Could long-term testosterone therapy have caused breast cancer in a 34-year-old transgender man with hormone-receptor-positive, HER2-negative, stage IIB invasive ductal carcinoma, considering his family history of colon cancer and leukemia?

Can Testosterone Therapy Cause Breast Cancer in Transgender Men?

The evidence does not support a direct causal link between testosterone therapy and breast cancer development in transgender men, though the relationship remains incompletely understood. 1

Understanding the Evidence

What We Know About Testosterone and Breast Cancer Risk

The most recent 2025 guidelines from the Multinational Association of Supportive Care in Cancer explicitly state that "there are no prospective clinical data to inform or estimate the risk of GAHT (gender-affirming hormone therapy) on the progression of a hormone-sensitive cancer." 1 The associations between exogenous testosterone and breast cancer development are conflicting 1:

Theoretical concerns exist:

• Early preclinical studies suggest testosterone in high concentrations may increase estrogen-dependent cancer progression because testosterone aromatizes to estrogen 1
• Some preclinical studies show androgen receptor activation by testosterone may promote breast cancer growth 1

However, more recent evidence suggests the opposite:

• Recent data from Cedars-Sinai Medical Center found that androgen receptor activation may actually prevent or reduce hormonally driven breast cancers in transgender men 1
• A 2026 single-cell RNA sequencing study demonstrated that high testosterone levels in transgender men on therapy suppress sex hormone signaling in the breast, showing dramatically reduced expression of estrogen signaling pathway genes in hormone receptor-positive luminal epithelial cells 2
• Epidemiological data suggest breast cancer incidence is lower in transmasculine individuals compared to cisgender women 3

Clinical Reality in Your Patient

For this 34-year-old transgender man:

The breast cancer is likely NOT caused by testosterone therapy because:

1. Breast cancer incidence in transgender men on testosterone remains lower than in cisgender women 3
2. The most recent mechanistic data suggests testosterone may be protective rather than causative 2
3. Many transgender men retain residual breast tissue after top surgery, and cancer can develop from this tissue independent of hormone therapy 4

More relevant considerations:

• The family history (colon cancer in grandparent, leukemia in mother) does not suggest a hereditary breast cancer syndrome, though genetic counseling may still be warranted
• Breast cancer in transgender men tends to occur at younger ages and is predominantly hormone receptor-positive 3, 4, as seen in this patient
• At least 50% of documented cases in transgender men were incidentally found on pathology after gender-affirming mastectomy 4

Critical Treatment Decisions Ahead

Regarding Continuation of Testosterone

This is a nuanced, patient-centered decision that must balance cancer treatment with quality of life. 1

The 2025 guidelines emphasize that:

• For some transgender individuals, gender-affirming hormone therapy is life-saving, improving gender dysphoria, quality of life, and reducing depression, anxiety, and suicidality 1
• In surveys, 35% of transgender individuals stated they would continue hormone therapy even after diagnosis of a hormonally dependent cancer 1
• Patient autonomy must be respected and paternalism avoided 1

Key counseling points:

• Explain that we lack prospective data on whether continuing testosterone affects cancer outcomes 1
• Discuss that testosterone can aromatize to estrogen, which theoretically could promote hormone receptor-positive cancer 1
• Reassure that identity-affirming changes (facial hair, voice depth) persist after testosterone cessation 5
• Consider endocrinology consultation to discuss implications 5
• Document that at least 17% of transgender men with breast cancer in published cases continued testosterone therapy 4

Regarding Standard Cancer Treatment

Treat this stage IIB invasive ductal carcinoma according to standard breast cancer guidelines for hormone receptor-positive, HER2-negative disease:

1. Surgical management: Ensure adequate oncologic resection if prior chest masculinization surgery was performed—this is NOT equivalent to oncologic mastectomy 1

2. Adjuvant endocrine therapy: Standard options include tamoxifen or aromatase inhibitors 6, 7

   • Critical caveat: It's unclear whether breast cancer endocrine therapy (tamoxifen or aromatase inhibitors) can effectively block testosterone's effects and its aromatization to estrogen if the patient continues gender-affirming testosterone at typical doses 1
   • Testosterone doses in gender-affirming therapy are much higher than those used in cisgender women for symptom management 1

3. Consider chemotherapy: Based on standard risk stratification for stage IIB disease 7

4. Radiation therapy: As indicated by standard guidelines, with attention to remaining breast tissue location 1

Common Pitfalls to Avoid

• Do not assume testosterone caused the cancer—the evidence does not support this
• Do not mandate testosterone cessation—this must be a shared decision respecting patient autonomy 1
• Do not treat prior chest masculinization surgery as adequate oncologic treatment—review imaging with breast radiology to understand remaining tissue 1
• Do not overlook the patient's gender identity needs when discussing treatment options that may affect body image 1

Bottom Line

Counsel this patient that testosterone therapy likely did not cause his breast cancer, but discuss the theoretical uncertainties about continuing testosterone during treatment for hormone receptor-positive disease. Proceed with standard oncologic care while respecting his gender identity and involving multidisciplinary input including endocrinology, breast surgery, medical oncology, and radiation oncology as appropriate.