人类表皮生长因子受体2（HER2）是由ERBB2基因编码的细胞膜表面受体酪氨酸激酶蛋白质。HER2阳性乳腺癌的特征为ERBB2基因扩增、HER2过度表达，恶性程度较高，通常对曲妥珠单抗、拉帕替尼等HER2靶向治疗药物有效。不过，并非所有HER2阳性乳腺癌能够对HER2靶向治疗获益。ERBB2基因扩增水平和PI3K通路激活可能是单纯HER2靶向治疗效果的关键决定因素。
2019年3月23日，欧洲肿瘤内科学会《肿瘤学报》在线发表美国贝勒医学院、范德堡大学、伯明翰阿拉巴马大学、芝加哥大学、梅奥医学中心、休斯顿卫理公会医院、斯霍普金斯大学西德尼凯莫尔综合癌症中心、哈佛大学达纳法伯癌症研究所、纽约纪念医院斯隆凯特林癌症中心、西班牙巴塞罗那大学医院的乳腺癌转化研究联盟（TBCRC）006研究报告，探讨了预测HER2阳性乳腺癌患者术前新辅助拉帕替尼＋曲妥珠单抗不化疗效果的生物标志。
TBCRC006: A Phase II Trial of Lapatinib and Trastuzumab With or Without Endocrine Therapy in Locally Advanced HER2 Overexpressing Breast Cancer Patients (NCT00548184)
该研究由中心实验室通过荧光原位杂交（FISH）对56例HER2阳性乳腺癌患者拉帕替尼＋曲妥珠单抗新辅助治疗前HER2阳性肿瘤标本的ERBB2基因扩增水平进行测定，其中41例肿瘤测得ERBB2拷贝数与FISH之比并且通过免疫组织化学测得PI3K通路状态（PIK3CA突变或PTEN水平）。最后，将测定结果与病理学缓解（乳房无残留浸润肿瘤）进行关联。
结果，13例患者（23%）实现病理学缓解。11例ERBB2拷贝数与FISH之比<4和/或拷贝数<10的患者均未实现病理学缓解，而实现病理学缓解的13例患者（29%）ERBB2拷贝数与FISH之比≥4和/或拷贝数≥10（P=0.0513）。
18例患者的肿瘤PTEN高表达或PIK3CA为野生型（PI3K通路完整），其中7例（39%）实现病理学缓解，而23例患者的肿瘤PI3K通路突变，其中仅1例（4%）实现病理学缓解（P=0.0133）。
16例患者的肿瘤ERBB2拷贝数与FISH之比≥4且PI3K通路完整，其中7例（44%）实现病理学缓解，而25例患者的肿瘤ERBB2拷贝数与FISH之比<4且PI3K通路突变，其中仅1例（4%）实现病理学缓解（P=0.0031）。
因此，该研究结果表明，乳腺癌存在ERBB2基因扩增水平高且PI3K通路完整的临床亚型，其对不化疗的HER2靶向治疗特别敏感，故有必要对HER2靶向治疗不化疗患者进行ERBB2拷贝数与FISH之比结合PI3K通路状态验证，以避免不必要的化疗。
Ann Oncol. 2019 Mar 23. [Epub ahead of print]
A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.
Veeraraghavan J, De Angelis C, Mao R, Wang T, Herrera S, Pavlick AC, Contreras A, Nuciforo P, Mayer IA, Forero A, Nanda R, Goetz MP, Chang JC, Wolff AC, Krop IE, Fuqua SAW, Prat A, Hilsenbeck SG, Weigelt B, Reis-Filho JS, Gutierrez C, Osborne CK, Rimawi MF, Schiff R.
Baylor College of Medicine, Houston, USA; Hospital Clinic de Barcelona, Barcelona, Spain; Vanderbilt University, Nashville, USA; University of Alabama at Birmingham, Birmingham, USA; University of Chicago, Chicago, USA; Mayo Clinic, Rochester, USA; Houston Methodist Hospital, Houston, USA; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA; Dana-Farber Cancer Institute, Boston,USA; Memorial Sloan Kettering Cancer Center, New York, USA.
BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.
PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab (with endocrine therapy for estrogen receptor (ER)+ tumors) in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by FISH (n=56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).
RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN < 10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥ 10 attained pCR (P=0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared to 1/23 (4%) with PI3K pathway alterations (P=0.0133). Seven of 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P=0.0031).
CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.
KEYWORDS: ErbB2 receptor tyrosine kinase, Breast cancer, Fluorescent in situ hybridization, PIK3CA mutations, PTEN protein, Precision medicine
DOI: 10.1093/annonc/mdz076
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