HER2弱阳性乳腺癌大有文章
编者按：现在的中青年医师无论写病史还是写论文都喜欢把HER2阳性简写为HER2+。此类简写如果被当年严格的老教授们看到，大多会被责问：这是免疫组化1个“+”还是原位杂交阳性？因为，免疫组化1～2个“+”属于HER2弱阳性，抗HER2药物通常疗效不佳。结果，此类病史或论文通常会被勒令全部重写，要知道当年电脑尚未普及，病史或论文都是用钢笔蘸蓝黑墨水一笔一划写出来的。
众所周知，抗HER2药物仅限用于HER2阳性乳腺癌患者。不过，大分子HER2抗体与小分子化疗药的缀合物（旧称偶联物）为HER2低表达或弱阳性乳腺癌患者带来了新的治疗选择。
2021年7月9日，英国《柳叶刀》肿瘤学分册在线发表德国乳腺学组、马尔堡大学、国家肿瘤疾病中心、德国癌症研究中心、德累斯顿理工大学、柏林大学夏里特医学院、比勒费尔德肿瘤学医院、法兰克福肿瘤医院、奥芬巴赫萨纳医院、伊丽莎白医院、埃森米特医院、萨尔大学、慕尼黑妇女医院、慕尼黑红十字医院、埃尔朗根纽伦堡大学、法兰克福大学、乌尔姆大学、科隆大学、海德堡大学、罗斯托克大学、美因茨大学、亚琛理工大学、滨肿瘤聚焦实践、慕尼黑肿瘤医院、柏林布赫太阳神医院的研究报告，对乳腺癌术前新辅助治疗4项前瞻临床试验的患者个体数据进行汇总分析，比较了HER2低表达与HER2零表达乳腺癌的临床特征和分子特征，包括对术前新辅助化疗的效果和结局。
该研究对2012年7月30日～2019年3月20日乳腺癌术前新辅助治疗4项前瞻临床试验随机入组前进行集中HER2检测的2310例患者个体数据进行汇总分析：
GeparSepto (NCT01583426): A Randomized Phase III Trial Comparing Nanoparticle-based Paclitaxel With Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Patients With Early Breast Cancer
GeparOcto (NCT02125344): A Randomized Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer
GeparX (NCT02682693): Investigating Denosumab as an add-on Neoadjuvant Treatment for RANK-positive or RANK-negative Primary Breast Cancer and Two Different Nab-Paclitaxel Schedules ; 2x2 Factorial Design
GAIN-2 (NCT01690702): Neo-/Adjuvant Phase III Trial to Compare Intense Dose-dense Chemotherapy to Tailored Dose-dense Chemotherapy in Patients With High-risk Early Breast Cancer
根据美国临床肿瘤学会与美国病理医师学院指南，HER2低表达定义为免疫组化1～2个“+”且原位杂交阴性，HER2零表达定义为免疫组化0。
从GeparX之外全部试验获得1694例患者的无病生存和总体生存数据，中位随访46.6个月（四分位：35.0～52.3）。
根据预设统计学分析计划对病理完全缓解、无病生存和总体生存终点进行双因素和多因素逻辑回归模型和多因素比例风险回归模型分析。
结果，其中HER2低表达肿瘤1098例、HER2零表达肿瘤1212例（47.5%比52.5%）。
HER2低表达肿瘤与HER2零表达肿瘤相比：
激素受体阳性率较低：36.7%比64.0%（P<0.0001）
病理完全缓解率较低：29.2%比39.0%（P=0.0002）
三年无病生存率较高：83.4%比76.1%（95%置信区间：80.5～85.9、72.9～79.0，分层对数秩检验P=0.0084）
三年总体生存率较高：91.6%比85.8%（95%置信区间：84.9～93.4、83.0～88.1，分层对数秩检验P=0.0016）
对于激素受体阴性肿瘤患者，HER2低表达肿瘤与HER2零表达肿瘤相比：
病理完全缓解率相似：50.1%比48.0%（P=0.21）
三年无病生存率较高：84.5%比74.4%（95%置信区间：79.5～88.3、70.2～78.0，分层对数秩检验P=0.0076）
三年总体生存率较高：90.2%比84.3%（95%置信区间：86.0～93.2、80.7～87.3，分层对数秩检验P=0.016）
对于激素受体阳性肿瘤患者，HER2低表达肿瘤与HER2零表达肿瘤相比：
病理完全缓解率较低：17.5%比23.6%（P=0.024）
三年无病生存率相似：82.8%比79.3%（95%置信区间：79.1～85.9、73.9～83.7，分层对数秩检验P=0.39）
三年总体生存率相似：92.3%比88.4%（95%置信区间：89.6～94.4、83.8～91.8，分层对数秩检验P=0.13）
因此，该研究结果表明，HER2低表达肿瘤与HER2零表达肿瘤相比，激素受体阳性率、病理完全缓解率、无病生存率、总体生存率有所不同，故可根据标准化免疫组化划分为新的乳腺癌亚组。HER2低表达肿瘤具有独特的生物学特征，治疗效果和生存结局有所不同，尤其对于治疗耐药、激素受体阴性肿瘤。该研究结果为更好地了解乳腺癌亚型生物学特征、完善未来诊断治疗策略奠定了基础。
对此，意大利帕多瓦大学威尼托肿瘤研究所发表同期评论：HER2——永不结束的故事。
相关链接
Lancet Oncol. 2021 Jul 9. Online ahead of print.
Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials.
Carsten Denkert, Fenja Seither, Andreas Schneeweiss, Theresa Link, Jens-Uwe Blohmer, Marianne Just, Pauline Wimberger, Almuth Forberger, Hans Tesch, Christian Jackisch, Sabine Schmatloch, Mattea Reinisch, Erich F Solomayer, Wolfgang D Schmitt, Claus Hanusch, Peter A Fasching, Kristina Lübbe, Christine Solbach, Jens Huober, Kerstin Rhiem, Frederik Marmé, Toralf Reimer, Marcus Schmidt, Bruno V Sinn, Wolfgang Janni, Elmar Stickeler, Laura Michel, Oliver Stotzer, Eric Hahnen, Jenny Furlanetto, Sabine Seiler, Valentina Nekljudova, Michael Untch, Sibylle Loibl.
Philipps-Universitat Marburg and University Hospital of Giessen and Marburg, Marburg, Germany; German Breast Group, Neu-Isenburg, Germany; Nationales Centrum für Tumorerkrankungen, Universitatsklinikum und Deutsches Krebsforschungszentrum, Heidelberg, Germany; Universitatsklinikum Carl Gustav Carus Dresden, Technische Universitat Dresden, Dresden, Germany; Charité Universitatsmedizin Berlin, Berlin, Germany; Onkologische Schwerpunktpraxis Bielefeld, Bielefeld, Germany; Onkologie Bethanien Krankenhaus Frankfurt, Frankfurt, Germany; Sana Klinikum Offenbach, Offenbach, Germany; Elisabeth Krankenhaus, Kassel, Germany; Kliniken Essen Mitte, Essen, Germany; University of Saarland, Homburg, Germany; Charité - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Institute of Pathology, Berlin, Germany; Frauenklinik München, Rotkreuzklinikum München, München, Germany; University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; DIAKOVERE Henriettenstift Gynakologie, Hannover, Germany; University Hospital Frankfurt, Frankfurt, Germany; University Hospital Ulm, University of Ulm, Ulm, Germany; University of Cologne, Cologne, Germany; Medizinische Fakultat Mannheim, Universitat Heidelberg, Universitatsfrauenklinik Mannheim, Germany; University of Rostock, Rostock, Germany; Universitatsmedizin Mainz, Mainz, Germany; Rheinisch-Westfalische Technische Hochschule Aachen University, Aachen, Germany; Hamatoonkologische Schwerpunktpraxis, München, Germany; Helios-Klinikum Berlin Buch, Germany; Goethe University of Frankfurt, Frankfurt, Germany.
BACKGROUND: The development of anti-HER2 antibody-drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis.
METHODS: In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426; GeparOcto, NCT02125344; GeparX, NCT02682693; Gain-2 neoadjuvant, NCT01690702) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46.6 months (IQR 35.0-52.3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival.
FINDINGS: A total of 1098 (47.5%) of 2310 tumours were HER2-low-positive and 1212 (52.5%) were HER2-zero. 703 (64.0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36.7%) of 1212 patients with HER2-zero tumours (p<0.0001). HER2-low-positive tumours had a significantly lower pathological complete response rate than HER2-zero tumours (321 [29.2%] of 1098 vs 473 [39.0%] of 1212, p=0.0002). Pathological complete response was also significantly lower in HER2-low-positive tumours versus HER2-zero tumours in the hormone receptor-positive subgroup (123 [17.5%] of 703 vs 105 [23.6%] of 445, p=0.024), but not in the hormone receptor-negative subgroup (198 [50.1%] of 395 vs 368 [48.0%] of 767, p=0.21). Patients with HER2-low-positive tumours had significantly longer survival than did patients with HER2-zero tumours (3-year disease-free survival: 83.4% [95% CI 80.5-85.9] vs 76.1% [72.9-79.0]; stratified log-rank test p=0.0084; 3-year overall survival: 91.6% [84.9-93.4] vs 85.8% [83.0-88.1]; stratified log-rank test p=0.0016). Survival differences were also seen in patients with hormone receptor-negative tumours (3-year disease-free survival: 84.5% [95% CI 79.5-88.3] vs 74.4% [70.2-78.0]; stratified log-rank test p=0.0076; 3-year overall survival: 90.2% [86.0-93.2] vs 84.3% [80.7-87.3], stratified log-rank test p=0.016), but not in patients with hormone receptor-positive tumours (3-year disease-free survival 82.8% [79.1-85.9] vs 79.3% [73.9-83.7]; stratified log-rank test p=0.39; 3-year overall survival 92.3% [89.6-94.4] vs 88.4% [83.8-91.8]; stratified log-rank test p=0.13).
INTERPRETATION: Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies.
FUNDING: German Cancer Aid (Deutsche Krebshilfe).
DOI: 10.1016/S1470-2045(21)00301-6
Lancet Oncol. 2021 Jul 9. Online ahead of print.
HER2: a never ending story.
Maria Vittoria Dieci, Federica Miglietta.
University of Padova, Padova, Italy; Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
Access to anti-HER2 agents for breast cancer is restricted to patients with HER2-positive tumours. However, the promising activity of novel anti-HER2 antibody–drug conjugates in patients with tumours with HER2-low-positive expression is challenging the dichotomy of HER2-positive versus HER2-negative breast cancer.
DOI: 10.1016/S1470-2045(21)00349-1