Metaplastic Breast Carcinoma

Metaplastic breast carcinoma is a heterogeneous group of invasive breast cancers in which part or all of the carcinoma shows squamous, spindle cell or mesenchymal (chondroid, osseous, rhabdoid) differentiation. It is usually triple negative and chemoresistant.

It accounts for 0.2% to 1% of breast cancers. Median age at diagnosis is in the 50s to 60s, later than for other triple negative tumours, and tumours are often large at diagnosis.

Associations are those of other triple negative cancers, with no distinct hereditary syndrome.

Pathophysiology. Epithelial-to-mesenchymal transition, Wnt activation and basal like and claudin low profiles are common. PIK3CA mutations (about half), TP53, PTEN and TERT promoter alterations are frequent.

Subtypes. Low grade adenosquamous carcinoma and fibromatosis like metaplastic carcinoma are indolent and have a low rate of distant spread. Squamous cell, spindle cell, matrix producing (chondroid, osseous), and mixed forms are aggressive. Biphasic and sarcomatoid types are the most chemoresistant.

Behaviour. Nodal metastasis is uncommon (about 20%), with haematogenous spread to lung, bone and brain, and local recurrence of about 20% to 30%. Pathological complete response to neoadjuvant chemotherapy is about 10% or less, and 5-year overall survival is about 60% to 70% for stages I to III.

• Rapidly growing, firm, often painless mass, commonly over 4 cm, sometimes with cystic change or skin ulceration.
• Axillary nodes are less often involved than the tumour size predicts.
• Metastatic features: cough, dyspnoea, bone pain, headache.

• Imaging shows a well circumscribed round or lobulated mass that may appear benign, with cystic and necrotic components. MRI shows rim enhancement.
• Core biopsy with a broad panel: pan cytokeratin (AE1/AE3), high-molecular-weight cytokeratins (CK5/6, 34βE12), p63 and p40 identify epithelial differentiation in spindle cell tumours. ER, PR and HER2 are usually negative. Sampling error is common because of heterogeneous histology, so excision may be needed.
• Staging by CT chest, abdomen and pelvis plus bone scan for stage II or higher disease. MRI brain for symptoms.
• Germline testing, and tumour molecular profiling in metastatic disease (PIK3CA, PD-L1, tumour mutational burden).

Differential diagnosis.

• Malignant phyllodes tumour
• Primary breast sarcoma (angiosarcoma, liposarcoma, fibrosarcoma)
• Metastatic melanoma and metastatic sarcoma
• Squamous cell carcinoma from skin or lung
• Invasive ductal carcinoma with squamous or spindle cell change
• Fibromatosis and spindle cell lesions (nodular fasciitis, myofibroblastoma)

Evidence comes from retrospective series, so treatment follows the triple negative framework with surgery given the greater weight.

Surgery. Mastectomy or breast conservation with negative margins. Sentinel node biopsy for clinically node negative disease. Low grade adenosquamous and fibromatosis like tumours are treated by wide excision, and chemotherapy is not given.

Radiotherapy. Whole breast 40 Gy in 15 fractions after conservation, and a low threshold for post-mastectomy chest wall radiotherapy (including T2 or larger, close margins and positive nodes) because of local recurrence.

Systemic therapy for aggressive subtypes (stage II to III). The triple negative backbone is used, though benefit is smaller. Neoadjuvant therapy allows response assessment, and early progression leads to prompt surgery.

• Paclitaxel: 80 mg/m2 IV weekly for 12 weeks; maximum 80 mg/m2 each week; monitoring: FBC, liver tests, neuropathy at each visit; premedication with dexamethasone, an antihistamine and an H2 blocker; adjustment: reduce by about 25% in moderate hepatic impairment, avoid when bilirubin is over 5 times the upper limit, no renal adjustment.
• Carboplatin: AUC 5 IV every 3 weeks for 4 cycles with paclitaxel; dose in mg is AUC x (GFR + 25), GFR capped at 125 mL/min; maximum dose about 750 mg; monitoring: FBC (nadir around days 14 to 21), creatinine, magnesium; adjustment: recalculate with each creatinine, avoid when GFR is under 20 mL/min.
• Doxorubicin: 60 mg/m2 IV on day 1 every 3 weeks for 4 cycles (every 2 weeks with pegfilgrastim 6 mg subcutaneously 24 to 72 hours after each cycle is an option); maximum cumulative working ceiling 450 mg/m2; monitoring: echocardiography at baseline and after completion, FBC before each cycle; adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid; consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Cyclophosphamide: 600 mg/m2 IV on day 1 with doxorubicin, on the same schedule, for 4 cycles; maximum 600 mg/m2 each cycle; monitoring: FBC, hydration, urinary symptoms (haemorrhagic cystitis); adjustment: reduce by about 25% to 50% when eGFR is under 30 mL/min/1.73 m2, reduce in severe hepatic impairment.
• Pembrolizumab: 200 mg IV every 3 weeks (or 400 mg every 6 weeks) with chemotherapy for 8 cycles before surgery, then 9 cycles of 200 mg every 3 weeks after surgery regardless of response; maximum 200 mg each 3-week dose; monitoring: thyroid function, liver tests, creatinine and glucose before each dose, morning cortisol if symptomatic, infusion reactions; adjustment: no renal or hepatic dose adjustment, withhold for grade 2 immune toxicity, stop permanently for grade 3 to 4 events (except endocrinopathies controlled on replacement); for grade 2 or worse pneumonitis, colitis or hepatitis give prednisolone 1 to 2 mg/kg daily, tapered over at least 4 to 6 weeks. Metaplastic tumours were poorly represented in the evidence, so benefit is extrapolated.

Metastatic disease.

• Systemic therapy by molecular profile: chemotherapy (taxane, platinum, anthracycline), checkpoint inhibitor therapy for PD-L1 positive tumours, PARP inhibitors for germline BRCA variants, and PIK3CA or mTOR-targeted agents in selected cases. Sarcoma type chemotherapy is used for spindle cell and matrix producing tumours.
• Surgery or stereotactic radiotherapy for oligometastatic disease in fit patients.

Monitoring. Clinical review every 3 months for 2 years, then 6 monthly to year 5. Chest imaging every 6 to 12 months for 3 years in aggressive subtypes, because pulmonary relapse is common.

Referral and escalation.

• Specialist sarcoma or breast multidisciplinary review when histology shows heterologous elements.
• Same day oncology for febrile neutropenia, cord compression, hypercalcaemia or neurological deficit.

Special groups.

• Pregnancy: chemotherapy from the second trimester. Checkpoint inhibitors and PARP inhibitors are avoided.
• Older adults: surgery and radiotherapy with reduced intensity chemotherapy if fit.
• Low grade subtypes: avoid overtreatment with chemotherapy.