Current Oncology Reports

, 19:64 | Cite as

Immunotherapy in Breast Cancer: the Emerging Role of PD-1 and PD-L1

  • François BertucciEmail author
  • Anthony Gonçalves
Breast Cancer (B Overmoyer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Breast Cancer


Purpose of Review

The purpose of the review is to summarize the data regarding PD-L1 expression in breast cancer and the results of first clinical trials with PD-1 or PD-L1 inhibitors in patients with metastatic breast cancer.

Recent Findings

PD-L1 expression is heterogeneous across primary breast cancers, and is generally associated with the presence of tumor-infiltrating lymphocytes and the presence of poor-prognosis features such as high grade, and aggressive molecular subtypes (triple-negative (TN), basal, HER2-enriched). Early phase clinical trials using PD-1 or PD-L1 inhibitors alone or in combination have shown objective tumor responses and durable long-term disease control, in heavily pre-treated patients, notably in the TN subtype.


Blockade of PD-1 or PD-L1 shows impressive antitumor activity in some subsets of breast cancer patients. Many clinical trials are ongoing in the metastatic and neoadjuvant setting, alone and in combination with chemotherapy, targeted therapy, radiotherapy, and/or other immune therapy. The identification of biomarkers predictive for a clinical benefit is warranted.


Breast cancer Expression Immune response Monoclonal antibodies PD-1 PD-L1 


Compliance with Ethical Standards

Conflict of Interest

François Bertucci declares that he has no conflict of interest.

Anthony Gonçalves has received research support through grants from Novartis, Roche, and Eisai; has received compensation from Roche and Eisai for service as a consultant; and has received non-financial support from Novartis, Roche, Eisai, Amgen, and Pfizer.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology (Williston Park). 2015;29(5):375–85.Google Scholar
  2. 2.
    Bertucci F, Finetti P, Cervera N, Charafe-Jauffret E, Mamessier E, Adelaide J, et al. Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res. 2006;66(9):4636–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Ridolfi RL, Rosen PP, Port A, Kinne D, Mike V. Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer. 1977;40(4):1365–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A. 2012;109(8):2796–801. doi: 10.1073/pnas.1104303108.CrossRefPubMedGoogle Scholar
  5. 5.
    Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. Harmonization of the evaluation of tumor infiltrating lymphocytes (TILs) in breast cancer: recommendations by an international TILs-working group 2014. Ann Oncol. 2014; doi: 10.1093/annonc/mdu450.
  6. 6.
    Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28(1):105–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25(8):1536–43. doi: 10.1093/annonc/mdu191.CrossRefPubMedGoogle Scholar
  8. 8.
    Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50. doi: 10.1093/annonc/mdu112.CrossRefPubMedGoogle Scholar
  9. 9.
    Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009;11(2):R15.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sabatier R, Finetti P, Mamessier E, Raynaud S, Cervera N, Lambaudie E, et al. Kinome expression profiling and prognosis of basal breast cancers. Mol Cancer. 2011;10:86.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 2007;8(8):R157.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, et al. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol. 2010;28(28):4316–23. doi: 10.1200/JCO.2009.27.2419.CrossRefPubMedGoogle Scholar
  13. 13.
    Sabatier R, Finetti P, Cervera N, Lambaudie E, Esterni B, Mamessier E, et al. A gene expression signature identifies two prognostic subgroups of basal breast cancer. Breast Cancer Res Treat. 2011;126(2):407–20.CrossRefPubMedGoogle Scholar
  14. 14.
    • Ali HR, Chlon L, Pharoah PD, Markowetz F, Caldas C. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med. 2016;13(12):e1002194. doi: 10.1371/journal.pmed.1002194. Computational approach (CIBERSORT) applied to bulk gene expression profiles of almost 11,000 tumours to infer the proportions of 22 subsets of immune cells. Shows large differences in the cellular composition of the immune infiltrate in breast tumours, and correlations with both prognosis and response to treatment. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    • Bense RD, Sotiriou C, Piccart-Gebhart MJ, Haanen JB, van Vugt MA, de Vries EG et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J Natl Cancer Inst. 2017;109(1). doi: 10.1093/jnci/djw192. In silico analyses (CIBERSORT) of gene expression profiles of 7,270 non-metastatic breast cancer samples showing the fraction of 22 immune cell types and their relations with pathological complete response, disease-free survival, and overall survival .
  16. 16.
    Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri 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. 2014;25(3):611–8. doi: 10.1093/annonc/mdt556.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011;8(3):151–60. doi: 10.1038/nrclinonc.2010.223.CrossRefPubMedGoogle Scholar
  18. 18.
    Ma Y, Conforti R, Aymeric L, Locher C, Kepp O, Kroemer G, et al. How to improve the immunogenicity of chemotherapy and radiotherapy. Cancer Metastasis Rev. 2011;30(1):71–82. doi: 10.1007/s10555-011-9283-2.CrossRefPubMedGoogle Scholar
  19. 19.
    Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C, et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology. 2013;2(10):e27025. doi: 10.4161/onci.27025.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70(8):3052–61. doi: 10.1158/0008-5472.CAN-09-3690.CrossRefPubMedGoogle Scholar
  21. 21.
    Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537–44. doi: 10.1182/blood-2008-12-195792.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. doi: 10.1038/nm730.PubMedGoogle Scholar
  23. 23.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29. doi: 10.1084/jem.20090847.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hamel KM, Cao Y, Wang Y, Rodeghero R, Kobezda T, Chen L, et al. B7-H1 expression on non-B and non-T cells promotes distinct effects on T- and B-cell responses in autoimmune arthritis. Eur J Immunol. 2010;40(11):3117–27. doi: 10.1002/eji.201040690.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–77. doi: 10.1038/nri2326.CrossRefPubMedGoogle Scholar
  26. 26.
    Buque A, Bloy N, Aranda F, Castoldi F, Eggermont A, Cremer I, et al. Trial Watch: immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2015;4(4):e1008814. doi: 10.1080/2162402X.2015.1008814.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293–7. doi: 10.1073/pnas.192461099.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Reiss KA, Forde PM, Brahmer JR. Harnessing the power of the immune system via blockade of PD-1 and PD-L1: a promising new anticancer strategy. Immunotherapy. 2014;6(4):459–75. doi: 10.2217/imt.14.9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. doi: 10.1056/NEJMoa1200694.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. doi: 10.1056/NEJMoa1200690.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62. doi: 10.1038/nature13904.CrossRefPubMedGoogle Scholar
  32. 32.
    •• Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. doi: 10.1056/NEJMoa1411087. Clinical trial showing strong efficacy of Nivolumab (87% objective response rate) in 23 patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma. CrossRefPubMedGoogle Scholar
  33. 33.
    •• Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. doi: 10.1056/NEJMoa1507643. Randomized phase 3 study showing longer overall survival with nivolumab than with docetaxel in 582 patients with advanced non-squamous NSCLC that had progressed during or after platinum-based chemotherapy . CrossRefPubMedGoogle Scholar
  34. 34.
    •• Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. doi: 10.1056/NEJMoa1504627. Randomized phase 3 study showing longer overall survival with nivolumab than with docetaxel in 272 patients with advanced squamous NSCLC that had progressed during or after platinum-based chemotherapy. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016; doi: 10.1200/JCO.2016.68.1478.
  36. 36.
    •• Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. doi: 10.1056/NEJMoa1501824. Phase 1 study showing anti-tumor activity of pembrolizumab in 495 patients with advanced NSCLC. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy. CrossRefPubMedGoogle Scholar
  37. 37.
    •• Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. doi: 10.1056/NEJMoa1510665. Randomized phase 3 study showing longer overall survival with nivolumab than with everolimus in 821 pre-treated patients with advanced renal-cell carcinoma CrossRefPubMedGoogle Scholar
  38. 38.
    •• Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for pd-l1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. doi: 10.1056/NEJMoa1606774. Randomized phase 3 study showing longer progression-free and overall survival with pembrolizumab than with platinum-based chemotherapy in 305 previously untreated patients with advanced squamous NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing EGFR mutation or ALK translocation . CrossRefPubMedGoogle Scholar
  39. 39.
    •• Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. doi: 10.1056/NEJMoa1412082. Randomized phase 3 study showing longer progression-free and overall survival with nivolumab than with dacarbazine in 418 previously untreated patients with advanced melanoma without BRAF mutation . CrossRefPubMedGoogle Scholar
  40. 40.
    •• Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. doi: 10.1056/NEJMoa1503093. Randomized phase 3 study showing longer progression-free and overall survival with nivolumab than with ipilimumab in 834 previously untreated patients with advanced melanoma . CrossRefPubMedGoogle Scholar
  41. 41.
    •• Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50. doi: 10.1016/S0140-6736(15)01281-7. Randomized phase 2/3 study showing longer overall survival with pembrolizumab than with docetaxel in 1,034 previously treated patients with advanced NSCLC with PD-L1-positive tumor. CrossRefPubMedGoogle Scholar
  42. 42.
    •• Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374–85. doi: 10.1016/S1470-2045(16)30364-3. Phase 2 study showing durable anti-tumor activity (31.8% objective response rate) of avelumab in 88 previously treated patients with stage IV Merkel cell carcinoma . CrossRefPubMedGoogle Scholar
  43. 43.
    •• Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25. doi: 10.1200/JCO.2016.67.9761. Phase 1/2 study showing anti-tumor activity (31% objective response rate) of durvalumab in 61 previously treated patients with advanced urothelial bladder cancer. PD-L1 expression in at least 25% of tumor cells correlated with activity. CrossRefPubMedGoogle Scholar
  44. 44.
    Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74. doi: 10.1158/1078-0432.CCR-13-3271.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7. doi: 10.1038/nature14011.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71. doi: 10.1038/nature13954.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006;8(3):190–8. doi: 10.1593/neo.05733.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ghebeh H, Tulbah A, Mohammed S, Elkum N, Bin Amer SM, Al-Tweigeri T, et al. Expression of B7-H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer. 2007;121(4):751–8. doi: 10.1002/ijc.22703.CrossRefPubMedGoogle Scholar
  49. 49.
    •• Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015;6(7):5449–64. Largest retrospective study analysing the mRNA expression of PD-L1 in 5,454 primary breast cancer samples and showing PD-L1 upregulation is more frequent in basal breast cancers and is associated with increased T-cell cytotoxic immune response. In the basal or TN subtype, upregulation is associated with better survival and pathological response to chemotherapy. CrossRefPubMedGoogle Scholar
  50. 50.
    Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014;20(10):2773–82. doi: 10.1158/1078-0432.CCR-13-2702.CrossRefPubMedGoogle Scholar
  51. 51.
    Soliman H, Khalil F, Antonia S. PD-L1 expression is increased in a subset of basal type breast cancer cells. PLoS One. 2014;9(2):e88557. doi: 10.1371/journal.pone.0088557.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, et al. PD-L1 expression in triple-negative breast cancer. Cancer immunology research. 2014;2(4):361–70. doi: 10.1158/2326-6066.CIR-13-0127.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    •• Ali HR, Glont SE, Blows FM, Provenzano E, Dawson SJ, Liu B, et al. PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol. 2015;26(7):1488–93. doi: 10.1093/annonc/mdv192. Largest retrospective study analysing the protein expression of PD-L1 in 3,916 primary breast cancer samples and showing PD-L1 upregulation is rare in breast cancers, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. CrossRefPubMedGoogle Scholar
  54. 54.
    Bae SB, Cho HD, Oh MH, Lee JH, Jang SH, Hong SA, et al. Expression of programmed death receptor ligand 1 with high tumor-infiltrating lymphocytes is associated with better prognosis in breast cancer. J Breast Cancer. 2016;19(3):242–51. doi: 10.4048/jbc.2016.19.3.242.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol. 2016;47(1):78–84. doi: 10.1016/j.humpath.2015.09.006.CrossRefPubMedGoogle Scholar
  56. 56.
    Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, 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; doi: 10.1158/1055-9965.EPI-14-0654.
  57. 57.
    Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146(1):15–24. doi: 10.1007/s10549-014-2988-5.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Qin T, Zeng YD, Qin G, Xu F, Lu JB, Fang WF, et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget. 2015;6(32):33972–81. doi: 10.18632/oncotarget.5583.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    •• Wimberly H, Brown JR, Schalper K, Haack H, Silver MR, Nixon C, et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res. 2015;3(4):326–32. doi: 10.1158/2326-6066.CIR-14-0133. Retrospective study analysing the protein expression of PD-L1 in pre-treatment biopsies from 105 patients with breast cancer ftreated with neoadjuvant chemotherapy and showing PD-L1 expression is associated with higher pCR rate. CrossRefPubMedGoogle Scholar
  60. 60.
    Beckers RK, Selinger CI, Vilain R, Madore J, Wilmott JS, Harvey K, et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology. 2016;69(1):25–34. doi: 10.1111/his.12904.CrossRefPubMedGoogle Scholar
  61. 61.
    Botti G, Collina F, Scognamiglio G, Rao F, Peluso V, De Cecio R et al. Programmed death ligand 1 (PD-L1) tumor expression is associated with a better prognosis and diabetic disease in triple negative breast cancer patients. International journal of molecular sciences. 2017;18(2). doi: 10.3390/ijms18020459.
  62. 62.
    Dill EA, Gru AA, Atkins KA, Friedman LA, Moore ME, Bullock TN, et al. PD-L1 expression and Intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am J Surg Pathol. 2017;41(3):334–42. doi: 10.1097/PAS.0000000000000780.CrossRefPubMedGoogle Scholar
  63. 63.
    Li X, Wetherilt CS, Krishnamurti U, Yang J, Ma Y, Styblo TM, et al. Stromal PD-L1 expression is associated with better disease-free survival in triple-negative breast cancer. Am J Clin Pathol. 2016;146(4):496–502. doi: 10.1093/ajcp/aqw134.CrossRefPubMedGoogle Scholar
  64. 64.
    Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, et al. The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer. Oncotarget. 2017;8(9):15584–92. doi: 10.18632/oncotarget.14698.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Park IH, Kong SY, Ro JY, Kwon Y, Kang JH, Mo HJ, et al. Prognostic implications of tumor-infiltrating lymphocytes in association with programmed death ligand 1 expression in early-stage breast cancer. Clin Breast Cancer. 2016;16(1):51–8. doi: 10.1016/j.clbc.2015.07.006.CrossRefPubMedGoogle Scholar
  66. 66.
    Tsang JY, Au WL, Lo KY, Ni YB, Hlaing T, Hu J, et al. PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients. Breast Cancer Res Treat. 2017;162(1):19–30. doi: 10.1007/s10549-016-4095-2.CrossRefPubMedGoogle Scholar
  67. 67.
    • Bertucci F, Finetti P, Colpaert C, Mamessier E, Parizel M, Dirix L, et al. PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget. 2015;6(15):13506–19. First retrospective study analysing the mRNA expression of PD-L1 in 112 pre-treatment inflammatory breast cancer (IBC) samples and showing PD-L1 upregulation is more frequent in IBC than in non-IBC and is correlated with higher pCR rate to neo-adjuvant chemotherapy. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7. doi: 10.1200/JCO.2011.41.0902.CrossRefPubMedGoogle Scholar
  69. 69.
    Ono M, Tsuda H, Shimizu C, Yamamoto S, Shibata T, Yamamoto H, et al. Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat. 2012;132(3):793–805. doi: 10.1007/s10549-011-1554-7.CrossRefPubMedGoogle Scholar
  70. 70.
    Thompson E, Taube JM, Elwood H, Sharma R, Meeker A, Warzecha HN, et al. The immune microenvironment of breast ductal carcinoma in situ. Mod Pathol. 2016;29(3):249–58. doi: 10.1038/modpathol.2015.158.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Chen S, Wang RX, Liu Y, Yang WT, Shao ZM. PD-L1 expression of the residual tumor serves as a prognostic marker in local advanced breast cancer after neoadjuvant chemotherapy. Int J Cancer. 2017;140(6):1384–95. doi: 10.1002/ijc.30552.CrossRefPubMedGoogle Scholar
  72. 72.
    • Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, et al. Frequent expression of PD-L1 on circulating breast cancer cells. Molecular oncology. 2015;9(9):1773–82. doi: 10.1016/j.molonc.2015.05.009. First report showing evidence that PD-L1 is frequently expressed on metastatic cells circulating in the blood of hormone receptor-positive, HER2-negative breast cancer patients. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol. 2015;33(31):3541–3. doi: 10.1200/JCO.2015.61.6870.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20. doi: 10.1158/1078-0432.CCR-09-1624.CrossRefPubMedGoogle Scholar
  75. 75.
    Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48. doi: 10.1016/j.ejca.2015.11.016.CrossRefPubMedGoogle Scholar
  76. 76.
    Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559–74. doi: 10.1093/annonc/mdv623.CrossRefPubMedGoogle Scholar
  77. 77.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. doi: 10.1038/nrc3239.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. doi: 10.1056/NEJMoa1504030.CrossRefPubMedGoogle Scholar
  79. 79.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17. doi: 10.1056/NEJMoa1414428.CrossRefPubMedGoogle Scholar
  80. 80.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. doi: 10.1056/NEJMoa1302369.CrossRefPubMedGoogle Scholar
  81. 81.
    Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920–8. doi: 10.1158/1078-0432.CCR-16-1741.CrossRefPubMedGoogle Scholar
  82. 82.
    Saada-Bouzid E, Defaucheux C, Karabajakian A, Palomar Coloma V, Servois V, Paoletti X, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017; doi: 10.1093/annonc/mdx178.
  83. 83.
    Kato S, Goodman AM, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyper-progressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017; doi: 10.1158/1078-0432.CCR-16-3133.
  84. 84.
    Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84. doi: 10.1016/S1470-2045(15)70076-8.CrossRefPubMedGoogle Scholar
  85. 85.
    Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011;117(10):2192–201. doi: 10.1002/cncr.25747.CrossRefPubMedGoogle Scholar
  86. 86.
    Rimm D, Schalper K, Pusztai L. Unvalidated antibodies and misleading results. Breast Cancer Res Treat. 2014;147(2):457–8. doi: 10.1007/s10549-014-3061-0.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Investig. 2014;94(1):107–16. doi: 10.1038/labinvest.2013.130.CrossRefPubMedGoogle Scholar
  88. 88.
    McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA oncology. 2016;2(1):46–54. doi: 10.1001/jamaoncol.2015.3638.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Ilie M, Hofman V, Dietel M, Soria JC, Hofman P. Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch. 2016;468(5):511–25. doi: 10.1007/s00428-016-1910-4.CrossRefPubMedGoogle Scholar
  90. 90.
    Sholl LM, Aisner DL, Allen TC, Beasley MB, Borczuk AC, Cagle PT, et al. Programmed death ligand-1 immunohistochemistry—a new challenge for pathologists: a perspective from members of the pulmonary pathology society. Arch Pathol Lab Med. 2016;140(4):341–4. doi: 10.5858/arpa.2015-0506-SA.CrossRefPubMedGoogle Scholar
  91. 91.
    Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8. doi: 10.1038/nature12213.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    •• Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8. doi: 10.1126/science.aaa1348. Retrospective study of whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab showing that higher non-synonymous mutation burden in tumors is associated with improved objective response, durable clinical benefit, and progression-free survival . CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Campesato LF, Barroso-Sousa R, Jimenez L, Correa BR, Sabbaga J, Hoff PM, et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget. 2015;6(33):34221–7. doi: 10.18632/oncotarget.5950.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74. doi: 10.1126/science.aaa4971.CrossRefPubMedGoogle Scholar
  95. 95.
    •• Le DT UJN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. doi: 10.1056/NEJMoa1500596. Phase 2 prospective study testing the clinical activity of pembrolizumab in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency: patients with mismatch-repair deficiency (colo-rectal and non-colo-rectal) show higher OR rate and longer PFS than patients without mismatch-repair deficie ncy (colo-rectal). CrossRefGoogle Scholar
  96. 96.
    Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer discovery. 2016;6(8):827–37. doi: 10.1158/2159-8290.CD-15-1545.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    •• Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165(1):35–44. doi: 10.1016/j.cell.2016.02.065. Retrospective analysis of somatic mutanomes and transcriptomes of pre-treatment melanoma biopsies from patients treated with anti-PD-1 therapy. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    •• Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017; doi: 10.1038/nature22079. Retrospective immune profiling of peripheral blood from patients with stage IV melanoma before and after pembrolizumab and identification of pharmacodynamic changes in circulating exhausted-phenotype CD8 T-cells (Tex cells). Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response .
  99. 99.
    •• 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. doi: 10.1200/JCO.2015.64.8931. First study showing anti-tumor activity (18.5% objective response rate) of pembrolizumab in 111 previously treated patients with advanced triple-negative breast cancer. CrossRefPubMedGoogle Scholar
  100. 100.
    •• Emens LA, Braiteh FS, Cassier PA, Delord JP, Eder JP, Fasso M et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Cancer Res. 2015;75(9 Suppl):Abstract PD1–6. Phase 1a study showing anti-tumor activity (33% 24-week PFS rate and 24% OR rate) of atezolizumab in 21 previously treated patients with advanced PD-L1-positive triple-negative breast cancer . Google Scholar
  101. 101.
    •• Dirix LY, Takacs I, Nikolinakos P, Jerusalem G, Arkenau HT, Hamilton EP et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase Ib JAVELIN solid tumor trial. Cancer Res. 2016;76(4 Suppl):Abstract S1–04. Phase 1b study of avelumab in 168 previously treated patients with advanced breast cancer. In the 57 TNBC patients, the response rate was 8.8%, lower than observed in atezolizumab and pembrolizumab studies (in which patients had PD-L1 positive tumors). In the 9 TNBC patients with “hot spot” of PD-L1-positive immune cells within the tumor, the response rate was higher (44%). Google Scholar
  102. 102.
    •• Adams S, Diamond J, Hamilton E, Pohlmann P, Tolaney S, Molinero L et al. Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Cancer Res. 2016;76(4 Suppl):Abstract P2–11-06. One arm of a multicenter, multi-arm Phase Ib study evaluating atezolizumab in combination with weekly nab-paclitaxel in patients with metastatic TNBC: overall, the response rate was 41.7%, but reached nearly 90% for patients treated in the first-line setting. Responses were seen both in PD-L1-positive and -negative tumors . Google Scholar
  103. 103.
    Pusztai L, Karn T, Safonov A, Abu-Khalaf MM, Bianchini G. New strategies in breast cancer: immunotherapy. Clin Cancer Res. 2016;22(9):2105–10. doi: 10.1158/1078-0432.CCR-15-1315.CrossRefPubMedGoogle Scholar
  104. 104.
    Rugo HS, Delord JP, Im SA, Ott PA, Piha-Paul SA, L. BP et al. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. Cancer Res. 2016;76(4 Suppl):Abstract S5–07.Google Scholar
  105. 105.
    Bedognetti D, Maccalli C, Bader SB, Marincola FM, Seliger B. Checkpoint inhibitors and their application in breast cancer. Breast care. 2016;11(2):108–15. doi: 10.1159/000445335.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Hartkopf AD, Taran FA, Wallwiener M, Walter CB, Kramer B, Grischke EM, et al. PD-1 and PD-L1 immune checkpoint blockade to treat breast cancer. Breast care. 2016;11(6):385–90. doi: 10.1159/000453569.CrossRefPubMedGoogle Scholar
  107. 107.
    Hendrickx W, Simeone I, Anjum S, Mokrab Y, Bertucci F, Finetti P, et al. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology. n6(2):e1253654. doi: 10.1080/2162402X.2016.1253654.

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Medical OncologyInstitut Paoli-CalmettesMarseilleFrance
  2. 2.Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS U7258, INSERM U1068MarseilleFrance
  3. 3.Faculty of MedicineAix-Marseille UniversityMarseilleFrance

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