West German Study Group, Moenchengladbach; Breast Center Niederrhein, Ev. Bethesda Hospital, Moenchengladbach.
West German Study Group, Moenchengladbach; Women's Clinic, University Clinics Schleswig-Holstein, Luebeck.
Ann Oncol. 2016 Jun;27(6):1035-1040. doi: 10.1093/annonc/mdw070. Epub 2016 Feb 18.
Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC).
In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459).
Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients.
In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone.
The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.
早期、中危乳腺癌（BC）的潜在预后和预测标志物包括组织学分级、Ki-67、基因组特征，如基因组分级指数（GGI）和固有亚型。它们在激素受体（HR：ER 和/或 PR）阳性/HER2- BC 中的预后/预测作用存在争议。WSG-AGO EC-Doc 研究表明，在接受表柔比星/环磷酰胺-多西他赛（EC-Doc）治疗的 1-3 个阳性淋巴结的患者中，无事件生存（EFS）优于 5-氟尿嘧啶/表柔比星/环磷酰胺（FEC）。
在代表性试验亚组中，我们量化了用于临床化疗指征的因素之间的一致性。我们研究了中心组织学（n=772）、内在分型和 IHC4 的免疫组织化学以及二分类（GG）或连续（GGI）基因组分级（n=472）对患者结局和 taxane 化疗获益的影响，重点关注 HR+/HER2-患者（n=459）。
局部分级（LG）与中心（CG）或基因组分级的一致性中等。在 HR+/HER2-患者中，低（GG-1：16%）、不确定（GG-EQ：17%）和高（GG-3：67%）GG 分别与各自的 5 年 EFS 为 100%、93%和 85%相关。在所有 LG 亚组和 CG3 中，GGI 是 EFS 的预后因素，而 IHC4 仅在 CG3 肿瘤中具有预后作用。在未选择和 HR+/HER2-患者中，CG3 和 luminal-A 样亚型进入多变量 EFS 模型，但 IHC4 或 GG 未进入。在整个人群中，连续 GGI 进入模型[第 75 百分位与第 25 百分位的危险比（HR）为 2.79；P=0.01]，取代 luminal-A 样亚型；在 HR+/HER2-（HR=5.36；P<0.001）中，GGI 是唯一剩余的预后因素。在多变量交互分析（包括中心和基因组分级）中，luminal-B 样亚型[HR+和（Ki-67≥20%或 HER2+）]对 EC-Doc 与 FEC 的获益具有预测作用，但在 HR+/HER2-患者中无预测作用。
在 WSG-AGO EC-Doc 中间风险 BC 试验中，CG、内在亚型（通过 IHC）和 GG 提供预后信息。连续 GGI（而非 IHC4）提供了预后信息，即使 IHC 亚型和 CG 可用。最后，组织学分级的观察者间变异性高，Ki-67 仍未得到验证，因此不能仅基于这些单一因素来指示或避免辅助化疗。
WSG-AGO/EC-Doc 试验在 ClinicalTrials.gov 上注册，编号为 NCT02115204。
