中国晚期乳腺癌患者依维莫司相关肺炎

　　哺乳动物雷帕霉素靶蛋白mTOR是乳腺癌内分泌治疗耐药的重要靶点，mTOR抑制剂依维莫司联合雌激素芳香酶抑制剂可显著改善晚期乳腺癌内分泌治疗耐药患者的无进展生存。不过，依维莫司相关肺炎是令人担忧的药物不良事件之一，尤其对于亚洲患者。

　　2020年12月7日，美国转化肿瘤学会《肿瘤学家》在线发表复旦大学附属肿瘤医院龚成成、肖勤、李毅、顾雅佳、张剑、王磊苹、曹君、陶中华、赵燕南、胡夕春、王碧芸等学者的YOUNGBC-5研究报告，调查了中国晚期乳腺癌患者依维莫司相关肺炎的发生率、影像学特征、临床结局和风险因素，为指导依维莫司相关肺炎的早期诊断和有效治疗提供了循证依据。

NCT03730428 (YOUNGBC-5): Everolimus Related Pneumonitis in MBC (Drug-related Pneumonitis During mTOR Inhibitor Therapy in Patients With Metastatic Breast Cancer: A Radiographic Patternbased Approach)

　　该单中心回顾研究利用复旦大学附属肿瘤医院医疗电子数据库系统，对2013年6月～2017年6月依维莫司治疗晚期乳腺癌的86例患者基线数据和胸部CT随访数据进行回顾分析。由两位放射科医师对这些患者的CT扫描结果进行独立复核。通过对数秩检验和多因素比例风险回归模型，对依维莫司相关肺炎发生时间进行分析。

　　结果，其中45例（52.3%）通过影像学检查发现依维莫司相关肺炎。超过80%的肺炎发生于依维莫司治疗前4个月内。仅14例（31.1%）有症状。症状包括咳嗽、发热和呼吸急促。肺炎大多分布于双肺和下肺。大多数可见磨玻璃影和网状影。老年患者与年轻患者相比，依维莫司相关肺炎发生比例较高。

　　发生与未发生依维莫司相关肺炎的患者相比：

• 无进展生存显著较长：中位6.8比4.1个月（P=0.024）

• 总生存时间显著较长：中位42.8比21.3个月（P=0.016）

　　根据多因素比例风险回归模型，对年龄、是否绝经、是否肝转移、化疗方案等其他影响因素进行校正后，发生与未发生依维莫司相关肺炎的患者相比：

• 进展死亡风险低41%（风险比：0.59，95%置信区间：0.35～1.00，P=0.051）

• 全因死亡风险低51%（风险比，0.49，95%置信区间，0.25～0.97，P=0.040）

　　因此，该单中心小样本回顾研究结果表明，依维莫司治疗晚期乳腺癌患者超过半数可见依维莫司相关肺炎，超过八成发生于依维莫司治疗早期，仅不到三分之一有症状。发生与未发生依维莫司相关肺炎的患者相比，无进展生存和总生存较好，依维莫司相关肺炎或许可以成为晚期乳腺癌依维莫司疗效的预测指标之一，故有必要进一步开展多中心大样本回顾研究进行验证。密切监测、及时诊断、适当治疗依维莫司相关肺炎，对于维持患者生活质量、实现治疗获益最大化而言至关重要。

Oncologist. 2020 Dec 7. Online ahead of print.

Everolimus-Related Pneumonitis in Patients with Metastatic Breast Cancer: Incidence, Radiographic Patterns, and Relevance to Clinical Outcome.

Gong C, Xiao Q, Li Y, Gu Y, Zhang J, Wang L, Cao J, Tao Z, Zhao Y, Xie Y, Hu X, Wang B.

Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University, Shanghai, China.

Evidence-based guidelines for early diagnosis and effective treatment of everolimus-related pneumonitis are urgently needed. This article reports on incidence, radiograph findings, and risk factors for everolimus-related pneumonitis in patients with metastatic breast cancer.

BACKGROUND: This study investigated the incidence, radiographic patterns, and relevance to clinical outcome of everolimus-related pneumonitis (ERP) in patients with metastatic breast cancer (MBC).

MATERIALS AND METHODS: Data of patients with MBC treated with everolimus who had baseline and at least one follow-up chest computed tomography (CT) were obtained from a medical electronic database system. An independent review of the CT scans of these patients was conducted by two radiologists (NCT 03730428). Log-rank and Cox proportional hazard regression analyses were used for time-to-event analyses.

RESULTS: ERP was radiographically detected in 45 of 86 patients (52.3%). In more than 80% of these patients, ERP occurred during the first 4 months of everolimus treatment. Only 14 of the 45 patients with ERP were symptomatic (31.1%). Symptoms included cough, fever, and shortness of breath. Bilateral and lower distribution of the pneumonitis was most common. In most of the cases, ground-glass opacities and reticular opacities were noticed. Elderly patients were more likely to develop ERP. Patients with ERP had significantly longer progression-free survival (PFS; 6.8 vs. 4.1 months, p = .024) and overall survival (OS; 42.8 vs. 21.3 months, p = .016). ERP was a predictor of OS improvement confirmed by multivariate Cox analysis (hazard ratio, 0.49; 95% confidence interval, 0.25-0.97; p = .040).

CONCLUSIONS: ERP was noted in half of the patients with MBC treated with everolimus. Our data suggested that ERP was associated with improved prognosis and may be used as a biomarker for the efficacy of everolimus in MBC. Close monitoring, prompt diagnosis, and proper treatment for ERP are essential to maintain the quality of life of patients and achieve maximum treatment benefits.

IMPLICATIONS FOR PRACTICE: Everolimus-related pneumonitis (ERP) is one of the most worrying drug adverse events, especially in Asian patients. However, little has been known about the clinical and radiographic details of ERP in patients with metastatic breast cancers (MBCs) treated with everolimus. The present study investigated the clinical characteristics, radiographic patterns, and its correlation with treatment outcome in patients with MBC. ERP was identified in more than half of patients with MBC during everolimus therapy and was associated with improved outcome. Close monitoring and prompt diagnosis and appropriate treatment for ERP are critical for the preservation of patients' quality of life and achievement of maximal treatment benefits.

KEYWORDS: Metastatic breast cancer; mTOR inhibitor; Everolimus; Pneumonitis; Drug toxicity

PMID: 33191524

DOI: 10.1002/onco.13594