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Whether Elderly Patients with Her-2 Positive Breast Cancer but Without Heart Disease Should Receive Targeted Therapy?
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摘要: 随着我国人口老龄化，乳腺癌治疗需要面对更多的老年患者。近年来，靶向治疗作为人表皮生长因子受体2(human epidermal growth factor receptor 2，HER-2)阳性乳腺癌全身治疗的重要方法，在乳腺癌治疗中的地位越来越重要。无心脏基础疾病的老年HER-2阳性乳腺癌患者是否应使用曲妥珠单克隆抗体进行靶向治疗存在争议。目前证据表明，60~70岁老年HER-2阳性乳腺癌患者可从曲妥珠单克隆抗体治疗中获益，心脏事件风险较低且可逆，但70岁以上患者目前无大规模试验证据支持。在选择辅助治疗方案时需平衡获益与风险，综合考虑患者本人意愿和身体状况，进行个体化治疗。若治疗选择曲妥珠单克隆抗体，需避免与蒽环类化疗药物联用并监测心功能，及时发现和处理心脏事件。Abstract: With a nationwide increase in elderly population, an increased number of breast cancer diagnosed in older women is expected. Nowadays, targeted therapy is an important systemic treatment for human epidermal growth factor 2 (HER-2) positive breast cancer, which has been playing an important role in the treatment for breast cancer. It is controversial whether trastuzumab should be used for targeted therapy in elderly Her-2 positive breast cancer patients with moderate risk and no cardiac disease. Current evidence suggests that patients aged 60-70 years old with a moderate risk of Her-2 positive breast cancer may benefit from trastuzumab with an acceptable and reversible risk of heart events. Yet there is no enough evidence for elderly patients beyond 70 years old. Therefore, we should balance the benefit and risk when considering targeted therapy for elderly patients with breast cancer. Management of breast cancer in the elderly should take the will of the patients, the physical condition, and comorbidities in to consideration. Anthracycline-based chemotherapy should not be used together with targeted therapy. It is necessary to monitor cardiac function and deal with heart events timely.
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Keywords:
- old women /
- breast cancer /
- targeted therapy
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乳腺癌是全世界女性最常见的恶性肿瘤，每年新增患者168万例，占女性年新增癌症患者的20%[1]。目前乳腺癌的平均发病年龄为61岁，70岁以上老年人占发病总人数的30%[2]。伴随人口老龄化，乳腺癌治疗将面对更多的老年患者[3-4]。近年来，靶向治疗作为人表皮生长因子受体2(human epidermal growth factor receptor 2，HER-2)阳性乳腺癌全身治疗的重要方法，显示出越来越重要的地位。乳腺癌靶向治疗的最大优势即利用肿瘤细胞表达、正常细胞很少或不表达的特定基因或基因产物，形成相对或绝对靶点，最大程度杀灭肿瘤细胞，并减轻不良反应。但由于心血管系统的部分细胞表达与肿瘤细胞靶向治疗药物存在某些相同抗原，靶向治疗药物在杀灭肿瘤细胞的同时，亦对患者心血管系统造成损伤。美国国家综合癌症网络(National Comprehensive Cancer Network，NCCN)指南明确指出，在使用曲妥珠单克隆抗体治疗时需平衡其心脏毒性，并避免其与蒽环类药物同时使用[5]。临床研究表明，既往有高血压及冠状动脉硬化性心脏病史的患者在使用曲妥珠单克隆抗体治疗时，心脏事件出现的风险明显高于无心血管疾病患者，此类患者的治疗需慎用曲妥珠单克隆抗体[6]。在无心血管基础疾病的老年乳腺癌患者中，是否可应用曲妥珠单克隆抗体进行靶向治疗目前尚无定论，故本文将对这一问题进行深入探讨。
1. 老年乳腺癌患者特点
随着全球老龄化，世界卫生组织预测，2015至2050年间，全世界老年人口将成倍增长，由12%达到22%[7]。老年乳腺癌患者具有其独特的特点，如身体机能退化，合并高血压、糖尿病等全身基础疾病，治疗依从性差等，这些特点必将会影响乳腺癌治疗的选择和预后，同时也对乳腺癌个体化治疗提出新的挑战[8]。
与年轻乳腺癌患者相比，老年乳腺癌患者的分型更倾向于雌孕激素受体阳性、合并或不合并HER-2阳性[9]。文献报道，肿瘤大小及淋巴结受累的概率均随着年龄增加而降低，这提示老年患者的肿瘤可能存在不同表现[10]，70岁以上老年人的预后明显优于40~70岁乳腺癌患者[11-13]。但由于老年人经常被排除在临床试验之外，目前老年人治疗选择的证据通常来自年轻人群临床试验结果[14-17]，这使老年乳腺癌患者进行精准治疗困难加大，同时也是老年乳腺癌患者是否应进行曲妥珠单克隆抗体治疗存在争议的主要原因。
2. 老年Her-2阳性乳腺癌患者使用曲妥珠单克隆抗体治疗的适应证
部分研究认为，老年Her-2阳性乳腺癌患者应进行曲妥珠单克隆抗体靶向治疗。在St.Gallen共识中，无淋巴结转移的HER-2阳性乳腺癌患者属于中度风险患者[18]，其使用曲妥珠单克隆抗体治疗具有充足的证据。4项有关Her-2阳性乳腺癌的关键临床研究(HERA、B006、N9831、B31， > 12 000例患者)得出的结论相一致，即曲妥珠单克隆抗体的应用明显改善了患者的总生存率(overall survival，OS)和无病生存率(disease-free survival，DFS)。这4项研究同时确立了18周期(1年)辅助曲妥珠单克隆抗体治疗作为HER-2阳性早期乳腺癌标准治疗的地位[19-22]。在HERA试验和N9831试验延长时间的随访分析中，分别在11年后及8.4年后仍可看到DFS及OS获益[23-24]。在疗效方面，B31试验和N9831试验中接受曲妥珠单克隆抗体治疗的60岁以上老年人在OS(HR=0.51, 95% CI：0.37~0.69)及DFS(HR=0.63, 95% CI：0.49~0.82)方面的获益与总体人群一致[22]。HERA研究的11年随访结果亦显示，60岁以上老年人在曲妥珠单克隆抗体治疗中的获益与总体人群获益趋势相一致(HR=0.82，95% CI：0.62~1.08)[21]。一项纳入HERA试验、N9831试验及B31试验的荟萃分析显示，60岁及以上患者可从曲妥珠单克隆抗体治疗中获益(pooled HR=0.53，95% CI：0.36~0.77)[25]。
然而另一方面，由于上述4项关于HER-2阳性乳腺癌的研究均除外了70岁以上老年人，故对于70岁以上老年人是否适用这4项研究结果，仍存在争议。HERA研究中虽然提示60岁以上老年人对曲妥珠单克隆抗体治疗的获益与总体人群的获益趋势一致(HR=0.82，95% CI：0.62~1.08)，但由于该试验在入组时并未对年龄进行预设分层，故在对年龄因素进行回顾性分析时，统计学意义方面存在欠缺[23]。鉴于目前研究，60~70岁老年HER-2阳性乳腺癌患者可从曲妥珠单克隆抗体治疗中获益，但对于70岁以上老年患者，尚无足够的证据支持。
3. 老年Her-2阳性乳腺癌使用靶向治疗的风险
有学者认为，虽然曲妥珠单克隆抗体体联合化疗时的心脏毒性不容忽视，但其所造成的心脏毒性称为Ⅱ型化疗相关心脏功能障碍，与Ⅰ型功能障碍相比，最显著的区别是其所造成的心脏功能损害可逆[26-27]。研究数据表明，化疗联合曲妥珠单克隆抗体治疗所造成的严重心脏损害出现概率不高，且多可在治疗结束后恢复。B006试验中，在应用化疗联合曲妥珠单克隆抗体治疗的患者中可观察到左心室射血分数下降，但下降的幅度在安全范围内，且在治疗结束后可以恢复[21]。HERA研究显示，患者接受曲妥珠单克隆抗体治疗后，在2年治疗组及1年治疗组中分别有9.4%和5.2%的患者出现心脏不良事件，但前者中87.2%的患者在中位时间7.2个月即可恢复，后者中79.5%的患者在中位时间6.6个月即可恢复[26]。需要指出的是，有心脏风险的患者并未包括在这项研究中。NSABP-B31研究结果显示，7年随访中试验组4%的患者出现心脏事件，而对照组则为1.3%[27]。但大部分患者在结束曲妥珠单克隆抗体治疗后可恢复至正常水平。该研究对部分使用曲妥珠单克隆抗体的患者进行了心内膜活检，并未发现明显异常改变[27]。其他研究显示，曲妥珠单克隆抗体用于辅助治疗时，出现严重心力衰竭的发生率为1%~4%[28]。在一项纳入9535例66岁以上乳腺癌患者的多中心观察性研究中，23%的患者使用了曲妥珠单克隆抗体，与未使用者相比，出现心脏事件的比例更高(P < 0.01)，该研究的多因素分析显示，心脏事件多发生于年龄 > 80岁、曲妥珠单克隆抗体周疗、既往有高血压/冠状动脉硬化性心脏病史的患者。无心脏基础疾病的老年患者风险相对较低[6]。Dall等[29]在2006至2012年间，对339个研究机构中的3940例HER-2阳性乳腺癌患者进行了前瞻性观察，507例患者为65~69岁，另507例患者年龄≥70岁；所有患者均接受化疗联合曲妥珠单克隆抗体治疗，并每年进行随访，结果显示曲妥珠单克隆抗体具有良好的心脏耐受性，心脏事件可预测且可管理。在紫杉醇联合曲妥珠单克隆抗体辅助治疗淋巴结阴性、HER-2阳性乳腺癌前瞻性单臂试验中，34%的患者为60岁以上老年患者，仅2例出现有症状的充血性心力衰竭，且在终止曲妥珠单克隆抗体治疗后左心室射血分数可恢复，表明正常患者出现心脏事件的风险较低[30]。综合以上研究，应用曲妥珠单克隆抗体治疗，特别是联合化疗方案存在心脏毒性，但风险在可接受范围内。
另有学者认为，无心脏基础疾病的老年乳腺癌患者使用曲妥珠单克隆抗体的安全性目前证据尚有限。上述的一项多中心观察性研究中，尽管分析显示心脏事件多发生于年龄 > 80岁、曲妥珠单克隆抗体周疗、既往有高血压/冠状动脉硬化性心脏病史的患者，无心脏基础疾病的老年患者风险相对较低，但仍高于未使用曲妥珠单克隆抗体的患者[6]。靶向药物联合化疗药物特别是蒽环类药物时，心脏事件发生风险明显增加。2011年，Slamon等[19]的一项蒽环类药物联合曲妥珠单克隆抗体治疗晚期乳腺癌患者的研究中，两者联合应用可延缓疾病进展，降低患者1年病死率，但在143例接受蒽环类联合曲妥珠单克隆抗体治疗的患者中，27%出现了美国国立癌症研究所通用毒性标准Ⅲ或Ⅳ级心脏毒性。另一项纳入47 806例65岁以上老年乳腺癌患者的研究中，蒽环类联合曲妥珠单克隆抗体治疗的患者，第一年充血性心力衰竭累积发病率为5.5%，5年充血性心力衰竭累积发病率为15.5 %；与未进行化疗及靶向治疗的患者相比，充血性心力衰竭发生风险明显增加(HR=1.19, 95% CI：1.05~1.34)[31]。故在老年乳腺癌辅助治疗中应避免蒽环类药物与曲妥珠单克隆抗体联合应用。
4. 小结
2012年国际老年肿瘤协会、欧洲乳腺癌协会共识指出，无心脏基础疾病的中风险老年乳腺癌患者应接受曲妥珠单克隆抗体治疗[10]。2017年St.Gallen专家共识也指出，对于老年乳腺癌患者，年龄并非治疗方案的决定性因素。患者的个体因素、既往疾病、预期寿命以及患者意愿均是是否进行靶向治疗的关键因素，治疗时间目前尚未明确。目前证据表明，曲妥珠单克隆抗体在老年患者中具有良好的心脏耐受性[32]。2018年NCCN指南进行了更新，推荐使用紫衫类或紫衫类联合环磷酰胺的化疗方案与紫衫类+曲妥珠单克隆抗体或紫杉类+环磷酰胺+曲妥珠单克隆抗体联合方案为相对低风险HER-2阳性乳腺癌患者辅助治疗方案，避免与蒽环类药物联用，可降低心脏事件的发生风险[5]。
综上，HER-2阳性老年乳腺癌患者术后辅助治疗是否应用曲妥珠单克隆抗体目前尚无定论，当前证据表明，60~70岁老年HER-2阳性乳腺癌患者可从曲妥珠单克隆抗体治疗中获益，心脏事件风险较低且可逆，70岁以上患者尚无大规模试验证据支持。选择辅助治疗方案时需平衡获益与风险，综合考虑患者本人意愿和身体状况进行个体化治疗，若选择应用曲妥珠单克隆抗体，需避免与蒽环类化疗药物联用并监测心功能，及时发现和处理心脏事件。
利益冲突 无 -
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1. 王禾，方琦，王秀. TCbHP在老年HER-2阳性乳腺癌患者新辅助化疗中的应用效果. 中外医学研究. 2024(18): 129-132 . 
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