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Treatment landscape of triple-negative breast cancer — expanded options, evolving needs

Abstract

Tumour heterogeneity and a long-standing paucity of effective therapies other than chemotherapy have contributed to triple-negative breast cancer (TNBC) being the subtype with the least favourable outcomes. In the past few years, advances in omics technologies have shed light on the relevance of the TNBC microenvironment heterogeneity, unveiling a close dynamic relationship with cancer cell features. An improved understanding of tumour–immune system co-evolution supports the need to adopt a more comprehensive view of TNBC as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody–drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease. The current therapeutic scenario is only the tip of the iceberg, as hundreds of new compounds and combinations are in development. The translation of these experimental therapies into clinical benefit is a welcome and ongoing challenge. In this Review, we describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can define different levels of risk and provide improved opportunities for tailoring treatment.

Key points

  • Improved understanding of the interplay between triple-negative breast cancer (TNBC) tumour cells and their microenvironment supports the adoption of a new comprehensive view of this cancer type as an ecosystem.

  • Tumour–immune co-evolution from early-stage disease through to the metastatic process is accompanied by profound changes in immune cell dynamics that explain variations in the activity of immune-checkpoint inhibitors in different disease settings.

  • Chemotherapy remains the reference treatment of TNBC, although the optimal use of platinum-based agents, dose-dense therapy and post-neoadjuvant capecitabine remains to be clarified.

  • Targeted agents, such as PARP inhibitors and antibody–drug conjugates, are established additions in the therapeutic landscape of TNBC.

  • The key role of immune-checkpoint inhibitors in the treatment of TNBC is being defined and a plethora of ongoing trials testing different combination approaches will provide additional insights to improve the efficacy of immunotherapy.

  • The application of a breast cancer immunogram describing the TNBC ecosystem will help to successfully implement precision immunology and fulfil the promise of immunotherapy in TNBC.

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Fig. 1: Molecular features of the TNBC ecosystem.
Fig. 2: Targeting signalling pathways and oncogenic vulnerabilities in TNBC.
Fig. 3: The challenge of optimizing immunotherapies for TNBC.
Fig. 4: Landscape of immunotherapy trials in TNBC.

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Acknowledgements

The authors receive support from the Associazione Italiana per la Ricerca sul Cancro (IG2018–ID21787 project grant to G.B.), Breast Cancer Research Foundation (grants to L.G.), Cancer Prevention and Research Institute of Texas (RP140102), Conquer Cancer Foundation — Gianni Bonadonna Breast Cancer Research Fellowship (grants to C.D.A.), Fondazione Michelangelo (grants to G.B.) and Italian Ministry of Health (Ricerca Finalizzata 2018) (grants to G.B.). The authors thank L. Pusztai (Yale School of Medicine) for helpful comments on the manuscript.

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G.B. is a consultant and/or advisory board member for Amgen, AstraZeneca, Chugai, Daiichi Sankyo, EISAI, Eli Lilly, Genomic Health, Merck Sharp & Dohme, Neopharm, Novartis, Pfizer, Roche and Sanofi. C.D.A. is a consultant and/or advisory board member for AstraZeneca, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer and Roche. L.L. is a consultant for Eli Lilly and Novartis. L.G. is a consultant and/or advisory board member for ADC Therapeutics, Amgen, AstraZeneca, Biomedical Insights, Celgene, Eli Lilly, Forty Seven (CD47 programmes), G1 Therapeutics, GENENTA, Genentech, Genomic Health, Hexal Sandoz, Menarini Ricerche, Merck Sharp & Dohme, METIS Precision Medicine, Novartis, Odonate Therapeutics, Oncolytics Biotech, Onkaido Therapeutics, Pfizer, Revolution Medicines, Roche, Sanofi–Aventis, Seattle Genetics, Synaffix, Synthon, Taiho Pharmaceutical and Zymeworks.

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Bianchini, G., De Angelis, C., Licata, L. et al. Treatment landscape of triple-negative breast cancer — expanded options, evolving needs. Nat Rev Clin Oncol 19, 91–113 (2022). https://doi.org/10.1038/s41571-021-00565-2

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