The relationship of altered androgen and estrogen on breast cancer risk is poorly understood. The risk for breast cancer due to exogenous hormones prescribed for transgender individuals is informed by studies of estrogen and androgens in the general population. Use of relatively short-term combined exogenous estrogen and progesterone in post-menopausal cisgender women was associated with increased breast cancer incidence; however, exogenous estrogen alone was not associated with increased risk, according to data from the Women’s Health Initiative [34]. According to an analysis of nine prospective studies of endogenous hormone levels and breast cancer risk in post-menopausal women, breast cancer is associated with elevated levels of circulating estrogen and androgens in post-menopausal women [35,36,37]. Based on these studies, it is reasonable to hypothesize that breast cancer risk might be elevated for transgender women treated with hormone replacement therapy.

Conversely, though there are abundant androgen receptors in normal breast tissue and androgen receptors are also frequently expressed in breast cancers, there is no evidence for increased breast cancer incidence in women with hyperandrogenism such as polycystic ovary syndrome, or in transgender men receiving testosterone treatment [21]. This is somewhat counterintuitive, as there is aromatization of androgens to estrogen in the peripheral blood of transgender men on testosterone, which may result in maintenance of estradiol levels [12]. Breast cancer risk in transgender women is potentially reduced due to a relatively shorter duration of lifetime exposure to estrogen compared to cisgender women. It has been demonstrated that early menarche and late menopause are associated with increased risk of breast cancer in cisgender women [38].

Prospective and Retrospective Cohort Analysis

It is not possible to derive cancer incidence in transgender individuals from existing U.S. cancer registries because transgender status is not documented. Misclassification of sex/gender assignment in U.S. cancer registries is a well-known phenomenon which may also result in under reporting of breast cancers in cisgender males [39]. Although there are no population-based studies that document incidence of breast cancer in transgender patients, in a study from the Netherlands following a cohort of 2,307 transgender patients, breast cancer was diagnosed in one transgender male and in two transgender females. The authors calculated that these findings translated into a cancer rate of 4.1 per 100,000 life years in transgender females and 5.9 per 100,000 transgender males, similar to the approximately 1.2 in 100,000 cisgender males and significantly lower than the rate of 170 in 100,000 in cisgender females [40]. These authors concluded that the risk for breast cancer in male to female patients is similar to natal male sex and breast cancer risk in female to male patients also is quite low.

A descriptive study performed in the U.S. published in 2015 measured breast cancer incidence in a cohort of 5,135 transgender veterans [41]. Chart review revealed three cancers in transgender women and seven cancers in transgender men yielding a rate of 20 per 100,000 years. The three transgender women all had advanced disease which the authors use as evidence for the need for screening using standard guidelines. One of the seven transgender men had undergone mastectomy including chest contouring. These data may be unreliable because terminology was not uniform, there was a lack of follow-up outside the VA system, and no specific data on hormone use were provided.

Transgender Women

Apart from the prospective and retrospective cohorts from the Netherlands and U.S. referred to above, there are a small number of case reports of breast cancers in transgender women. As of 2014, there were ten reported cases of breast cancer in transgender women on hormone treatment. Among those ten cases we observed that age at diagnosis tended to be younger than in cisgender populations, with a median age 48 compared to age 61 in cisgender females. In addition, five out of eight cases had ER negative cancer, and lobular development was similar to that of an adolescent girl [17]. Our series included a case of DCIS detected by screening, one of the few such screen detected cancers in the literature [17]. This highlights the need for more data to assess the role of screening in this population. It is likely that the low incidence of breast cancers is a result of under reporting.

Transgender Men

It appears that risk for breast cancer in trans men on testosterone treatment is low and it has been hypothesized that testosterone treatment reduces risk [42•]. There are five case reports of breast cancer in transgender men all of whom were treated with testosterone. Of these five cases, four of the cancers were ER positive and three were PR negative. Invasive duct cancers that were ER + PR- were found in two trans men who had not had mastectomy, one at age 27 and the second at age 53 [43]. The three additional invasive duct cancers were residual breast tissue in trans men following subcutaneous mastectomy. One was in the nipple and the second was areolar diagnosed at age 33 following 13 years of hormone treatment and at age 42 following 1 ½ years on hormone treatment, respectively [44, 45]. The third case is a 41 year old who developed invasive duct carcinoma in the left lower outer quadrant after 15 years on hormone treatment [46].