Male Breast Cancer

Male breast cancer is a malignant tumour of the male breast, most often invasive ductal carcinoma, and is usually ER positive. It presents later than breast cancer in women, and stage-for-stage outcomes are similar.

It accounts for about 1% of all breast cancers and under 1% of cancers in men. Lifetime risk is about 1 in 1,000, median age at diagnosis is 60 to 70, and incidence is higher in parts of sub-Saharan Africa and the Middle East.

Risk factors are germline BRCA2 variants (lifetime risk about 6% to 7%), BRCA1, PALB2 and CHEK2 variants, Klinefelter syndrome (risk raised about 20 to 60-fold), obesity, cirrhosis, hyperoestrogenic states, testicular disease, chest radiation, family history and, in some regions, schistosomiasis with liver disease. Gynaecomastia is not itself premalignant.

Pathophysiology. Male breast tissue has ducts with few lobules, so ductal carcinoma is almost universal and lobular carcinoma is rare. Oestrogen and androgen balance drives risk.

Histology and receptors. Invasive ductal carcinoma accounts for about 90%, DCIS for about 5% and lobular carcinoma for 1% to 2%. ER is positive in 90% to 95%, PR in about 80% and androgen receptor in most. HER2 is positive in 5% to 15%, and triple negative disease is rare.

Behaviour. About half have node positive disease at diagnosis, and spread is to bone, lung, liver and brain. Five year overall survival is about 80% across stages.

• Painless, firm, eccentric subareolar mass (commonest), nipple retraction, bloodstained nipple discharge, ulceration or Paget disease of the nipple, and axillary lump.
• Skin fixation and fixation to the chest wall are more frequent than in women, because of the small breast volume.
• Symptoms at presentation have usually been present for 6 to 12 months.

• Triple assessment. Mammography shows an eccentric, spiculated or well circumscribed mass, with calcification less often. Gynaecomastia gives a concentric flame shaped retroareolar density. Ultrasound shows a hypoechoic irregular mass.
• Core biopsy with ER, PR, HER2 and androgen receptor.
• Axillary ultrasound with sampling of suspicious nodes.
• Staging with CT chest, abdomen and pelvis and bone scan for stage III or symptoms.
• Germline testing for every man with breast cancer (BRCA2, BRCA1, PALB2, CHEK2, and others). Karyotype if Klinefelter syndrome is suspected.
• Baseline bone density if an aromatase inhibitor is planned, with testosterone, oestradiol, LH, FSH and prolactin when hormonal causes are suspected.

Differential diagnosis.

• Gynaecomastia (usually bilateral and concentric)
• Lipomastia (pseudogynaecomastia)
• Lipoma and epidermal inclusion cyst
• Breast abscess
• Metastasis to the breast (prostate, lung, lymphoma)
• Papilloma and other benign epithelial lesions

Treatment is based on evidence from women, with adjustment for the male endocrine environment.

Surgery. Modified radical mastectomy is usual. Breast conservation is possible when the tumour is small relative to the breast. Sentinel node biopsy for clinically node negative disease, with axillary clearance by the indications used in women.

Radiotherapy. Chest wall radiotherapy (40 Gy in 15 fractions) for T3 to T4 disease or 4 or more positive nodes, and considered for 1 to 3 positive nodes. Whole breast radiotherapy after conservation.

Adjuvant endocrine therapy for ER-positive disease is the mainstay.

• Tamoxifen: 20 mg orally once daily for 5 years (up to 10 years in selected higher risk men); maximum 20 mg daily; monitoring: venous thromboembolism symptoms, sexual dysfunction, mood, liver tests, vision; adjustment: avoid strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion), avoid in severe hepatic impairment, no renal adjustment.
• Aromatase inhibitor with a gonadotropin releasing hormone analogue (when tamoxifen is not tolerated or contraindicated): anastrozole 1 mg orally once daily plus goserelin 3.6 mg subcutaneously every 28 days, for 5 years; maximum 1 mg and 3.6 mg respectively; monitoring: oestradiol and testosterone by sensitive assay, bone mineral density at baseline then every 1 to 2 years, calcium and vitamin D; adjustment: none in mild to moderate renal or hepatic impairment. An aromatase inhibitor alone is less effective in men, because testicular feedback raises oestrogen.

Chemotherapy and targeted therapy. Chemotherapy and anti-HER2 therapy follow the indications used in women, by stage and receptor status. Evidence in men is limited.

Metastatic disease. ER-positive disease: endocrine therapy with a gonadotropin releasing hormone analogue and a CDK4/6 inhibitor.

• Ribociclib: 600 mg orally once daily on days 1 to 21 of each 28-day cycle with an aromatase inhibitor or fulvestrant, until progression; maximum 600 mg daily; monitoring: FBC and liver tests every 2 weeks for 2 cycles then at the start of the next 4 cycles; ECG for QTc before starting, on day 14 of cycle 1 and at the start of cycle 2; adjustment: reduce stepwise to 400 mg then 200 mg for toxicity, 400 mg in moderate to severe hepatic impairment, 200 mg in severe renal impairment, no use with QTcF over 450 ms or strong CYP3A inhibitors.
• Fulvestrant: 500 mg IM on days 1, 15 and 29, then every 28 days, until progression; maximum 500 mg each dose; monitoring: liver tests, injection site reactions, bleeding risk with anticoagulants; adjustment: 250 mg in moderate hepatic impairment, caution when creatinine clearance is under 30 mL/min.
• Germline BRCA carriers: PARP inhibitors by the indications used in women.

Monitoring. Clinical review every 3 to 6 months for 3 years, then annually, with annual mammography of the contralateral breast. Bone density when on an aromatase inhibitor.

Referral and escalation.

• Urgent breast clinic referral for any unilateral breast lump, nipple retraction or bloodstained discharge in a man.
• Genetic counselling for every patient.

Special groups.

• BRCA2 carriers: annual PSA screening from age 40, and discuss pancreatic and melanoma surveillance.
• Klinefelter syndrome: endocrine review and testosterone management.
• Older adults: endocrine therapy alone is reasonable for ER-positive node negative disease.
• Region specific: late presentation with ulcerated disease is common. Liver disease with raised oestrogen is a recognised contributor.