Skip to main content

Advertisement

SpringerLink
Log in

Clinical Development of PD-1/PD-L1 Inhibitors in Breast Cancer: Still a Long Way to Go

  • Breast Cancer (WJ Gradishar, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Currently, only patients with metastatic triple-negative breast cancer whose tumors are PD-L1 positive are eligible for receiving immunotherapy. Other studies have explored new combinations with PD-1/PD-L1 inhibitors in different disease settings and populations. Data from neoadjuvant trials testing the addition of PD-1/PD-L1 inhibitors to standard treatment are promising and have led to increases in pathologic complete response rates; however, data on survival outcomes are still immature. There is still much work needed to optimize benefits of immunotherapy in breast cancer and correlative studies in patients treated with immunotherapy are urgently needed to inform the best strategies for further development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

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

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  PubMed  Google Scholar 

  2. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol. 2019;37(7):559–69.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Park JH, Jonas SF, Bataillon G, Criscitiello C, Salgado R, Loi S, et al. Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann Oncol. 2019;30(12):1941–9.

    Article  CAS  PubMed  Google Scholar 

  5. Kovacs A, Stenmark Tullberg A, Werner Ronnerman E, et al. Effect of radiotherapy after breast-conserving surgery depending on the presence of tumor-infiltrating lymphocytes: a long-term follow-up of the SweBCG91RT Randomized Trial. J Clin Oncol. 2019;37(14):1179–87.

    Article  CAS  PubMed  Google Scholar 

  6. Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19(1):40–50.

    Article  PubMed  Google Scholar 

  7. Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1 (PD-1) and its Ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomark Prev. 2014;23(12):2965–70.

    Article  CAS  Google Scholar 

  8. Luen S, Virassamy B, Savas P, Salgado R, Loi S. The genomic landscape of breast cancer and its interaction with host immunity. Breast. 2016;29:241–50.

    Article  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  PubMed  Google Scholar 

  11. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Cortes J, Lipatov O, Im S, et al. KEYNOTE-119: phase 3 study of pembrolizumab versus single-agent chemotherapy for metastatic triple-negative breast cancer (mTNBC) [abstract]. Ann Oncol. 2019;30(suppl_5):V851–934.

    Google Scholar 

  15. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690–714.

    Article  CAS  PubMed  Google Scholar 

  16. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202(12):1691–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wanderley CW, Colon DF, Luiz JPM, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res. 2018;78(20):5891–900.

    CAS  PubMed  Google Scholar 

  18. Adams S, Diamond JR, Hamilton E, 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. 2019;5(3):334–42.

  19. •• 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 This study established the combination of the anti-PD-L1 atezolizumab with nab-paclitaxel as the standard first-line therapy for patients with metastatic triple-negative breast cancer with PD-L1-positive tumors.

    Article  CAS  PubMed  Google Scholar 

  20. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im S-A, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P. 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.

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. Tolaney SM, Kalinsky K, Kaklamani VG, et al. Abstract PD6–13: phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Cancer Res. 2018;78(4_Suppl):Abstract nr PD6–13.

    Google Scholar 

  23. • Voorwerk L, Slagter M, Horlings HM, Sikorska K, van de Vijver K, de Maaker M, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019;25(6):920–8 This study suggests that anthracyclines are an ideal partner to immune checkpoint inhibitors in breast cancer.

    Article  CAS  PubMed  Google Scholar 

  24. Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014;20(11):1301–9.

    Article  CAS  PubMed  Google Scholar 

  25. Shen J, Zhao W, Ju Z, et al. PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness. Cancer Res. 2019;79(2):311–319.

  26. Ding L, Kim HJ, Wang Q, et al. PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer. Cell Rep. 2018;25(11):2972–-2980.e5.

  27. Domchek S, Bang YJ, Coukos G, et al. MEDIOLA: a phase I/II, open-label trial of olaparib in combination with durvalumab (MEDI4736) in patients (pts) with advanced solid tumours [abstract]. Ann Oncol. 2016;27:1103TiP.

    Article  Google Scholar 

  28. Domchek S, Postel-Vinay S, Im SA, et al. Abstract PD5-04: an open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Cancer Res. 2019;79:PD5–04.

    Article  Google Scholar 

  29. Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.1029.

  30. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

    Article  CAS  Google Scholar 

  31. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395–9.

    Article  CAS  PubMed  Google Scholar 

  33. Bertucci F, Ng CKY, Patsouris A, et al. Genomic characterization of metastatic breast cancers. Nature. 2019;569(7757):560–4.

    Article  CAS  PubMed  Google Scholar 

  34. Schmid P, Loirat D, Savas 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) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT049. 2019.

  35. Jiang W, Chan CK, Weissman IL, Kim BYS, Hahn SM. Immune priming of the tumor microenvironment by radiation. Trends Cancer. 2016;2(11):638–45.

    Article  PubMed  Google Scholar 

  36. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  37. Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18(5):313–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1(6):365–72.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lim JY, Gerber SA, Murphy SP, Lord EM. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother. 2014;63(3):259–71.

    Article  CAS  PubMed  Google Scholar 

  40. Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011;71(7):2488–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41(5):843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu Y, Dong Y, Kong L, Shi F, Zhu H, Yu J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol. 2018;11(1):104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ho AY, Barker CA, Arnold BB, Powell SN, Hu ZI, Gucalp A, et al. A phase 2 clinical trialassessing theefficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. Cancer. 2020;126(4):850–60.

    Article  CAS  PubMed  Google Scholar 

  46. Tolaney SB, Spira AC, Cho D, et al. Clinical activity of BEMPEG plus NIVO observed in metastatic TNBC: preliminary results from the TNBC cohort of the Ph1/2 PIVOT-02 study [abstract]. Presented at CICON, September 23–26, 2019, Paris, France. https://www.nektar.com/application/files/9215/6949/4543/PIVOT-02_TNBC_CICON_2019_Poster.pdf. 2019.

  47. Rugo HS, Delord JP, Im SA, et al. Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res. 2018;24(12):2804–11.

    Article  CAS  PubMed  Google Scholar 

  48. Tolaney SM, Barroso-Sousa R, Keenan T, et al. Randomized phase II study of eribulin mesylate (E) with or without pembrolizumab (P) for hormone receptor-positive (HR+) metastatic breast cancer (MBC) [abstract]. J Clin Oncol. 2019;37(15_suppl):1004.

    Article  Google Scholar 

  49. Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019;20(3):371–82.

    Article  CAS  PubMed  Google Scholar 

  50. Emens LA, Esteva FJ, Beresford M, et al. Overall survival (OS) in KATE2, a phase 2 study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (ATEZO)+trastuzumab emtansine (T-DM1) vs placebo (PBO)+T-DM1 in previously treated HER2+ advanced breast cancer (BC) [abstract]. Ann Oncol. 2019;30:v104–42.

    Article  Google Scholar 

  51. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.

    Article  CAS  PubMed  Google Scholar 

  52. Hutchinson KE, Yost SE, Chang CW, et al. Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts. Clin Cancer Res. 2020;26(3):657–68.

  53. • Szekely B, Bossuyt V, Li X, et al. Immunological differences between primary and metastatic breast cancer. Ann Oncol. 2018;29(11):2232–9 The studies 49 and 50 have shown that metastatic tumors are less immunogenic that primary breast tumors and provide a rationale that using immunotherapy in early-stage breast cancer can be more effective than in the metastatic setting.

    Article  CAS  PubMed  Google Scholar 

  54. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80.

    Article  CAS  PubMed  Google Scholar 

  55. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20(1):25–39.

    Article  CAS  PubMed  Google Scholar 

  57. Pitt JM, Vetizou M, Daillere R, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity. 2016;44(6):1255–69.

    Article  CAS  PubMed  Google Scholar 

  58. • Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann Oncol. 2019;30(Suppl_5):v851–934 This study is the first phase 3 study to show that the addition of an immune checkpoint inhibitor to preoperative chemotherapy increases the rates of pathologic complete response compared to chemotherapy alone.

    Google Scholar 

  59. Gianni L, Huang CS, Egle D, et al. 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 [abstract]. 2019 San Antonio Breast Cancer Symposium. 2019.

  60. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33.

    Article  CAS  PubMed  Google Scholar 

  62. Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thorac Oncol. 2017;12(2):208–22.

    Article  PubMed  Google Scholar 

  63. Tsao MS, Kerr KM, Kockx M, Beasley MB, Borczuk AC, Botling J, et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J Thorac Oncol. 2018;13(9):1302–11.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Reisenbichler ES, Han G, Pelekanou V, et al. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays in triple negative breast cancer [abstract]. 2019 San Antonio Breast Cancer Symposium. 2019.

  65. Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213(13):2835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362(6411):eaar3593.

  67. Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37(4):318–27.

    Article  PubMed  Google Scholar 

  68. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1–2):48–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kreiter S, Vormehr M, van de Roemer N, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015;520(7549):692–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012;482(7385):405–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;17(4):1206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321–30.

    Article  CAS  PubMed  Google Scholar 

  74. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.

    Article  CAS  PubMed  Google Scholar 

  75. Barroso-Sousa R, Jain E, Cohen O, et al. Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann Oncol. 2020;31(3):387–94.

  76. Barroso-Sousa R, Keenan TE, Pernas S, et al. Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer. Clin Cancer Res. 2020. https://doi.org/10.1158/1078-0432.CCR-19-3507.

  77. Alva AS, Mangat PK, Garrett-Mayer E, 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 [abstract]. J Clin Oncol. 2019;37(15_suppl):1014.

    Article  Google Scholar 

  78. Stenzinger A, Allen JD, Maas J, Stewart MD, Merino DM, Wempe MM, et al. Tumor mutational burden standardization initiatives: recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions. Genes Chromosomes Cancer. 2019;58(8):578–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30(1):44–56.

    Article  CAS  PubMed  Google Scholar 

  80. Keenan TE, Burke KP, Van Allen EM. Genomic correlates of response to immune checkpoint blockade. Nat Med. 2019;25(3):389–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16.

    Article  CAS  PubMed  Google Scholar 

  82. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine Leiomyosarcoma. Immunity. 2017;46(2):197–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Loi S, Adams S, Schmid P, 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 [abstract]. Ann Oncol. 2017;28(suppl_5):v605–49.

    Google Scholar 

  84. Barroso-Sousa R, Thommen TL. Gut microbiome and breast cancer in the era of cancer immunotherapy. Curr Breast Cancer Rep. 2019;11(4):272–6.

    Article  CAS  Google Scholar 

  85. Tolaney SM, Kabos P, Dickler MN, et al. Updated efficacy, safety, & PD-L1 status of patients with HR+, HER2- metastatic breast cancer administered abemaciclib plus pembrolizumab. 2018;36(15_suppl):1059.

  86. Barroso-Sousa R, Krop IE, Trippa L, et al. A phase II study of pembrolizumab in combination with palliative radiotherapy for hormone receptor-positive metastatic breast cancer. Clin Breast Cancer. 2020. https://doi.org/10.1016/j.clbc.2020.01.012.

  87. Schmid P, Salgado R, Park YH, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment for high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 2020 Feb;14 [Epub ahead of print]. https://doi.org/10.1016/j.annonc.2020.01.072.

  88. Nanda R, Liu MC, Yau C, 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. https://doi.org/10.1001/jamaoncol.2019.6650. This study was the first study in the preoperative setting to suggest that the addition of immunotherapy to chemotherapy increases the rates of pathologic complete response in patients with HER2-negative breast cancer.

  89. Liu MC, Robinson PA, Yau C, et al. Evaluation of a pembrolizumab-8 cycle neoadjuvant regimen without AC for high-risk earlystage HER2-negative breast cancer: results from the I-SPY 2 TRIAL. Presented at the 2019 San Antonio Breast Cancer Symposium, December 10–14, 2019 San Antonio, Texas. Abstract P3-09-02. 2019.

  90. Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, 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;30(8):1279–88.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We kindly thank Kate Bifolck for her editorial support to this work.

Author information

Authors and Affiliations

  1. Oncology Center, Hospital Sírio-Libanês, SGAS 613/614 Conjunto E Lote 95, Brazília, DF, 70200-730, Brazil

    Romualdo Barroso-Sousa MD, PhD

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Sara M. Tolaney MD, MPH

Authors
  1. Romualdo Barroso-Sousa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara M. Tolaney MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sara M. Tolaney MD, MPH.

Ethics declarations

Conflicts of Interest

Dr.Barroso-Sousa has received reimbursement for travel accommodations/expenses from Roche, has received honoraria from Eli Lilly, Roche, Bristol-Myers Squibb, Novartis, Libbs and Pfizer, and has served as an advisor/consultant for Eli Lilly and Roche. Dr. Tolaney has received institutional research funding from Novartis, Genentech, Eli Lilly, Pfizer, Merck, Exelixis, Eisai, Bristol-Myers Squibb, AstraZeneca, Cyclacel, Immunomedics, Odonate, and Nektar, and has received compensation from Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics, Nektar, Tesaro, Paxman, Athenex, Oncopop, Daiichi-Sankyo, and NanoString for service as an advisor/consultant.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Breast Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barroso-Sousa, R., Tolaney, S.M. Clinical Development of PD-1/PD-L1 Inhibitors in Breast Cancer: Still a Long Way to Go. Curr. Treat. Options in Oncol. 21, 59 (2020). https://doi.org/10.1007/s11864-020-00756-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-020-00756-6

Keywords

Search

Navigation