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Abstract：
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.
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.
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.
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.
NCT00513292, NCT00353483.
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.
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.
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.
NCT00513292, NCT00353483.
摘要：
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，抵抗仍然是死亡的主要原因。美国外科医生学会肿瘤学小组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。但最终确定没有区别。
在37例Z1041的组织补充中，11例类似治疗的病例来自一项单一机构研究(NCT00353483)。我们从这48例的治疗前肿瘤活检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。与这些努力相吻合，我们已经从42例肿瘤活检中产生了RNA-seq谱.在这个队列中的患者中，24(50%)取得了pCR。
我们已经表征了HER2阳性乳腺癌的基因组景观，并研究了基因组特征与pCR之间的关联。与管腔相比，通过RNA-seq分析分配给HER2富集亚型的病例更有可能实现pCR，基底样，或正常样亚型（19/27对3/15;P=0.0032）。突变事件导致推定活性新抗原的产生，但总体上与pCR无关。ERBB2和GRB7是在融合事件中最常见的基因，和ERBB2基因座的基因组拷贝数分析表明，没有可观察到的或低水平的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的案例中，肿瘤一致表达的免疫特征可能有助于治疗反应。
对这些特征的识别表明，有可能预测，在诊断时，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.
NCT00513292，NCT00353483。
在37例Z1041的组织补充中，11例类似治疗的病例来自一项单一机构研究(NCT00353483)。我们从这48例的治疗前肿瘤活检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。与这些努力相吻合，我们已经从42例肿瘤活检中产生了RNA-seq谱.在这个队列中的患者中，24(50%)取得了pCR。
我们已经表征了HER2阳性乳腺癌的基因组景观，并研究了基因组特征与pCR之间的关联。与管腔相比，通过RNA-seq分析分配给HER2富集亚型的病例更有可能实现pCR，基底样，或正常样亚型（19/27对3/15;P=0.0032）。突变事件导致推定活性新抗原的产生，但总体上与pCR无关。ERBB2和GRB7是在融合事件中最常见的基因，和ERBB2基因座的基因组拷贝数分析表明，没有可观察到的或低水平的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的案例中，肿瘤一致表达的免疫特征可能有助于治疗反应。
对这些特征的识别表明，有可能预测，在诊断时，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.
NCT00513292，NCT00353483。
