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2013年，美国临床肿瘤学会（ASCO）和美国病理医师学院（CAP）更新了乳腺癌人表皮生长因子受体2（HER2）检测临床实践指南。 2016年8月29日，ASCO官方期刊《临床肿瘤学杂志》在线发表南加利福尼亚大学诺里斯综合癌症中心、加利福尼亚大学洛杉矶分校格芬医学院、美国肿瘤学研究网络弗吉尼亚癌症专家组织、德克萨斯大学MD安德森癌症中心、德国汉堡大学、德国红十字会妇科医院、比利时国际药物开发研究所、波兰研究生医学教育中心、爱尔兰圣文森特大学医院、爱尔兰肿瘤学研究协作组、西班牙马德里（康普斯顿）大学格雷戈里奥·马拉尼翁健康研究所、加拿大阿尔伯塔大学、加拿大埃德蒙顿和法国巴黎的癌症国际研究组织（CIRG）肿瘤学转化研究（TRO）的研究报告。 该研究运用2013年ASCO-ACP乳腺癌HER2检测临床实践指南，对乳腺癌国际研究组织（BCIRG）既往3项临床试验（2000～2003年BCIRG-005、2001～2004年BCIRG-006、BCIRG-007）10468例入组患者的HER2荧光原位杂交（FISH）与临床结局的相关性进行了回顾性评估，临床结局指标包括无病生存（DFS）、总生存（OS）、曲妥珠单抗疗法获益（风险比）。 根据HER2与第17号染色体着丝粒比值、每个肿瘤细胞的平均HER2基因拷贝，患者被分为5组：
结果发现，5组患者分别占40.8%、0.7%、0.5%、4.1%、53.9%，与入组时的分布相似。FISH第1组乳腺癌与免疫组织化学（IHC）3+状态有强烈相关性（P＜0.0001），第2、3、4、5组则无相关性；然而，第2、4、5组与免疫组织化学（IHC）0/1+状态有强烈相关性（所有P＜0.0001），第3组则无相关性。在BCIRG-005患者中，第4组与第5组相比，与显著较差的DFS或OS无相关性。在BCIRG-006患者中，仅第1组显示对曲妥珠单抗疗法显著获益（DFS风险比：0.71，95%置信区间：0.60～0.83，P＜0.0001；OS风险比：0.69，95%置信区间：0.55～0.85，P=0.0006），第2组则无。 因此，该研究结果支持BCIRG/TRO试验通过FISH状态对HER2的原始分类。 J Clin Oncol. 2016 Aug 29. [Epub ahead of print] HER2 Gene Amplification Testing by Fluorescent In Situ Hybridization (FISH): Comparison of the ASCO-College of American Pathologists Guidelines With FISH Scores Used for Enrollment in Breast Cancer International Research Group Clinical Trials. Michael F. Press, Guido Sauter, Marc Buyse, Hélène Fourmanoir, Emmanuel Quinaux, Denice D. Tsao-Wei, Wolfgang Eiermann, Nicholas Robert, Tadeusz Pienkowski, John Crown, Miguel Martin, Vicente Valero, John R. Mackey, Valerie Bee, Yanling Ma, Ivonne Villalobos, Anaamika Campeau, Martina Mirlacher, Mary-Ann Lindsay, Dennis J. Slamon. University of Southern California Norris Comprehensive Cancer Center; Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA; Virginia Cancer Specialists/US Oncology Research Network, Fairfax, VA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Hamburg, Hamburg; Frauenklinik vom Roten Kreuz, Munich, Germany; International Drug Development Institute, Louvain-la-Neuve, Belgium; Postgraduate Medical Education Center, Warsaw, Poland; Irish Cooperative Onoclogy Research Group, St Vincent's University Hospital, Dublin, Ireland; Instituto de Investigación Sanitaria Gregorio Maranón, Universidad Complutense, Madrid, Spain; University of Alberta; Cancer International Research Group/Translational Research in Oncology, Edmonton, Alberta, Canada; Cancer International Research Group/Translational Research in Oncology, Paris, France. PURPOSE: ASCO and the College of American Pathologists (ASCO-CAP) recently recommended further changes to the evaluation of human epidermal growth factor receptor 2 gene (HER2) amplification by fluorescent in situ hybridization (FISH). We retrospectively assessed the impact of these new guidelines by using annotated Breast Cancer International Research Group (BCIRG) -005, BCIRG-006, and BCIRG-007 clinical trials data for which we have detailed outcomes. PATIENTS AND METHODS: The HER2 FISH status of BCIRG-005/006/007 patients with breast cancers was re-evaluated according to current ASCO-CAP guidelines, which designates five different groups according to HER2 FISH ratio and average HER2 gene copy number per tumor cell: group 1 (in situ hybridization [ISH]-positive): HER2-to-chromosome 17 centromere ratio ≥ 2.0, average HER2 copies ≥ 4.0; group 2 (ISH-positive): ratio ≥ 2.0, copies < 4.0; group 3 (ISH-positive): ratio < 2.0, copies ≥ 6.0; group 4 (ISH-equivocal): ratio < 2.0, copies ≥ 4.0 and < 6.0; and group 5 (ISH-negative): ratio < 2.0, copies < 4.0. We assessed correlations with HER2 protein, clinical outcomes by disease-free survival (DFS) and overall survival (OS) and benefit from trastuzumab therapy (hazard ratio [HR]). RESULTS: Among 10,468 patients with breast cancers who were successfully screened for trial entry, 40.8% were in ASCO-CAP ISH group 1, 0.7% in group 2; 0.5% in group 3, 4.1% in group 4, and 53.9% in group 5. Distributions were similar in screened compared with accrued subpopulations. Among accrued patients, FISH group 1 breast cancers were strongly correlated with immunohistochemistry 3+ status (P < .0001), whereas groups 2, 3, 4, and 5 were not; however, groups 2, 4 and, 5 were strongly correlated with immunohistochemistry 0/1+ status (all P < .0001), whereas group 3 was not. Among patients accrued to BCIRG-005, group 4 was not associated with significantly worse DFS or OS compared with group 5. Among patients accrued to BCIRG-006, only group 1 showed a significant benefit from trastuzumab therapy (DFS HR, 0.71; 95% CI, 0.60 to 0.83; P < .0001; OS HR, 0.69; 95% CI, 0.55 to 0.85; P = .0006), whereas group 2 did not. CONCLUSION: Our findings support the original categorizations of HER2 by FISH status in BCIRG/Translational Research in Oncology trials. Supported in part by grants from the Breast Cancer Research Foundation, California Breast Cancer Research Program, Tower Cancer Research Foundation (Jessica M. Berman Senior Investigator Award), a gift from Dr. Richard Blach, and Entertainment Industry Foundation as well as an endowed chair, the Harold E. Lee Chair for Cancer Research. The project was also supported in part by Grant No. P30CA014089 from the National Cancer Institute. Support for these trials was provided to the Breast Cancer International Research Group (BCIRG), now Translational Research in Oncology. The sponsor and major funder of the BCIRG-006 trial was Sanofi, with additional support provided by Genentech. Trastuzumab was provided by Genentech free of charge for study patients in the United States and was purchased by Sanofi for all study patients in other countries. Docetaxel was provided by Sanofi for all study patients. The BCIRG-005 trial was sponsored by Sanofi. The BCIRG-007 trial was sponsored by F. Hoffman-La Roche Ltd and Genentech. Clinical trial information: NCT00021255 and NCT00312208 DOI: 10.1200/JCO.2016.66.6693
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