The Impact of a Breast Cancer Risk Assessment on the Decision for Gender-Affirming Chest Masculinization Surgery in Transgender and Gender-Diverse Individuals: A Pilot Single-Arm Educational Intervention Trial

Abstract

Background.

Persons assigned female or intersex at birth and identify as transgender and/or gender-diverse (TGD) may undergo gender-affirming chest masculinization surgery (GACMS); however, GACMS is not considered equivalent to risk-reducing mastectomies (RRM). This study aimed to estimate the prevalence of elevated breast cancer (BC) risk in TGD persons, compare self-perceived versus calculated risk, and determine how risk impacts the decision for GACMS versus RRM.

Methods.

A prospective single-arm pilot educational intervention trial was conducted in individuals assigned female or intersex at birth, age ≥ 18 years, considering GACMS, without a BC history or a known pathogenic variant. BC risk was calculated using the Tyrer–Cuzik (all) and Gail models (age ≥ 35 years). Elevated risk was defined as ≥ 17%.

Results.

Twenty-five (N = 25) participants were enrolled with a median age of 24.0 years (interquartile range, IQR 20.0–30.0 years). All were assigned female sex at birth, most (84%) were Non-Hispanic (NH)-White, 48% identified as transgender and 40% as nonbinary, and 52% had a first- and/or second-degree family member with BC. Thirteen (52%) had elevated risk (prevalence 95% confidence interval (CI) 31.3–72.2%). Median self-perceived risk was 12% versus 17.5% calculated risk (p = 0.60). Of the 13 with elevated risk, 5 (38.5%) underwent/are scheduled to undergo GACMS, 3 (23%) of whom underwent/are undergoing RRM.

Conclusions.

Over half of the cohort had elevated risk, and most of those who moved forward with surgery chose to undergo RRM. A BC risk assessment should be performed for TGD persons considering GACMS. Future work is needed to examine BC incidence and collect patient-reported outcomes.

The number of individuals identifying as transgender and/or gender-diverse (TGD) is steadily increasing, and approximately 2.6 million adult Americans currently identify as TGD.^1–3 Simultaneously, the number of TGD persons seeking gender-affirming therapies is also continuously increasing.^4,5 Gender-affirming chest masculinization surgery (GACMS), colloquially called “top surgery,” removes most fibroglandular breast tissue in persons assigned female or intersex sex at birth and allows the chest to appear masculine.⁶ Residual breast tissue is often left during GACMS to allow for appropriate cosmetic contouring of the chest; therefore, GACMS is generally not considered equivalent to oncologic risk-reducing mastectomies (RRM), which aim to remove all fibroglandular breast tissue to maximally reduce future breast cancer incidence.^6–10 Recently, there have been reports of TGD individuals developing breast cancer after GACMS,^11–13 and while GACMS is associated with improved mental health and social outcomes,¹⁴ its impact on breast cancer risk reduction is not currently well understood.^7,15–17

Current average lifetime breast cancer risk for cisgender women is approximately 13% in the USA.¹⁸ Two well-validated models are commonly used to estimate an individual’s lifetime breast cancer risk: the Gail m odel^19–22 and the Tyrer–Cuzick Breast Cancer Risk Evaluation Tool (IBIS).^23–26 Cisgender women with moderately elevated lifetime breast cancer risk, defined as ≥ 17–30%,²⁷ can be offered breast cancer screening at a younger age, enhanced breast cancer screening with magnetic resonance imaging (MRI), or risk-reducing medications such as tamoxifen.^28–31 Similarly, cisgender women with highly elevated lifetime breast cancer risk, defined as ≥ 30%,²⁷ and/or a pathogenic germline variant, can be offered increased breast cancer screening and risk-reducing medications, and may also consider RRM to reduce future breast cancer incidence.^9,32–35 Approximately 15.2% of American cisgender women have elevated lifetime breast cancer risk.³⁶

While self-perceived breast cancer risk in cisgender women influences risk-modifying behaviors and uptake of breast cancer screening, and influences the decision for RRM,^37,38 there are no data on perceived breast cancer risk in TGD persons, which may potentially influence an individual’s decision to undergo GACMS or consider RRM as part of GACMS.¹⁵ Given the lack of data, this pilot investigation sought to estimate the prevalence of TGD persons assigned female or intersex at birth considering GACMS who have elevated breast cancer risk, determine the percentage of those at elevated risk who choose to undergo RRM as part of GACMS, and assess and compare self-perceived breast cancer risk versus calculated risk. We hypothesized that, while the prevalence of elevated breast cancer risk would be similar to cisgender women, TGD persons would underestimate their breast cancer risk and that most TGD persons with elevated risk would choose to undergo RRM as part of GACMS.

METHODS

A single-arm pilot educational intervention trial was conducted from March to December 2023 at a single academic institution in the Midwestern USA. Individuals assigned female or intersex at birth, age ≥ 18 years, and considering GACMS were eligible to enroll. Exclusion criteria included male sex assigned at birth, age < 18 years, a previously known pathogenic germline variant linked to an increased breast cancer risk (e.g., BRCA1, BRCA2, CHEK2, ATM, etc.), previous GACMS, and previous or current breast cancer diagnosis (including ductal carcinoma in situ). Patients considering GACMS were voluntarily recruited from our institution’s outpatient Plastic Surgery clinics and our center’s Comprehensive LGBTQIA+ outpatient clinic. This investigation was approved by the Medical College of Wisconsin Cancer Center’s Scientific Review Committee and the Medical College of Wisconsin Institutional Review Board, and the study protocol was registered with ClinicalTrials.org (NCT06239766).

After confirmation of participant eligibility and informed consent were obtained, participants underwent a personalized breast cancer risk assessment using the Gail model (for those age ≥ 35 years per the model’s validation) and/or the IBIS model (for all ages) via telephone or video call (per subject preference). Calculated risk was defined as the highest calculated risk of the two models. Prior to participants’ being informed of their calculated risk, participants reported their self-perceived lifetime breast cancer risk on the visual analog scale³⁹ using a 0–100% scale where 13% was marked as average risk (Supplementary File 1). Study participants with family history suggestive of a hereditary cancer syndrome and/or a pathogenic germline variant based on 2023 National Comprehensive Cancer Network (NCCN) guidelines were offered a referral to meet with a certified genetic counselor for further evaluation and possible germline genetic testing.⁴⁰

Lifetime breast cancer risk thresholds were determined by the National Institute for Health and Care Excellence (NICE) criteria, which generally defines elevated risk as ≥ 17%.²⁷ Participants with average lifetime risk, defined as < 17%,²⁷ were recommended that they may undergo GACMS with no further recommendations at this time. Those with a moderately elevated lifetime risk, defined as ≥ 17–30%,²⁷ were counseled on risk-reducing measures and the option to consider RRM as part of GACMS given the unclear long-term breast cancer risk reduction from GACMS alone.^7,8,12,15 Participants with highly elevated lifetime risk, defined as ≥ 30%, and/or those found to harbor a pathogenic germline variant²⁷ were counseled on the potential benefit of undergoing RRM as part of GACMS to reduce future breast cancer incidence.^41–46 Participants considering RRM as part of GACMS were offered formal consultations with our Breast Surgical Oncology and Plastic Surgery teams for surgical planning (our current standard clinical workflow for cisgender women seeking RRM).

Descriptive statistics were used to summarize participant characteristics and study outcomes with medians and interquartile ranges (IQRs) used for continuous variables, while counts and percentages were used for categorical variables. Wilcoxon rank-sum and chi-squared tests were used to compare continuous and categorical variables by calculated breast cancer risk. To assess and compare self-perceived breast cancer risk versus calculated risk, medians were calculated and compared using the signed-rank test.

RESULTS

A total of 25 (N = 25) participants enrolled and underwent a personalized breast cancer risk assessment during the study period. Median patient age was 24.0 years (IQR 20.0–30.0 years); all participants had their breast cancer risk calculated using the IBIS model, but only two had their risk calculated using the Gail model. Most participants were non-Hispanic White (84%), 12% were Hispanic White, and 4% were NH-Black. All were assigned female sex at birth, had obtained at least a high school education, and were insured (Table 1). Median body mass index (BMI) was 30.2 kg/m² (IQR 23.2–40.3 kg/m²). The majority reported their gender to be transgender man (48%), followed by nonbinary (40%), genderfluid (8%), and agender (4%). Gender identity was concordant with gender expression among all subjects, and no participants identified as heterosexual (Fig. 1). Twenty participants (80%) were currently using and/or had previously used gender-affirming testosterone therapy with a median duration of 29 months (IQR 15.5–60 months), and no participants had previously undergone any type of gender-affirming surgery.

TABLE 1.

Participant demographic characteristics for the entire TGD study cohort and by calculated breast cancer risk where average is risk ≤ 17% and elevated risk is ≥ 17%

Variable	All N = 25 (%)	Average BC risk n = 12 (%)	Elevated BC risk N = 13 (%)	p-value*
Age (years)				0.01
Median (IQR)	24.0 (20.0–30.0)	21.5 (19.5–24.5)	27.0 (24.0–32.0)
Weight (pounds)				0.71
Median (IQR)	181.0 (140.0–238.0)	181.5 (147.5–237.0)	181.0 (135.0–244.0)
Height (inches)				0.23
Median (IQR)	66.0 (63.0–67.0)	66.5 (63.5–70.0)	65.0 (63.0–66.0)
BMI (kg/m2)				0.95
Median (IQR)	30.2 (23.2–40.3)	31.0 (23.9–39.0)	30.2 (21.8–40.3)
Race				1.0
Mixed	1 (4.0)	0	1 (7.7)
White	24 (96.0)	12 (100)	12 (92.3)
Ethnicity				0.59
Hispanic	3 (12.0)	2 (16.7)	1 (7.7)
Non-Hispanic	22 (88.0)	10 (83.3)	12 (92.3)
Highest education				0.67
High School	12 (48.0)	4 (33.3)	2 (15.4)
Trade School	1 (4.0)	0 (0.0)	1 (7.7)
Bachelors	9 (36.0)	3 (25.0)	5 (38.5)
Some college	8 (32.0)	5 (41.7)	4 (30.8)
Masters	1 (4.0)	0 (0.0)	1 (7.7)
Gender identity				1.00
Agender	1 (4.0)	0 (0.0)	1 (7.7)
Genderfluid	2 (8.0)	1 (8.3)	1 (7.7)
Nonbinary	10 (40.0)	5 (41.7)	5 (38.5)
Transgender	12 (48.0)	6 (50.0)	6 (46.2)
Gender expression				1.00
Agender	1 (4.0)	0 (0.0)	1 (7.7)
Feminine	2 (8.0)	1 (8.3)	1 (7.7)
Genderfluid	1 (4.0)	0 (0.0)	1 (7.7)
Genderqueer	1 (4.0)	1 (8.3)	0 (0.0)
Masculine	15 (60.0)	7 (58.3)	8 (61.5)
Nonbinary	5 (20.0)	3 (25.0)	2 (15.4)
Sexual identity				0.60
Asexual	1 (4.0)	0 (0.0)	1 (7.7)
Bisexual	5 (20.0)	3 (25.0)	2 (15.4)
Fluid	2 (8.0)	1 (8.3)	1 (7.7)
Gay/lesbian	7 (28.0)	4 (33.3)	3 (23.1)
Pansexual	3 (12.0)	0 (0.0)	3 (23.1)
Queer	7 (28.0)	4 (33.3)	3 (23.1)
History of GAHT				0.64
No	5 (20.0)	3 (25.0)	2 (15.4)
Yes	20 (80.0)	9 (75.0)	11 (84.6)
GAHT duration (n = 20) (months)				0.61
Median (IQR)	29.0 (15.5–60.0)	20.0 (18.0–39.0)	36.0 (12.0–72.0)
Age at first menstrual cycle (years)				0.75
≤ 11	6 (24.0)	2 (16.7)	4 (30.8)
12–13	14 (56.0)	7 (58.3)	7 (53.8)
≥ 14	5 (20.0)	3 (25.0)	2 (15.4)
Previous breast biopsy				1.00
No	23 (92.0)	11 (91.7)	12 (92.3)
Yes	2 (8.0)	1 (8.3)	1 (7.7)
Ashkenazi Jewish Inheritance				0.39
No	21 (84.0)	9 (75.0)	12 (92.3)
Yes	3 (12.0)	2 (16.7)	1 (7.7)
Unsure	1 (4.0)	1 (8.3)	0 (0.0)
First- and/or second-degree FH of BC				< 0.001
No	12 (48.0)	11 (91.7)	1 (7.7)
Yes	13 (52.0)	1 (8.3)	12 (92.3)
First- and/or second-degree FH of OC				0.32
No	21 (84.0)	11 (91.7)	10 (76.9)
Yes	4 (16.0)	1 (8.3)	3 (23.1)

BC breast cancer, IQR interquartile range, kg/m² kilograms per meter squared, GAHT gender-affirming hormone therapy, FH family history, OC ovarian cancer

^*p-value comparing average-risk with elevated-risk groups (Wilcoxon rank-sum test is used for comparing continuous variables and chi-squared test for comparing categorical variables)

FIG. 1.

Sexual and gender identity breakdown for the cohort (N = 25) by a gender identity, b gender expression, and c sexual identity. TG transgender, NB nonbinary

Three subjects (12%) had a portion of their family history that was unknown: two participants had a single parent who was adoptive, and one participant had no known data on their paternal family history. While 16% of the cohort had a first-degree family member with breast cancer, over half (52%) of the cohort had a first- and/or second-degree relative with breast cancer history. Two subjects (8%) had a first-degree family member with ovarian cancer, while 16% had a first- and/or second-degree relative with ovarian cancer. Breast biopsies had previously been performed in 8% of the cohort (both benign findings without atypia or in situ disease), and 12% reported an Ashkenazi Jewish inheritance.

While no participants had a highly elevated risk (defined as ≥ 30%), 13 (52%) were found to have a moderately elevated lifetime breast cancer risk (≥ 17–30%) and recommended that they could consider RRM as part of GACMS, while 12 (48%) were found to be at average risk (< 17%) for breast cancer. This finding resulted in an estimated elevated breast cancer risk prevalence in TGD persons of 52.0% (95% CI 31.3–72.2%), which is higher compared with a 15.2% prevalence of elevated breast cancer risk seen in cisgender women.³⁶ Median self-perceived risk was 12% (IQR 10.0–25.0%) versus median calculated risk of 17.5% (IQR 13.0–22.8%) and was not statistically different (p = 0.60) (Fig. 2). When comparing the 48% average-risk subjects with the 52% elevated-risk subjects, those with elevated risk were older in age (median age of 27 versus 21.5 years, p = 0.01) and had a higher number of individuals with a first- and/or second-degree family member with breast cancer history (92.3% versus 8.3%, p < 0.001) (Table 1). Of the 13 subjects with elevated breast cancer risk, 5 (38.5%) underwent and/or are currently scheduled to undergo GACMS, 3 (23%) of whom are scheduled to undergo RRM as part of their operation. The remaining eight participants with elevated breast cancer risk (61.5%) had not yet scheduled GACMS or RRM at the time of data analysis. Six study participants (24%) were recommended to meet with a genetic counselor on the basis of their family history, all of whom met with a counselor, met NCCN criteria for pathogenic germline variant testing; however, none were found to harbor a pathogenic germline mutation.

FIG. 2.

Bar graph comparing each participant’s self-perceived breast cancer (BC) risk (blue) versus their calculated BC risk (orange). Median self-perceived risk of 12% versus median calculated risk of 17.5% (p = 0.60)

DISCUSSION

In this single-arm pilot educational intervention trial, over half of TGD persons considering GACMS in this cohort were found to have elevated risk for breast cancer, largely driven by family history, which is a higher prevalence of elevated breast cancer risk compared with that seen in cisgender women. Of those participants with elevated risk who moved forward with GACMS, over half chose to undergo RRM as part of GACMS. Additionally, several individuals met NCCN criteria owing to a family history that suggested they may harbor a pathogenic germline variant, and all sought further genetic evaluation. This is the first clinical trial to investigate how a personalized breast cancer risk assessment impacts the surgical decision for GACMS and RRM in TGD persons and identify patients who may benefit from RRM to reduce future breast cancer incidence. Data support the need for future work to measure patient-reported outcomes (PROs) and determine long-term breast cancer incidence after GACMS versus RRM.

Evolving data on the implications of gender-affirming surgery and gender-affirming hormone therapy on future oncologic risk have called for specialized considerations in both clinical practice and in research development, particularly for hormonally mediated malignances such as breast, prostate, and cervical cancer.^15–17 While data are overall sparse, this does suggest that there may be alterations in both breast cancer risk⁴⁷ and differences observed in breast cancer screening behaviors in TGD persons.^48,49 Surgeons caring for TGD patients in any setting can support TGD persons by considering their modifiable and nonmodifiable risk factors, particularly around identifying those who may be at risk for hereditary cancer syndromes and may warrant increased screening, risk-reducing medications, or even consideration of risk-reducing operations.¹⁵ While the risk models used in this study are well validated, they do not include factors such as history of radiation, particularly at a young age, that may alter breast cancer risk, breast density, or history of gender-affirming testosterone therapy.^50,51 Nevertheless, this study’s findings demonstrate a clear utility of formalized breast cancer risk assessment to aid in the decision for GACMS and whether RRM may be a more appropriate option for some patients with elevated risk. Risk assessment may be performed by breast care specialist, but there is an opportunity to formally train and education plastic surgeons and their teams and this warrants implementation investigation.

Despite the decreased breast cancer incidence seen after RRM, TGD persons must be educated that RRM does not completely negate their future breast cancer risk.⁵² Given this low but nevertheless remaining risk after RRM, current guidelines recommend that patients and their healthcare providers perform routine chest examination to detect changes in the chest wall, remaining skin and, for some, nipple–areolar complex that may indicate breast cancer development.^53–55 Variability in the amount of fibroglandular breast tissue is to be expected with GACMS to allow appropriate chest contouring;⁶ however, residual breast tissue has also been demonstrated on noncontrast breast MRI after both skin-sparing and nipple-sparing mastectomies,^56,57 which supports the potential role for routine clinical chest examination after mastectomy. While RRM reduce breast cancer risk, there are no current data on the amount of residual breast tissue after GACMS, how that residual tissue itself, or in the setting of gender-affirming hormone therapy, may influence the incidence of future breast cancer, or how TGD persons with residual breast tissue should be ideally screened for breast cancer through routine breast/chest imaging and/or physical chest/breast examination.⁷ With an increasing number of young adults undergoing GACMS,^4,5 critical work must begin now to elucidate how GACMS may influence future breast cancer risk and requires inclusive data capture, study design, and most importantly, TGD stakeholder engagement.^17,58

Several retrospective cohort studies have examined incidental breast lesions found on surgical pathology after GACMS and have revealed incidental lesions such as atypia and even ductal carcinoma in situ (DCIS) and invasive disease.^59–62 Atypical lesions cannot always be accounted for in a preoperative risk assessment unless a patient has undergone a biopsy for an abnormality seen on imaging, even though atypia will result in an increased risk when applying both the IBIS and Gail models. However, it should be noted that some forms of atypia, specifically atypical lobular hyperplasia and lobular carcinoma in situ (LCIS), will falsely elevate the risk calculated using the IBIS model, and therefore clinical judgement and appropriate interpretation are key when counseling patients.^63,64 Given these instances of abnormal pathology found on GACMS surgical specimens, screening mammography should be considered for select patients preoperatively, as would typically be performed prior to reduction mammplasty,⁶⁵ to screen for clinically occult atypia, DCIS, LCIS, or invasive breast cancer. However, surgeons and patients should be aware that screening mammography may not be covered by insurance for some TGD persons on the basis of sex assigned at birth and gender identity,⁶⁶ and the risks and benefits of screening and potential costs should be discussed with patients.

This pilot study was designed to explore and inform the feasibility and utility of personalized breast cancer risk prior to GACMS and focused on surgical decision-making in response to participants’ learning their calculated breast cancer risk. Future qualitative work will be required to understand which factors are most significant in making the decision for GACMS versus RRM. Additionally, short- and long-term data on patient-reported outcomes (PROs) are needed to understand how the decision for GACMS versus RRM in elevated-risk TGD persons may influence PROs and surgical satisfaction.⁶⁷ While the BREAST-Q^© has been validated in cisgender women undergoing mastectomy, with or without reconstruction for breast cancer treatment and risk reduction, and is a widely used and accepted tool to measure PROs, recently, the BREAST-Q^© team has developed the GENDER-Q^© to measure PROs after GACMS, and this will undoubtably be a valuable tool in understanding satisfaction in TGD persons once validation studies mature.^68,69

While this study’s findings are novel and present significant clinical implications, several notable limitations exist. While the cohort comprises gender-diverse individuals, the racial and ethnic makeup of this population was largely homogeneous and requires future work to expand and collaborate with other centers outside of our geographic catchment area to recruit a population that is more representative of the current racial and ethnic makeup of the American population. There is also concern for self-selection bias among participants who enrolled into this study, as those TGD persons with family history of breast cancer were likely more apt to participate in a study focused on determining breast cancer risk, and this may explain why the prevalence of those at elevated risk was higher in our cohort than that seen in cisgender women (52.0% (95% CI 31.3–72.2%), compared with 15.2% in cisgender women). Given the pilot design of this study, statistical interpretation is limited owing to the small sample size; however, this investigation provides insightful and critical data to inform how a formalized breast cancer risk assessment can assist in informed surgical decision-making among TGD persons considering GACMS and opportunities for surgeons to ensure that patients receive the appropriate gender-affirming operation to reduce future breast cancer risk.

CONCLUSION

In this study of TGD persons assigned female or intersex at birth considering GACMS, over half were found to have elevated breast cancer risk, a higher prevalence compared with cisgender women. However, there was no difference in self-perceived versus calculated breast cancer risk. In those with elevated risk who moved forward with GACMS, over half chose to undergo RRM. Findings demonstrate the clinical utility of formal breast cancer risk assessment prior to GACMS given its direct impact on the decision for RRM versus GACMS and support that surgeons should incorporate breast cancer risk assessment for all patients considering GACMS. Additionally, data demonstrate the need for a larger powered prospective cohort study to understand how RRM and GACMS impact long-term BC incidence in TGD persons, investigate patient-reported outcomes, and develop supportive tools for surgeons and patients to aid in informed patient-centric surgical decision-making.