Triple-Negative Breast Cancer
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Direct answer
Strip the oestrogen receptor, the progesterone receptor and HER2 from a breast carcinoma and a distinct clinical animal remains: high grade, early-relapsing, visceral-metastasising and dependent on chemotherapy plus, increasingly, immunotherapy and antibody-drug conjugates. Triple-negative breast cancer is defined operationally — ER and PR under 1% by immunohistochemistry with negative HER2 testing — but molecularly it is heterogeneous, with roughly three-quarters belonging to the basal-like expression class. Key exam anchors are the ER-low-positive (1-10%) category that breaks the triple-negative label, tumour-infiltrating lymphocytes as a prognostic and predictive feature, the BRCA1 linkage, and PD-L1 CPS 10 or more as the pembrolizumab threshold in metastatic disease.
What you must remember
- Definition with teeth: ER under 1% AND PR under 1% AND HER2 negative (IHC 0/1+ or 2+ with negative ISH); ER-positive in 1-10% of cells is "ER-low positive" — its own reporting category, not triple-negative.
- Basal-like overlap: about 75-80% of triple-negative tumours are basal-like on expression profiling; the terms are not interchangeable, a distinction examiners insist on.
- Lehmann subtypes: BL1, BL2, immunomodulatory, mesenchymal(-stem-like), luminal androgen receptor (LAR) and mesenchymal — LAR tumours are AR-positive with apocrine morphology and have been explored for androgen-receptor blockade.
- Morphology: high Nottingham grade, medullary-like features — circumscribed pushing borders, syncytial sheets, dense lymphocytes — and high stromal TILs; high TILs predict better pCR to neoadjuvant chemotherapy and better prognosis.
- Genetics: germline BRCA1 (and BRCA2) mutations are enriched; guidelines recommend offering testing for triple-negative disease, commonly for diagnosis at or under 60-65 years and increasingly for all such patients.
- Therapy anchors: platinum sensitivity in BRCA-associated tumours and PARP inhibitors (olaparib, talazoparib); pembrolizumab with chemotherapy where PD-L1 CPS is 10 or more in metastatic disease and in high-risk early disease (neoadjuvant, KEYNOTE-522 logic); sacituzumab govitecan (Trop-2 conjugate) in later lines.
- Relapse pattern: early — the hazard peaks in the first 2-3 years — with visceral and brain metastases; no endocrine or anti-HER2 option exists.
The report that refuses the label
A 44-year-old woman's carcinoma stains ER at 2% weak nuclear positivity, PR at 0, HER2 IHC 1+. Calling it triple-negative would be wrong: 2% ER makes it ER-low positive, a category created precisely because these tumours sit between worlds. The oncology discussion changes — endocrine therapy offers marginal benefit at best, and trial eligibility that requires true ER-negativity is forfeited. The correct report states ER low positive (1-10%), PR negative, HER2 negative, and flags germline BRCA testing given the age and phenotype. This scenario is a favourite because it tests whether the candidate knows the 1% cut-off both directions: below it the tumour is ER-negative for label purposes, at 1% or more it is technically endocrine-responsive. Molecular subtyping then does quiet work in the background: a basal-like profile with high TILs and a medullary pattern predicts a better pCR from platinum-containing neoadjuvant chemotherapy than an LAR apocrine tumour would.
Where students slip
Equating triple-negative with basal-like is the first error — the overlap is large but incomplete, and LAR tumours are triple-negative yet hormonally driven at the androgen receptor. The second slip is the PR cut-off: older practice used 20%, current ASCO/CAP guidance uses 1%, and reports must name the scoring system. Third, medullary carcinoma is no longer a separate WHO diagnostic entity — it is "carcinoma with medullary pattern," often BRCA1-associated, so a viva answer that lists "medullary carcinoma" as an independent type dates itself. Finally, students forget that the relapse curve of triple-negative disease is front-loaded: five-year survival data overstate lifetime risk comparisons with luminal tumours.
Frequently asked questions
What are the exact receptor cut-offs for triple-negative breast cancer?
ER under 1% and PR under 1% by IHC with negative HER2 (0/1+, or 2+ with negative ISH); ER of 1-10% is ER-low positive instead.
Are triple-negative and basal-like the same?
No — roughly three-quarters of triple-negative tumours are basal-like on molecular profiling, but LAR and other subtypes break the equivalence.
Why test germline BRCA in triple-negative disease?
Mutation enrichment is high, the result guides platinum and PARP inhibitor therapy, and it triggers cascade testing of relatives.
What role do tumour-infiltrating lymphocytes play?
High stromal TILs correlate with better pathological complete response to neoadjuvant chemotherapy and better prognosis in early triple-negative disease.
When is pembrolizumab used in metastatic triple-negative cancer?
With chemotherapy when PD-L1 combined positive score is 10 or more, per the KEYNOTE-355 evidence.