BACKGROUND High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. PATIENTS AND METHODS We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. RESULTS The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pembrolizumab-based therapies derived an objective and durable response to therapy. CONCLUSION Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

中文翻译：

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乳腺癌中高肿瘤突变负担的患病率和突变决定因素。

背景技术高的肿瘤突变负担（TMB）可以有益于多种肿瘤类型的免疫治疗，但是高突变乳腺癌的患病率并未得到很好的描述。这项研究的目的是评估超突变乳腺癌的频率，突变模式和基因组概况。患者和方法我们使用了来自六个不同的可公开获得的基因组研究的原发性或转移性乳腺癌患者的去鉴定数据。在进行了全外显子组测序或基因组测序的3969名患者样品中，确定了高突变乳腺癌的患病率。如果样本每兆碱基（mut / Mb）≥10个突变，则将其归类为高TMB。从Dana-Farber癌症研究所的队列中确定了另外8名患者，以纳入超突变队列。在高TMB患者中，确定突变模式和基因组谱。部分患者接受了包含PD-1抑制剂的治疗方案。结果中位TMB为2.63 mut / Mb。中位数TMB根据肿瘤亚型（HR- / HER2-> HER2 +> HR + / HER2-，P <0.05）和样品类型（转移性>原发性，P = 2.2×10-16）显着变化。在198例患者中发现了超突变的肿瘤（5％），其中转移性肿瘤与原发性肿瘤比较丰富（8.4％比2.9％，P = 6.5×10-14）。APOBEC活性（59.2％），其次是失配修复缺陷（MMRd； 36.4％），是超突变肿瘤中最常见的突变过程。三名患有超突变乳腺癌的患者-包括两名具有基于Pembrolizumab的疗法治疗的APOBEC活性显着性特征和一名具有MMRd显性性特征的患者，对治疗产生了客观而持久的反应。结论高突变发生在所有乳腺癌中有5％，且转移性肿瘤丰富。该群体中存在不同的突变特征，其中APOBEC活性是最常见的显性过程。初步数据表明，高度突变的乳腺癌更有可能受益于PD-1抑制剂。