老年三阴性乳腺癌患者的临床困境和系统治疗策略

doi:10.19401/j.cnki.1007-3639.2023.05.011

摘要/Abstract

摘要：

三阴性乳腺癌（triple-negative breast cancer，TNBC）缺乏明确的生物标志物，现有治疗手段以化疗为主，疗效有限且不良反应大。10% ~ 21%的TNBC为老年患者，多伴随心、脑、肾疾病等诸多慢性合并症，对化疗耐受性差，是临床诊疗实践的一大难题。同时，专门针对老年TNBC患者的临床研究较少，导致这部分患者的安全及合理用药缺乏充足的循证医学证据，在疾病诊疗方面存在很多难点和争议。此外，老年TNBC有其特征，非肿瘤因素所致死亡率较高。因此，患者生存获益与生活质量及耐受性之间的平衡尤为重要。本文主要针对老年TNBC的流行病学、疾病生物学行为及特征、诊疗现状及未被满足的治疗需求等进行总结分析，并初步探索新型抗体药物偶联物（antibody-drug conjugate，ADC）在老年TNBC中的获益，以期为老年TNBC系统治疗策略的选择提供参考。

关键词: 三阴性乳腺癌, 老年患者, 系统治疗, 抗体药物偶联物

Abstract:

There is no specific biomarker for triple-negative breast cancer (TNBC), and chemotherapy remains as backbone but with limited efficacy and more side effects. 10%-21% TNBC are elderly patients with high prevalence of concomitant cardio-cerebrovascular and renal complications, which may lead to intolerance of chemotherapy. How to properly treat these elderly TNBC patients becomes a big challenge during daily clinical practice. To date, few clinical trials specifically focus on elderly TNBC patients, thus no enough evidence-based safety and efficacy data are provided to support the proper therapy to this population. There are also challenges and controversies in the diagnosis and treatment. Elderly TNBC patients have special age-related disease characteristics and high non-cancer related mortality. Therefore, it is very important to balance survival benefit and quality of life during the treatment. This paper summarized data of the epidemiology, tumor biological behavior, current diagnosis and treatment status and the huge unmet medical needs of elderly TNBC patients, and explored the benefits of novel antibody-drug conjugate (ADC), to provide certain guidance on systemic treatment strategies for elderly TNBC patients.

Key words: Triple-negative breast cancer, Elderly patients, Systemic treatment, Antibody-drug conjugate

中图分类号:

R737.9

陈君瑶, 张文涛, 刘巧, 聂建云. 老年三阴性乳腺癌患者的临床困境和系统治疗策略[J]. 中国癌症杂志, 2023, 33(5): 506-516.

CHEN Junyao, ZHANG Wentao, LIU Qiao, NIE Jianyun. Clinical dilemma and systemic treatment strategy of triple-negative breast cancer in the elderly[J]. China Oncology, 2023, 33(5): 506-516.

图/表 2

表1

晚期TNBC治疗相关研究汇总"

Study	Regimen	Line of therapy	Elderly patient n (%)	Primary endpoint result	TEAE (grade≥3)/%
CALG-B^[32]	Paclitaxel	≥1	≥65 years old: 272/1 048 (26%)	Objective response: 1st is 37% (95% CI: 33%-41%); 2nd is 24% (95% CI: 20%-29%)	Leucocytopenia (P=0.009 9), neutropenia (P=0.022), anorexia (P=0.028), increased bilirubin (P=0.003 5), neurotoxicity (P<0.000 1)
EMBRACE^[33][NCT00388726]	Eribulin vs TPC	≥2	Median age: 55 years old (27-85 years old)	OS: 13.1 months vs 10.6 months (HR=0.81,95% CI: 0.66-0.99, P=0.041); PFS: 3.7 months vs 2.2 months (HR=0.87, 95% CI: 0.71-1.05, P=0.137)	Neutropenia (45% vs 21%), leucopenia (14% vs 6%), asthenia/fatigue (9% vs 10%), peripheral neuropathy (8% vs 2%)
LOTUS^[34][NCT02162719]	Ipatasertib + paclitaxel vs placebo + paclitaxel	1	≥50 years old: 51/124 (41%)	PFS: 6.2 months vs 4.9 months (HR=0.60, 95% CI: 0.37-0.98, P=0.037)	54% vs 42%
IMpassion130^[35][NCT02425891]	Atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel	1	≥65 years old: 219/902 (24%)	PD-L1 + (immune cell expression≥1%) PFS: 7.5 months vs 5.3 months (HR=0.63, 95% CI: 0.50-0.80, P<0.000 1); PD-L1 + (immune cell expression≥1%) OS：25.4 months vs 17.9 months (HR=0.67, 95% CI: 0.53-0.86)	49% vs 43%
IMpassion131^[36][NCT03125902]	Atezolizumab + paclitaxel vs placebo + paclitaxel	1		PD-L1 + (immune cell expression≥1%) PFS: 6.0 months vs 5.7 months (HR=0.82, 95% CI: 0.60-1.12, P=0.20); PD-L1 + (immune cell expression≥1%) OS: 22.1 months vs 28.3 months (HR=1.11, 95% CI: 0.76-1.64)	53% vs 46%
KEYNOTE-355^[37][NCT02819518]	Pembrolizumab + TPC vs placebo + TPC	1	≥65 years old: 180/847 (21%)	PD-L1 + (combined positive score≥10) PFS: 9.7 months vs 5.6 months (HR=0.65, 95% CI: 0.49-0.86, P=0.001 2); PD-L1 + (combined positive score≥10) OS: 23.0 months vs 16.1 months (HR=0.73, 95% CI: 0.55-0.95, P=0.009 3)	68% vs 67%
OlympiAD^[38][NCT02000622]	Olaparib vs TPC	1-3	≥65 years old: 15/302 (5%)	TNBC PFS: 5.6 months vs 2.9 months (HR=0.43, 95% CI: 0.29-0.63); TNBC OS: 17.4 months vs 14.9 months (HR=0.93, 95% CI: 0.62-1.43)	38% vs 49.5%
EMBRACA^[39][NCT01945775]	Talazoparib vs TPC	1-4	≥65 years old: 37/431 (8%)	TNBC PFS: 5.8 months vs 2.9 months (HR=0.60, 95% CI: 0.41-0.87, P=0.075); OS:19.3 months vs 19.5 months (Whole population: HR=0.848, 95% CI: 0.55-1.06, P=0.17; TNBC: HR=0.899, 95% CI: 0.63-1.28)	55% vs 38%

表1

表2

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Regimen	Line of therapy	elderly patients n (%)	Primary endpoint result	TEAE (grade≥3)/%
SG vs TPC^[56,60][NCT02574455]	3	≥65 years old: 44/235 (19%)	ORR: 35% vs 5%; (Elderly subgroup: 50% vs 0%）; PFS: 5.6 months vs 1.7 months (HR=0.39, 95% CI: 0.31-0.49, P<0.001); Elderly subgroup: 7.1 months vs 2.4 months (HR=0.22, 95% CI: 0.12-0.40); OS: 12.1 months vs 6.7 months (HR=0.48, 95% CI: 0.38-0.59, P<0.001); Elderly subgroup: 15.3 months vs 8.2 months (HR=0.37, 95% CI: 0.22-0.64)	64% vs 47%
T-DXd (DS-8201)^[61][NCT02564900]	7.5	Elderly proportion currently unknown, 7 (HER2 low-TNBC)	ORR: 14.3%	63% (neutropenia, interstitial pneumonia)
T-DXd (DS-8201)^[62][NCT04132960]	5	Elderly proportion currently unknown, 15 (HER2 low-TNBC)	ORR: 40%; PFS: 3.5 months; OS: 6.6 months
T-DXd (DS-8201) vs TPC^[50][NCT03734029]	3	Elderly proportion currently unknown, 40 (HER2 low-TNBC)	ORR: 50% vs 16.7%; PFS: 8.5 months vs 1.9 months （HR=0.46, 95% CI: 0.24-0.89); OS: 18.2 months vs 8.3 months (HR=0.48, 95% CI: 0.24~0.95)	52.6% vs 67.4% (fatal adverse events: pneumonia [2 patients (0.5%)] and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, and sepsis [1 patient each (0.3%)]
DS-1062^[58][NCT03401385]	3	Elderly proportion currently unknown, 44	ORR: 34%	45% (neutropenia, stomatitis)
RC-48^[59][NCT02881138, NCT03052634]	≥3 (25%)	Elderly proportion currently unknown, 2 (HER2 low-TNBC)	ORR: 39.6% (HER2 low, include HR+, TNBC); PFS: 5.7 months (HER2 low, include HR+，TNBC)	45.8% (neutropenia, hepatotoxicity, neurotoxicity)