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目前，蒽环类（例如表柔比星、多柔比星、多柔比星脂质体）仍然是治疗乳腺癌的基本药物，被广泛用于治疗不同的乳腺癌，并且被作为早期乳腺癌手术前后的标准治疗药物。此外，蒽环类被推荐用于局部晚期或转移性乳腺癌。多柔比星常被用于美国，而表柔比星较多被用于欧洲。表柔比星与多柔比星相比，分子结构和治疗效果相似，毒性（尤其心脏毒性）可能较少。虽然有效的抗癌治疗越来越多，但是耐药仍然是导致治疗失败的主要问题。蒽环类的疗效似乎变化很大，缓解率为42%～79%。显然大部分患者对蒽环类治疗并未获得任何好处，但是仍然经历不良反应，此外延误了启动更有效的治疗。众所周知，当一线治疗失败时，二线治疗以及其他治疗获益变得更为困难。因此，有必要对乳腺癌的蒽环类疗效进行预测。丹麦赫斯霍尔姆医学预后研究所发明了一种基于细胞系和多基因信使核糖核酸（mRNA）的药物疗效预测法，根据药物相关遗传反应特征，将体外敏感性和基因表达，结合3000多例临床肿瘤标本的临床遗传信息，计算药物对特定肿瘤的可能疗效。 2018年8月11日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表丹麦哥本哈根大学海莱乌医院、哥本哈根大学王国医院、哥本哈根大学北西兰医院、罗斯基勒大学医院、奥尔堡大学医院、奥胡斯大学医院、西日德兰地区医院、瓦埃勒医院、南日德兰半岛医院、丹麦乳腺癌协作组、赫斯霍尔姆医学预后研究所的研究报告，评估了药物疗效预测法对于晚期乳腺癌表柔比星疗效的预测价值。 该丹麦乳腺癌协作组队列回顾前瞻单盲研究于1997年5月～2016年11月连续入组140例患者接受表柔比星治疗。患者知情同意后，从存档福尔马林固定石蜡包埋原发乳腺肿瘤组织分离mRNA，通过昂飞阵列进行分析。主要研究终点为治疗开始至疾病进展时间，根据药物疗效预测法，结合患者医疗记录回顾收集临床病理学数据，分析表柔比星的疗效。通过多因素比例风险回归模型按几线治疗进行统计学分析。 结果发现，治疗开始至疾病进展时间中位9.3个月，药物疗效预测法与进展时间显著相关（单侧P=0.03）。药物疗效预测法评分75%与25相比，进展时间分别为中位13个月、7个月，进展风险减少45%（风险比：0.55，单侧95%置信区间～0.93）。多因素比例风险回归模型分析表明，药物疗效预测法与年龄和转移数量无关。 因此，该研究前瞻验证了既往回顾分析证实药物疗效预测法对表柔比星疗效的预测能力，可使那些被预测为疗效不佳的患者较早选择有效替代药物，故有必要开展随机前瞻研究证明该方法能否显著改善总生存。 Breast Cancer Res Treat. 2018 Aug 11. Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study. Anna Sofie Kappel Buhl, Troels Dreier Christensen, Ib Jarle Christensen, Knud Mejer Nelausen, Eva Balslev, Ann Soegaard Knoop, Eva Harder Brix, Else Svensson, Vesna Glavicic, Adam Luczak, Sven Tyge Langkjer, Soren Linnet, Erik Hugger Jakobsen, Jurij Bogovic, Bent Ejlertsen, Annie Rasmussen, Anker Hansen, Steen Knudsen, Dorte Nielsen, Peter Buhl Jensen. Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Nordsjaellands Hospital, Copenhagen University Hospital, Hilleroed, Denmark; Zealand University Hospital, Roskilde, Naestved, Denmark; Aalborg University Hospital, Aalborg, Denmark; Aarhus University Hospital, Aarhus, Denmark; Regional Hospital West Jutland, Herning, Denmark; Vejle Sygehus, Vejle, Denmark; Hospital of Southern Jutland, Soenderborg, Denmark; The Danish Breast Cancer Cooperative Group, DBCG Secretariat, Rigshospitalet, Copenhagen, Denmark; Medical Prognosis Institute, Hoersholm, Denmark. PURPOSE: Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from >3000 clinical tumor samples. METHODS: From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients' medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line. RESULTS: Median TTP was 9.3 months. The DRP was significantly associated to TTP (P=0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI -0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases. CONCLUSION: The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival. KEYWORDS: Epirubicin Advanced breast cancer Precision medicine Predictive biomarker DOI: 10.1007/s10549-018-4918-4
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