Triple-Negative Breast Cancer

Triple negative breast cancer is invasive breast carcinoma that lacks ER and PR (under 1% of nuclei) and HER2 (immunohistochemistry 0, 1+, or 2+ with no in situ amplification). It has no targets for endocrine or conventional anti-HER2 therapy and has the highest early relapse rate of the subtypes.

It makes up 10% to 15% of breast cancers in most populations and 20% to 30% in women of West African ancestry and in younger women. Peak recurrence is within the first 3 years and relapse after 5 years is uncommon.

Associations are age under 50, BRCA1 germline variants, higher parity with no breastfeeding, obesity and young age at first birth. About 10% of cases carry a germline BRCA1 or BRCA2 pathogenic variant, higher in age under 40.

Pathophysiology. About 70% are basal like (high proliferation, TP53 mutation, CK5/6 and EGFR expression, homologous recombination deficiency in BRCA-related cases). Rare special types include medullary like, adenoid cystic and secretory carcinoma, which behave more favourably.

HER2-low and ER-low. About a third of triple negative cancers are HER2-low (1+, or 2+ with no amplification), which allows antibody drug conjugate therapy. ER 1% to 10% (ER-low) behaves like triple negative disease and is treated with it.

Immune biology. Tumour infiltrating lymphocytes are high in many cases and predict pathological response. PD-L1 combined positive score (10 or more) selects patients for checkpoint inhibitor therapy in metastatic disease.

Behaviour. Visceral and brain metastases are frequent, and median survival in metastatic disease is about 1 to 1.5 years with chemotherapy alone. Residual disease after neoadjuvant therapy carries a high recurrence risk, and complete pathological response is associated with excellent survival (5-year event free survival over 90%).

• Rapidly growing palpable mass, often noticed over weeks, round and well circumscribed (it may mimic a fibroadenoma), with a short interval between screening mammograms.
• Axillary nodal involvement is less frequent than for luminal tumours of the same size, and distant spread is early.
• Metastatic symptoms: cough, dyspnoea, pleural effusion, bone pain, hepatomegaly, headache and seizure.

Red flags.

• Progressive dyspnoea, cough or pleuritic pain (lymphangitic, pleural or lung disease).
• New severe headache, vomiting, focal deficit, seizure or visual change (brain metastases).
• Back pain with limb weakness, sensory level or sphincter disturbance (cord compression).
• Jaundice or rapid rise in bilirubin or liver enzymes.
• Thirst, confusion and polyuria (hypercalcaemia).
• Rapid skin change or erythema within weeks (inflammatory presentation).

• Triple assessment. Ultrasound often shows a hypoechoic round mass with posterior enhancement. Core biopsy shows grade 3, high mitotic count, pushing borders and necrosis.
• Repeat ER, PR and HER2 testing if results are borderline. Record ER-low and HER2-low categories and PD-L1 (combined positive score) for metastatic disease.
• Staging with CT chest, abdomen and pelvis plus bone scan (or PET-CT) for clinical stage II or higher. MRI brain for neurological symptoms.
• Germline testing in all patients (BRCA1, BRCA2, PALB2 at least), because results change therapy.
• Baseline FBC, creatinine, liver tests, calcium, thyroid function, glucose, morning cortisol, echocardiography, pregnancy test and DPYD status where available.

Differential diagnosis.

• Fibroadenoma and phyllodes tumour
• Metaplastic carcinoma and other special type cancers
• Lymphoma
• Breast abscess and granulomatous mastitis
• Metastasis to the breast (melanoma, lung, ovary)
• Fat necrosis

Stage I (T1a to T1b, node negative). Surgery with adjuvant chemotherapy for tumours over 5 mm (paclitaxel and carboplatin or cyclophosphamide based). Tumours of 5 mm or under need no chemotherapy.

Stage II to III (T1c node positive, or T2 or larger). Neoadjuvant chemotherapy with pembrolizumab, then surgery, then adjuvant therapy chosen by the pathological result.

• 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.
• 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. Weekly carboplatin AUC 1.5 for 12 weeks is an alternative.
• 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. Epirubicin 90 mg/m2 every 3 weeks (cumulative ceiling 900 mg/m2) is an alternative.
• 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.

After surgery.

• Pathological complete response: continue pembrolizumab to complete 9 cycles. Residual disease: continue pembrolizumab and add capecitabine (no germline BRCA variant) or olaparib (germline BRCA variant).
• Capecitabine (residual disease, no germline BRCA variant): 1250 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle for 6 to 8 cycles; maximum 2500 mg/m2 daily; monitoring: FBC, creatinine, liver tests each cycle, hand foot syndrome, diarrhoea; adjustment: reduce to 75% when creatinine clearance is 30 to 50 mL/min, contraindicated under 30 mL/min, test DPYD before starting, avoid warfarin.
• Olaparib (residual disease with germline BRCA variant): 300 mg orally twice daily for 1 year; maximum 600 mg daily; monitoring: FBC monthly for the first year, creatinine; adjustment: 200 mg twice daily when creatinine clearance is 31 to 50 mL/min, not advised under 30 mL/min, 100 mg twice daily with strong CYP3A inhibitors and 150 mg twice daily with moderate inhibitors, stop if myelodysplasia or acute myeloid leukaemia is confirmed.

Radiotherapy. Whole breast 40 Gy in 15 fractions after conservation, or post-mastectomy radiotherapy for T3 to T4 disease or positive nodes after neoadjuvant therapy, because locoregional recurrence is higher in this subtype.

Metastatic disease.

• PD-L1 combined positive score of 10 or more: pembrolizumab 200 mg IV every 3 weeks with chemotherapy (paclitaxel 90 mg/m2 on days 1, 8 and 15 of a 28-day cycle, or gemcitabine 1000 mg/m2 with carboplatin AUC 2 on days 1 and 8 of a 21-day cycle).
• Germline BRCA variant: olaparib 300 mg orally twice daily; maximum 600 mg daily; monitoring: FBC monthly, creatinine; adjustment: 200 mg twice daily when creatinine clearance is 31 to 50 mL/min, not advised under 30 mL/min, 100 mg twice daily with strong CYP3A inhibitors and 150 mg twice daily with moderate inhibitors, stop if myelodysplasia or acute myeloid leukaemia is confirmed; or talazoparib 1 mg orally once daily with food; maximum 1 mg daily; monitoring: FBC monthly; adjustment: 0.75 mg once daily when eGFR is 30 to 59 mL/min/1.73 m2, 0.5 mg once daily when eGFR is 15 to 29, reduce stepwise for toxicity.
• Sacituzumab govitecan (after one or more earlier lines): 10 mg/kg IV on days 1 and 8 of each 21-day cycle until progression; maximum 10 mg/kg each dose; monitoring: FBC before each dose, diarrhoea, hypersensitivity; adjustment: reduce by 25% steps for neutropenia or diarrhoea, hold when absolute neutrophil count is under 1.5 x 10^9/L on day 1, increased neutropenia risk in UGT1A1*28 homozygotes, avoid UGT1A1 inducers and inhibitors.
• Trastuzumab deruxtecan (HER2-low, after earlier chemotherapy): 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.

Monitoring. Clinical review every 3 months for 2 years, every 6 months to year 5, then annually. Routine imaging is not advised in asymptomatic patients. Surveillance of immune related toxicity continues for 12 months or more after checkpoint therapy.

Referral and escalation.

• Febrile neutropenia needs same day admission and an intravenous antipseudomonal beta lactam within 1 hour.
• Immune related toxicity of grade 3 to 4 (colitis, hepatitis, pneumonitis, myocarditis, adrenal crisis) needs urgent admission and corticosteroids.
• Same day oncology for cord compression, brain metastases or hypercalcaemia.
• Radiotherapy and neurosurgery for brain metastases.

Special groups.

• Pregnancy: chemotherapy from the second trimester. Pembrolizumab, PARP inhibitors and antibody drug conjugates are avoided.
• Germline BRCA carriers: consider risk reducing bilateral mastectomy and salpingo oophorectomy.
• Africa: triple negative disease is common and young. Prioritise early neoadjuvant chemotherapy, because checkpoint inhibitors and PARP inhibitors may be unavailable.
• Older adults: reduce chemotherapy intensity, adjusted to geriatric assessment.