Back to Journals » Breast Cancer: Targets and Therapy » Volume 17
Triple-Negative Breast Cancer on the Rise or…? [Letter]
Authors Lønning PE 
, Nikolaienko O , Knappskog S
Received 13 August 2025
Accepted for publication 27 August 2025
Published 25 September 2025 Volume 2025:17 Pages 875—876
DOI https://doi.org/10.2147/BCTT.S560499
Checked for plagiarism Yes
Editor who approved publication: Professor Robert Clarke
Per Eystein Lønning,1 Oleksii Nikolaienko,1,2 Stian Knappskog1,2
1Cancer Clinic, Haukeland University Hospital, Bergen, Norway; 2Department of Clinical Science, University of Bergen, Bergen, Norway
Correspondence: Per Eystein Lønning, Email [email protected]
View the original paper by Dr Agelidis and colleagues
A Response to Letter has been published for this article.
Dear editor
The recent review by Agelidis et al in the Journal1 discusses triple-negative breast cancer (TNBC) epidemiology and therapy, two timely subjects. We are concerned about their statement regarding a rising incidence of TNBC. Among the two papers cited in relation to this statement, one2 confirms an increasing incidence of breast cancer (BC) in general among young women. The other3 reveals a contemporary trend for an increased incidence of estrogen receptor-positive (ER+) BC, particularly among young women, in the USA, contrasting with a non-significant trend for a reduced incidence of TNBC across all age groups. While trends in TNBC incidence may vary somewhat between studies, partly related to ethnicity,4,5 a consistent finding is that the increase in BC incidence mainly relates to ER+ disease among young as well as postmenopausal women, with limited or no increase in TNBC incidence for several decades.6–8 Taken together, these epidemiological findings strongly indicate different aetiologies for most TNBC and ER+ BCs.
While TNBC tumors present a certain heterogeneity in biological characteristics such as gene expression profiles, the majority reveal a basal-like gene expression profile and genomic signatures related to defects in homologous recombination repair (HRR), a characteristic of most BCs arising in women harboring pathogenic BRCA1 variants.9,10 Although a number of patients diagnosed with TNBC harbor germline pathogenic BRCA1 variants, and some pathogenic variants in BRCA2, the contribution from such germline variants and variants in other genes,11 as well as somatic mutations in BRCA1/2 or other genes involved in HRR,10,12 only explains a minor fraction of TNBCs carrying HRR defects (HRDs). However, recent evidence has shown 25–30% of TNBCs to harbor BRCA1 epimutations, ie, promoter hypermethylation,13,14 in most cases arising as clonal expansions from constitutional (prenatal, normal tissue) BRCA1 epimutations.14–17 While constitutional epimutations in other tumor-suppressor genes, eg, MLH1, have been recorded,18 these cases are rare. The fact that around 20% of all TNBC are associated with BRCA1 constitutional epimutations, and that these tumors reveal a genomic biology mirroring tumors arising in BRCA1 germline mutation carriers,13 establishes BRCA1 constitutional epimutations as a major underlying cause of TNBC. These findings raise the question of whether epimutations affecting other genes involved in HRR also cause TNBC. While some cases carrying constitutional epimutations in RAD51C have been described,19 the potential importance of this finding remains to be learned.
The different incidence trend between TNBC and ER+ BC may signal different biological mechanisms of carcinogenesis, a pivotal finding in understanding contemporary trends. Apart from BCs related to germline mutations, TNBC represents the only subtype for which a distinct underlying molecular cause, i.e. prenatal BRCA1 constitutional epimutations, has been identified. Whether these epimutations themselves are caused by internal cellular processes or external environmental factors remains to be learned. Similarly, the potential role of early epimutations in other genes remains to be explored. Addressing these questions may significantly expand our understanding of TNBC risk, biology, and, not least, therapy.
Disclosure
PE Lønning reports speakers’ honoraria from Illumina. S Knappskog reports speakers’ honoraria from Novartis and Pfizer, and project support from Illumina. The authors report no other conflicts of interest in this communication.
References
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