九周？一年？乳腺癌术后靶向治疗选择
对于HER2阳性早期乳腺癌，术后曲妥珠单抗标准疗程长达1年。根据有效性、安全性、经济性，能否将1年缩短至9周，目前仍然存在较大争议。意大利随机对照试验Short-HER对HER2阳性早期乳腺癌术后辅助化疗联合9周与1年曲妥珠单抗的效果进行比较，结果未能表明9周曲妥珠单抗的非劣效性。不过，9周给药可以减少严重心脏毒性风险，并且可以作为治疗期间有心脏事件患者和复发风险较低患者的选择。那么，乳腺癌术后曲妥珠单抗疗程应该如何选择？
2020年11月，英国《柳叶刀》肿瘤学分册正式发表西班牙乳腺癌研究协作组、巴塞罗那医院、奥古斯特·皮·苏尼尔生物医学研究所、巴塞罗那大学、巴伦西亚大学、希伯伦谷肿瘤研究所、加泰罗尼亚医学研究所、巴利亚利群岛大学医院、阿纳尔德斯·维拉诺瓦医院、巴塞罗纳肿瘤研究所、马德里大学、圣地亚哥德孔波斯特拉大学、意大利帕多瓦大学、威尼托肿瘤研究所、费拉拉大学圣安娜医院、雷焦艾米利亚医院、博洛尼亚医院、帕尔马大学医院、圣马蒂诺综合医院、那不勒斯腓特烈二世大学、摩德纳大学、美国北卡罗来纳大学的研究报告，开发出结合多种数据的预后定量评分方法HER2DX，可预测新诊断HER2阳性乳腺癌患者的生存结局，有助于决定术后靶向治疗能否缩短。
该研究对Short-HER入组患者的临床病理数据进行回顾，结合间质肿瘤浸润淋巴细胞、50基因（PAM50）亚型、55基因表达，建立预后模型。Short-HER入组患者共1254例，为新诊断HER2阳性乳腺癌淋巴结阳性或淋巴结阴性但是存在至少一种风险因素（例如肿瘤大小>2厘米、组织学3级、淋巴血管浸润、Ki67>20%、年龄≤35岁、激素受体阴性），术后给予蒽环类和紫杉类联合化疗，并随机分为两组，接受9周或1年的曲妥珠单抗治疗。1年曲妥珠单抗用法为静脉注射，首次8mg/kg，随后每3周6mg/kg，共18次；9周曲妥珠单抗用法为静脉注射，首次4mg/kg，随后每周2mg/kg，共9次；都从首次紫杉类化疗开始。中位随访91.4个月（四分位75.1～105.6）。主要终点为无远处转移生存（随机分组至远处复发或复发前死亡的时间），探索性终点为无远处转移生存相关预后评分。将435例（35%）建模数据集患者样本分为训练集（演算组）290例和检验集（验算组）145例，两组患者的复发或死亡事件和治疗方案分布平衡。对训练集进一步分层，进行蒙特卡洛交叉验证。通过多因素比例风险回归模型对建模样本进行分析。对多达92个特征进行评定。利用来自其他4项研究（PAMELA、CHER-LOB、Hospital Clinic、Padova）267例HER2阳性早期乳腺癌不同术前和术后HER2靶向治疗患者独立数据集，对最终预后模型进行评估。
结果，组成最终模型（HER2DX）的17项指标包括：
肿瘤大小（T1与其余相比）
淋巴结分期（N0与其余相比）
肿瘤浸润淋巴细胞数量（连续变量）
分子亚型（HER2高表达、基底样与其余相比）
13个基因（包括CDC6、EXO1、RRM2、TMEM45B、FGFR4、CDH3、BAG1、KRT5、KRT14、MLPH、MYC、PHGDH）
HER2DX评分与无远处转移生存显著相关（P < 0.0001）。
HER2DX评分1～2分被确定为低风险患者的临界值；3分和4分分别为中风险和高风险患者的临界值。
5年无远处转移生存比例：
低风险患者：98.1%（95%置信区间：96.3～99.9）
中风险患者：88.9%（95%置信区间：83.2～95.0）
高风险患者：73.9%（95%置信区间：66.0～82.7）
低风险与高风险患者相比，远处转移或死亡风险低96%（风险比：0.04，95%置信区间：0.0～0.1，P<0.0001）。
对于评估队列，随着HER2DX评分递增，无病生存比例递减（风险比：2.77，95%置信区间：1.4～5.6，P=0.0040）；低风险与高风险患者相比，远处转移或死亡风险低73%（风险比：0.27，95%置信区间：0.1～0.7，P=0.005）。低风险、高风险患者的5年无病生存比例分别为93.5%、81.1%（95%置信区间：89.0～98.3%、71.5～92.1）。
因此，该研究结果表明，HER2DX联合预后评分可确定哪些HER2阳性早期乳腺癌患者术后辅助治疗需要升级或降级，故有必要进一步在不同情况下对HER2DX进行临床验证，尤其术前新辅助治疗。
对此，美国洛杉矶加利福尼亚大学萨拉·贺维茨教授发表同期评论：HER2DX可能有助于HER2阳性乳腺癌治疗方案选择。萨拉·贺维茨教授也是廖宁教授周三见国际会诊团队专家之一。
相关争议
Lancet Oncol. 2020 Nov 2;21(11):1455-1464.
A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.
Prat A, Guarneri V, Paré L, Griguolo G, Pascual T, Dieci MV, Chic N, González-Farré B, Frassoldati A, Sanfeliu E, Cejalvo JM, Munoz 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.
SOLTI Breast Cancer Research Group, Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; University of Barcelona, Barcelona, Spain; Hospital Clínico Universitario of Valencia, Valencia, Spain; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Institut Català d'Oncologia Hospitalet, Hospitalet de Llobregat, Spain; Hospital Universitario Son Espases, Carretera de Valldemossa, Palma de Mallorca, Spain; Hospital Arnau de Vilanova, Valencia, Spain; IOB Institute of Oncology, Quiron Group, Barcelona, Spain; Hospital 12 de Octubre, Madrid, Spain; Complejo Universitario de Santiago de Compostela-CIBERONC, Santiago de Compostela, Spain; University of Padova, Padova, Italy; Istituto Oncologico Veneto, IRCCS, Padova, Italy; S Anna University Hospital, Ferrara, Italy; Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Emilia-Romagna, Italy; Azienda Unità Sanitaria Locale di Bologna-IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy; University Hospital of Parma, Piacenza, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy; University of Naples Federico II, Naples, Italy; University of Modena and Reggio Emilia, Modena, Italy; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
BACKGROUND: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer.
METHODS: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus 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 in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91.4 months (IQR 75.1-105.6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. 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 group. 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 assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data.
FINDINGS: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0.0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, 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 (low-risk vs high-risk hazard ratio [HR] 0.04, 95% CI 0.0-0.1, p<0.0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2.77, 95% CI 1.4-5.6, p=0.0040) and as group categories (low-risk vs high-risk HR 0.27, 0.1-0.7, p=0.005). 5-year disease-free survival in the HER2DX low-risk group was 93.5% (89.0-98.3%) and in the high-risk group was 81.1% (71.5-92.1).
INTERPRETATION: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.
FUNDING: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Espanola Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, Veneto Institute of Oncology, Italian Association for Cancer Research.
PMID: 33152285
DOI: 10.1016/S1470-2045(20)30450-2
Lancet Oncol. 2020 Nov 2;21(11):1392-1393.
HER2DX: a tool that might inform treatment choices for HER2-positive breast cancer.
Hurvitz SA.
David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
PMID: 33152281
DOI: 10.1016/S1470-2045(20)30552-0