Breast cancer is the most common non-cutaneous cancer diagnosed in cisgender women, affecting approximately 1 in 8 (~143 cases per 100,000 person years) (17). Breast cancer in cisgender men accounts for less than 1% of all breast cancer diagnoses and affects approximately 1 in 833 (~1 case per 100,000 person years) (17). Transgender individuals carry an intermediate risk of breast cancer. One study reported a collective ~43 cases per 100,000 person years for a cohort of 2,260 transgender women and 1,229 transgender men (18). The rate of breast cancer in the transgender population, however, is highly variable and dependent upon the type and duration of gender-affirming hormone therapy these individuals receive (19–22). Estrogens promote development of mammary tissue in transgender women. These changes, including the formation of ducts, lobules, and acini, may become histologically and radiographically indistinguishable from cisgender women (23–26). Receipt of feminizing hormones also leads to a higher frequency of benign breast processes (such as cysts and fibroadenomas) and malignant transformation of breast tissue. Conversely, testosterone causes atrophy of breast tissue in transgender men, which may lower the risk of malignant transformation (18).

Transgender individuals face significant healthcare disparities and limited access to appropriate breast cancer screening; this contributes to delayed diagnosis and suboptimal care (27, 28). Progress has been made, however, to standardize screening practices for the gender-diverse patient population. The American College of Radiology published a comprehensive list of Appropriateness Criteria for transgender breast cancer screening in 2021 and an update of Appropriateness Criteria for cisgender female breast cancer screening in 2024 (29, 30). Table 1 summarizes the organization’s recommendations, including which imaging modalities are “usually appropriate” or “may be appropriate,” depending on risk classification, age, gender identity, hormone therapy use, and if the patient underwent bilateral mastectomies. Annual screening breast imaging (including mammography and digital breast tomosynthesis) starting at age 40 is offered to all average-risk cisgender women, average-risk transgender women with at least five years of hormone use, and average-risk transgender men who have not undergone bilateral mastectomies.

In the non-oncologic setting, the goal of gender-affirming mastectomies for transgender men is to achieve a flat, masculine chest contour through glandular excision, skin recontouring, and modification of the nipple-areolar complex (31, 32). Incorporating chest masculinization into the surgical management of cisgender men and transgender men with breast cancer is appropriate when desired by the patient and safe from an oncologic standpoint (33). The choice of mastectomy incision, flap, and closure technique depends on a patient’s anatomy and aesthetic expectation. The double incision with free nipple graft provides broad exposure for glandular excision and masculinized contouring, making it well-suited for moderate to large chests (33, 34). Periareolar incision techniques may be appropriate for smaller chests but may leave residual retroareolar tissue, potentially limiting oncologic adequacy (31, 32). The wide-base bipedicled (WIBB) flap, utilized in nipple-sparing mastectomy, incorporates a mastopexy design to improve contour and closure during oncologic and gender-affirming procedures (35). The Angel Wing technique, developed for aesthetic flat closure following mastectomy, extends the incision laterally and superiorly to excise excess tissue in an elliptical fashion, improving lateral chest wall contour and symmetry by eliminating dog-ears or lateral adiposity. This approach is especially useful in patients not pursuing breast mound reconstruction (36). Adjunctive procedures such as pectoral implants that enhance chest projection may further support masculinization, particularly in delayed reconstruction (37). The Goldilocks procedure, which utilizes deepithelialized local tissue for volume restoration, may benefit patients who decline prosthetics but still desire chest projection in a non-delayed fashion (38). The patient in our case study underwent flat closure following his mastectomies and is considering delayed masculinization surgery.

Following an oncologic mastectomy, cisgender women and transgender women may be candidates for implant-based reconstruction, using either a two-stage approach with placement of a tissue expander followed by an exchange for a permanent implant, or a single-stage, direct-to-implant approach (39). Alternatively, autologous reconstruction uses the patient’s own tissue—most commonly from the abdomen, back, or thighs—to recreate a natural breast mound. Combination techniques may integrate implants, fat grafting, or autologous reconstruction to enhance contour, symmetry, or volume.

The administration of radiation therapy with respect to target volumes and organs at risk are similar among patients, regardless of gender identity, and depend on a patient’s anatomy and cancer stage. A discussion regarding potential radiation related toxic effects and their management is important and includes potential treatment related complications regarding breast/chest wall reconstruction (40–42). The patient in this case report had a pathologic complete response in the recovered lymph nodes, including the biopsied lymph node. A recent randomized clinical trial showed that regional nodal irradiation did not improve the invasive breast cancer recurrence-free interval at 5 years for select patients with clinical T1-3 and clinical N1 disease who convert to ypN0 disease following neoadjuvant systemic therapy (43). This trial, however, specifically excluded those with cN2 and cN3 disease. This trial’s design was consistent with previous data showing a significant disease-free survival benefit and overall survival benefit conferred by post-mastectomy irradiation for patients with clinical stage III disease (but not clinical stage I or II disease) after achieving a pathologic complete response to neoadjuvant chemotherapy (44). Many stage III patients in this study harbored cN3 disease. Considering the patient’s high axillary burden at diagnosis (including cN3 involvement), that only 3 sentinel lymph nodes were recovered, and the patient’s preference, his radiation oncologist recommended treatment. He received left chest wall and regional nodal irradiation with inclusion of the internal mammary chain. He received intensity modulated proton beam irradiation, which achieved significant reductions in integral dose to normal tissues, including the heart, left anterior descending artery, lung, and contralateral chest wall, compared to a rival photon plan. While modern techniques (such as deep inspiration breath hold, prone positioning, intensity-modulated radiation therapy, and volumetric modulate arc therapy) ensure that photon therapy is very safe for the majority of patients (45–48), proton therapy typically results in further reductions in dose to normal tissues. For select patients, this dosimetric advantage may confer a clinically meaningful decrease in the risk of pulmonary or cardiac toxic effects. Patients most likely to benefit from proton therapy include those who have challenging anatomy, a history of previous radiation therapy to the breast/thorax, a pathogenic germline variant in a cancer susceptibility gene (in which case sparing of non-target tissue decreases the risk for second malignancy), and those who require left-sided or bilateral regional nodal treatment (49–55). Multiple trials investigating the safety of de-escalating radiation therapy in select patients who respond well to neoadjuvant systemic therapy are ongoing and will help guide treatment recommendations for future patients.

Breast cancer is classified based on tumor gene expression and molecular characteristics, particularly the expression of ER, PR, and HER2 (3, 56, 57). Four main biological subtypes are used in clinical practice: Luminal A, Luminal B, HER2-enriched, and basal-like (which overlaps considerably with triple negative breast cancer). These subtypes carry prognostic value, predict therapy response, and guide systemic therapy recommendations. ER signaling, for example, is targeted with endocrine therapy (e.g., selective estrogen receptor modulators/degraders and aromatase inhibitors), while HER2 signaling is targeted with monoclonal antibodies and antibody-drug conjugates. Specific regimens of cytotoxic chemotherapy, immunotherapy, and a variety of small molecule inhibitors are also administered depending on cancer subtype (58–60).

Breast tissue normally expresses the AR, which binds primarily testosterone and 5α-dihydrotestosterone. While generally growth inhibitory to mammary epithelial cells, androgens are also precursors to estrogens, which in turn may drive the development of ER-positive breast cancer (61, 62). Androgens have also been associated with HER2 overexpression and the activation of the epidermal growth factor receptor; this explains how androgens may act to drive ER-negative breast cancer (63, 64). The AR is expressed in ~75% of all breast cancers but more commonly in ER-positive disease (80-90%), compared to ER-negative disease (30-50%), HER2-positive disease (50-60%, regardless of ER status), and triple negative breast cancer (20-40%) (2–6, 65). Higher levels of circulating androgens, either because of higher endogenous production or exogenous testosterone use, may amplify signaling crosstalk among the AR, ER, and HER2.

A retrospective review of pathology specimens from female-to-male transgender patients undergoing gender-affirming mastectomies investigated the impact of exogenous androgens on breast tissue (66). This study showed that androgen-exposed breast tissue revealed dense fibrotic stroma, lobular atrophy, thickened lobular basement membranes, and gynecomastoid changes. Longer duration of androgen exposure was associated with more pronounced changes. The study also showed that ER and AR expression were highest in patients with intermediate duration of androgen exposure. Two additional studies compared pathology specimens from gender-affirming chest-contouring surgery in patients who did and did not receive testosterone therapy (67, 68). Longer duration of testosterone was associated with higher degrees of lobular atrophy but not fibrous content, decreasing amounts of epithelium and stroma, and a higher incidence of cysts, fibroadenomas, pseudoangiomatous stromal hyperplasia, and papillomas. For a subset of transmasculine patients who had a portion of the nipple-areolar complex available for evaluation, these specimens were compared to those of cisgender women who underwent a total mastectomy (69). The presence of Toker cell hyperplasia was higher in transmasculine patients than in cisgender women, and in cases of Toker cell hyperplasia, the rate of gland formation was higher in transmasculine patients. Further, the majority (90%) of Toker cells were AR-positive. These data underscore the complexity of extrapolating AR-targeted therapy evidence from cisgender women to gender-diverse populations.

The impact that AR expression has on breast cancer progression and prognosis is variable, depending on the co-expression or absence of ER and HER2 (7–15). A clinical meta-analysis evaluating over 10,000 patients with breast cancer reported a subgroup analysis of those with either ER-positive, ER-negative, ER-negative and HER2-positive, or triple negative disease. AR expression conferred improved disease-free survival and overall survival in all patients with ER-positive breast cancer (9). The same study showed a similar positive association with AR expression and clinical outcomes in patients with triple negative breast cancer. AR expression, however, did not improve clinical outcomes in all patients with ER negative breast cancer and was associated with worse overall survival in patients with ER-negative, HER2-positive breast cancer. These trends have been supported by multiple preclinical and clinical studies (3, 7, 10–13, 65, 70, 71) and have informed efforts to target AR signaling in patients with breast cancer.

While androgen deprivation has been a long-standing treatment approach for other AR-positive cancers—notably prostate cancer—the AR remains an emerging target in the treatment of breast cancer (72, 73). A phase II clinical trial enrolled patients with AR-positive, ER/PR-negative breast cancer and reported that bicalutamide, a nonsteroidal antiandrogen, produced a 19% clinical benefit rate at 6 months (74). Another phase II trial evaluated the efficacy and safety of the second-generation antiandrogen enzalutamide in patients with AR-positive triple negative locally advanced or metastatic breast cancer. This study showed 25% and 33% clinical benefit rates at 16 weeks in the intent-to-treat population and evaluable subgroup, respectively (75). Enobosarm, a novel oral selective androgen receptor modulator (SARM), was recently shown in a randomized, phase 2 clinical trial to have anti-tumor activity in patients with previously treated AR-positive, ER-positive, HER2-negative locally advanced or metastatic breast cancer (76). These and other drugs that modulate AR signaling, including 17 α-hydroxylase/17,20 lyase (CYP17) inhibitors, exogenous androgens (dehydroepiandrosterone, 4-OH-testosterone), androgen synthesis inhibitors, and AR-specific antisense oligonucleotides, are currently being investigated in clinical trials (72, 77).

AR signaling may be particularly relevant in patients with high levels of circulating androgens. Whether data from clinical trials investigating AR modulation (which enroll almost exclusively cisgender women) can be generalized to cisgender men and transgender men should be confirmed. In cisgender men with ER-positive breast cancer, the AR is typically targeted albeit inadvertently. Because of the conversion of androstenediones to estradiol through aromatase, current guidelines support the administration of gonadotropin-releasing hormone agonists with aromatase inhibitors in cisgender men. Tamoxifen is usually recommended first line, however, because of good tolerability and lack of high-level prospective studies in this patient population (78, 79).

The positive benefits that gender-affirming hormone therapy (GAHT) provide transgender individuals are well established. GAHT has been shown to improve mental health and quality of life measures, alleviate gender dysphoria by facilitating appearance congruence, and improve body satisfaction and social functioning (80–83). Thus, the significance of withdrawing GAHT should not be taken lightly: the potential oncological risk of continued GAHT should be weighed against the profound impact that withdrawal of this treatment might have on the patient’s gender identity and mental health. Ultimately, the treatment approach should be determined through shared decision-making with the patient. In addition to a multi-disciplinary cancer treatment team, mental health support, including social workers, counselors, family members, and patient interest groups is essential.

Cessation of testosterone in transgender men may result in a decrease in masculinization (e.g., decreased muscle mass, body hair, and libido), a return of feminine features (e.g., fat redistribution to the gluteofemoral region and increased pitch in voice), and mood disturbances related to gender dysphoria. Transgender men who have undergone menopause may experience symptoms related to estrogen deficiency, including vasomotor symptoms, fatigue, arthralgias, cognitive dysfunction, and disturbances in mood, sleep, and sexual function. Hormonal therapies are generally contraindicated in breast cancer survivors. Testosterone is not approved by the U.S. Food and Drug Administration for use in cisgender men with breast cancer (Depo testosterone package insert), and the existing data do not support the use of testosterone in transgender men with breast cancer. Hormone replacement with estrogen and progesterone has been associated with increased risk for breast cancer recurrence in a randomized clinical trial (HABITS) and a meta-analysis, especially in those with ER-positive tumors and cannot be recommended (84, 85). There is a lack of data investigating the impact that GAHT has on breast cancer in the transgender population. Further investigation is needed to determine if resuming GAHT after a period of cancer-free survival or if continuing on a reduced dose of GAHT (provided there are no other contraindications to this treatment) is safe from an oncological standpoint in the transgender population.

Nonhormonal options to manage vasomotor symptoms include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, gabapentin, oxybutynin, clonidine, and fezolinetant (86, 87). These and other symptoms related to the withdrawal of sex hormones may also be managed with dietary supplements, mind-body techniques (e.g., cognitive behavioral therapy, hypnosis), and various lifestyle modifications, including exercise, weight loss, trigger avoidance, and yoga (88).