Two studies provide insights into the biological basis of triple-negative breast cancer

Molecular heterogeneity segregates triple-negative breast cancer (TNBC) into several subtypes based on driver genomic alterations – immunomodulatory, basal-like, mesenchymal, mesenchymal stem-like, and luminal androgen receptor subtypes – and chromosomal instability is increasingly recognised as a driver of tumour evolution but immune escapet is not well understood yet (Nat Commun. 2024;15:10232; Histopathology. 2023;82:17–35; Breast Cancer (Dove Med Press). 2023;15:189–211).

Whole-exome sequencing analysis of TNBC from 140 treatment-naïve patients enrolled in the Breast TRACERx trial, presented at MAP Congress 2026 (London, 10–11 September), revealed that mutations or deletions in key tumour suppressor genes – TP53, BRCA1, RB1 and PTEN – occurred at an early stage of tumour evolution and that whole-chromosome loss of heterozygosity precedes whole-genome doubling (Abstract 4O). “This has implications for chromosomal instability – linked to whole-genome doubling – which in turn is associated with immune evasion and the poor survival of these patients,” comments Prof. Christos Sotiriou from Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium. Whole-genome doubling may lead to loss of genes important for antigen presentation and reduced response to interferon gamma, a mechanism of immune evasion seen in TNBCs (Cancer Cell. 2026;44:1418–1436.e12).

The study also found two novel pathogenic germline BRCA1 mutations and novel non-canonical FAT4 mutations linked to chromosomal instability. Moreover, despite 61% of the TNBCs harbouring wild-type BRCA1, they displayed a homologous recombination deficiency (HRD)-high phenotype. “Regardless of the BRCA1 wild-type genotype, these TNBCs behave like BRCA1-mutated tumours with an HRD-high phenotype, which may result in response to PARP inhibitors,” suggests Sotiriou. However, the analyses were done on tumours prior to treatment and there are no correlative outcome data. “The clinical significance of these findings are unknown, but a potential future study could determine whether whole-genome doubling, chromosome instability or HRD status could be used as biomarkers for response to PARP inhibitor therapy,” Sotiriou adds.

A further finding of the study was that immunologically ‘cold’ tumours showed early clonal loss of heterozygosity in the HLA-type genes responsible for antigen presentation, while immunologically ‘hot’ tumours developed loss of heterozygosity in HLA-type genes subclonally under adaptive immune pressure. “This could be why some TNBCs with high immune infiltration fail to respond to immunotherapy – there is loss of antigen presentation and no immune activation,” he explains.

Patients with TNBC who achieve a complete pathological response with neoadjuvant chemoimmunotherapy usually have a very positive outcome, but for patients who do not, outcomes tend to be poor, with evidence from an analysis of clinical trials suggesting that ~24–39% of patients with residual disease experience recurrence and that ~69–89% of these occur within 2 years (Clin Cancer Res. 2025;31:3916–3921). Understanding the biology of these rapidly recurring tumours was the focus of a second presentation at the Congress, which showed that in a retrospective analysis of patients with TNBC who had received neoadjuvant chemotherapy, those who had rapid metastatic recurrence (within 12 months of treatment; n=35) had tumour cells displaying superior cellular fitness than patients who did not have recurrence (n=26) (Abstract 16RO). Compared with non-recurring tumours, rapidly recurring tumours had elevated expression of basal keratin, and cell cycle and regulatory genes, both before and after treatment. In biopsies of rapidly-recurring tumours analysed pre-treatment there was elevated expression of CKMT1A and post-treatment, upregulated SOX10, indicative of a highly aggressive molecular profile. No differences were observed between pre- and post-treatment samples from tumour-infiltrating lymphocyte (TIL)-high tumours. However, among TIL-low tumours, compared to patients with no recurrence, patients with rapid recurrence had elevated CCNE1 expression pre-treatment, and elevated expression of several genes promoting proliferation and cell survival post-treatment. “One caveat to this study is that patients received chemotherapy, not the standard chemoimmunotherapy,” cautions Sotiriou, “However despite this, it raises interesting questions around identifying patients at risk of rapid recurrence prior to treatment. Most likely, multiple biomarkers will be needed to be combined to accurately distinguish high-risk patients.” Sotiriou thinks that for patients unlikely to benefit from immunotherapy, treatment could be tailored to include an antibody–drug conjugate, while for those with HRD-high status, a PARP inhibitor could be offered after neoadjuvant chemoimmunotherapy. “Avoiding recurrence is key in these high-risk patients,” he concludes.