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Emerging Therapeutics for Patients with Triple-Negative Breast Cancer

  • Breast Cancer (AS Zimmer, Section Editor)
  • Published:
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Abstract

Purpose of review

Triple negative breast cancer (TNBC) accounts for approximately 10–15% of all breast cancers and it is associated with a poor prognosis. However, recent new effective treatment strategies have improved its outcomes. The aim of this review is to provide an overview on the emerging therapeutics for TNBC, describing both previously approved therapies that are currently being repurposed, as well as new target therapies that may improve patient outcomes.

Recent findings

Emerging therapies are forthcoming in TNBC’s treatment landscape, including new post-neoadjuvant chemotherapy strategies, PARP inhibitors, immune checkpoint inhibitors, and antibody-drug conjugates. Combination of different therapies such as AKT/PI3K/mTOR-inhibitors, other immunotherapeutic agents, CDK-inhibitors, antiandrogens, antiangiogenics, and histone deacetylase inhibitors is under clinical investigation.

Summary

The treatment landscape for TNBC is gradually evolving towards a more personalized approach with promising expectations.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ CK. Cancer Statistics Review, 1975-2016 - SEER Statistics. based on November 2018 SEER data submission, posted to the SEER web site, April 2019.

  2. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15):4429–34. https://doi.org/10.1158/1078-0432.CCR-06-3045.

    Article  PubMed  Google Scholar 

  3. Caparica R, Lambertini M, de Azambuja E. How I treat metastatic triple-negative breast cancer. ESMO Open. 2019;4(Suppl 2):e000504. https://doi.org/10.1136/esmoopen-2019-000504.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Reis-Filho JS, Tutt ANJ. Triple negative tumours: A critical review. Vol. 52, Histopathology. Histopathology. 2008:108–18. https://doi.org/10.1111/j.1365-2559.2007.02889.x.

  5. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. Vol. 363, New England Journal of Medicine. Massachussetts Medical Society. 2010:1938–48. https://doi.org/10.1056/NEJMra1001389.

  6. Denkert C, Liedtke C, Tutt A, von Minckwitz G. Molecular alterations in triple-negative breast cancer—the road to new treatment strategies. The Lancet. Lancet Publishing Group. 2017;389:2430–42. https://doi.org/10.1016/S0140-6736(16)32454-0.

    Article  CAS  Google Scholar 

  7. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67. https://doi.org/10.1172/JCI45014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SAW, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res. 2015;21(7):1688–98. https://doi.org/10.1158/1078-0432.CCR-14-0432.

    Article  CAS  PubMed  Google Scholar 

  9. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(8):1194–220. https://doi.org/10.1093/annonc/mdz173.

    Article  CAS  Google Scholar 

  10. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) †. Ann Oncol. 2018;29(8):1634–57. https://doi.org/10.1093/annonc/mdy192.

    Article  CAS  PubMed  Google Scholar 

  11. Paluch-Shimon S, Pagani O, Partridge AH, Abulkhair O, Cardoso MJ, Dent RA, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast. 2017;35:203–17. https://doi.org/10.1016/j.breast.2017.07.017.

    Article  PubMed  Google Scholar 

  12. Poggio F, Bruzzone M, Ceppi M, Pondé NF, La Valle G, Del Mastro L, et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol. 2018;29(7):1497–508. https://doi.org/10.1093/annonc/mdy127.

    Article  CAS  PubMed  Google Scholar 

  13. Balic M, Thomssen C, Würstlein R, Gnant M, Harbeck N. St. Gallen/Vienna. A brief summary of the consensus discussion on the optimal primary breast cancer treatment. Vol. 14, Breast Care. S. Karger AG. 2019;2019:103–10. https://doi.org/10.1159/000499931.

    Article  Google Scholar 

  14. Torrisi R, Zuradelli M, Agostinetto E, Masci G, Losurdo A, De Sanctis R, et al. Platinum salts in the treatment of BRCA-associated breast cancer: A true targeted chemotherapy? Vol. 135, Critical Reviews in Oncology/Hematology. Elsevier Ireland Ltd; 2019. p. 66–75. Doi: https://doi.org/10.1016/j.critrevonc.2019.01.016

  15. Zhang J, Yao L, Liu Y, Ouyang T, Li J, Wang T, et al. Impact of the addition of carboplatin to anthracycline-taxane-based neoadjuvant chemotherapy on survival in BRCA1/2-mutated triple-negative breast cancer. Int J cancer. 2020;148:941–9. https://doi.org/10.1002/ijc.33234.

    Article  CAS  PubMed  Google Scholar 

  16. Pandy JGP, Balolong-Garcia JC, Cruz-Ordinario MVB, Que FVF. Triple negative breast cancer and platinum-based systemic treatment: a meta-analysis and systematic review. BMC Cancer. 2019;19(1):1065. https://doi.org/10.1186/s12885-019-6253-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu K-D, Ye F-G, He M, Fan L, Ma D, Mo M, 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. 2020;6:1390–6. https://doi.org/10.1001/jamaoncol.2020.2965.

    Article  PubMed  Google Scholar 

  18. •• Masuda N, Lee S-J, Ohtani S, Im Y-H, Lee E-S, Yokota I, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376(22):2147–59. https://doi.org/10.1056/NEJMoa1612645This trial demonstrated an improvement in survival by adding capecitabine in the adjuvant setting for HER2-negative BC with residual disease after neoadjuvant chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  19. van Mackelenbergh M, Seither F, Möbus V, O’Shaugnessy J, Martin M, Joenssuu H, 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. In: Cancer Research. American Association for Cancer Research (AACR); 2020. p. GS1-07-GS1-07.

    Google Scholar 

  20. Denduluri N, Chavez-MacGregor M, Telli ML, Eisen A, Graff SL, Hassett MJ, et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(23):2433–43. https://doi.org/10.1200/JCO.2018.78.8604.

    Article  CAS  PubMed  Google Scholar 

  21. Li J, Yu K, Pang D, Wang C, Jiang J, Yang S, et al. Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010): An Open-Label, Randomized, Multicenter, Phase III Trial. J Clin Oncol. 2020;38(16):JCO.19.02474. https://doi.org/10.1200/JCO.19.02474.

    Article  Google Scholar 

  22. Wang X, Wang S-S, Huang H, Cai L, Peng R-J, Zhao L, et al. Phase III trial of metronomic capecitabine maintenance after standard treatment in operable triple-negative breast cancer (SYSUCC-001). J Clin Oncol. 2020;38(15_suppl):507–507. https://doi.org/10.1200/JCO.2020.38.15_suppl.507.

    Article  Google Scholar 

  23. Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer. J Clin Oncol. 2014;33(4):304–11. https://doi.org/10.1200/JCO.2014.57.1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pothuri B. BRCA1- and BRCA2-related mutations: therapeutic implications in ovarian cancer. Ann Oncol. 2013;24:viii22–7. https://doi.org/10.1093/annonc/mdt307.

    Article  PubMed  Google Scholar 

  25. Nijman SMB. Synthetic lethality: General principles, utility and detection using genetic screens in human cells. FEBS Letters. Elsevier B.V. 2011;585:1–6. https://doi.org/10.1016/j.febslet.2010.11.024.

    Article  CAS  Google Scholar 

  26. Kelley MR, Logsdon D, Fishel ML. Targeting DNA repair pathways for cancer treatment: What’s new? Future Oncology. Future Medicine Ltd. 2014;10:1215–37. https://doi.org/10.2217/fon.14.60.

    Article  CAS  Google Scholar 

  27. Ledermann JA, Pujade-Lauraine E. Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer. Therapeutic Advances in Medical Oncology. SAGE Publications Inc. 2019;11. https://doi.org/10.1177/1758835919849753.

  28. •• Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523–33. https://doi.org/10.1056/NEJMoa1706450This trial led to approval of olaparib for metastatic BC in patient with a germline BRCA mutation.

    Article  CAS  PubMed  Google Scholar 

  29. •• Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753–63. https://doi.org/10.1056/NEJMoa1802905This trial led to approval of talazoparib in patients with advanced BC and a germline BRCA mutation.

    Article  CAS  PubMed  Google Scholar 

  30. Robson ME, Tung N, Conte P, Im S-A, Senkus E, Xu B, 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. 2019 Apr 1;30(4):558–66. https://doi.org/10.1093/annonc/mdz012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Litton J, Hurvitz S, Mina L, Rugo H. Talazoparib (TALA) in germline BRCA1/2 (gBRCA1/2)-mutated human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC): Final overall survival (OS) results from randomized Phase 3 EMBRACA trial. In: Proceedings of the 111th Annual Meeting of the American Association for Cancer Research; 2020 June 22-24. Philadelphia (PA): AACR; 2020.

    Google Scholar 

  32. Zimmer AS, Gillard M, Lipkowitz S, Lee JM. Update on PARP Inhibitors in Breast Cancer. Current Treatment Options in Oncology. Springer New York LLC. 2018;19. https://doi.org/10.1007/s11864-018-0540-2.

  33. Diéras V, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub J-P, 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. 2020;21:1269–82. https://doi.org/10.1016/S1470-2045(20)30447-2.

    Article  PubMed  Google Scholar 

  34. Papadimitriou M, Mountzios G, Papadimitriou CA. The role of PARP inhibition in triple-negative breast cancer: Unraveling the wide spectrum of synthetic lethality. Cancer Treat Rev. 2018 Jun 1;67:34–44. https://doi.org/10.1016/j.ctrv.2018.04.010.

    Article  CAS  PubMed  Google Scholar 

  35. Telli ML, Stover DG, Loi S, Aparicio S, Carey LA, Domchek SM, et al. Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer. Breast Cancer Res Treat. 2018;171(1):21–31. https://doi.org/10.1007/s10549-018-4807-x.

    Article  CAS  PubMed  Google Scholar 

  36. Chopra N, Tovey H, Pearson A, Cutts R, Toms C, Proszek P, et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nat Commun. 2020;11(1):2662. https://doi.org/10.1038/s41467-020-16142-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sharma P, Rodler E, Barlow WE, Gralow J, Huggins-Puhalla SL, Anders CK, 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. 2020;38(15_suppl):1001–1001.

    Google Scholar 

  38. Mouw KW, Goldberg MS, Konstantinopoulos PA, D’Andrea AD. DNA damage and repair biomarkers of immunotherapy response. Cancer Discovery. American Association for Cancer Research Inc. 2017;7:675–93. https://doi.org/10.1158/2159-8290.CD-17-0226.

    Article  CAS  Google Scholar 

  39. Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, et al. Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell. 2018;33(5):843-852.e4. https://doi.org/10.1016/j.ccell.2018.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pusztai L, et al. Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL. In: Proceedings of the 111th Annual Meeting of the American Association for Cancer Research; 2020 June 22-24. Philadelphia (PA): AACR. p. 2020.

  41. Budczies J, Bockmayr M, Denkert C, Klauschen F, Lennerz JK, Györffy B, et al. Classical pathology and mutational load of breast cancer - integration of two worlds. J Pathol Clin Res. 2015 Jul 20;1(4):225–38. https://doi.org/10.1002/cjp2.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gao G, Wang Z, Qu X, Zhang Z. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer. 2020;20(1):179. https://doi.org/10.1186/s12885-020-6668-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Loi S, Adams S, Schmid P, Cortés J, Cescon DW, Winer EP, 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. 2017;28:v608. https://doi.org/10.1093/annonc/mdx440.005.

    Article  Google Scholar 

  44. Adams S, Goldstein LJ, Sparano JA, Demaria S, Badve SS. Tumor infiltrating lymphocytes (TILs) improve prognosis in patients with triple negative breast cancer (TNBC). Oncoimmunology. 2015 Sep;4(9):e985930. https://doi.org/10.4161/2162402X.2014.985930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fuchs TL, Pearson A, Pickett J, Diakos C, Dewar R, Chan D, et al. Why pathologists and oncologists should know about tumour-infiltrating lymphocytes (TILs) in triple-negative breast cancer: an Australian experience of 139 cases. Pathology. 2020 Jun;52:515–21. https://doi.org/10.1016/j.pathol.2020.04.004.

    Article  PubMed  Google Scholar 

  46. Loi S, Winer E, Lipatov O, Im S-A, Goncalves A, Cortes J, 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. 2020;80(4 Supplement):PD5-03 LP-PD5-03. https://doi.org/10.1158/1538-7445.SABCS19-PD5-03.

    Article  Google Scholar 

  47. • Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810–21. https://doi.org/10.1056/NEJMoa1910549This trial showed a significant increase in pathological complete response with the addition of pembrolizumab to neoadjuvant chemotherapy for TNBC patients.

    Article  CAS  PubMed  Google Scholar 

  48. Gianni L, Huang C-S, Egle D, Bermejo B, Zamagni C, Thill M, 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. AACR. 2020.

  49. Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer J-U, 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. 2019 Aug 1;30(8):1279–88. https://doi.org/10.1093/annonc/mdz158.

    Article  CAS  PubMed  Google Scholar 

  50. Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, 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. 2020 May 1;6(5):676–84. https://doi.org/10.1001/jamaoncol.2019.6650.

    Article  PubMed  Google Scholar 

  51. •• Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–21. https://doi.org/10.1056/NEJMoa1809615This trial led to approval of atezolizumab and nab-paclitaxel as first-line of treatment in advanced, PD-L1-positive TNBC patients.

    Article  CAS  PubMed  Google Scholar 

  52. Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44–59. https://doi.org/10.1016/S1470-2045(19)30689-8.

    Article  CAS  PubMed  Google Scholar 

  53. Cortés J, Lipatov O, Im S-A, Gonc¸alves A, Lee KS, Schmid P, et al. KEYNOTE-119: Phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple negative breast cancer (mTNBC). Annals of Oncology. 2019;30(suppl_5):v851–934. https://doi.org/10.1093/annonc/mdz394.

    Article  Google Scholar 

  54. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im S-A, Yusof MM, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(15_suppl):1000. https://doi.org/10.1200/JCO.2020.38.15_suppl.1000.

    Article  Google Scholar 

  55. Dalenc F, Garberis I, Filleron T, Lusque A, Bachelot T, Arnedos M, et al. Abstract GS3-02: Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: Results from phase II randomized trial SAFIR02-IMMUNO. AACR. 2020. https://doi.org/10.1158/1538-7445.SABCS19-GS3-02.

  56. Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, 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. 2018;167(3):671–86. https://doi.org/10.1007/s10549-017-4537-5.

    Article  CAS  PubMed  Google Scholar 

  57. Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):397–404. https://doi.org/10.1093/annonc/mdy517.

    Article  CAS  PubMed  Google Scholar 

  58. Emens LA, Cruz C, Eder JP, Braiteh F, Chung C, Tolaney SM, 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. 2019;5(1):74–82. https://doi.org/10.1001/jamaoncol.2018.4224.

    Article  PubMed  Google Scholar 

  59. Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, 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. 2019;30(3):405–11. https://doi.org/10.1093/annonc/mdy518.

    Article  CAS  PubMed  Google Scholar 

  60. Lemery S, Keegan P, Pazdur R. First FDA Approval Agnostic of Cancer Site — When a Biomarker Defines the Indication. N Engl J Med. 2017 Oct 11;377(15):1409–12. https://doi.org/10.1056/NEJMp1709968.

    Article  PubMed  Google Scholar 

  61. Cheng AS, Leung SCY, Gao D, Burugu S, Anurag M, Ellis MJ, et al. Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort. Breast Cancer Res Treat. 2020;179(1):3–10. https://doi.org/10.1007/s10549-019-05438-y.

    Article  CAS  PubMed  Google Scholar 

  62. Barroso-Sousa R, Trippa L, Lange P, Andrews C, McArthur HL, Haley BB, et al. Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer. J Clin Oncol. 2019;37(15_suppl):TPS1115–TPS1115. https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS1115.

    Article  Google Scholar 

  63. •• Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019;380(8):741–51. https://doi.org/10.1056/NEJMoa1814213This trial led to approval of sacituzumab govitecan in refractory metastatic TNBC patients.

    Article  CAS  PubMed  Google Scholar 

  64. ASCENT-Study of Sacituzumab Govitecan in Refractory/Relapsed Triple-Negative Breast Cancer - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02574455

  65. Han H (Heather), Diab S, Alemany C, Basho R, Brown-Glaberman U, Meisel J, 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. In: Cancer Research. American Association for Cancer Research (AACR); 2020. p. PD1-06-PD1-06. https://doi.org/10.1158/1538-7445.SABCS19-PD1-06.

    Chapter  Google Scholar 

  66. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610–21. https://doi.org/10.1056/NEJMoa1914510.

    Article  CAS  PubMed  Google Scholar 

  67. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142(11):1364–82. https://doi.org/10.5858/arpa.2018-0902-SA.

    Article  PubMed  Google Scholar 

  68. Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, et al. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020;38(5):444–53. https://doi.org/10.1200/JCO.19.01455.

    Article  CAS  PubMed  Google Scholar 

  69. Modi S, Ohtani S, Lee C, Wang Y, Saxena K, Cameron DA. Abstract OT1-07-02: A phase 3, multicenter, randomized, open-label trial of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs investigator’s choice in HER2-low breast cancer (DESTINY-Breast04). Cancer Res. 2020;80(4 Supplement):OT1-07-02 LP-OT1-07–02. https://doi.org/10.1158/1538-7445.SABCS19-OT1-07-02.

    Article  Google Scholar 

  70. Cossu-Rocca P, Orrù S, Muroni MR, Sanges F, Sotgiu G, Ena S, et al. Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer. PLoS One. 2015;10(11):e0141763. https://doi.org/10.1371/journal.pone.0141763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Costa RLB, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018;169(3):397–406. https://doi.org/10.1007/s10549-018-4697-y.

    Article  CAS  PubMed  Google Scholar 

  72. Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, 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 Off J Am Soc Clin Oncol. 2020;38(5):423–33. https://doi.org/10.1200/JCO.19.00368.

    Article  CAS  Google Scholar 

  73. Dent R, Oliveira M, Isakoff SJ, Im S-A, Espié M, Blau S, et al. 139O Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31:S64–S5. https://doi.org/10.1016/j.annonc.2020.03.239.

    Article  Google Scholar 

  74. Oliveira M, Saura C, Nuciforo P, Calvo I, Andersen J, Passos-Coelho JL, 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. 2019;30(8):1289–97. https://doi.org/10.1093/annonc/mdz177.

    Article  CAS  PubMed  Google Scholar 

  75. Spring LM, Wander SA, Andre F, Moy B, Turner NC, Bardia A. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet. 2020;395(10226):817–27. https://doi.org/10.1016/S0140-6736(20)30165-3.

    Article  CAS  PubMed  Google Scholar 

  76. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. https://doi.org/10.1186/bcr2419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10(5):R75. https://doi.org/10.1186/bcr2142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tan AR, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019;20(11):1587–601. https://doi.org/10.1016/S1470-2045(19)30616-3.

    Article  CAS  PubMed  Google Scholar 

  79. Mitri Z, Karakas C, Wei C, Briones B, Simmons H, Ibrahim N, et al. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. Invest New Drugs. 2015;33(4):890–4. https://doi.org/10.1007/s10637-015-0244-4.

    Article  CAS  PubMed  Google Scholar 

  80. Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM, et al. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J Exp Med. 2012;209(4):679–96. https://doi.org/10.1084/jem.20111512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chien AJ, Rahmaputri S, Dittrich HF, Majure MC, Rugo HS, Melisko ME, et al. A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC). J Clin Oncol. 2019;37(15_suppl):1072. https://doi.org/10.1200/JCO.2019.37.15_suppl.1072.

    Article  Google Scholar 

  82. Wang C, Pan B, Zhu H, Zhou Y, Mao F, Lin Y, et al. Prognostic value of androgen receptor in triple negative breast cancer: A meta-analysis. Oncotarget. 2016;7(29):46482–91. https://doi.org/10.18632/oncotarget.10208.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Bareche Y, Venet D, Ignatiadis M, Aftimos P, Piccart M, Rothe F, et al. Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(4):895–902. https://doi.org/10.1093/annonc/mdy024.

    Article  CAS  Google Scholar 

  84. Pascual J, Turner NC. Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(7):1051–60. https://doi.org/10.1093/annonc/mdz133.

    Article  CAS  Google Scholar 

  85. Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res. 2013;19(19):5505–12. https://doi.org/10.1158/1078-0432.CCR-12-3327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, et al. Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer. J Clin Oncol. 2018;36(9):884–90. https://doi.org/10.1200/JCO.2016.71.3495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dent R, Schmid P, Cortes J, Kim S-B, Andre F, Abramson V, et al. Abstract OT3-02-02: ENDEAR: A randomized international phase 3 study comparing the efficacy and safety of enzalutamide in combination with paclitaxel chemotherapy or as monotherapy vs placebo with paclitaxel in patients with advanced diagnostic-positive triple-negative breast cancer. In: Cancer Research. American Association for Cancer Research (AACR); 2017. p. OT3-02-02-OT3-02–02. https://doi.org/10.1158/1538-7445.SABCS16-OT3-02-02.

  88. Patel JM, Goss A, Garber JE, Torous V, Richardson ET, Haviland MJ, et al. Retinoblastoma protein expression and its predictors in triple-negative breast cancer. npj Breast Cancer. 2020;6(1):19. https://doi.org/10.1038/s41523-020-0160-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gucalp A, Boyle LA, Alano T, Arumov A, Gounder MM, Patil S, et al. Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor (+) metastatic breast cancer. J Clin Oncol. 2020;38(15_suppl):1017. https://doi.org/10.1200/JCO.2020.38.15_suppl.1017.

    Article  Google Scholar 

  90. Arab S, Hadjati J. Adenosine Blockage in Tumor Microenvironment and Improvement of Cancer Immunotherapy. Immune Netw. 2019;19(4):e23–e23. https://doi.org/10.4110/in.2019.19.e23.

    Article  Google Scholar 

  91. Buisseret L, Pommey S, Allard B, Garaud S, Bergeron M, Cousineau I, et al. Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(4):1056–62. https://doi.org/10.1093/annonc/mdx730.

    Article  CAS  Google Scholar 

  92. Zhou X, Zhi X, Zhou P, Chen S, Zhao F, Shao Z, et al. Effects of ecto-5’-nucleotidase on human breast cancer cell growth in vitro and in vivo. Oncol Rep. 2007;17(6):1341–6. https://doi.org/10.3892/or.17.6.1341.

    Article  CAS  PubMed  Google Scholar 

  93. Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci U S A. 2013;110(36):14711–6. https://doi.org/10.1073/pnas.1308209110.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Maurer C, Eiger D, Velghe C, Aftimos PG, Maetens M, Gaye J, et al. 195TiP - SYNERGY: Phase I and randomized phase II trial to investigate the addition of the anti-CD73 antibody oleclumab to durvalumab, paclitaxel and carboplatin for previously untreated, locally recurrent inoperable or metastatic triple-negative breast c. Ann Oncol. 2019;30:iii62. https://doi.org/10.1093/annonc/mdz100.046.

    Article  Google Scholar 

  95. Schmid P, Nunes AT, Lall R, D&#039, Cruz C, Grinsted L, et al. Abstract OT3-01-01: BEGONIA: Phase Ib/II open-label, platform study of safety and efficacy of durvalumab, paclitaxel and other novel oncology therapy agents as first-line (1L) therapy in patients with metastatic triple negative breast cancer (mTNBC). Cancer Res. 2019;79(4 Supplement):OT3-01-01 LP-OT3-01–01. https://doi.org/10.1158/1538-7445.SABCS18-OT3-01-01.

    Article  Google Scholar 

  96. Barroso-Sousa R, Jain E, Cohen O, Kim D, Buendia-Buendia J, Winer E, et al. Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann Oncol. 2020 Mar 1;31(3):387–94. https://doi.org/10.1016/j.annonc.2019.11.010.

    Article  CAS  PubMed  Google Scholar 

  97. O’Day S, Borges VF, Chmielowski B, Rao RD, Abu-Khalaf MM, Stopeck A, et al. An open label, multicenter phase II study combining imprime PGG (PGG) with pembrolizumab (P) in previously treated metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2019;37(15_suppl):2550. https://doi.org/10.1200/JCO.2019.37.15_suppl.2550.

    Article  Google Scholar 

  98. Chan ASH, Jonas AB, Qiu X, Ottoson NR, Walsh RM, Gorden KB, et al. Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation. PLoS One. 2016;11(11):e0165909. https://doi.org/10.1371/journal.pone.0165909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Montero AJ, Escobar M, Lopes G, Glück S, Vogel C. Bevacizumab in the treatment of metastatic breast cancer: friend or foe? Curr Oncol Rep. 2012;14(1):1–11. https://doi.org/10.1007/s11912-011-0202-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias V, Mavroudis D, Mauri D. Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat. 2010;122(1):1–7. https://doi.org/10.1007/s10549-009-0727-0.

    Article  CAS  PubMed  Google Scholar 

  101. de Aguiar RB, de Moraes JZ. Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors. Front Immunol. 2019;10:1023. https://doi.org/10.3389/fimmu.2019.01023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ozaki Y, Mukohara T, Tsurutani J, Takahashi M, Matsumoto K, Futamura M, et al. Abstract PD1-03: A multicenter phase II study evaluating the efficacy of nivolumab plus paclitaxel plus bevacizumab triple-combination therapy as a first-line treatment in patients with HER2-negative metastatic breast cancer: WJOG9917B NEWBEAT trial. In: Cancer Research. American Association for Cancer Research (AACR); 2020. p. PD1-03-PD1-03. https://doi.org/10.1158/1538-7445.SABCS19-PD1-03.

    Chapter  Google Scholar 

  103. Miles DW, Diéras V, Cortés J, Duenne A-A, Yi J, O’Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol. 2013;24(11):2773–80. https://doi.org/10.1093/annonc/mdt276.

    Article  CAS  PubMed  Google Scholar 

  104. Zimmer AS, Nichols E, Cimino-Mathews A, Peer C, Cao L, Lee M-J, et al. A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women’s cancers with biomarker analyses. J Immunother cancer. 2019;7(1):197. https://doi.org/10.1186/s40425-019-0680-3.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010;107(5):2201–6. https://doi.org/10.1073/pnas.0904783107.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Hafez N, Soliman HH, Fu S, Gelmon KA, Abdul Razak AR, Munster PN, et al. Preliminary efficacy data of triple-negative breast cancer cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors. J Clin Oncol. 2020;38(15_suppl):1077. https://doi.org/10.1200/JCO.2020.38.15_suppl.1077.

    Article  Google Scholar 

  107. Del Castillo M, Chibon F, Arnould L, Croce S, Ribeiro A, Perot G, et al. Secretory Breast Carcinoma: A Histopathologic and Genomic Spectrum Characterized by a Joint Specific ETV6-NTRK3 Gene Fusion. Am J Surg Pathol. 2015;39(11):1458–67. https://doi.org/10.1097/PAS.0000000000000487.

    Article  PubMed  Google Scholar 

  108. Ross J, Chung J, Elvin J, Vergilio J-A, Ramkissoon S, Suh J, et al. Abstract P2-09-15: NTRK fusions in breast cancer: Clinical, pathologic and genomic findings. In: Cancer Research. American Association for Cancer Research (AACR); 2018. p. P2-09-15-P2-09–15. https://doi.org/10.1158/1538-7445.SABCS17-P2-09-15.

    Chapter  Google Scholar 

  109. Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(Suppl_8):viii23–30. https://doi.org/10.1093/annonc/mdz282.

    Article  CAS  Google Scholar 

  110. Garmpis N, Damaskos C, Garmpi A, Kalampokas E, Kalampokas T, Spartalis E, et al. Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises. Cancer Genomics Proteomics. 2017;14(5):299–313. https://doi.org/10.21873/cgp.20041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. O’Shaughnessy J, Moroose RL, Babu S, Baramidze K, Chan D, Leitner SP, 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. 2020;38(15_suppl):1014. https://doi.org/10.1200/JCO.2020.38.15_suppl.1014.

    Article  Google Scholar 

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  1. Academic Trials Promoting Team, Institut Jules Bordet and l’Université Libre de Bruxelles (U.L.B), Rue Héger-Bordet 1, 1000, Brussels, Belgium

    Elisa Agostinetto, Daniel Eiger & Evandro de Azambuja

  2. Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center – IRCCS, Humanitas Cancer Center, via Manzoni 56, 20089, Rozzano, Milan, Italy

    Elisa Agostinetto

  3. Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium

    Kevin Punie

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Elisa Agostinetto has no potential conflicts of interest.

Daniel Eiger: funding for his ESMO Fellowship (2018-2019) from Novartis. Speaker honoraria from Janssen.

Kevin Punie: Honoraria for advisory/consultancy roles for AstraZeneca, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Hoffmann/La Roche, Teva and Vifor Pharma (paid to institution); speaker fees for Eli Lilly, Mundi Pharma, Novartis, Pfizer and Hoffmann/La Roche (paid to institution); research funding from Pfizer and Sanofi (paid to institution); travel support from AstraZeneca, Novartis, Pfizer, PharmaMar and Hoffmann/La Roche.

Evandro de Azambuja: Honoraria and advisory board from Roche/GNE, Novartis, Seattle Genetics and Zodiacs; Travel grants from Roche/GNE and GSK/Novartis; Research grant to my institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier.

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Agostinetto, E., Eiger, D., Punie, K. et al. Emerging Therapeutics for Patients with Triple-Negative Breast Cancer. Curr Oncol Rep 23, 57 (2021). https://doi.org/10.1007/s11912-021-01038-6

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