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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Novel roles of RNA-binding proteins in drug resistance of breast cancer: from molecular biology to targeting therapeutics
Cell Death Discovery Open Access 09 February 2023
Endoplasmic reticulum stress targeted therapy for breast cancer
Cell Communication and Signaling Open Access 07 November 2022
Combined atezolizumab and nab-paclitaxel in the treatment of triple negative breast cancer: a meta-analysis on their efficacy and safety
BMC Cancer Open Access 05 November 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Bianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E. & Gianni, L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol. 13, 674–690 (2016).
Azizi, E. et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293–1308.e36 (2018).
Ali, H. R. et al. Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer. Nat. Cancer 1, 163–175 (2020).
Wagner, J. et al. A single-cell atlas of the tumor and immune ecosystem of human breast cancer. Cell 177, 1330–1345.e18 (2019).
Keren, L. et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174, 1373–1387.e19 (2018).
Savas, P. et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 24, 986–993 (2018).
Wellenstein, M. D. & de Visser, K. E. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity 48, 399–416 (2018).
Jackson, H. W. et al. The single-cell pathology landscape of breast cancer. Nature 578, 615–620 (2020).
Bareche, Y. et al. Unraveling triple-negative breast cancer tumor microenvironment heterogeneity: towards an optimized treatment approach. J. Natl Cancer Inst. 112, 708–719 (2020).
Lehmann, B. D. et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750–2767 (2011).
Lehmann, B. D. et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE 11, e0157368 (2016).
Jiang, Y. Z. et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell 35, 428–440.e5 (2019).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Safonov, A. et al. Immune gene expression is associated with genomic aberrations in breast cancer. Cancer Res. 77, 3317–3324 (2017).
Karn, T. et al. Association between genomic metrics and immune infiltration in triple-negative breast cancer. JAMA Oncol. 3, 1707–1711 (2017).
Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017).
Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).
Wellenstein, M. D. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019).
Ghosh, M. et al. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cancer Cell 39, 494–508.e5 (2021).
Li, Y. et al. Targeted immunotherapy for HER2-low breast cancer with 17p loss. Sci. Transl. Med. 13, eabc6894 (2021).
Parkes, E. E. et al. Activation of STING-dependent innate immune signaling by S-phase-specific DNA damage in breast cancer. J. Natl Cancer Inst. 109, djw199 (2016).
Sharma, P. et al. Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial. J. Clin. Oncol. 37, 3484–3492 (2019).
Samstein, R. M. et al. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy. Nat. Cancer 1, 1188–1203 (2020).
Prestipino, A. & Zeiser, R. Clinical implications of tumor-intrinsic mechanisms regulating PD-L1. Sci. Transl. Med. 11, eaav4810 (2019).
Bachelot, T. et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase II SAFIR02-BREAST IMMUNO trial. Nat. Med. 27, 250–255 (2021).
Qin, G. et al. NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer. Nat. Commun. 11, 1669 (2020).
Sayaman, R. W. et al. Germline genetic contribution to the immune landscape of cancer. Immunity 54, 367–386.e8 (2021).
Loi, S. et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J. Clin. Oncol. 37, 559–569 (2019).
Bianchini, G. et al. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J. Clin. Oncol. 28, 4316–4323 (2010).
Callari, M. et al. Subtype-specific metagene-based prediction of outcome after neoadjuvant and adjuvant treatment in breast cancer. Clin. Cancer Res. 22, 337–345 (2016).
Gruosso, T. et al. Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers. J. Clin. Invest. 129, 1785–1800 (2019).
Bertucci, F. et al. Genomic characterization of metastatic breast cancers. Nature 569, 560–564 (2019).
Hutchinson, K. E. et al. Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts. Clin. Cancer Res. 26, 657–668 (2020).
Zhu, L. et al. Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors. J. Immunother. Cancer 7, 265 (2019).
Stover, D. G. et al. Association of cell-free DNA tumor fraction and somatic copy number alterations with survival in metastatic triple-negative breast cancer. J. Clin. Oncol. 36, 543–553 (2018).
Szekely, B. et al. Immunological differences between primary and metastatic breast cancer. Ann. Oncol. 29, 2232–2239 (2018).
Hu, Z., Li, Z., Ma, Z. & Curtis, C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat. Genet. 52, 701–708 (2020).
Ogiya, R. et al. Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer. Oncotarget 8, 103671–103681 (2017).
Rozenblit, M. et al. Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers. J. Immunother. Cancer 8, e001558 (2020).
Li, Y. et al. Prevalence study of PD-L1 SP142 assay in metastatic triple-negative breast cancer. Appl. Immunohistochem. Mol. Morphol. 29, 258–264 (2021).
Rugo, H. S. et al. LBA20 - Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): post-hoc analysis of IMpassion130. Ann. Oncol. 30, v858–v859 (2019).
Crispe, I. N. Hepatic T cells and liver tolerance. Nat. Rev. Immunol. 3, 51–62 (2003).
Poggio, F. et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann. Oncol. 29, 1497–1508 (2018).
Fu, D., Calvo, J. A. & Samson, L. D. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat. Rev. Cancer 12, 104–120 (2012).
Tung, N. et al. TBCRC 031: randomized phase II study of neoadjuvant cisplatin versus doxorubicin-cyclophosphamide in germline BRCA carriers with HER2-negative breast cancer (the INFORM trial). J. Clin. Oncol. 38, 1539–1548 (2020).
Yu, K.-D. et al. Effect of adjuvant paclitaxel and carboplatin on survival in women with triple-negative breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 6, 1390–1396 (2020).
Pandy, J. G. P., Balolong-Garcia, J. C., Cruz-Ordinario, M. V. B. & Que, F. V. F. Triple negative breast cancer and platinum-based systemic treatment: a meta-analysis and systematic review. BMC Cancer 19, 1065 (2019).
Tutt, A. et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat. Med. 24, 628–637 (2018).
Diéras, V. et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 21, 1269–1282 (2020).
Joensuu, H. et al. Adjuvant capecitabine in combination with docetaxel, epirubicin, and cyclophosphamide for early breast cancer: the randomized clinical FinXX Trial. JAMA Oncol. 3, 793–800 (2017).
Masuda, N. et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N. Engl. J. Med. 376, 2147–2159 (2017).
O’Shaughnessy, J. et al. Patients with slowly proliferative early breast cancer have low five-year recurrence rates in a phase III adjuvant trial of capecitabine. Clin. Cancer Res. 21, 4305–4311 (2015).
Ohno, S. et al. Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil–epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy. Breast Cancer Res. Treat. 142, 69–80 (2013).
von Minckwitz, G. et al. Response-guided neoadjuvant chemotherapy for breast cancer. J. Clin. Oncol. 31, 3623–3630 (2013).
von Minckwitz, G. et al. Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40 — GeparQuattro). Ann. Oncol. 25, 81–89 (2014).
Lluch, A. et al. Phase III trial of adjuvant capecitabine after standard neo-/adjuvant chemotherapy in patients with early triple-negative breast cancer (GEICAM/2003-11_CIBOMA/2004-01). J. Clin. Oncol. 38, 203–213 (2020).
Wang, X. et al. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with early-stage triple-negative breast cancer who had received standard treatment: the SYSUCC-001 randomized clinical trial. JAMA 325, 50–58 (2021).
van Mackelenbergh, M. et al. Abstract GS1-07: Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients. Cancer Res. 80, GS1-07 (2020).
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet 393, 1440–1452 (2019).
Cameron, D. et al. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 18, 929–945 (2017).
Citron, M. L. et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J. Clin. Oncol. 21, 1431–1439 (2003).
Del Mastro, L. et al. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet 385, 1863–1872 (2015).
Venturini, M. et al. Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial. J. Natl Cancer Inst. 97, 1724–1733 (2005).
Polak, P. et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 49, 1476–1486 (2017).
Staaf, J. et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat. Med. 25, 1526–1533 (2019).
den Brok, W. D. et al. Homologous recombination deficiency in breast cancer: a clinical review. JCO Precis. Oncol. https://doi.org/10.1200/PO.16.00031 (2017).
Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).
Litton, J. K. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N. Engl. J. Med. 379, 753–763 (2018).
Robson, M. E. et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann. Oncol. 30, 558–566 (2019).
Litton, J. K. et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann. Oncol. 31, 1526–1535 (2020).
Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).
Murai, J. et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72, 5588–5599 (2012).
Rugo, H. S. et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N. Engl. J. Med. 375, 23–34 (2016).
Loibl, S. et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 19, 497–509 (2018).
Fasching, P. A. et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann. Oncol. 32, 49–57 (2021).
Litton, J. K. et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J. Clin. Oncol. 38, 388–394 (2020).
Litton, J. K. et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): results of a phase 2 study. J. Clin. Oncol. 39, 505 (2021).
Tutt, A. N. J. et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N. Engl. J. Med. 384, 2394–2405 (2021).
Tung, N. M., Zakalik, D. & Somerfield, M. R. Adjuvant PARP inhibitors in patients with high-risk early-stage HER2-negative breast cancer and germline BRCA mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update. J. Clin. Oncol. 39, 2959–2961 (2021).
Sharma, P. et al. Results of a phase II randomized trial of cisplatin +/- veliparib in metastatic triple-negative breast cancer (TNBC) and/or germline BRCA-associated breast cancer (SWOG S1416). J. Clin. Oncol. 38, 1001 (2020).
Tung, N. M. et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J. Clin. Oncol. 38, 4274–4282 (2020).
Diamond, J. R. et al. A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer. Breast Cancer Res. 20, 82 (2018).
Drago, J. Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 18, 327–344 (2021).
Bardia, A. et al. Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J. Clin. Oncol. 35, 2141–2148 (2017).
Cubas, R., Zhang, S., Li, M., Chen, C. & Yao, Q. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol. Cancer 9, 253 (2010).
Lin, H. et al. Significantly upregulated TACSTD2 and cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. Exp. Mol. Pathol. 94, 73–78 (2013).
Bardia, A. et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N. Engl. J. Med. 380, 741–751 (2019).
Bardia, A. et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N. Engl. J. Med. 384, 1529–1541 (2021).
Bardia, A. et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann. Oncol. 32, 1148–1156 (2021).
Taylor, K. M. et al. The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Mol. Med. 13, 396–406 (2007).
Manning, D. L. et al. Oestrogen-regulated genes in breast cancer: association of pLIV1 with lymph node involvement. Eur. J. Cancer 30a, 675–678 (1994).
Yamashita, S. et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature 429, 298–302 (2004).
Modi, S. et al. Abstract PD3-14: phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer. Cancer Res. 78, PD3-14 (2018).
Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).
Modi, S. et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J. Clin. Oncol. 38, 1887–1896 (2020).
Cardillo, T. M. et al. Synthetic lethality exploitation by an anti-trop-2-SN-38 antibody-drug conjugate, IMMU-132, plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin. Cancer Res. 23, 3405–3415 (2017).
Coats, S. et al. Antibody–drug conjugates: future directions in clinical and translational strategies to improve the therapeutic index. Clin. Cancer Res. 25, 5441–5448 (2019).
Yonemori, K. et al. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: updated results from a phase I/II trial. Ann. Oncol. 30, iii48 (2019).
Hoxhaj, G. & Manning, B. D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 20, 74–88 (2020).
Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Dent, R. et al. Abstract GS3-04: double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC): primary results from IPATunity130 Cohort A. Cancer Res. 81, GS3-04 (2021).
Pascual, J. & Turner, N. C. Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann. Oncol. 30, 1051–1060 (2019).
Sharma, P. et al. Clinical and biomarker results from phase I/II study of PI3K inhibitor alpelisib plus nab-paclitaxel in HER2-negative metastatic breast cancer. Clin. Cancer Res. 27, 3896–3904 (2021).
Davies, B. R. et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 11, 873–887 (2012).
Kim, S. B. et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 18, 1360–1372 (2017).
Schmid, P. et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J. Clin. Oncol. 38, 423–433 (2020).
Oliveira, M. et al. FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann. Oncol. 30, 1289–1297 (2019).
Kalinsky, K. et al. Effect of capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial. JAMA Oncol. 7, 271–278 (2021).
Dhillon, A. S., Hagan, S., Rath, O. & Kolch, W. MAP kinase signalling pathways in cancer. Oncogene 26, 3279–3290 (2007).
Sinkala, M., Nkhoma, P., Mulder, N. & Martin, D. P. Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies. Commun. Biol. 4, 9 (2021).
Schafer, J. M. et al. Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors. Sci. Transl. Med. 12, eaaw8275 (2020).
Logue, J. S. & Morrison, D. K. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev. 26, 641–650 (2012).
Schmid, P. et al. A study of vistusertib in combination with selumetinib in patients with advanced cancers: TORCMEK phase Ib results. J. Clin. Oncol. 35, 2548 (2017).
Burstein, M. D. et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin. Cancer Res. 21, 1688–1698 (2015).
Bareche, Y. et al. Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis. Ann. Oncol. 29, 895–902 (2018).
Michmerhuizen, A. R., Spratt, D. E., Pierce, L. J. & Speers, C. W. ARe we there yet? Understanding androgen receptor signaling in breast cancer. NPJ Breast Cancer 6, 47 (2020).
Kono, M. et al. Androgen receptor function and androgen receptor-targeted therapies in breast cancer: a review. JAMA Oncol. 3, 1266–1273 (2017).
Traina, T. A. et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J. Clin. Oncol. 36, 884–890 (2018).
Gucalp, A. et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin. Cancer Res. 19, 5505–5512 (2013).
Bonnefoi, H. et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann. Oncol. 27, 812–818 (2016).
Lehmann, B. D. et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 16, 406 (2014).
Gordon, M. A. et al. Synergy between androgen receptor antagonism and inhibition of mTOR and HER2 in breast cancer. Mol. Cancer Ther. 16, 1389–1400 (2017).
Lehmann, B. D. et al. TBCRC 032 IB/II multicenter study: molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+ metastatic triple-negative breast cancer. Clin. Cancer Res. 26, 2111–2123 (2020).
Asghar, U. S. et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin. Cancer Res. 23, 5561–5572 (2017).
Fassl, A. et al. Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Sci. Adv. 6, eabb2210 (2020).
Gucalp, A. et al. Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor+ metastatic breast cancer. J. Clin. Oncol. 38, 1017 (2020).
Cocco, E., Scaltriti, M. & Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 15, 731–747 (2018).
Okamura, R. et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis. Oncol. https://doi.org/10.1200/po.18.00183 (2018).
Wilson, T., Sokol, E. S., Ross, J. S. & Maund, S. L. 131P NTRK1/2/3 fusions in secretory versus non-secretory breast cancers. Ann. Oncol. 31, S292 (2020).
Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).
Pereira, B. et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat. Commun. 7, 11479 (2016).
Smyth, L. M. et al. Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer. Cancer Discov. 10, 198–213 (2020).
Adams, S. et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 405–411 (2019).
Adams, S. et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 397–404 (2019).
Bian, L. et al. JS001, an anti-PD-1 mAb for advanced triple negative breast cancer patients after multi-line systemic therapy in a phase I trial. Ann. Transl. Med. 7, 435 (2019).
Dirix, L. Y. et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res. Treat. 167, 671–686 (2018).
Emens, L. A. et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 5, 74–82 (2019).
Nanda, R. et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 Study. J. Clin. Oncol. 34, 2460–2467 (2016).
O’Shaughnessy, J. et al. Results of ENCORE 602 (TRIO025), a phase II, randomized, placebo-controlled, double-blinded, multicenter study of atezolizumab with or without entinostat in patients with advanced triple-negative breast cancer (aTNBC). J. Clin. Oncol. 38, 1014 (2020).
Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).
Winer, E. P. et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 22, 499–511 (2021).
Park, Y. H. et al. Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome. Nat. Commun. 11, 6175 (2020).
Loi, S. et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin. Cancer Res. 22, 1499–1509 (2016).
Junttila, M. R. & de Sauvage, F. J. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501, 346–354 (2013).
Bianchini, G. et al. LBA13 Tumour infiltrating lymphocytes (TILs), PD-L1 expression and their dynamics in the NeoTRIPaPDL1 trial. Ann. Oncol. 31, S1145–S1146 (2020).
Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).
Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Emens, L. A. et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann. Oncol. 32, 983–993 (2021).
Cortes, J. et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396, 1817–1828 (2020).
Rugo, H. S. et al. Abstract GS3-01: additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. Cancer Res. 81, GS3-01 (2021).
Merck. Merck announces phase 3 KEYNOTE-355 trial met primary endpoint of overall survival (OS) in patients with metastatic triple-negative breast cancer whose tumors expressed PD-L1 (CPS ≥10). Merck https://www.merck.com/news/merck-announces-phase-3-keynote-355-trial-met-primary-endpoint-of-overall-survival-os-in-patients-with-metastatic-triple-negative-breast-cancer-whose-tumors-expressed-pd-l1-cps-≥10/ (2021).
Miles, D. et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann. Oncol. 32, 994–1004 (2021).
FDA. Final summary minutes of the oncologic drugs advisory committee meeting April 27–29, 2021. FDA https://www.fda.gov/media/150755/download (2021).
Roche. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. Roche https://www.roche.com/media/releases/med-cor-2021-08-27.htm (2021).
Arbour, K. C. et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non–small-cell lung cancer. J. Clin. Oncol. 36, 2872–2878 (2018).
Iorgulescu, J. B. et al. Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma. Clin. Cancer Res. 27, 276–287 (2021).
Cullis, J. et al. Macropinocytosis of Nab-paclitaxel drives macrophage activation in pancreatic cancer. Cancer Immunol. Res. 5, 182–190 (2017).
Brufsky, A. et al. A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis. Ann. Oncol. 32, 652–660 (2021).
Tolaney, S. M. et al. A phase Ib/II study of eribulin (ERI) plus pembrolizumab (PEMBRO) in metastatic triple-negative breast cancer (mTNBC) (ENHANCE 1). J. Clin. Oncol. 38, 1015 (2020).
Sohn, J. et al. Preliminary safety and efficacy of GX-I7, a long-acting interleukin-7, in combination with pembrolizumab in patients with refractory or recurrent metastatic triple negative breast cancer (mTNBC): dose escalation period of phase Ib/II study (KEYNOTE-899). J. Clin. Oncol. 38, 1072 (2020).
Miles, D. W. et al. LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann. Oncol. 31, S1147–S1148 (2020).
Lwin, Z. et al. LBA41 LEAP-005: phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours. Ann. Oncol. 31, S1170 (2020).
Han, H. et al. Abstract PD1-06: open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer. Cancer Res. 80, PD1-06 (2020).
Domchek, S. M. et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 21, 1155–1164 (2020).
Vinayak, S. et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 5, 1132–1140 (2019).
Schmid, P. et al. Abstract CT049: phase Ib study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC as first-line (1L) therapy for locally advanced/metastatic triple-negative breast cancer (TNBC). Cancer Res. 79, CT049 (2019).
Adams, S. et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a phase 1b clinical trial. JAMA Oncol. 5, 334–342 (2019).
Schmid, P. et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann. Oncol. 31, 569–581 (2020).
Schmid, P. et al. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 382, 810–821 (2020).
Nanda, R. et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 Trial. JAMA Oncol. 6, 676–684 (2020).
Mittendorf, E. A. et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396, 1090–1100 (2020).
Gianni, L. et al. Abstract GS3-04: pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. Cancer Res. 80, GS3-04 (2020).
Loibl, S. et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann. Oncol. 30, 1279–1288 (2019).
Patel, S. A. & Minn, A. J. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 48, 417–433 (2018).
Lee, W. S., Yang, H., Chon, H. J. & Kim, C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp. Mol. Med. 52, 1475–1485 (2020).
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G. & Galluzzi, L. Immunomodulation by targeted anticancer agents. Cancer Cell 39, 310–345 (2021).
Schmid, P. et al. BEGONIA: phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC) — initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd). J. Clin. Oncol. 39, 1023 (2021).
Messenheimer, D. J. et al. Timing of PD-1 blockade is critical to effective combination immunotherapy with anti-OX40. Clin. Cancer Res. 23, 6165–6177 (2017).
Schmid, P. et al. VP7-2021: KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann. Oncol. 32, 1198–1200 (2021).
FDA. Pembrolizumab oncologic drugs advisory committee briefing document. FDA https://www.fda.gov/media/145654/download (2021).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).
Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).
Hegde, P. S. & Chen, D. S. Top 10 challenges in cancer immunotherapy. Immunity 52, 17–35 (2020).
Loibl, S. et al. Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC). J. Clin. Oncol. 39, 506 (2021).
Korn, E. L., Sachs, M. C. & McShane, L. M. Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann. Oncol. 27, 10–15 (2016).
Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).
Dieci, M. V. et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann. Oncol. 25, 611–618 (2014).
Pusztai, L., Karn, T., Safonov, A., Abu-Khalaf, M. M. & Bianchini, G. New strategies in breast cancer: immunotherapy. Clin. Cancer Res. 22, 2105–2110 (2016).
Gianni, L. et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 15, 640–647 (2014).
Bianchini, G. & Gianni, L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 15, e58–e68 (2014).
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
Brockwell, N. K. et al. Neoadjuvant interferons: critical for effective PD-1-based immunotherapy in TNBC. Cancer Immunol. Res. 5, 871–884 (2017).
O’Donnell, J. S., Hoefsmit, E. P., Smyth, M. J., Blank, C. U. & Teng, M. W. L. The promise of neoadjuvant immunotherapy and surgery for cancer treatment. Clin. Cancer Res. 25, 5743–5751 (2019).
Oliver, A. J. et al. Primary and metastatic breast tumors cross-talk to influence immunotherapy responses. Oncoimmunology 9, 1802979 (2020).
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).
Loi, S. et al. Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): results from KEYNOTE-086. Ann. Oncol. 28, v608 (2017).
Alva, A. S. et al. Pembrolizumab (P) in patients (pts) with metastatic breast cancer (MBC) with high tumor mutational burden (HTMB): results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. J. Clin. Oncol. 37, 1014 (2019).
Emens, L. A. et al. 296P Tumour mutational burden and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: exploratory analysis of the phase III IMpassion130 trial. Ann. Oncol. 31, S360–S361 (2020).
Karn, T. et al. Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo. Ann. Oncol. 31, 1216–1222 (2020).
Winer, E. P. et al. Association of tumor mutational burden (TMB) and clinical outcomes with pembrolizumab (pembro) versus chemotherapy (chemo) in patients with metastatic triple-negative breast cancer (mTNBC) from KEYNOTE-119. J. Clin. Oncol. 38, 1013 (2020).
Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).
Blank, C. U., Haanen, J. B., Ribas, A. & Schumacher, T. N. The “cancer immunogram”. Science 352, 658–660 (2016).
McGrail, D. J. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32, 661–672 (2021).
Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).
Goodman, A. M. et al. Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. JAMA Oncol. 4, 1237–1244 (2018).
Doroshow, D. B. et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 18, 345–362 (2021).
Rugo, H. S. et al. PD-L1 immunohistochemistry assay comparison in atezolizumab plus nab-paclitaxel-treated advanced triple-negative breast cancer. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djab108 (2021).
Sobral-Leite, M. et al. Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival. Oncoimmunology 7, e1509820 (2018).
Loibl, S. et al. Abstract PD2-07: mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC) — results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial. Cancer Res. 79, PD2-07 (2019).
Loi, S. et al. Abstract PD5-03: relationship between tumor-infiltrating lymphocytes (TILs) and outcomes in the KEYNOTE-119 study of pembrolizumab vs chemotherapy for previously treated metastatic triple-negative breast cancer (mTNBC). Cancer Res. 80, PD5-03 (2020).
Emens, L. A. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer: biomarker evaluation of the IMpassion130 study. J. Natl Cancer Inst. 113, 1005–1016 (2021).
Zou, Y. et al. Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis. Ther. Adv. Med. Oncol. 12, 1758835920940928 (2020).
Hiam-Galvez, K. J., Allen, B. M. & Spitzer, M. H. Systemic immunity in cancer. Nat. Rev. Cancer 21, 345–359 (2021).
Elinav, E., Garrett, W. S., Trinchieri, G. & Wargo, J. The cancer microbiome. Nat. Rev. Cancer 19, 371–376 (2019).
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.
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.
Peer review information
Nature Reviews Clinical Oncology thanks F. Montemurro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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
This article is cited by
Novel roles of RNA-binding proteins in drug resistance of breast cancer: from molecular biology to targeting therapeutics
Cell Death Discovery (2023)
Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial
Nature Medicine (2023)
Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade
Journal of Experimental & Clinical Cancer Research (2022)
Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial
Molecular Cancer (2022)
Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR
BMC Medicine (2022)