A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.
A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.
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DOI：
10.1016/s1470-2045(20)30450-2
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发表时间：
2020-11
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通讯作者：
Conte P
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作者：
Prat A;Guarneri V;Paré L;Griguolo G;Pascual T;Dieci MV;Chic N;González-Farré B;Frassoldati A;Sanfeliu E;Cejalvo JM;Muñoz M;Bisagni G;Brasó-Maristany F;Urso L;Vidal M;Brandes AA;Adamo B;Musolino A;Miglietta F;Conte B;Oliveira M;Saura C;Pernas S;Alarcón J;Llombart-Cussac A;Cortés J;Manso L;López R;Ciruelos E;Schettini F;Villagrasa P;Carey LA;Perou CM;Piacentini F;D'Amico R;Tagliafico E;Parker JS;Conte P
在早期HER 2阳性（HER 2+）乳腺癌中，全身治疗的升级或降级是一个有争议的话题。作为治疗决策的辅助手段，我们提出了一种预后分析，该分析整合了多种数据类型，用于预测新诊断的HER 2+乳腺癌的生存结局。临床病理学数据、间质肿瘤浸润淋巴细胞（TIL）、PAM 50亚型和55种基因的表达来自435名参与Short-HER III期试验的患者（34.7%），该试验随机分配了新诊断的淋巴结阳性HER 2+乳腺癌患者，或者如果淋巴结阴性，则至少有一种风险因素（肿瘤大小> 2.0 cm，组织学分级3级，淋巴-血管浸润，Ki-67> 20%，年龄≤35岁，或激素受体阴性），与辅助蒽环类/紫杉烷类药物联合曲妥珠单抗治疗9周或1年。曲妥珠单抗静脉给药，每3周一次（第一周期负荷剂量为8 mg/kg，此后为6 mg/kg），持续18次，或每周一次（第一周负荷剂量为4 mg/kg，此后为2 mg/kg），持续9周，与首次紫杉烷给药同时开始。本研究的主要目的是推导和评价与无远处转移生存率（DMFS）相关的综合评分。将训练数据集中的患者样本分为训练集（n=290）和测试集（n=145），平衡事件和治疗组。训练集进一步分层为100次蒙特-卡罗交叉验证（MCCV）迭代。使用Elastic-Net将考克斯比例风险模型拟合至MCCV训练样本。最多评价了92个特征。在267例接受不同新辅助和辅助抗HER 2联合治疗的早期HER 2+乳腺癌患者的独立组合数据集中评价了最终预后模型，并提供了无病生存期（DFS）结局数据。在Short-HER中，肿瘤分期（T1与静息）、淋巴结分期（N 0与静息）、TIL（连续变量）、亚型（HER 2富集和基底样与静息）和13个基因组成了最终模型（HER 2DX）。HER 2DX作为连续变量与DMFS显著相关（p<0.001）。两个临界值定义了低风险（50%），中等风险（25%）和高风险（25%）人群。低、中和高风险人群的5年DMFS分别为98.1%（95%CI 96.3 - 99.9）、88.9%（83.2 - 95.0）和73.9%（66.0 - 82.7）（低风险与高风险的风险比[HR]= 0.04，0.0 - 0.1，p<0.0001）。在评价队列中，HER 2DX作为连续变量（HR= 2.77，1.4 - 5.6，p= 0.0040）和组分类（低风险vs.高风险HR= 0.27，0.1 - 0.7，p= 0.010）与DFS显著相关。HER 2DX低风险组的5年和8年DFS分别为93.5%（89.0 - 98.3%）和91.7%（86.2 - 97.6%）。HER 2DX可识别早期HER 2+乳腺癌候选患者，以进行升级或降级的全身治疗。HER 2DX的未来临床验证似乎是必要的。卡洛斯三世健康研究所、拯救母亲研究所、Pas a Pas研究所、AECC研究所、SEOM研究所、NIH研究所、意大利药物研究所、IARC研究所和韦内托肿瘤研究所。
In early-stage HER2-positive (HER2+) breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we present a prognostic assay that integrates multiple data types for predicting survival outcome in newly diagnosed HER2+ breast cancer. Clinicopathological data, stromal tumour infiltrating-lymphocytes (TILs), PAM50 subtypes and expression of 55 genes were obtained from 435 patients (34·7%) who participated in the Short-HER phase III trial, which randomised patients with newly diagnosed node-positive HER2+ breast cancer or, if node negative, with at least one risk factor (tumour size > 2·0 cm, histological grade 3, lympho-vascular invasion, Ki-67>20%, age ≤35 years, or hormone receptor negativity), to adjuvant anthracycline/taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose at first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. The primary objective of this study was to derive and evaluate a combined score associated with distant metastasis-free survival (DMFS). Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment arm. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were evaluated. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2+ breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and disease-free survival (DFS) outcome data. In Short-HER, tumour stage (T1 vs. rest), nodal stage (N0 vs. rest), TILs (continuous variable), subtype (HER2-enriched and Basal-like vs. rest) and 13 genes composed the final model (HER2DX). HER2DX was significantly associated with DMFS as a continuous variable (p<0·001). Two cut-offs defined low-risk (50%), med-risk (25%) and high-risk (25%) populations. The 5-year DMFS of the low-, med- and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0) and 73·9% (66·0–82·7), respectively (hazard ratio [HR] low- vs. high-risk=0·04, 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with DFS as a continuous variable (HR=2·77, 1·4–5·6, p=0·0040) and as group categories (low- vs. high-risk HR=0·27, 0·1–0·7, p=0·010). The 5- and 8-year DFS of the HER2DX low-risk group was 93·5% (89·0–98·3%) and 91·7% (86·2–97·6%), respectively. HER2DX identifies patients with early-stage HER2+ breast cancer candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted. Instituto Salud Carlos III, Save the Mama, Pas a Pas, AECC, SEOM, NIH, Agenzia Italiana del Farmaco, IARC and Veneto Institute of Oncology.