EvidenceTriple-negative breast cancer (TNBC)

NCCN is the source of the category grades on the triple-negative breast cancer page and the first major guideline to place an antibody-drug conjugate first line for the disease.

Residual-disease testing may not need the tumour to be sequenced first, which would remove the slowest step of tumour-informed assays; the comparison with tumour-informed results in the same patients is the evidence that matters.

The latest in a line of negative targeted-therapy trials in triple-negative disease (EGFR, VEGF, iniparib, now AKT): a modest delay in progression that did not translate into survival, in the same year that an antibody-drug conjugate did. It is why the roadmap treats pathway-targeted small molecules as the road not taken.

The first-line overall survival result that made an antibody-drug conjugate the standard for PD-L1-negative or immunotherapy-ineligible metastatic triple-negative disease, and the reason the sequencing question (which TROP2 drug first, what after it) is now urgent.

Three-quarters of chemotherapy-naive TNBC would be low or ultralow by the DESTINY-Breast06 definitions, but ultralow is unlabelled in TNBC and carries no prognostic weight.

This is what the NHS R208 pathway yields in practice: a one-in-seven positive rate among the eligible, at the cost of clinician time spent on eligibility scoring.

Answers the two questions that hung over adjuvant olaparib, durability and late leukaemia, in its favour; the remaining question is whether carriers who also received pembrolizumab or capecitabine, whom the trial did not study, get the same benefit.

An argument for universal rather than criteria-based germline testing at diagnosis, with turnaround fast enough to inform surgery; for TNBC patients, who are already eligible, the lesson is timing.

Platinum and immunotherapy are now consensus for early triple-negative disease; the open votes have moved to who can safely receive less.

For a fast-moving disease the living guideline, not the 2021 paper, is where European recommendations for triple-negative breast cancer now change; readers should check the website rather than the journal.

This is the European standard the UK page for triple-negative breast cancer is compared against; NICE guidance covers the same ground with a narrower set of funded drugs.

For TNBC, which is diagnosed young and is the PARP inhibitor-eligible subtype, the guideline makes germline testing part of the diagnostic workup rather than a referral decision.

The evidence behind the stage I de-escalation statement on the triple-negative page: an ordinary haematoxylin and eosin slide identifies a fifth of patients whose outcome without chemotherapy matches treated cohorts. A prospective trial of chemotherapy omission is the missing step.

Screening programmes short of radiologists can read this as prospective evidence that a well-validated AI reader can take the second reader's seat without lowering cancer detection. It is a paired-reader study in one hospital, not a randomised trial, so MASAI and real-world follow-up carry the argument further.

This is the population-based prevalence for the two label thresholds in early TNBC, and it shows the KEYNOTE-355 CPS 10 gate would admit only about a quarter of unselected patients.

ctDNA and RCB measure different things and both should stratify post-neoadjuvant TNBC trials; an RCB-II patient with negative ctDNA has an 87% three-year event-free survival.

AI can take over one reader's work in double-reading screening programmes while finding more cancers. Whether the extra cancers found are ones that would have harmed women, and whether interval cancers fall, is the question the trial's primary endpoint will answer.

The first prospective test of acting on ctDNA in triple-negative disease, and a negative one: with a quarterly, single-mutation assay the window between detectable DNA and visible metastasis was too short to intervene. Later designs use tumour-informed assays, earlier sampling and drugs with more single-agent activity.

St Gallen is where de-escalation questions in triple-negative disease (who needs the full KEYNOTE-522 regimen, who can skip adjuvant pembrolizumab) are first put to a vote; the 2023 panel framed intensity and duration as the central problem.

It replaces self-reported race with measured ancestry and shows the immune microenvironment of TNBC differs with it, a variable immunotherapy trials have not stratified on.

Confirms that the TROP2 antibody-drug conjugates are given without a TROP2 test and that PD-L1 remains the one selection assay in metastatic triple-negative disease, which is why assay harmonisation matters.

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.

For stage II-III triple-negative breast cancer, chemotherapy plus pembrolizumab before surgery and pembrolizumab alone afterwards is now the standard approach worldwide, and the survival gain is real, not just a surrogate. It does not apply to stage I disease or to hormone-receptor-positive or HER2-positive cancers. The price is a year of immunotherapy with a meaningful chance of a permanent endocrine side effect such as hypothyroidism or adrenal insufficiency.

The third trial to show carboplatin's benefit persists beyond pathological complete response and the trial that closed the neoadjuvant PARP inhibitor route in unselected triple-negative disease; PARP inhibition survives only in germline BRCA carriers.

The survival result that moved adjuvant olaparib from a disease-free survival approval to an undisputed standard, and the reason germline testing at diagnosis of triple-negative breast cancer is now a treatment decision rather than a family history exercise.

The external validation the 2017 paper asked for; it is why residual cancer burden is reported in UK and European pathology and used as a trial entry criterion rather than an MD Anderson curiosity.

Shows how quickly the standard moved: the 2021 guideline and its reversal are 15 months apart.

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.

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

ctDNA clearance may refine pCR as a surrogate: a patient with residual disease but no ctDNA may not need escalation, the hypothesis behind ctDNA-guided post-neoadjuvant trials.

The trial-grade HER2-low share for TNBC is about a third, and the survival difference hints that HER2-zero triple-negative disease is the more aggressive group.

HER2-low is a drug eligibility label, not a biological subtype, in triple-negative disease; because a third of patients qualify for trastuzumab deruxtecan on a score pathologists disagree about, re-scoring and digital assistance for HER2 0 versus 1+ is a practical gap.

The document that made immunotherapy, PARP inhibition and the first antibody-drug conjugate the European standard for metastatic triple-negative disease; every later first-line change is an amendment to it.

This is the scientific basis for pairing ivermectin with checkpoint antibodies in the Cedars-Sinai and ICONIC trials. Its key figure is now in doubt, which makes those trials more important, not less, as the only way to find out whether the effect is real.

MSI testing has a very low yield in TNBC; TMB and PD-L1 are the immunotherapy biomarkers worth pursuing.

It gives the PD-L1-negative mesenchymal subtype, the group immunotherapy leaves behind, a mechanistic route back to immune visibility, and explains why immune infiltration and subtype are coupled.

The last major guideline written before KEYNOTE-522 changed the standard; the 2022 rapid update reversed the immunotherapy line within a year.

Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.

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.

The proof that a blood test can split residual-disease patients into those likely to relapse and those likely cured, the premise of the ctDNA-guided adjuvant idea; no completed trial has yet acted on the result.

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.

Sets the surgical and systemic rules for the one in nine to one in six triple-negative patients who carry a germline BRCA variant (11 to 17 percent by cohort); the adjuvant gap it named was filled by OlympiA the following year.

Rare MSI-high TNBC exists and qualifies for tumour-agnostic pembrolizumab, so comprehensive genomic profiling should report MSI even though dedicated testing is low-yield.

TMB-high is uncommon but not negligible in TNBC, rises at relapse, and the tumour-agnostic pembrolizumab indication makes it worth measuring on a metastatic biopsy.

Multi-variant tracking beats a TP53-only assay in TNBC and supports response-adapted designs that read ctDNA mid-chemotherapy.

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.

It links the Lehmann subtypes to the spatial immune classes of Gruosso and gives a rationale for pairing checkpoint inhibitors with the immunomodulatory subtype and stromal or metabolic agents with the cold ones.

For TNBC, where brain metastases are common, the blind spot matters: a negative ctDNA test does not exclude intracranial relapse.