Advances in the study of PD-1/PD-L1 inhibitors in breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Jiaqi ¹ ,  JIA Hongyan ²

1. The First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, P. R. China;
2. Department of Breast, The First Hospital of Shanxi Medical University, Taiyuan 030001, P. R. China;

Corresponding author：

JIA Hongyan, Email: swallow_jhy@163.com

Keywords：

breast cancer; immunotherapy; programmed cell death protein 1; programmed cell death ligand-1; biomarker

DOI：

10.7507/1007-9424.202012128

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the mechanism of action of programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, the application in breast cancer in recent years and the advances in the study of their bio-markers of effects. Method Relevant literatures on PD-1/PD-L1 inhibitors and the study in the field of breast cancer were reviewed and summarized.Results In recent years, the monotherapy of immune checkpoint inhibitors represented by PD-1/PD-L1 inhibitors or in combination with other therapies had brought new hope for patients with breast cancer especially triple-negative breast cancer (TNBC). However, only a small number of patients could benefit from breast cancer immunotherapy. The current researchers think that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), high level of microsatellite instability (MSI-H) and deficient mismatch repair (dMMR).Conclusion Breast cancer can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, but formulating personalized medicine model, finding biomarkers that can predict efficacy and selecting patients with breast cancer who can benefit from it for targeted therapy are the new requirements in the new era of breast cancer immunotherapy.

Citation： ZHANG Jiaqi, JIA Hongyan. Advances in the study of PD-1/PD-L1 inhibitors in breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(11): 1530-1535. doi: 10.7507/1007-9424.202012128 Copy

1.	Latest global cancer data: Cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in 2020. https://www.iarc.who.int/news-events/latest-global-cancer-data-cancer-burden-rises-to-19-3-million-new-cases-and-10-0-million-cancer-deaths-in-2020/. December 15, 2020.
2.	Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med, 2016, 8(328): 328rv4.
3.	Abdou Y, Pandey M, Sarma M, et al. Mechanism-based treatment of cancer with immune checkpoint inhibitor therapies. Br J Clin Pharmacol, 2020, 86(9): 1690-1702.
4.	Vranic S, Cyprian FS, Gatalica Z, et al. PD-L1 status in breast cancer: Current view and perspectives. Semin Cancer Biol, 2019 Dec 26, Online ahead of print.
5.	Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol, 2018, 18(3): 153-167.
6.	Kowanetz M, Zou W, Gettinger SN, et al. Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci U S A, 2018, 115(43): E10119-E10126.
7.	Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med, 2015, 373(16): 1490-1492.
8.	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 Biomarkers Prev, 2014, 23(12): 2965-2970.
9.	Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget, 2015, 6(7): 5449-5464.
10.	Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res, 2014, 2(4): 361-370.
11.	Ali HR, Glont SE, Blows FM, 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): 1488-1493.
12.	Kim A, Lee SJ, Kim YK, et al. Programmed death-ligand 1 (PD-L1) expression in tumour cell and tumour infiltrating lymphocytes of HER2-positive breast cancer and its prognostic value. Sci Rep, 2017, 7(1): 11671.
13.	Zhang M, Sun H, Zhao S, et al. Expression of PD-L1 and prognosis in breast cancer: a meta-analysis. Oncotarget, 2017, 8(19): 31347-31354.
14.	Huang W, Ran R, Shao B, et al. Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis. Breast Cancer Res Treat, 2019, 178(1): 17-33.
15.	Qin T, Zeng YD, Qin G, et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget, 2015, 6(32): 33972-33981.
16.	Yuan C, Liu Z, Yu Q, et al. Expression of PD-1/PD-L1 in primary breast tumours and metastatic axillary lymph nodes and its correlation with clinicopathological parameters. Sci Rep, 2019, 9(1): 14356.
17.	Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ⅰb KEYNOTE-012 study. J Clin Oncol, 2016, 34(21): 2460-2467.
18.	Adams S, Schmid P, Rugo HS, 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.
19.	Adams S, Loi S, Toppmeyer D, 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): 405-411.
20.	Winer EP, Lipatov O, Im SA, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(4): 499-511.
21.	Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lance, 2020, 396(10265): 1817-1828.
22.	Schmid P, Salgado R, Park YH, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol, 2020, 31(5): 569-581.
23.	Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med, 2020, 382(9): 810-821.
24.	Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med, 2018, 379(22): 2108-2121.
25.	Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest, 2014, 124(2): 687-695.
26.	Voorwerk L, Slagter M, Horlings HM, 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): 920-928.
27.	Gyawali B, Niraula S. Lessons from adaptive randomization: spying the I-spy2 trial in breast cancer. J Natl Compr Canc Netw, 2020, 18(11): 1441-1444.
28.	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): 371-382.
29.	Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26): 2509-2520.
30.	Herbst RS, Baas P, Kim DW, 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): 1540-1550.
31.	Nasser NJ, Gorenberg M, Agbarya A. First line immunotherapy for non-small cell lung cancer. Pharmaceuticals (Basel), 2020, 13(11): 373.
32.	Horn L, Spigel DR, Vokes EE, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol, 2017, 35(35): 3924-3933.
33.	Chae YK, Pan A, Davis AA, et al. Biomarkers for PD-1/PD-L1 blockade therapy in non-small-cell lung cancer: is PD-L1 expression a good marker for patient selection? Clin Lung Cancer, 2016, 17(5): 350-361.
34.	Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer, 2019, 19(3): 133-150.
35.	中国抗癌协会肿瘤病理专业委员会, 中国临床肿瘤学会肿瘤病理专家委员会, 中国临床肿瘤学会非小细胞肺癌专家委员会. 中国非小细胞肺癌PD-L1表达检测临床病理专家共识. 中华肿瘤杂志, 2020, 42(7): 513-521.
36.	Link JT, Overman MJ. Immunotherapy progress in mismatch repair-deficient colorectal cancer and future therapeutic challenges. Cancer J, 2016, 22(3): 190-195.
37.	Smyth EC, Wotherspoon A, Peckitt C, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol, 2017, 3(9): 1197-1203.
38.	Gelsomino F, Barbolini M, Spallanzani A, et al. The evolving role of microsatellite instability in colorectal cancer: A review. Cancer Treat Rev, 2016, 51: 19-26.
39.	Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017, 357(6349): 409-413.
40.	Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site—When a biomarker defines the indication. N Engl J Med, 2017, 377(15): 1409-1412.
41.	Mills AM, Dill EA, Moskaluk CA, et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol, 2018, 42(2): 183-191.
42.	Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
43.	Chang H, Sasson A, Srinivasan S, et al. Bioinformatic methods and bridging of assay results for reliable tumor mutational burden assessment in non-small-cell lung cancer. Mol Diagn Ther, 2019, 23(4): 507-520.
44.	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): 387-394.
45.	Criscitiello C, Esposito A, Trapani D, et al. Prognostic and predictive value of tumor infiltrating lymphocytes in early breast cancer. Cancer Treat Rev, 2016, 50: 205-207.
46.	Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol, 2015, 26(2): 259-271.
47.	Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer, 2017, 24(1): 3-15.
48.	Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer, 2016, 4: 59.
49.	Gu-Trantien C, Loi S, Garaud S, et al. CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest, 2013, 123(7): 2873-2892.
50.	Teng MW, Ngiow SF, Ribas A, et al. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res, 2015, 75(11): 2139-2145.
51.	Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer, 2018, 6(1): 157.

1. Latest global cancer data: Cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in 2020. https://www.iarc.who.int/news-events/latest-global-cancer-data-cancer-burden-rises-to-19-3-million-new-cases-and-10-0-million-cancer-deaths-in-2020/. December 15, 2020.
2. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med, 2016, 8(328): 328rv4.
3. Abdou Y, Pandey M, Sarma M, et al. Mechanism-based treatment of cancer with immune checkpoint inhibitor therapies. Br J Clin Pharmacol, 2020, 86(9): 1690-1702.
4. Vranic S, Cyprian FS, Gatalica Z, et al. PD-L1 status in breast cancer: Current view and perspectives. Semin Cancer Biol, 2019 Dec 26, Online ahead of print.
5. Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol, 2018, 18(3): 153-167.
6. Kowanetz M, Zou W, Gettinger SN, et al. Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci U S A, 2018, 115(43): E10119-E10126.
7. Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med, 2015, 373(16): 1490-1492.
8. 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 Biomarkers Prev, 2014, 23(12): 2965-2970.
9. Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget, 2015, 6(7): 5449-5464.
10. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res, 2014, 2(4): 361-370.
11. Ali HR, Glont SE, Blows FM, 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): 1488-1493.
12. Kim A, Lee SJ, Kim YK, et al. Programmed death-ligand 1 (PD-L1) expression in tumour cell and tumour infiltrating lymphocytes of HER2-positive breast cancer and its prognostic value. Sci Rep, 2017, 7(1): 11671.
13. Zhang M, Sun H, Zhao S, et al. Expression of PD-L1 and prognosis in breast cancer: a meta-analysis. Oncotarget, 2017, 8(19): 31347-31354.
14. Huang W, Ran R, Shao B, et al. Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis. Breast Cancer Res Treat, 2019, 178(1): 17-33.
15. Qin T, Zeng YD, Qin G, et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget, 2015, 6(32): 33972-33981.
16. Yuan C, Liu Z, Yu Q, et al. Expression of PD-1/PD-L1 in primary breast tumours and metastatic axillary lymph nodes and its correlation with clinicopathological parameters. Sci Rep, 2019, 9(1): 14356.
17. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ⅰb KEYNOTE-012 study. J Clin Oncol, 2016, 34(21): 2460-2467.
18. Adams S, Schmid P, Rugo HS, 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.
19. Adams S, Loi S, Toppmeyer D, 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): 405-411.
20. Winer EP, Lipatov O, Im SA, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(4): 499-511.
21. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lance, 2020, 396(10265): 1817-1828.
22. Schmid P, Salgado R, Park YH, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol, 2020, 31(5): 569-581.
23. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med, 2020, 382(9): 810-821.
24. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med, 2018, 379(22): 2108-2121.
25. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest, 2014, 124(2): 687-695.
26. Voorwerk L, Slagter M, Horlings HM, 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): 920-928.
27. Gyawali B, Niraula S. Lessons from adaptive randomization: spying the I-spy2 trial in breast cancer. J Natl Compr Canc Netw, 2020, 18(11): 1441-1444.
28. 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): 371-382.
29. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26): 2509-2520.
30. Herbst RS, Baas P, Kim DW, 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): 1540-1550.
31. Nasser NJ, Gorenberg M, Agbarya A. First line immunotherapy for non-small cell lung cancer. Pharmaceuticals (Basel), 2020, 13(11): 373.
32. Horn L, Spigel DR, Vokes EE, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol, 2017, 35(35): 3924-3933.
33. Chae YK, Pan A, Davis AA, et al. Biomarkers for PD-1/PD-L1 blockade therapy in non-small-cell lung cancer: is PD-L1 expression a good marker for patient selection? Clin Lung Cancer, 2016, 17(5): 350-361.
34. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer, 2019, 19(3): 133-150.
35. 中国抗癌协会肿瘤病理专业委员会, 中国临床肿瘤学会肿瘤病理专家委员会, 中国临床肿瘤学会非小细胞肺癌专家委员会. 中国非小细胞肺癌PD-L1表达检测临床病理专家共识. 中华肿瘤杂志, 2020, 42(7): 513-521.
36. Link JT, Overman MJ. Immunotherapy progress in mismatch repair-deficient colorectal cancer and future therapeutic challenges. Cancer J, 2016, 22(3): 190-195.
37. Smyth EC, Wotherspoon A, Peckitt C, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol, 2017, 3(9): 1197-1203.
38. Gelsomino F, Barbolini M, Spallanzani A, et al. The evolving role of microsatellite instability in colorectal cancer: A review. Cancer Treat Rev, 2016, 51: 19-26.
39. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017, 357(6349): 409-413.
40. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site—When a biomarker defines the indication. N Engl J Med, 2017, 377(15): 1409-1412.
41. Mills AM, Dill EA, Moskaluk CA, et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol, 2018, 42(2): 183-191.
42. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
43. Chang H, Sasson A, Srinivasan S, et al. Bioinformatic methods and bridging of assay results for reliable tumor mutational burden assessment in non-small-cell lung cancer. Mol Diagn Ther, 2019, 23(4): 507-520.
44. 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): 387-394.
45. Criscitiello C, Esposito A, Trapani D, et al. Prognostic and predictive value of tumor infiltrating lymphocytes in early breast cancer. Cancer Treat Rev, 2016, 50: 205-207.
46. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol, 2015, 26(2): 259-271.
47. Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer, 2017, 24(1): 3-15.
48. Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer, 2016, 4: 59.
49. Gu-Trantien C, Loi S, Garaud S, et al. CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest, 2013, 123(7): 2873-2892.
50. Teng MW, Ngiow SF, Ribas A, et al. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res, 2015, 75(11): 2139-2145.
51. Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer, 2018, 6(1): 157.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Advances in the study of PD-1/PD-L1 inhibitors in breast cancer

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