the increasing number of out transgender youth.¹ While approximately 0.6% of US adults identify as transgender or gender diverse (TGD), 1.4% of US youth identify as TGD.¹ Among transgender adults, 38.5% identify as women, 35.9% as men, and 25.6% do not identify with a single gender identity.¹ These individuals are sometimes reluctant to disclose their identity, and so the reported numbers are likely an underestimate of this growing population.

Harrowingly, approximately 40% of TGD people attempt suicide.² Thus, for many TGD people, gender-affirming therapy, including hormonal therapies, can be viewed as lifesaving. A systematic review of 20 studies substantiates that gender-affirming therapy improves gender dysphoria, psychological functioning, sexual function, and quality of life, with a decrease in depression and anxiety among TGD people.³

TGD individuals also are at risk for cancer-related disparities. They are less likely to engage with healthcare systems and undergo cancer screening, including screening mammography for breast cancer.^2,3 This is driven in part by poor social determinants of health and high levels of discrimination. For instance, TGD people suffer from high rates of underinsurance (fueled by factors such as workforce discrimination), outright exclusion by healthcare systems, and violence due to expressions of their gender identities.^4,5 Lack of clinician education and inadequate research on cancer risk among TGD individuals likely also exacerbates poor screening.^6–9 Clinicians may be unaware of screening guidelines for TGD individuals or may not understand cancer risks after gender affirming surgeries; furthermore, current breast cancer risk calculators are likely not accurate for TGD individuals on gender affirming hormone therapy.^6–9 Cancer screening mammography in TGD individuals is challenging because breasts are notably gender-affirming or gender-non-affirming organs – circumstances that make such screening problematic and emotionally charged for TGD people. A cross-sectional study of slightly over 1000 TGD individuals eligible for a screening mammogram reported that transgender men assigned female sex at birth were less likely to have had even one screening mammogram compared to cisgender women (OR 0.32, 95% CI 0.31–0.32), and TGD individuals assigned male at birth were even less likely to have had a mammogram (OR 0.02, 95% CI 0.02–0.02).⁴ Another single-institution study included 253 TGD patients and reported that between 2–50% TGD individuals assigned female at birth and 7–48% of TGD individuals assigned male at birth received screening mammography within 2 years.⁵ These rates are abysmal compared to screening rates of over 75% in cisgender women.^5,6

Furthermore, TGD individuals are diagnosed at locally advanced or metastatic stages of cancer at higher rates than the general population; they are are also less likely to receive treatments directed towards their cancer and are more likely to die from their cancer than the general population.^5–10 Although previous studies corroborate the above statements, these disparities are likely more severe than the data indicate as TGD individuals are often invisible in oncology clinics, suggesting a crisis in cancer care among TGD individuals. Data sources – from institutional tumor registries to national databases -- have historically not asked about gender identity.^11–21 Even as recently as 2022, only 58% of oncology practices nationwide reported routinely asking about gender identity.^11–13 Furthermore, TGD individuals are often absent, and even excluded from cancer clinical trials.¹⁰ This absence of data hinders our ability to optimize cancer care in TGD people with breast cancer. In the largest study to date of TGD individuals with cancer in the United States (total n of TGD people=589), only 35 had breast cancer, a small sample size that limits our ability to define standards of care relevant to this group of patients (other published data involve case series or single cases).^8,10

TGD individuals with breast cancer, in particular, experience numerous unmet needs. While GAHT can be lifesaving, pivotal questions remain as to associations between GAHT, particularly exogenous estradiol and testosterone (but also progesterone and androgen receptor blockers), and risks for breast cancer development, risks for cancer progression, and risks for poorer outcomes because of potentially competing hormonal interventions.

Risks for Breast Cancer Development among TGD People on GAHT

The risk for breast cancer, particularly hormone receptor-positive (HR+) breast cancer, is poorly understood among TGD individuals receiving estradiol-containing GAHT. While data are limited, one study found that transgender women, who receive estradiol-based GAHT, experience a 46-times higher risk for invasive breast cancer compared with cisgender men.²³ Most of the breast cancers identified among transgender women are hormone-receptor positive (HR+). Furthermore, transgender women often have dense breasts, which is an independent risk factor for breast cancer, at least in cisgender women.²⁴ However, transgender women still appear to experience a lower rate of breast cancer than cisgender women (standardized incidence ratio of 0.3, 95% confidence interval 0.2–0.4).²³

The risk for breast cancer, particularly HR+ breast cancer, among TGD individuals who receive testosterone-containing GAHT is also poorly understood. Among transgender men, the risk for breast cancer is often mediated by an individual’s pursuit of gender-affirming “top” surgery – 97% of transgender men have or plan to have top surgery.²⁶ Top surgery, which typically consists of bilateral subcutaneous mastectomies, reduces risk for breast cancer significantly. However, top surgery is not equivalent to a breast cancer risk-reducing bilateral mastectomy, as some breast tissue still remains post-operatively. Bilateral oophorectomy may also reduce the risk of breast cancer by decreasing endogenous estrogen exposure, but this procedure is less frequently pursued. Indeed, epidemiologic cohort studies, including two conducted in the United States, suggest that transgender men are less likely to carry a diagnosis of breast cancer than cisgender women (these studies did not control for top surgery); however, transgender men are more likely to be diagnosed with breast cancer compared with cisgender men.^10,23,24,27 As far as breast cancer biology in transgender men, one systematic review of the 31 cases of breast cancer in transgender men in the literature reported that 21 were HR+ and 6 were estrogen receptor negative (of note, 8 were androgen receptor positive and 2 were androgen-receptor negative; only 10 were tested for androgen receptor).²⁸ According to a large cohort study from the Netherlands, age of diagnosis was younger in transgender men with breast cancer (median age at diagnosis was 47 years), but the genetic predisposition for breast cancer among individuals in this cohort was unknown.²³

Risks for Breast Cancer Progression among TGD People on GAHT

Data on risks of estrogen-based GAHT on breast cancer progression are sparse, and conclusions need to be extrapolated from studies of cisgender women who receive hormone replacement therapy (HRT) to treat symptoms of a menopausal transition. While lifetime exposures to estrogen among transgender women may be less than lifetime exposures among cisgender women (depending on timing of initiation of GAHT), doses of the exogenous estradiol in GAHT are typically much higher than doses of estradiol in HRT. Therefore, extrapolating findings from cisgender women to transgender women might lead to inaccurate conclusions. Generally, estradiol utilized as a part of HRT is contraindicated among women with HR+ breast cancer, as proliferation of estrogen receptor positive breast cancers is induced by estrogen; HRT has been associated with higher risk for breast cancer recurrence.²⁵ Therefore, it is likely that estradiol-containing GAHT would also pose significant risks for HR+ breast cancer proliferation, although such risks have not been well-characterized.

There are also limited data regarding risk for breast cancer progression among transgender men who are receiving testosterone-based GAHT. The existent data are primarily from pre-clinical studies and conflicting in their conclusions. In one histologic study of tissue gleaned from TGD individuals on testosterone therapy, testosterone was found to reduce glandular breast tissue and increase fibrous tissue.²⁹ As far as associations between testosterone exposure and estrogen concentrations, of 6 studies that report on estrogen (as measured by E2) concentrations among TGD patients who received testosterone, results varied greatly; 2 demonstrated reduced serum E2, one reported no significant changes, and 3 reported an increase in serum E2, likely reflective of variable patient populations in regards to age, menopausal status, and medications.^28,30,31 Animal studies suggest that testosterone may be protective against breast carcinogenesis but that high concentrations drive breast cancer proliferation.^28,32

Interactions between Endocrine therapy and GAHT, Potentially Increasing Risks for Poorer Breast Cancer Outcomes

Minimal evidence guides TGD individuals and their healthcare providers on interactions between GAHT and breast cancer-directed therapies. The challenge of defining the best care in the face of GAHT is particularly great considering hormone-modulating endocrine therapies, which are used to treat HR+ breast cancer, the most common subtype.²² Standard-of-care first- and second-line HR+ breast cancer-directed therapies entail endocrine therapies, which block the action of estrogen (which can be derived from testosterone) on cancer cell proliferation. Commonly prescribed medications, such as tamoxifen, aromatase inhibitors (letrozole, anastrozole, or exemestane), and fulvestrant, with or without a gonadotropin releasing hormone (GnRH) analog, function in this manner.

Interactions between HR+ breast cancer-directed therapies and GAHT in the form of estradiol and testosterone (at the doses utilized in GAHT) are largely unknown. Endocrine therapies, such as tamoxifen, block estrogen’s interactions with its receptor. Theoretically, these receptor effects are downstream from the action of exogenous estrogen and testosterone and may counteract effects of GAHT. Other endocrine therapies, such as the aromatase inhibitors, block the development of estrogen from hormones such as testosterone. While aromatase inhibitors would not be effective in blocking exogenous estrogen given as GAHT for transgender women, these medications might block testosterone given as GAHT for transgender men. Studies report that testosterone-mediated growth of breast cancer lines is suppressed by aromatase inhibitors; clinical trials utilizing testosterone in women with HR+ breast cancer on aromatase inhibitors report no elevation in estradiol levels.^33,34 However, it is unknown how cancer progression among transgender men with breast cancer may be impacted by the doses of testosterone utilized as a part of GAHT in conjunction with (or without) endocrine therapy.

Understanding the risks — or benefits — of combining GAHT with these therapies are of paramount importance in treating cancer in TGD individuals who are receiving GAHT. And, yet, to ask a TGD individual to choose between relinquishing lifesaving GAHT and compromised breast cancer-directed therapies in the absence of data-driven recommendations appears unjust and detrimental. Case reports describe that some TGD people stop GAHT upon diagnosis of breast cancer and some do not.^35–43 Primary concerns of stopping GAHT and/or starting endocrine therapy include detrimental effects on a TGD person’s core gender identity and the mental and physical health risks of untreated gender dysphoria, that appears to be associated with high suicide rates. Concerns with stopping GAHT are likely exacerbated by TGD patients’ prior experiences with stigma and discrimination within the healthcare system, lack of health insurance coverage and financial means, and related issues that span the spectrum of social determinants of health.^2,35–43 On the other hand, other TGD individuals may decide to start antineoplastic endocrine therapy and maintain their GAHT, while others may make the choice to maintain GAHT and decline to initiate endocrine therapy. Further information is sorely needed to help guide the risks versus benefits facing TGD individuals with HR+ breast cancer.

Additional Unique Concerns Facing TGD Individuals with Breast Cancer

As TGD people face significant discrimination and stigma, maintaining their privacy and safety throughout the cancer care continuum is of upmost importance. The issue of privacy is particularly salient in lieu of recent events; one medical center in Tennessee released private medical records of TGD individuals with connections to the government to the state’s attorney general. This prompted a federal civil rights investigation. Unfortunately, outright discrimination causing safety issues has also been highlighted by interviews of TGD cancer survivors. In one collection of qualitative interviews involving individuals with cancer conducted by Kerr et al, a transgender man described his post-operative transfer to a hospital ward with 3 women and stated, “I had this big burly bloody security guard turn up, poking his finger in my chest saying ‘women do not behave like you.’ I canceled all my postoperative appointments, everything, never went back near them again.”⁴⁴ In another qualitative interview study conducted by Lisy et al, a person who required home health care after cancer-directed therapies reported, “It’s been a real battle to get any help that’s appropriate, and in-home nurses that come, they just send you a new one, every single time it’s a different person and if you can appreciate the anxiety of trying to get someone that you’ll think you’ll be safe with, um, and some were accepting and some weren’t, some were really rough, yeah, when they sort of found out, and just walked off.”⁴⁵ Healthcare systems will only improve upon the significant disparities facing TGD people with breast cancer if they are able to ensure each patient’s privacy and security, and if they hire professionals – from nursing professionals to security guards -- who will treat all people with care and respect, irregardless of their gender identities.

Another serious concern among TGD individuals receiving cancer care is the potential negation of their core gender identity by cancer diagnoses and subsequent cancer-directed therapy. Transgender men presenting to breast cancer clinics, particularly those identified as “women’s cancer” centers, report being asked repeatedly if they were in the wrong place, and hoping to “be as invisible as possible.”⁴⁶ Cancer-directed surgeries may worsen gender dysphoria; alternatively, to others, some surgeries may be gender affirming: in one interview conducted by Lisy et al one non-binary person reported, post-bilateral mastectomy, “I really was what I always wanted to be, flat-chested, and I was really happy with the surgery.”⁴⁵ Other TGD individuals report that oncology clinicians were unable to inform them about how their cancer treatments would influence their gender-affirming care.⁴⁶

Breast Cancer-Related Symptoms in TGD Individuals

TGD individuals with cancer face unique symptoms that may go unaddressed. TGD breast cancer survivors report sexual side effects: “I can’t have sex. I spent years with gender dysphoria, not being happy with what was there, and then I get to the stage where I can finally fix that and then two years later I can’t use the thing, yes, I’m a little bit distressed about that” and “at no point had anyone ever said anything other than, ‘you might suffer some dryness’ so I was a little disappointed with that, not having been given the full story, not having that time to prepare for that mentally.”⁴⁵ One transgender man with breast cancer at our institution experienced a decline in libido, which was multifactorial in nature, presumably related to stress from a cancer diagnosis, endocrine therapy, and low testosterone levels, and required a collaborative approach with healthcare providers from endocrinology, palliative care, and oncology.

Furthermore, survivorship issues are only beginning to emerge among TGD individuals who have been diagnosed with cancer. Cancer-directed therapies can cause infertility, but discussions of and options for fertility preservation are often overlooked among TGD people; 82% of sexual and gender minority cancer survivors reported that their oncology clinician did not discuss how to support plans for future fertility.⁴⁷ Moreover, TGD cancer survivors often face more significant overall health issues than cisgender cancer survivors. These health issues may exacerbate symptoms related to cancer diagnoses and treatments. For example, a cross-sectional study by Boehmer et al utilized the nationwide Behavioral Risk Factor Surveillance System and compared the needs of TGD cancer survivors to that of cisgender cancer survivors. Transgender cancer survivors were more likely to report unmet medical needs because of the cost of medical care, lack of continuity in medical record with no consistency in healthcare provider assignment, and high rates of cardiovascular disease and diabetes; gender nonconforming people reported higher levels of heavy alcohol use, depression, and physical inactivity.⁴⁸ Such complex comorbidities worsen overall health outcomes after cancer diagnoses.

Finally, for TGD inidividuals with breast cancer and cancer-related symptoms, few resources are available. Support groups are especially challenging to find, as pointed out in the following quotation, “…as a trans person I was just kind of, like, forgotten about, the language wasn’t there, there wasn’t information there.”⁴⁵ Social media could perhaps be employed to help fill this gap.Notably, while significantly more resources are needed, groups such as the National LGBT Cancer Network, CancerCare, the National LGBT Cancer Project, Cancer.net, and CoppaFeel have information specifically for TGD individuals.

Conclusion

TGD individuals with breast cancer experience numerous unmet needs, from poorly understood interactions between GAHT and breast cancer hormonal therapy, to inadequately managed symptoms of cancer-directed therapy. An increased awareness of an absence of data to guide cancer treatment and symptom palliation is needed now more before, particularly as this population of out patients is presumably growing in number.

People working in all aspects of cancer care can help to improve the breast cancer-related disparities experienced by TGD people: security personnel can protect TGD patient safety, nurses and nursing assistants can provide empathetic bedside care for people of differing anatomy, and clinicians can ask patients how they wish to be identified and address their sexual health needs. Systems providing cancer care need to make larger, systems-wide changes to combat disparities; TGD engagement within clinical trials will be one of the first steps needed to improve care for TGD people with breast cancer.

Highlights.

• Transgender and gender-diverse (TGD) individuals suffer significant breast cancer-related disparities and appear to have poorer outcomes.

• Gender-affirming hormone therapy may be lifesaving for TGD individuals.

• Investigations into associations between gender-affirming hormone therapy and breast cancer-directed therapies and outcomes are sorely needed.