HER2-Positive Breast Cancer

HER2-positive breast cancer is invasive breast carcinoma with HER2 protein overexpression (immunohistochemistry 3+) or ERBB2 gene amplification on in situ hybridisation. HER2-directed therapy has changed it from the worst prognosis group to one with high cure rates in early disease.

It accounts for 15% to 20% of invasive breast cancers. About half are also ER positive, and the remainder are hormone receptor negative.

Associations are younger age at diagnosis, higher grade and TP53 mutation. Lifetime risk is not clearly changed by known germline variants.

Pathophysiology. ERBB2 amplification at 17q12 leads to HER2 overexpression, ligand independent heterodimerisation (mainly with HER3), and signalling through the PI3K-AKT-mTOR and MAPK cascades, which drive proliferation, survival and invasion.

Subtypes. Hormone receptor positive HER2-positive tumours have lower pathological complete response rates and need endocrine therapy as well. Hormone receptor negative tumours respond best to neoadjuvant therapy.

Response and prognosis. Pathological complete response after dual HER2 blockade with chemotherapy is about 45% to 65% (higher in receptor negative disease) and predicts excellent outcomes. Residual disease after neoadjuvant therapy needs treatment escalation.

Behaviour. Early visceral relapse and brain metastases are common. Up to 30% to 50% of patients with metastatic disease develop brain involvement, often while systemic disease is controlled.

Cardiotoxicity. Trastuzumab causes reversible LVEF decline (type II toxicity) in about 2% to 4% when used alone, more with prior anthracycline.

• Palpable mass, often grade 3, with early axillary nodal involvement.
• Metastatic features: dyspnoea, cough, hepatic pain, bone pain, headache or focal deficit.
• Cardiac symptoms during therapy: dyspnoea, orthopnoea, oedema, fatigue.

• Triple assessment and core biopsy.
• HER2 testing on every invasive cancer. Immunohistochemistry 3+ (strong complete membrane staining in over 10% of cells) is positive. 2+ is equivocal and reflexed to in situ hybridisation, with positivity when the HER2/CEP17 ratio is 2.0 or more with average HER2 copy number 4.0 or more (other combinations need further review). Repeat testing on metastatic biopsy because discordance occurs.
• ER, PR, grade and proliferation. HER2-low (1+, or 2+ with no amplification) is separate disease for antibody drug conjugate therapy.
• Staging with CT chest, abdomen and pelvis and bone scan for stage III or symptoms. MRI brain for neurological symptoms in metastatic disease.
• Echocardiography (LVEF over 50% needed) before starting and every 3 months during treatment.

Differential diagnosis.

• Luminal B-like (HER2-low) cancer
• Triple negative cancer
• Fibroadenoma and phyllodes tumour
• Metastasis to the breast
• Lymphoma

Anti-HER2 agents used across settings.

• Trastuzumab: 8 mg/kg IV over 90 minutes as a loading dose, then 6 mg/kg IV over 30 minutes every 3 weeks (fixed dose subcutaneous 600 mg every 3 weeks is an alternative, with no loading dose); duration 12 months (about 17 cycles) in early disease and until progression in metastatic disease; maximum 12 months in early disease; monitoring: LVEF at baseline and every 3 months, infusion reactions; adjustment: withhold if LVEF falls under 50% with an absolute fall of 10 points or more, repeat in 4 weeks, stop if no recovery; no renal or hepatic adjustment; avoid pregnancy during and for 7 months after treatment.
• Pertuzumab: 840 mg IV as a loading dose, then 420 mg IV every 3 weeks with trastuzumab; duration 12 months in early disease and until progression in metastatic disease; maximum 840 mg for the loading dose; monitoring: LVEF every 3 months, diarrhoea, infusion reactions; adjustment: no dose reduction (withhold or stop for toxicity or LVEF decline), no renal adjustment in mild to moderate impairment.

Neoadjuvant therapy (tumours over 2 cm or node positive).

• Docetaxel: 75 mg/m2 IV every 3 weeks for 6 cycles, with dexamethasone 8 mg orally twice daily for 3 days starting the day before; maximum 75 mg/m2 each cycle (100 mg/m2 is not used in this setting); monitoring: FBC and liver tests before each cycle, oedema, neuropathy; adjustment: do not give when bilirubin is over the upper limit or AST/ALT over 1.5 times the upper limit with alkaline phosphatase over 2.5 times, reduce to 60 mg/m2 for febrile neutropenia or grade 3 toxicity.
• Carboplatin: AUC 6 IV every 3 weeks for 6 cycles; dose in mg is AUC x (GFR + 25), GFR capped at 125 mL/min; maximum dose about 900 mg; monitoring: FBC, creatinine, magnesium; adjustment: recalculate with each creatinine, avoid when GFR is under 20 mL/min.
• Docetaxel, carboplatin, trastuzumab and pertuzumab (anthracycline free) is preferred because it gives similar outcomes to anthracycline sequences with less cardiac toxicity.
• Complete a total of 12 months of trastuzumab and pertuzumab after surgery if pathological complete response is achieved.

Small, node negative tumours (3 cm or under). Paclitaxel 80 mg/m2 IV weekly for 12 weeks with trastuzumab weekly (4 mg/kg loading, then 2 mg/kg weekly), then trastuzumab every 3 weeks to complete 12 months. Maximum paclitaxel 80 mg/m2 each week. Monitoring: FBC, liver tests, neuropathy, LVEF every 3 months. Adjustment: reduce paclitaxel by about 25% in moderate hepatic impairment, avoid when bilirubin is over 5 times the upper limit.

Residual disease after neoadjuvant therapy.

• Trastuzumab emtansine: 3.6 mg/kg IV every 3 weeks for 14 cycles; maximum 3.6 mg/kg each dose; monitoring: platelets and liver tests before each dose, LVEF every 3 months, neuropathy; adjustment: reduce to 3.0 then 2.4 mg/kg for toxicity, withhold when platelets are under 25 x 10^9/L, stop for nodular regenerative hyperplasia or ALT over 3 times the upper limit with bilirubin over 2 times the upper limit.
• Neratinib (extended therapy for ER-positive, higher risk disease after completing trastuzumab): 240 mg orally once daily with food for 1 year; maximum 240 mg daily; monitoring: diarrhoea (start loperamide with the first dose, 4 mg three times daily in weeks 1 to 2, 4 mg twice daily in weeks 3 to 8, then as needed up to 16 mg daily), liver tests monthly for 3 months; adjustment: reduce to 200 then 160 mg for toxicity, 80 mg daily in severe hepatic impairment, avoid with strong CYP3A inhibitors and acid reducing agents.

Endocrine therapy. For hormone receptor positive disease, adjuvant endocrine therapy for 5 to 10 years follows chemotherapy, selected by menopausal status.

Radiotherapy. Usual hypofractionated whole breast radiotherapy after conservation (40 Gy in 15 fractions) and post-mastectomy radiotherapy by stage. Radiotherapy can be given with trastuzumab.

Metastatic disease.

• First line: docetaxel (75 mg/m2 IV every 3 weeks for at least 6 cycles, up to 100 mg/m2 if tolerated) with trastuzumab and pertuzumab, then trastuzumab and pertuzumab maintenance (with endocrine therapy for receptor positive disease) until progression. Trastuzumab deruxtecan with pertuzumab is an emerging first line option.
• Second line: trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks until progression; maximum 5.4 mg/kg each dose; monitoring: antiemetics for high emetogenic risk, FBC, LVEF every 12 weeks, symptoms and imaging for interstitial lung disease; adjustment: reduce to 4.4 then 3.2 mg/kg for toxicity, interstitial lung disease of grade 1 needs a hold and prednisolone about 0.5 mg/kg daily, grade 2 or worse needs permanent discontinuation and prednisolone 1 mg/kg daily.
• Third line and brain metastases: tucatinib 300 mg orally twice daily, continuously until progression, with trastuzumab and capecitabine; maximum 600 mg daily; monitoring: ALT, AST and bilirubin every 3 weeks, diarrhoea; adjustment: 200 mg twice daily in severe hepatic impairment, reduce stepwise for toxicity, avoid strong CYP2C8 inducers or inhibitors. Capecitabine in this regimen is 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle (maximum 2000 mg/m2 daily; reduce to 75% when creatinine clearance is 30 to 50 mL/min, contraindicated under 30 mL/min; test DPYD).
• Brain metastases: stereotactic radiosurgery for limited lesions and whole brain radiotherapy for extensive disease, with continued HER2-directed therapy.

Monitoring. LVEF every 3 months during HER2-directed therapy and at 6 and 12 months after completion. Clinical review every 3 to 6 months for 3 years, then 6 to 12 monthly.

Referral and escalation.

• Heart failure team for LVEF under 50% or symptoms. LVEF 40% or less stops trastuzumab and pertuzumab.
• Respiratory review for new cough, dyspnoea or hypoxia on trastuzumab deruxtecan (interstitial lung disease).
• Neuro oncology for new headache, vomiting, seizure or deficit.
• Febrile neutropenia needs same day admission and an intravenous antipseudomonal beta lactam within 1 hour.

Special groups.

• Pregnancy: trastuzumab, pertuzumab, trastuzumab emtansine and trastuzumab deruxtecan are contraindicated (oligohydramnios and foetal harm). Chemotherapy is possible from the second trimester, and HER2-directed therapy starts after delivery.
• Contraception during and for 7 months after trastuzumab, pertuzumab and trastuzumab emtansine, and for 7 months (women) or 4 months (men) after trastuzumab deruxtecan.
• Prior anthracycline or cardiac disease: LVEF monitoring every 6 to 8 weeks and cardio oncology review.
• Older adults: trastuzumab alone with endocrine therapy or low intensity chemotherapy is reasonable.
• Kidney impairment: no adjustment for antibodies, adjust capecitabine and carboplatin.