What is comingTriple-negative breast cancer (TNBC)

Residual disease after KEYNOTE-522: no approved escalation beyond capecitabine/olaparib; ctDNA-guided trials needed.

ADC sequencing: does a second TOP1-payload ADC work after the first? SATEEN/BRE-354 suggest limited efficacy; chemotherapy interposition debated.

Patient selection for TROP2 ADCs: IHC does not predict; TROP2 PET and ctDNA are candidates.

PD-L1-negative early disease has immunotherapy proven only in KEYNOTE-522's unselected population, no biomarker that spares anyone pembrolizumab, and no ADC yet in the curative setting.

Brain metastases (up to 30-45% of metastatic TNBC) remain undertreated; ADC CNS activity is emerging but unproven.

Mesenchymal/claudin-low biology (EMT, efflux pumps) resists chemotherapy, ADC payloads, and immunotherapy alike.

Disparities: Black women have twice the TNBC incidence and worse outcomes; trial enrolment does not reflect this.

No UK registry publishes triple-negative incidence or survival as a subtype; the UK share rests on Cancer Research UK's around 15 percent and on cohorts such as POSH, while SEER publishes rates by receptor status every year.

ER 1 to 10 percent tumours behave like triple-negative disease yet are excluded from most triple-negative trials, so the evidence for immunotherapy and ADCs in that band is thin (Yoder 2022; Acs 2024).

Chemoprevention for BRCA1 carriers: tamoxifen and anastrozole prevent ER-positive disease, which is not the cancer BRCA1 carriers mostly get; risk-reducing mastectomy and surveillance are the only proven options.

PD-L1 assays disagree on about a quarter of tumours (SP142 46 percent positive, 22C3 73 percent, concordance 69 percent in IMpassion130; 27 percent CPS 10 or more against 51 percent SP142-positive in the Swedish early cohort); only 22C3 combined positive score of 10 has an approved drug attached, laboratories are not harmonised, and no assay predicts benefit from the first-line antibody-drug conjugate plus pembrolizumab combinations.

Acting on ctDNA after residual disease failed once (c-TRAK TN: detection came after metastases were visible, and ctDNA misses brain-only relapse); the next design needs tumour-informed assays, a sample at surgery and an active drug, and has not been run.

The disparity is measured in the United States and was measured once in the UK (POSH, women under 41, recruited to 2008); NHS statistics do not report triple-negative outcomes by ethnicity, and women of African ancestry, who carry a distinct immune landscape, remain under-represented in the trials that set the biomarker thresholds.

Most homologous recombination deficiency in TNBC is not germline BRCA, yet the PARP inhibitor labels are germline-only and the HRD scores validated in ovarian cancer did not predict carboplatin benefit in advanced TNBC (TNT).

The Lehmann subtypes predict chemotherapy response retrospectively but no prospective subtype-directed trial has changed a guideline; the mesenchymal and LAR subtypes have no approved targeted therapy.

Capecitabine after residual disease (CREATE-X) was proven before pembrolizumab existed; no trial has tested it alongside adjuvant pembrolizumab, and the two ADC trials in that setting (ASCENT-05, TROPION-Breast03) will not report before 2027.

The independent contribution of adjuvant pembrolizumab is unknown: KEYNOTE-522 gave it before and after surgery, OptimICE-pCR asks whether it can be dropped after a complete response, and SWOG S1418 asks whether it helps after residual disease without prior immunotherapy.

Three atezolizumab phase 3 trials in early disease were negative or null while pembrolizumab succeeded; whether that is the drug, the PD-L1 rather than PD-1 target, the backbone or chance is unresolved, and it leaves PD-L1-negative early disease with immunotherapy proven only in KEYNOTE-522's unselected population.

In England HER2-low triple-negative disease cannot receive trastuzumab deruxtecan (NICE TA992 not recommended), the first-line ADC indications await appraisal, and atezolizumab remains commissioned on a licence the United States withdrew; the UK and US pathways for metastatic disease have diverged.

AKT inhibition failed twice in biomarker-selected metastatic disease (IPATunity130, CAPItello-290) despite positive phase 2 trials, so PIK3CA, AKT1 and PTEN alterations, present in a fifth to a quarter of tumours, are not actionable in triple-negative breast cancer today; PTEN loss may also mark immunotherapy resistance.