2024年度晚期乳腺癌共识与争议的现状及展望

doi:10.19401/j.cnki.1007-3639.2025.03.002

摘要/Abstract

摘要：

乳腺癌是女性发病率最高的恶性肿瘤，晚期乳腺癌患者的5年生存率不足20%。随着对乳腺癌发生、发展机制认识的深入，以及越来越多新药、新方案的问世，晚期乳腺癌患者的生存期不断延长。晚期乳腺癌的治疗进展推动了治疗共识的形成，但与此同时新的争议也在不断发生。本文基于2024年度关键临床研究证据，系统性梳理当前不同分子分型乳腺癌治疗的共识与争议，旨在为临床实践提供更全面的循证医学依据。针对人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）阳性晚期乳腺癌的一线治疗方案选择，尽管已经有CLEOPATRA研究结果使曲妥珠单抗和帕妥珠单抗联合紫杉类药物的治疗方案成为共识，但是PHILA研究结果提供了曲妥珠单抗和吡咯替尼联合紫杉类药物的新选择。两个研究亚组分析结果也为临床实践的差异化选择提供了参考。在晚期三阴性乳腺癌（triple-negative breast cancer，TNBC）的治疗中，对于程序性死亡蛋白配体-1（programmed death ligand-1，PD-L1）阳性患者，基于KEYNOTE-355、TORCHLIGHT研究，化疗联合程序性死亡蛋白-1（programmed death-1，PD-1）抑制剂治疗已成为标准推荐。然而，免疫治疗的选择人群、PD-L1阳性标准及免疫治疗药物的对应选择仍存在争议。新的抗体药物偶联物（antibody-drug conjugate，ADC）联合PD-L1抑制剂治疗的早期研究显示，不依赖于PD-L1表达，在晚期TNBC患者一线治疗中获得迄今最长的超过1年的无进展生存期（progression-free survival，PFS），可能是未来一线方案的最佳选择。激素受体阳性、HER2阴性晚期乳腺癌患者，细胞周期蛋白依赖性激酶（cyclin-dependent kinase，CDK）4/6抑制剂联合内分泌治疗已成为指南推荐的标准一线治疗。但SONIA研究设计对指南推荐和有效药物先用的传统治疗理念提出了挑战，SONIA研究结果提示并非所有的激素受体阳性、HER2阴性晚期乳腺癌一线治疗方案都应该选择CDK4/6抑制剂，同时SONIA研究的局限性也猝然显现，即CDK4/6抑制剂治疗失败后的治疗选择目前还无标准推荐，但基于现有循证医学证据建议有靶点突变优选靶点药物治疗，若无靶点突变可选择ADC药物、内分泌治疗等。脑转移是临床治疗的难点，随着更多的药物包括靶向HER2的小分子酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）药物和大分子ADC药物被证实对HER2阳性脑转移治疗有效，如何将药物治疗与局部治疗进行有机地结合，是需要深入研究的焦点。ADC药物是目前研发的热点领域，随着ADC药物越来越多，如何选择是目前临床研究的重点。未来的研究需要关注创新药物研发、整合各种治疗手段，给予患者精准个体化治疗，延长患者的生存期。

关键词: 晚期乳腺癌, 共识, 争议

Abstract:

Breast cancer remains the most prevalent malignancy in women, with a 5-year survival rate less than 20% in advanced stages. The deepening understanding of breast cancer pathogenesis and the emergence of novel therapeutic agents/regimens have progressively extended survival outcomes for advanced breast cancer patients. While therapeutic advancements have driven the formation of treatment consensus, new controversies continue to emerge. This article systematically reviews current consensus and controversies in managing different molecular subtypes of breast cancer based on pivotal 2024 clinical evidence, aiming to provide evidence-based guidance for clinical practice. For first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, the CLEOPATRA trial established the trastuzumab-pertuzumab-taxane regimen as standard care. However, the PHILA study proposed a new alternative combining trastuzumab, pyrotinib, and taxanes. Subgroup analyses from both trials provide valuable references for differentiated clinical decision-making. In triple-negative breast cancer (TNBC) management, KEYNOTE-355 and TORCHLIGHT trials established chemotherapy combined with programmed death-1 (PD-1) inhibitors as standard therapy for programmed death ligand-1 (PD-L1)-positive patients. Nevertheless, controversies persist regarding patient selection criteria, PD-L1 positivity thresholds, and optimal immunotherapy agents. Early-phase studies of antibody-drug conjugate (ADC)/PD-L1 inhibitor combinations demonstrated unprecedented progression-free survival (PFS) exceeding 12 months in the first-line TNBC treatment, independent of PD-L1 expression, potentially representing the future frontline regimen. For hormone receptor-positive/HER2-negative advanced breast cancer, cyclin-dependent kinase (CDK) 4/6 inhibitor-endocrine therapy combinations remain guideline-endorsed first-line treatment. The SONIA trial challenged conventional paradigms by demonstrating that not all patients required upfront CDK4/6 inhibitors. It also highlighted critical unresolved issues: no standard recommendations exist for post-CDK4/6 inhibitor therapy, though current evidence supports prioritizing targeted therapies for mutation-positive cases or ADC/endocrine therapies for mutation-negative scenarios. Brain metastasis management presents ongoing challenges. Emerging anti-HER2 agents, including tyrosine kinase inhibitor (TKI) and ADC with demonstrated intracranial efficacy, necessitate further investigation into optimal integration strategies with local therapies. ADC dominate therapeutic innovation, with current research prioritizing optimal sequencing strategies amidst expanding ADC options. Future directions should focus on novel drug development, multimodal treatment integration, and personalized precision therapies to prolong patient survival.

Key words: Advanced breast cancer, Consensus, Controversies

中图分类号:

R737.9

王小波, 王涛. 2024年度晚期乳腺癌共识与争议的现状及展望[J]. 中国癌症杂志, 2025, 35(3): 263-272.

WANG Xiaobo, WANG Tao. Current status and future perspectives on consensus and controversies in advanced breast cancer for 2024[J]. China Oncology, 2025, 35(3): 263-272.

图/表 2

表1

表2

TKI药物治疗HER2阳性乳腺癌脑转移患者的临床研究"

Study name	Reference	Intervention and patients	Outcomes
Lapatinib access into normal brain and metastases	[41]	Radiolabeled lapatinib and PET scans before and after oral lapatinib (8 d) in patients with or without 1 or more 1 cm BM	PET demonstrated lapatinib’s ability to penetrate BBB and shrink HER2-positive BM
Lapatinib in patients with brain metastases	[42]	Lapatinib in patients with CNS progression after previous trastuzumab and cranial radiotherapy	Objective CNS response in 20% of patients
Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breas	[43]	Lapatinib+capecitabine for previously untreated BM	Patients with >50% reduction of CNS volume had longer median PFS than patients with <50% reduction (3.38 months vs 2.07 months)
CEREBEL study (EGF111438)	[44]	Trastuzumab+capecitabine vs lapatinib 1 capecitabine in patients without baseline CNS metastases	No difference in the incidence of BM between the two treatment groups
NEfERT-T trial	[45]	Neratinib+trastuzumab vs trastuzumab+paclitaxel	Comparable PFS between the two treatment groups, but symptomatic or progressive CNS recurrences were more frequent in the trastuzumab 1 paclitaxel group (17% vs 8%, P=0.002)
Phase Ib study of tucatinib and T-DM1 in ERBB2-positive breast cancer	[46]	Tucatinib+T-DM1 in patients with previously treated ERBB2/HER2-positive metastatic breast cancer, both with and without BM	Acceptable toxicity and signs of antitumor activity. Median PFS of 6.7 months (95% CI: 4.1-10.2) and OR duration of 6.9 months (95% CI: 1.45-19.48) in patients with BM
HER2CLIMB study	[47]	Tucatinib+capecitabine+trastuzumab	42% of patients with BM achieved brain-specific OR
HER2CLIMB study comparing tucatinib with placebo	[48]	Tucatinib+capecitabine+trastuzumab vs placebo+capecitabine+trastuzumab (subgroup analysis of patients with BM at baseline)	Among patients with baseline BM, those in the Tucatinib combination group, vs the placebo combination group, had better median PFS (7.6 months vs 5.4 months), OS (HR=0.58, 95% CI: 0.40-0.85), and PFS (HR=0.48, 95% CI: 0.34-0.69)
PERMEATE study	[5]	Cohort A (untreated brain metastases, n=59) and Cohort B (progressive brain metastases after radiotherapy, n=19). All patients received pyrotinib plus capecitabine.	Median PFS: 10.9 months vs 5.7 months; Median OS: 35.9 months vs 30.6 months; Median CNS-PFS: 13.6 months vs 5.7 months

表2

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Study name	Intervention	mPFS vs placebo	mOS vs placebo
PALOMA-1 (n=165)^[18-19]	Patients randomized (1∶1) to palbociclib versus placebo^a as first-line therapy	20.2 months vs 10.2 months (HR=0.49, 95% CI: 0.32-0.75)	37.5 months vs 34.5 months (HR=0.90, 95% CI: 0.62-1.29, P=0.28)
PALOMA-2 (n=666)^[20-21]	Patients randomized (2∶1) to palbociclib versus placebo^a as first-line therapy	27.6 months vs 14.5 months (HR=0.56, 95% CI: 0.46-0.69, P<0.000 1)	53.9 months vs 51.2 months (HR=0.96, 95% CI: 0.78-1.18, P=0.34)
MONARCH-3 (n=493)^[22⇓-24]	Patients randomized (2∶1) to abemaciclib versus placebo^b as first-line therapy	28.2 months vs 14.8 months (HR=0.54, 95% CI: 0.42=0.70)	67.1 months vs 54.5 months (HR=0.75, 95% CI: 0.58-0.97, P=0.03)
MONALEESA-2 (n=668)^[25⇓-27]	Patients randomized (1∶1) to ribociclib versus placebo^a as first-line therapy	25.3 months vs 16.0 months (HR=0.57, 95% CI 0.46-0.70, P=9.63×10^-8)	63.9 months vs 51.4 months (HR=0.76, 95% CI 0.63-0.93, P=0.008)
MONALEESA-3 (n=726)^[28-29]	Patients randomized (2∶1) to ribociclib versus placebo^c as first-line or second-line therapy	20.5 months vs 12.8 months (HR=0.59, 95% CI: 0.48-0.73, P<0.001)	53.7 months vs 41.5 months (HR=0.73, 95% CI: 0.59-0.90)
MONALEESA-7^d (n=672)^[30]	Patients randomized (1∶1) to ribociclib versus placebo as first-line or second-line therapy	23.8 months vs 13 months (HR=0.55, 95% CI: 0.44-0.69, P<0.000 1)	58.7 months vs 48 months (HR=0.76, 95% CI: 0.61-0.96)
DAWNA-2 (n=456)^[31]	Patients randomized (2∶1) to Dalpiciclib versus placebo^b as first-line therapy	30.6 months vs 18.2 months (HR=0.51, 95% CI: 0.38-0.60, P<0.000 1)	The median OS has not yet matured