西德研究小组Ⅲ期临床研究报告：乳腺癌是否需要化疗？21基因检测告诉你

　　乳腺癌是女性最常见的恶性肿瘤之一，近年来以手术为主，放疗、化疗、靶向治疗、内分泌治疗为辅助的多学科综合治疗模式使乳腺癌的复发和病死率显著降低。

　　如果乳腺组织样本显示存在恶性肿瘤，医生的措施往往是手术，然后接受六个月药物治疗，以防止癌细胞扩散，其中就包括了化疗。化疗能够杀死残留癌细胞，但也有副作用，比如呕吐、脱发、疲劳，还有可能导致不孕不育以及一些器官受损。

　　乳腺癌患者害怕化疗，因为化疗副作用很多，比如身体不适、脱发，还可能造成肝肺和骨骼受损。研究表明，化疗对一些患者来说没有益处。

　　一种新的基因检测方法能够帮助医生知道哪些人不需要化疗。不用化疗意味着患者能够在手术后马上过上正常生活，只要定期去医院检查，确保无癌细胞即可。

　　这种被称为21基因检测（OncotypeDX）的新方法能够决定患者是否需要化疗。这种方法能够有效地告诉你：细胞内部运作，哪个特定基因变异诱发了哪种癌症。通过解读那些基因，医生能够知道，哪种肿瘤有可能会扩散到身体其他部位。

　　21基因检测（OncotypeDX）是几种基因检测方法之一，能够告诉医生癌症复发概率，这种方法在早期检测时准确率非常高。其他类似检测方法，如Prosigna和Endopredict，正在英国、德国和奥地利进行临床研究。OncotypeDX目前只适用于乳腺癌，但是对于其他癌症，可以研发类似检测方法。

　　雌激素受体阳性、HER2阴性早期乳腺癌是否需要辅助化疗通常根据TNM分期（肿块大小、淋巴结及其他器官转移情况）等情况综合判断。而基于乳腺癌基因表达谱分析发现乳腺癌具有高度异质性，甚至雌激素受体阳性、HER2阴性乳腺癌也可以分很多亚组。

　　21基因检测（OncotypeDX）利用简单的分子生物学方法，在患者乳腺癌病理切片上把上述各种因子作一综合分析，然后给出一个复发评分（RS）。这种检测方法已被临床证实可用于评估雌激素受体阳性、腋窝淋巴结阴性早期乳腺癌患者复发风险。

　　RS高的患者需要化疗，RS低的就不需要，RS位于中间的需要再进一步分析。然而，迄今为止，仅有很少的几项前瞻性研究结果评估OncotypeDX这一工具的有效性。

　　2016年2月29日，美国临床肿瘤学会（ASCO）官方期刊《临床肿瘤学杂志》（JCO）在线发表了西德研究小组的Ⅲ期临床研究报告：中心实验室和地方实验室病理学评估21基因RS检测与预后指标一致性的首项前瞻性结局数据。

　　在西德研究小组的Ⅲ期临床研究（PlanB）中，RS用来前瞻性确定一小部分只接受内分泌治疗患者的预后。这项回顾性研究来自中心实验室肿瘤数据库，2009～2011年期间一共入组3198例患者，中位年龄为56岁。其中41.1%患者淋巴结阳性，32.5%病变分级为3级。348例（15.3%）患者RS≤11分，未化疗。

　　中位随访35个月，RS≤11分仅接受内分泌治疗的患者3年无病生存率为98%，RS＞25分和12～25分、术后接受化疗的患者，无病生存率分别为92%和98%。

　　该前瞻性研究中，RS≤11分，临床风险大、未接受化疗的患者3年无病生存率较高。观察中传统预后指标与RS明显不一致，强调了对潜在标准化整合标准评估与支持的必要性，很好地证实了基因组检测如RS是有效的临床病理预后因素，可作为早期激素受体阳性乳腺癌化疗指征。

J Clin Oncol. 2016 Feb 29. [Epub ahead of print]

West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment.

Gluz O, Nitz UA, Christgen M, Kates RE, Shak S, Clemens M, Kraemer S, Aktas B, Kuemmel S, Reimer T, Kusche M, Heyl V, Lorenz-Salehi F, Just M, Hofmann D, Degenhardt T, Liedtke C, Svedman C, Wuerstlein R, Kreipe HH, Harbeck N.

West German Study Group; Evangelical Hospital Bethesda, Moenchengladbach; Medical School Hannover, Hannover; Mutterhaus der Borromäerinnen, Trier; University Clinics Cologne, Cologne; University Clinics Essen; Clinics Essen-Mitte, Essen; Clinics Suedstadt, Rostock; Marienhospital Aachen, Aachen; Asklepios Paulinen Clinics; Dr Horst-Schmidt Clinics, Wiesbaden; Oncologic Practice, Bielefeld; University of Munich, Munich; University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany; Genomic Health, Redwood City, CA.

PURPOSE: The 21-gene Recurrence Score (RS) assay is a validated prognostic/predictive tool in early hormone receptor-positive breast cancer (BC); however, only a few prospective outcome results have been available so far. In the phase III PlanB trial, RS was prospectively used to define a subset of patients who received only endocrine therapy. We present 3-year outcome data and concordance analysis (among biomarkers/RS).

PATIENTS AND METHODS: Central tumor bank was established prospectively from PlanB (intermediate and high-risk, locally human epidermal growth factor receptor 2-negative BC). After an early amendment, HR-positive, pN0-1 patients with RS ≤ 11 were recommended to omit chemotherapy.

RESULTS: From 2009 to 2011, PlanB enrolled 3,198 patients with a median age of 56 years; 41.1% had node-positive and 32.5% grade 3 disease. In 348 patients (15.3%), chemotherapy was omitted based on RS ≤ 11. After 35 months median follow-up, 3-year disease-free survival in patients with RS ≤ 11 and endocrine therapy alone was 98% versus 92% and 98% in RS > 25 and RS 12 to 25 in chemotherapy-treated patients, respectively. Nodal status, central and local grade, the Ki-67 protein encoded by the MKI67 gene, estrogen receptor, progesterone receptor, tumor size, and RS were univariate prognostic factors for disease-free survival; only nodal status, both central and local grade, and RS were independent multivariate factors. Histologic grade was discordant between central and local laboratories in 44%. RS was positively but moderately correlated with the Ki-67 protein encoded by the MKI67 gene and grade and negatively correlated with progesterone receptor and estrogen receptor.

CONCLUSION: In this prospective trial, patients with enhanced clinical risk and omitted chemotherapy on the basis of RS ≤ 11 had excellent 3-year survival. The substantial discordance observed between traditional prognostic markers and RS emphasizes the need for standardized assessment and supports the potential integration of standardized, well-validated genomic assays such as RS with clinicopathologic prognostic factors for chemotherapy indication in early hormone receptor-positive BC.

PMID: 26926676

PII: JCO635383

DOI: 10.1200/JCO.2015.63.5383