Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease
Open accessAbstract
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.
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Metastasis is the leading cause of death from breast cancer.
“Metastasis is the leading cause of death from breast cancer1, 37-39.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [38]
The Chemotherapy for TNBC section says fewer than 30% of women with metastatic breast cancer survive five years and that virtually all women with metastatic TNBC ultimately die of their disease. It does not establish that metastasis is the leading cause of death across all breast cancer cases. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDespite strong immunogenicity and a higher prevalence of tumor-infiltrating lymphocytes in TNBC, patients often progress to metastasis with poor clinical outcomes.
“Paradoxically, despite strong immunogenicity and a higher prevalence of tumor-infiltrating lymphocytes (TILs) in TNBC3, patients often progress to metastasis with poor clinical outcomes1.”
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective treatment.
“Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective treatment1,2.”
Previously reported targets including farnesyltransferase and sphingomyelinase may also play a role in mediating anti-cancer effects or other biological activities.
“Previously reported targets including farnesyltransferase and sphingomyelinase may also play a role in mediating anti-cancer effects or other biological activities 22,23.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [23]
Manumycin A has been shown to inhibit farnesyl transferase activity and sphingomyelinase activity.
“Manumycin A has also been show to inhibit farnesyl transferase activity and sphingomyelinase activity, but asukamycin is not known to inhibit these targets and its anti-cancer mechanism of action is unclear 19–23.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [23]
Asukamycin is not known to inhibit farnesyl transferase or sphingomyelinase and its anti-cancer mechanism of action is unclear.
“Manumycin A has also been show to inhibit farnesyl transferase activity and sphingomyelinase activity, but asukamycin is not known to inhibit these targets and its anti-cancer mechanism of action is unclear 19–23.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [23]
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References 196 · Cited by 3,079
- Authors
- Bianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E., & Gianni, L.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Gianni, Luca
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2016-05-17
- Volume
- 13
- Issue
- 11
- Pages
- 674-690
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- PMC
- PMC5461122
- OpenAlex
- W2402636472
- Cited by
- 3,079
- References
- 196
- Citations by year
- 2026: 334 · 2025: 345 · 2024: 338 · 2023: 398 · 2022: 389 · 2021: 413 · 2020: 343 · 2019: 229 · 2018: 166 · 2017: 100 · 2016: 20
- FWCI
- 15.76
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R00CA181491)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
- Keywords
- triple-negative breast cancer, tumor heterogeneity, actionable molecular targets, BRCA mutations, BRCAness, androgen receptor, tumor-infiltrating lymphocytes, immune checkpoint inhibitors, immunotherapy, chemotherapy, genetic alterations, molecular subtypes
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Phosphoinositide-3 Kinase Inhibitors, Androgen Antagonists, Clinical Trials as Topic, Female, Humans, Immune System, Immunotherapy, Mutation, Prognosis, Biomarkers, Tumor, Neoplastic Stem Cells, Mitogen-Activated Protein Kinases, BRCA2 Protein, Ubiquitin-Protein Ligases, Molecular Targeted Therapy, Triple Negative Breast Neoplasms
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