EvidenceMetastatic triple-negative breast cancer

Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.

PD-L1 testing with the combined positive score decides first-line treatment in metastatic triple-negative breast cancer; pembrolizumab-chemotherapy is the standard for scores of 10 or more.

TROP2 IHC does not gate sacituzumab govitecan: the label requires no test, and the corpus records TROP2 as an expression readout without a threshold.

The clearest demonstration that PD-L1 positive in triple-negative breast cancer means different things depending on the kit; with atezolizumab withdrawn, pembrolizumab's 22C3 combined positive score of 10 is the surviving standard, and roughly a quarter of patients get a different answer depending on which assay their laboratory runs.

Sacituzumab govitecan is a standard second-line or later treatment for metastatic triple-negative breast cancer, roughly doubling survival compared with the chemotherapies it was tested against. Patients should expect neutropenia and diarrhoea, which are manageable with growth factor support and loperamide. Trials are now testing it earlier, in first-line combinations with pembrolizumab and after surgery for residual disease.

PAKT gives the trial-based prevalence of PI3K-pathway alteration in first-line metastatic TNBC (one in five) and the strongest signal for AKT inhibition in that subgroup; the phase 3 CAPItello-290 did not confirm it.

PTEN loss, the most common PI3K-pathway lesion in TNBC, may mark primary immunotherapy resistance, and TMB may add to PD-L1 in choosing who gets checkpoint blockade.

Re-biopsy and re-sequencing at relapse can find repair defects and a higher mutation burden that the primary did not show, which matters for PARP inhibitor and immunotherapy eligibility in metastatic TNBC.

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Enzalutamide works modestly in AR-positive TNBC and is the reference for the LAR subtype's therapy implication; the AR threshold used for eligibility changes who counts as positive.

LOTUS and PAKT together made the PI3K/AKT/PTEN-altered subgroup the target population for AKT inhibitors in TNBC; the phase 3 IPATunity130 later failed to confirm it, which is why no AKT inhibitor is approved here.

Germline BRCA testing became part of metastatic breast cancer work-up, and olaparib (with talazoparib after EMBRACA) is a standard option, especially for triple-negative disease.

It fixes the AR-positive share of ER-negative disease at about one in eight and shows anti-androgens give modest, non-toxic benefit, the rationale for enzalutamide and later CDK4/6 and PI3K combinations in LAR tumours.