Onco'Zine

A detailed Overview for Clinicians

Triple-negative breast cancer (TNBC) is a clinically and molecularly heterogeneous subset of invasive breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal Growth factor Receptor 2 (HER2)-overexpression/amplification on immunohistochemistry. In 2011, Brian Lehmann and his colleagues published a foundational study in the Journal of Clinical Investigation revolutionizing how we understand TNBC. [1][2] The researchers used mRNA expression profiling to show that TNBC can be divided into six distinct subtypes:

• Basal-like 1 (BL1)
• Basal-like 2 (BL2)
• Imunomodulatory (IM)
• Mesenchymal (M)
• Mesenchymal stem-like (MSL),
• Luminal androgen receptor (LAR)

Each subtype* has unique gene expression patterns and is associated with different cellular signaling pathways.[1]

TNBC accounts for approximately 10–15% of all breast cancers and is more frequently diagnosed in younger women, those of African or Hispanic descent, and in individuals with BRCA1 germline mutations.[3]

Molecular and Pathological Features: Most TNBCs are high-grade invasive ductal carcinomas (many of which show a basal-like molecular profile) though TNBC is an operational rather than a molecular term. The pathogenesis of TNBC is driven by complex molecular alterations, including high rates of TP53 tumor suppressor gene mutations (up to 8% of TNBC cases feature TP53), BRCA1 pathway dysfunction, and pathway hyperactivity, genomic instability, and a proclivity for visceral and central nervous system metastases, which collectively fuel rapid tumor growth and genomic instability. [4] [5] TNBCs are often enriched for homologous recombination deficiency (HRD), especially in cases with BRCA1/2 mutations. Molecular drivers include:

• Genetic Mutations: High rates of TP53 causes unchecked cellular proliferation and genomic instability.
• Homologous Recombination Deficiency (HRD): Approximately 15–20% of TNBCs involve germline mutations in BRCA1 or BRCA2 genes. Even without inherited mutations, many TNBC tumors exhibit so-called BRCAness , a state in which HRD prevents the repair of double-strand DNA breaks, which leads to aggressive tumor evolution.
• Aberrant Signaling Pathways: Hyperactivation of survival and growth cascades (especially PI3K/AKT/mTOR and MAPK/ERK pathways) promote rapid, uncontrolled tumor growth and therapeutic resistance.

Risk Factors: Apart from the aforementioned demographics, risk is elevated by BRCA1 mutation, early menarche, high parity, and exposure to certain reproductive factors. The etiology is otherwise similar to other breast cancers.

Clinical Presentation and Diagnosis: TNBC presents similarly to other breast cancers, with a palpable mass, sometimes with rapid growth. Diagnosis is made via imaging (mammogram, ultrasound, MRI), core needle biopsy, and confirmation of triple-negative status via immunohistochemistry and/or molecular testing. Staging includes local and systemic imaging (PET/CT) as indicated.

Treatment: Due to the lack of hormone receptors and HER2, TNBC does not respond to endocrine or HER2-targeted therapies. Management relies primarily on surgery, radiation, and chemotherapy (anthracyclines, taxanes, and often platinum agents). In advanced/metastatic disease, options include chemotherapy, immunotherapy (PD-1/PD-L1 inhibitors for PD-L1 positive tumors), PARP inhibitors for BRCA-mutated TNBC, and antibody-drug conjugates. Clinical trials are exploring additional targeted agents.

Prognosis: TNBC is aggressive, with a higher risk of early recurrence and visceral metastases. Five-year relative survival is 91% for localized, 66–67% for regional, and 12–15% for distant/metastatic disease. Prognosis depends on stage, response to neoadjuvant chemotherapy (notably pathologic complete response), tumor grade, and underlying molecular features.

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Note: * The basal-like subtype accounting for aproximately 75% of all diagnosed cases This subtype expresses genes characteristic of basal epithelial cells, which include high-molecular weight basal cytokeratins (CK5/6, CK14, CK17), vimentin, p-cadherin, alpha B crystalline, caveolins 1 and 2 and EGFR. The expression of basal markers (basal cytokeratins and EGFR) is related to a worse prognosis and identifies a clinically distinct subgroup within the triple-negative breast cancer. [1]

Reference
[1] Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014. PMID: 21633166; PMCID: PMC3127435.
[2] Tseng LM, Chiu JH, Liu CY, Tsai YF, Wang YL, Yang CW, Shyr YM. A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women. Breast Cancer Res Treat. 2017 Jun;163(2):241-254. doi: 10.1007/s10549-017-4195-7. Epub 2017 Mar 15. PMID: 28299476; PMCID: PMC5410215. [3] Rastelli F, Biancanelli S, Falzetta A, Martignetti A, Casi C, Bascioni R, Giustini L, Crispino S. Triple-negative breast cancer: current state of the art. Tumori. 2010 Nov-Dec;96(6):875-88. PMID: 21388048.
[4] Derakhshan F, Reis-Filho JS. Pathogenesis of Triple-Negative Breast Cancer. Annu Rev Pathol. 2022 Jan 24;17:181-204. doi: 10.1146/annurev-pathol-042420-093238. PMID: 35073169; PMCID: PMC9231507.
[5] Li CJ, Tzeng YT, Chiu YH, Lin HY, Hou MF, Chu PY. Pathogenesis and Potential Therapeutic Targets for Triple-Negative Breast Cancer. Cancers (Basel). 2021 Jun 14;13(12):2978. doi: 10.3390/cancers13122978. PMID: 34198652; PMCID: PMC8232221.


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