Lesurf R, Griffith O L, Griffith M, Hundal J, Trani L, Watson M A, Aft R, Ellis M J, Ota D, Suman V J, Meric-Bernstam F, Leitch A M, Boughey J C, Unzeitig G, Buzdar A U, Hunt K K, Mardis E R
McDonnell Genome Institute at Washington University School of Medicine, St Louis, USA
Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, USA
Ann Oncol. 2017 May 1;28(5):1070-1077. doi: 10.1093/annonc/mdx048.
BACKGROUND: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. PATIENTS AND METHODS: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. RESULTS: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. CONCLUSION: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. CLINICALTRIALS.GOV IDENTIFIERS: NCT00513292, NCT00353483.
背景：HER2（ERBB2）基因扩增及其相应的过表达存在于15%-30%的浸润性乳腺癌中。虽然HER2靶向药物是有效的治疗方法，但耐药性仍然是主要的死亡原因。美国外科医师学会肿瘤学组Z1041试验（NCT00513292）旨在比较新辅助化疗和曲妥珠单抗不同方案的病理完全缓解（pCR）率，但最终未发现差异。 患者和方法：除了37例Z1041病例的组织外，还从一项单机构研究（NCT00353483）中获得了11例类似治疗的病例。我们从这48例病例的治疗前肿瘤活检组织和血液中提取了基因组DNA，并进行了全基因组（WGS）和外显子组测序。与此同时，我们从42例肿瘤活检组织中生成了RNA测序图谱。在该队列的患者中，24例（50%）实现了pCR。 结果：我们已经描绘了HER2阳性乳腺癌的基因组图谱，并研究了基因组特征与pCR之间的关联。通过RNA测序分析归类为HER2富集亚型的病例比管腔型、基底样型或正常样型亚型更有可能实现pCR（19/27对3/15；P=0.0032）。突变事件导致了可能具有活性的新抗原的产生，但总体上与pCR无关。ERBB2和GRB7是融合事件中最常观察到的基因，对ERBB2基因座的基因组拷贝数分析表明，未观察到或低水平ERBB2扩增的病例实现pCR的可能性较小（7/8对17/40；P=0.048）。此外，在实现pCR的病例中，肿瘤始终表达可能有助于治疗反应的免疫特征。 结论：这些特征的识别表明，在诊断时有可能预测那些对化疗和曲妥珠单抗治疗无反应的HER2阳性乳腺癌患者。 临床试验注册编号：NCT00513292，NCT00353483。
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