Progress in immunotherapy of breast cancer_West China Medical Journal

Authors：

ZUO Zejin ¹ , TIAN Tinglun ^2,3 ,  LUO Ting ^2,3

1. Clinical Research Management Department Ethics Office, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Breast Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LUO Ting, Email: luoting@wchscu.cn

Keywords：

Breast cancer; triple negative breast cancer; immunocheckpoint inhibitors

DOI：

10.7507/1002-0179.202212167

Video：

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Breast cancer is a malignancy with the highest incidence and mortality rate among women in the world. The current treatment methods include surgery, chemotherapy, radiotherapy, endocrine therapy and targeted therapy. Triple negative breast cancer (TNBC) has high manignant behavior and poor prognosis, lacks specific treatment targets, thus resulting in few effective treatment modalities. The emergence of immunotherapy has provided hopes for TNBC. The efficacy of immunocheckpoint inhibitors in neoadjuvant treatment of early TNBC and first-line treatment of programmed death-ligand 1 positive metastatic TNBC. Therefore, this article reviews the researches of immunocheckpoint inhibitors in the treatment of early and advanced breast cancer.

Citation： ZUO Zejin, TIAN Tinglun, LUO Ting. Progress in immunotherapy of breast cancer. West China Medical Journal, 2023, 38(11): 1766-1769. doi: 10.7507/1002-0179.202212167 Copy

1.	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2.	Naimi A, Mohammed RN, Raji A, et al. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal. 2022, 20(1): 44.
3.	Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J, 1992, 11(11): 3887-3895.
4.	Ahmadzadeh M, Johnson LA, Heemskerk B, 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): 1537-1544.
5.	Salmaninejad A, Valilou SF, Shabgah AG, et al. PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J Cell Physiol, 2019, 234(10): 16824-16837.
6.	Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001, 2(3): 261-268.
7.	Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal, 2012, 5(230): ra46.
8.	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.
9.	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, 6(5): 676-684.
10.	Schmid P, Cortes J, Dent R, et al. VP7-2021: KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol, 2021, 32(9); 1198-1200.
11.	Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet, 2020, 396(10257): 1090-1100.
12.	Loibl S, Untch M, Burchardi N, 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): 1279-1288.
13.	Gianni L, Huang CS, Egle D, et al. 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. Ann Oncol, 2022, 33(5): 534-543.
14.	Galluzzi L, Buqué A, Kepp O, Zitvogel L, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell, 2015, 28(6): 690-714.
15.	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.
16.	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.
17.	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.
18.	Dirix LY, Takacs I, Jerusalem G, 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): 671-686.
19.	Emens LA, Cruz C, Eder JP, 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.
20.	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): 334-342.
21.	Schmid P, Rugo HS, Adams S, et al. IMpassion130 investigators. 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.
22.	Miles D, Gligorov J, André F, et al. IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol, 2021, 32(8): 994-1004.
23.	Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet, 2020, 396(10265): 1817-1828.
24.	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, 5(8): 1132-1140.
25.	Senkus-Konefka E, Domchek S, Im SA, et al. Subgroup analysis of olaparib monotherapy versus chemotherapy by hormone receptor and BRCA mutation status in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: OlympiAD. Eur J Cancer, 2018, 92(Suppl 3): S19-S20.
26.	Schmid P, Kummel S, Loirat D, et al. Phase 1b study evaluating a triplet combination of ipatasertib, atezolizumab, and paclitaxel or nab-paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer. Cancer Res, 2019, 79(Suppl 13): CT049.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2. Naimi A, Mohammed RN, Raji A, et al. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal. 2022, 20(1): 44.
3. Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J, 1992, 11(11): 3887-3895.
4. Ahmadzadeh M, Johnson LA, Heemskerk B, 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): 1537-1544.
5. Salmaninejad A, Valilou SF, Shabgah AG, et al. PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J Cell Physiol, 2019, 234(10): 16824-16837.
6. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001, 2(3): 261-268.
7. Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal, 2012, 5(230): ra46.
8. 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.
9. 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, 6(5): 676-684.
10. Schmid P, Cortes J, Dent R, et al. VP7-2021: KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol, 2021, 32(9); 1198-1200.
11. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet, 2020, 396(10257): 1090-1100.
12. Loibl S, Untch M, Burchardi N, 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): 1279-1288.
13. Gianni L, Huang CS, Egle D, et al. 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. Ann Oncol, 2022, 33(5): 534-543.
14. Galluzzi L, Buqué A, Kepp O, Zitvogel L, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell, 2015, 28(6): 690-714.
15. 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.
16. 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.
17. 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.
18. Dirix LY, Takacs I, Jerusalem G, 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): 671-686.
19. Emens LA, Cruz C, Eder JP, 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.
20. 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): 334-342.
21. Schmid P, Rugo HS, Adams S, et al. IMpassion130 investigators. 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.
22. Miles D, Gligorov J, André F, et al. IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol, 2021, 32(8): 994-1004.
23. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355 investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet, 2020, 396(10265): 1817-1828.
24. 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, 5(8): 1132-1140.
25. Senkus-Konefka E, Domchek S, Im SA, et al. Subgroup analysis of olaparib monotherapy versus chemotherapy by hormone receptor and BRCA mutation status in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: OlympiAD. Eur J Cancer, 2018, 92(Suppl 3): S19-S20.
26. Schmid P, Kummel S, Loirat D, et al. Phase 1b study evaluating a triplet combination of ipatasertib, atezolizumab, and paclitaxel or nab-paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer. Cancer Res, 2019, 79(Suppl 13): CT049.

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