OBJECTIVE To select optimal therapies based on the detection of actionable genomic alterations in tumor samples is a major challenge in precision medicine. METHODS We describe an effective process (opened December 1, 2017) that combines comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensiona ex vivo models for drug screening to assess response to therapeutic agents targeting specific genomic alterations. The process was applied to a patient with widely metastatic, weakly hormone receptor positive, HER2 nonamplified, infiltrating lobular breast cancer refractory to standard therapy. RESULTS Clinical testing of liver metastasis identified BRIP1, NF1, CDH1, RB1, and TP53 mutations pointing to potential therapies including PARP, MEK/RAF, and CDK inhibitors. The comprehensive genomic analysis identified 395 mutations and several structural rearrangements that resulted in loss of function of 36 genes. Meta-analysis revealed biallelic inactivation of TP53, CDH1, FOXA1, and NIN, whereas only one allele of NF1 and BRIP1 was mutated. A novel ERBB2 somatic mutation of undetermined significance (P702L), high expression of both mutated and wild-type ERBB2 transcripts, high expression of ERBB3, and a LITAF-BCAR4 fusion resulting in BCAR4 overexpression pointed toward ERBB-related therapies. Ex vivo analysis validated the ERBB-related therapies and invalidated therapies targeting mutations in BRIP1 and NF1. Systemic patient therapy with afatinib, a HER1/HER2/HER4 small molecule inhibitor, resulted in a near complete radiographic response by 3 months. CONCLUSION Unlike clinical testing, the combination of tumor profiling, data integration, and functional validation accurately assessed driver alterations and predicted effective treatment.

中文翻译：

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综合基因组分析和受影响分子途径的功能筛选的综合信息，为癌症治疗提供依据。

目的基于对肿瘤样本中可操作的基因组变化的检测来选择最佳疗法是精密医学的主要挑战。方法我们描述了一个有效的流程（2017年12月1日开放），该流程结合了全面的基因组和转录组肿瘤概况分析，用于数据整合的定制算法和可视化软件以及用于药物筛选的临床前3维体外模型，以评估针对靶向特定治疗药物的反应基因组改变。该方法应用于具有广泛转移，激素受体呈弱阳性，HER2未扩增，浸润性小叶型乳腺癌的患者，对标准治疗无效。结果肝转移的临床测试确定了BRIP1，NF1，CDH1，RB1和TP53突变，这些突变指向潜在的疗法，包括PARP，MEK / RAF，和CDK抑制剂。全面的基因组分析确定了395个突变和几个结构重排，这些突变导致36个基因的功能丧失。荟萃分析显示TP53，CDH1，FOXA1和NIN的双等位基因失活，而仅NF1和BRIP1的一个等位基因被突变。具有不确定性的新型ERBB2体细胞突变（P702L），突变型和野生型ERBB2转录本的高表达，ERBB3的高表达以及导致BCAR4过表达的LITAF-BCAR4融合指向ERBB相关疗法。离体分析验证了与ERBB相关的疗法，并使针对BRIP1和NF1突变的疗法无效。用afatinib（一种HER1 / HER2 / HER4小分子抑制剂）进行的全身性患者治疗在3个月内导致了几乎完全的影像学反应。结论与临床测试不同，