乳腺癌免疫检查点抑制剂治疗的研究进展与探索方向

doi:10.19401/j.cnki.1007-3639.2025.02.006

摘要/Abstract

摘要：

乳腺癌是全球女性中发病率最高的恶性肿瘤。近年来，免疫检查点抑制剂（immune checkpoint inhibitor，ICI）作为一种新兴的治疗策略，在乳腺癌的不同分子分型中展现出重要的临床应用价值。本综述系统地总结ICI在激素受体（hormone receptor，HR）阳性型、人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）过表达型及三阴型乳腺癌（triple-negative breast cancer，TNBC）中的研究进展及临床应用前景。其中，在HR阳性乳腺癌中，KEYNOTE-756和CheckMate 7FL研究证实，ICI联合新辅助化疗可提高病理学完全缓解（pathological complete response，pCR）率，其中程序性死亡受体配体1（programmed cell death-ligand 1，PD-L1）阳性患者获益更明显。此外，PROMENADE研究表明，雌激素受体（estrogen receptor，ER）、低表达HER2阴性乳腺癌患者接受ICI治疗后的pCR率更接近TNBC，而非HR阳性乳腺癌。在转移性HR阳性乳腺癌中，SACI-IO和DOLAF研究提示，ICI联合抗体药物偶联物（antibody-drug conjugate，ADC）或多腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase，PARP]抑制剂可能为特定亚组患者带来临床获益。在HER2过表达乳腺癌中，Keyriched-1和Neo-PATH研究显示，ICI联合抗HER2治疗可能改善HR阴性/HER2阳性患者的pCR情况。然而，Impassion-050和KATE2研究未能证明ICI使HER2阳性乳腺癌患者获益。在TNBC中，KEYNOTE-522研究的长期随访数据显示，新辅助ICI联合化疗不仅提高pCR率，还能为患者带来长期的生存获益。Impassion-130、KEYNOTE-355和TORCHLIGHT等研究证实，ICI联合化疗可改善PD-L1阳性晚期TNBC患者的无进展生存期（progression-free survival，PFS）和总生存期（overall survival，OS）。此外，ICI联合抗血管生成治疗、PARP抑制剂及ADC的治疗策略在TNBC中呈现出良好的应用前景。目前，ICI联合化疗仍是主要的治疗模式，同时ICI与抗HER2治疗、内分泌治疗、ADC及抗血管生成治疗的联合方案亦在积极探索中。然而，ICI治疗仍面临耐药机制复杂、疗效异质性及免疫相关不良事件管理等挑战。未来应进一步优化患者分层管理并探索更精准的联合治疗策略，以使乳腺癌患者的生存长期获益。

关键词: 乳腺癌, 免疫检查点抑制剂, PD-L1, 精准治疗

Abstract:

Breast cancer is the most prevalent malignancy among women worldwide. In recent years, immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic strategy across different molecular subtypes of breast cancer, demonstrating significant clinical potential. This review systematically summarized the progress and clinical applications of ICIs in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-overexpressing (HER2-positive), and triple-negative breast cancer (TNBC). In HR-positive breast cancer, the KEYNOTE-756 and CheckMate 7FL trials demonstrated that ICIs combined with neoadjuvant chemotherapy significantly improved the pathological complete response (pCR) rate, with greater benefits observed in programmed cell death-ligand 1 (PD-L1)-positive patients. Furthermore, the PROMENADE study indicated that estrogen receptor (ER)-low HER2-negative breast cancer patients achieved a pCR rate closer to that of TNBC rather than HR-positive breast cancer following ICIs treatment. In metastatic HR-positive breast cancer, the SACI-IO and DOLAF studies suggested that ICIs combined with antibody-drug conjugates (ADC) or poly (ADP-ribose) polymerase (PARP) inhibitors may provide clinical benefits for specific subgroups of patients. For HER2-positive breast cancer, the Keyriched-1 and Neo-PATH studies revealed that ICIs combined with anti-HER2 therapy might improve pCR rates in HR-negative/HER2-positive patients. However, the Impassion-050 and KATE2 trials failed to demonstrate widespread clinical benefits of ICIs in HER2-positive breast cancer. In TNBC, long-term follow-up data from the KEYNOTE-522 study showed that ICIs combined with neoadjuvant chemotherapy not only improved pCR rates but also conferred long-term survival benefits. Additionally, the Impassion-130, KEYNOTE-355, and TORCHLIGHT studies confirmed that ICIs combined with chemotherapy prolonged both progression-free survival (PFS) and overall survival (OS) in PD-L1-positive advanced TNBC patients. Meanwhile, treatment strategies combining ICIs with anti-angiogenic therapy, PARP inhibitors and ADCs have demonstrated promising efficacy in TNBC (SPARK and BEGONIA trial). Currently, ICIs combined with chemotherapy remains the primary treatment approach, while combination strategies involving ICIs with anti-HER2 therapy, endocrine therapy, ADCs, and anti-angiogenic therapy are actively being explored. However, challenges remain, including complex resistance mechanisms, heterogeneous treatment responses, and the management of immune-related adverse events. Future research should focus on refining patient stratification strategies and developing more precise combination therapies to improve long-term survival outcomes for breast cancer patients.

Key words: Breast cancer, Immune checkpoint inhibitor, PD-L1, Precision therapy

中图分类号:

R737.9

曾成, 王沅怡, 王佳妮, 马飞. 乳腺癌免疫检查点抑制剂治疗的研究进展与探索方向[J]. 中国癌症杂志, 2025, 35(2): 195-204.

ZENG Cheng, WANG Yuanyi, WANG Jiani, MA Fei. Advances in immune checkpoint inhibitor therapy for breast cancer: research progress and future directions[J]. China Oncology, 2025, 35(2): 195-204.

参考文献 48

[1]	SIEGEL R L, GIAQUINTO A N, JEMAL A. Cancer statistics, 2024[J]. CA A Cancer J Clin, 2024, 74(1): 12-49.
[2]	HARBECK N, GNANT M. Breast cancer[J]. Lancet, 2017, 389(10074): 1134-1150. doi: S0140-6736(16)31891-8 pmid: 27865536
[3]	张琪, 修秉虬, 吴炅. 2023年中国乳腺癌重要临床研究成果及最新进展[J]. 中国癌症杂志, 2024, 34(2): 135-142. doi: 10.19401/j.cnki.1007-3639.2024.02.001
	ZHANG Q, XIU B Q, WU J. Progress of important clinical research of breast cancer in China in 2023[J]. Chin Oncol, 2024, 34(2): 135-142. doi: 10.19401/j.cnki.1007-3639.2024.02.001
[4]	HARBECK N, PENAULT-LLORCA F, CORTES J, et al. Breast cancer[J]. Nat Rev Dis Primers, 2019, 5(1): 66. doi: 10.1038/s41572-019-0111-2 pmid: 31548545
[5]	DALL’OLIO F G, MARABELLE A, CARAMELLA C, et al. Tumour burden and efficacy of immune-checkpoint inhibitors[J]. Nat Rev Clin Oncol, 2022, 19(2): 75-90.
[6]	CARDOSO F, O’SHAUGHNESSY J, LIU Z Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER⁺/HER2^- breast cancer: a randomized phase 3 trial[J]. Nat Med, 2025[Online ahead of print].
[7]	LOI S, SALGADO R, CURIGLIANO G, et al. Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial[J]. Nat Med, 2025[Online ahead of print].
[8]	CHERIFI F, CABEL L, BOUSRIH C, et al. PROMENADE: PembROlizuMab for early triple negative ER-low breast caNcer, reAl worlD FrEnch cohort[J]. Ann Oncol, 2024, 35: S312-S313.
[9]	CARDOSO F, MCARTHUR H L, SCHMID P, et al. LBA21 KEYNOTE-756: Phase Ⅲ study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER⁺/HER2^-breast cancer[J]. Ann Oncol, 2023, 34: S1260-S1261.
[10]	SCHMID P, CORTES J, PUSZTAI L, et al. Pembrolizumab for early triple-negative breast cancer[J]. N Engl J Med, 2020, 382(9): 810-821.
[11]	DE CALUWE A, DESMOULINS I, CAO K, et al. Primary endpoint results of the Neo-CheckRay phase Ⅱ trial evaluating stereotactic body radiation therapy (SBRT) +/- durvalumab (durva) +/- oleclumab (ole) combined with neo-adjuvant chemotherapy (NACT) for early-stage, high risk ER⁺/HER2^- breast cancer (BC)[J]. Ann Oncol, 2024, 35: S1205.
[12]	GARRIDO-CASTRO A C, KIM S E, DESROSIERS J, et al. SACI-IO HR⁺: a randomized phase Ⅱ trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer[J]. J Clin Oncol, 2024, 42(17_suppl): LBA1004.
[13]	GUIU LAHAYE S, BALMANA GELPI J, GAUTHIER L, et al. DOLAF: an international multicenter phase Ⅱ trial of durvalumab (MEDI4736) plus olaparib plus fulvestrant in patients with metastatic or locally advanced ER-positive, HER2-negative breast cancer selected using criteria that predict sensitivity to olaparib[J]. J Clin Oncol, 2022, 40(16_suppl): TPS1116.
[14]	SU S C, ZHAO J H, XING Y, et al. Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages[J]. Cell, 2018, 175(2): 442-457.e23. doi: S0092-8674(18)31179-6 pmid: 30290143
[15]	KUEMMEL S, GLUZ O, REINISCH M, et al. Abstract PD10-11: Keyriched-1-a prospective, multicenter, open label, neoadjuvant phase Ⅱ single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype[J]. Cancer Res, 2022, 82(4_Suppl): PD10-11-PD10-11.
[16]	GUAN J, SUN K, JAIN D, et al. Chemotherapy-free neoadjuvant regimen with durvalumab, trastuzumab and pertuzumab (DTP) in HER2-enriched early breast cancer: a prospective, open-label phase Ⅱ trial[J]. Cancer Res, 2022.
[17]	AHN H K, SIM S H, SUH K J, et al. Response rate and safety of a neoadjuvant pertuzumab, atezolizumab, docetaxel, and trastuzumab regimen for patients with ERBB2-positive stage Ⅱ/Ⅲ breast cancer: the neo-PATH phase 2 nonrandomized clinical trial[J]. JAMA Oncol, 2022, 8(9): 1271-1277.
[18]	HUOBER J, BARRIOS C H, NIIKURA N, et al. Atezolizumab with neoadjuvant anti-human epidermal growth factor receptor 2 therapy and chemotherapy in human epidermal growth factor receptor 2-positive early breast cancer: primary results of the randomized phase Ⅲ IMpassion050 trial[J]. J Clin Oncol, 2022, 40(25): 2946-2956.
[19]	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[J]. Lancet Oncol, 2019, 20(3): 371-382. doi: S1470-2045(18)30812-X pmid: 30765258
[20]	EMENS L A, ESTEVA F J, BERESFORD M, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial[J]. Lancet Oncol, 2020, 21(10): 1283-1295. doi: S1470-2045(20)30465-4 pmid: 33002436
[21]	LOI S, SCHNEEWEISS A, SONG E, et al. 329TiP KATE3: a phase Ⅲ study of trastuzumab emtansine (T-DM1) in combination with atezolizumab or placebo in patients with previously treated HER2-positive and PD-L1-positive locally advanced or metastatic breast cancer[J]. Ann Oncol, 2021, 32: S509.
[22]	CONTE P F, DIECI M V, BISAGNI G, et al. A-BRAVE trial: a phase Ⅲ randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy[J]. J Clin Oncol, 2024, 42(17_suppl): LBA500.
[23]	NEDERLOF I, ROLFES A L, GIELEN R C A M, et al. LBA11 Neoadjuvant nivolumab/relatlimab or nivolumab/ipilimumab in triple-negative breast cancer with high tumor-infiltrating lymphocytes (TILs)[J]. Ann Oncol, 2024, 35: S1206.
[24]	GEYER C. GS3-05: NSABP B-59/GBG-96-GeparDouze: a randomized double-blind phase Ⅲ clinical trial of neoadjuvant chemotherapy with atezolizumab or placebo followed by adjuvant atezolizumab or placebo in patients with stage Ⅱ and Ⅲ triple-negative breast cancer[C]. San Antonio Breast Cancer Conference, 2024, December 10-13, GS3-05.
[25]	SCHMID P, CORTES J, DENT R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer[J]. N Engl J Med, 2022, 386(6): 556-567.
[26]	PUSZTAI L, DENKERT C, O’SHAUGHNESSY J, et al. Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522[J]. Ann Oncol, 2024, 35(5): 429-436.
[27]	SCHMID P, CORTES J, DENT R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer[J]. N Engl J Med, 2024, 391(21): 1981-1991.
[28]	O’SHAUGHNESSY J. Exploratory biomarker analysis of the phase 3 KEYNOTE-522 study of neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage TNBC[C]. San Antonio Breast Cancer Symposium, 2024, December 10-13, LB1-07.
[29]	CHEN L, LI H, ZHANG H, et al. Camrelizumab vs placebo in combination with chemotherapy as neoadjuvant treatment in patients with early or locally advanced triple-negative breast cancer: the CamRelief randomized clinical trial[J]. JAMA, 2024 Dec 13 [Online ahead of print]
[30]	SHIMIZU T, SANDS J, YOH K, et al. First-in-human, phase Ⅰ dose-escalation and dose-expansion study of trophoblast cell-surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan in non-small cell lung cancer: TROPION-PanTumor01[J]. J Clin Oncol, 2023, 41(29): 4678-4687.
[31]	KHOURY K, MEISEL J L, YAU C, et al. Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial[J]. Nat Med, 2024, 30(12): 3728-3736.
[32]	BARDIA A, PUSZTAI L, ALBAIN K, et al. TROPION-Breast03: a randomized phase Ⅲ global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy[J]. Ther Adv Med Oncol, 2024, 16: 17588359241248336.
[33]	SCHMID P, ADAMS S, RUGO H S, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer[J]. N Engl J Med, 2018, 379(22): 2108-2121.
[34]	EMENS L A, ADAMS S, BARRIOS C H, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis[J]. Ann Oncol, 2021, 32(8): 983-993. doi: 10.1016/j.annonc.2021.05.355 pmid: 34272041
[35]	CORTES J, CESCON D W, RUGO H S, 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[J]. Lancet, 2020, 396(10265): 1817-1828. doi: 10.1016/S0140-6736(20)32531-9 pmid: 33278935
[36]	JIANG Z F, OUYANG Q C, SUN T, et al. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial[J]. Nat Med, 2024, 30(1): 249-256. doi: 10.1038/s41591-023-02677-x pmid: 38191615
[37]	MO H N, YU Y P, SUN X Y, et al. Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial[J]. Nat Med, 2024, 30(9): 2528-2539. doi: 10.1038/s41591-024-03088-2 pmid: 38969879
[38]	MILES D, GLIGOROV J, ANDRÉ F, et al. 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[J]. Ann Oncol, 2021, 32(8): 994-1004.
[39]	DENT R, ANDRÉ F, GONÇALVES A, et al. IMpassion132 double-blind randomised phase Ⅲ trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer[J]. Ann Oncol, 2024, 35(7): 630-642.
[40]	DOMCHEK S M, POSTEL-VINAY S, IM S A, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study[J]. Lancet Oncol, 2020, 21(9): 1155-1164.
[41]	VINAYAK S, TOLANEY S M, SCHWARTZBERG L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer[J]. JAMA Oncol, 2019, 5(8): 1132-1140.
[42]	CHEN W Z, SHEN L S, JIANG J X, et al. Antiangiogenic therapy reverses the immunosuppressive breast cancer microenvironment[J]. Biomark Res, 2021, 9(1): 59. doi: 10.1186/s40364-021-00312-w pmid: 34294146
[43]	LIU J Q, LIU Q, LI Y, et al. Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase Ⅱ trial[J]. J Immunother Cancer, 2020, 8(1): e000696.
[44]	LIU X, SUI X, XU Y, et al. Tislelizumab plus sitravatinib and nab-paclitaxel in patients with untreated locally recurrent or metastatic triple-negative breast cancer (TNBC): updated efficacy and safety results[C]. San Antonio Breast Cancer Symposium, 2024, December 10-13: PS3-01.
[45]	国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2020版)[J]. 中华肿瘤杂志, 2020, 42(10): 781-797.
	Breast Cancer Expert Committee of National Cancer Quality Control Center, Breast Cancer Expert Committee of China Anti-Cancer Association, Cancer Drug Clinical Research Committee of China Anti-Cancer Association. Guidelines for clinical diagnosis and treatment of advanced breast cancer in China (2020 edition)[J]. Chin J Oncol, 2020, 42(10): 781-797.
[46]	TOLANEY S M, DE AZAMBUJA E, EMENS L A, et al. 276TiP ASCENT-04/KEYNOTE-D19: Phase Ⅲ study of sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs treatment of physician’s choice (TPC) plus pembro in first-line (1L) programmed death-ligand 1-positive (PD-L1⁺) metastatic triple-negative breast cancer (mTNBC)[J]. Ann Oncol, 2022, 33: S664-S665.
[47]	SCHMID P, WYSOCKI P J, MA C X, et al. 379MO Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase Ⅰb/Ⅱ study[J]. Ann Oncol, 2023, 34: S337.
[48]	SCHMID P, OLIVEIRA M, O’SHAUGHNESSY J, et al. 261TiP TROPION-Breast05: phase (Ph) Ⅲ study of datopotamab deruxtecan (Dato-DXd) ± durvalumab (D) vs chemotherapy (CT) + pembrolizumab (pembro) in patients (pts) with PD-L1⁺ locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC)[J]. ESMO Open, 2024, 9: 103282.