Background Recent advances have been made in targeting the phosphoinositide 3-kinase pathway in breast cancer. Phosphatase and tensin homolog (PTEN) is a key component of that pathway. Objective To understand the changes in PTEN expression over the course of the disease in patients with triple-negative breast cancer (TNBC) and whether PTEN copy number variation (CNV) by next-generation sequencing (NGS) can serve as an alternative to immunohistochemistry (IHC) to identify PTEN loss. Methods We compared PTEN expression by IHC between pretreatment tumors and residual tumors in the breast and lymph nodes after neoadjuvant chemotherapy in 96 patients enrolled in a TNBC clinical trial. A correlative analysis between PTEN protein expression and PTEN CNV by NGS was also performed. Results With a stringent cutoff for PTEN IHC scoring, PTEN expression was discordant between pretreatment and posttreatment primary tumors in 5% of patients (n = 96) and between posttreatment primary tumors and lymph node metastases in 9% (n = 33). A less stringent cutoff yielded similar discordance rates. Intratumoral heterogeneity for PTEN loss was observed in 7% of the patients. Among pretreatment tumors, PTEN copy numbers by whole exome sequencing (n = 72) were significantly higher in the PTEN-positive tumors by IHC compared with the IHC PTEN-loss tumors (p < 0.0001). However, PTEN-positive and PTEN-loss tumors by IHC overlapped in copy numbers: 14 of 60 PTEN-positive samples showed decreased copy numbers in the range of those of the PTEN-loss tumors. Conclusion Testing various specimens by IHC may generate different PTEN results in a small proportion of patients with TNBC; therefore, the decision of testing one versus multiple specimens in a clinical trial should be defined in the patient inclusion criteria. Although a distinct cutoff by which CNV differentiated PTEN-positive tumors from those with PTEN loss was not identified, higher copy number of PTEN may confer positive PTEN, whereas lower copy number of PTEN would necessitate additional testing by IHC to assess PTEN loss. Trial registration NCT02276443.

中文翻译：

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三阴性乳腺癌中的 PTEN：治疗前和治疗后标本中的蛋白质表达和基因组改变。

背景 乳腺癌中磷酸肌醇 3-激酶通路的靶向治疗取得了最新进展。磷酸酶和张力蛋白同源物 (PTEN) 是该途径的关键组成部分。目的 了解三阴性乳腺癌 (TNBC) 患者病程中 PTEN 表达的变化，以及二代测序 (NGS) 检测 PTEN 拷贝数变异 (CNV) 是否可以作为免疫组化的替代方法。 IHC) 来识别 PTEN 丢失。方法 我们通过 IHC 比较了参加 TNBC 临床试验的 96 名患者的治疗前肿瘤与新辅助化疗后乳腺和淋巴结残留肿瘤之间的 PTEN 表达。还通过 NGS 进行了 PTEN 蛋白表达与 PTEN CNV 之间的相关性分析。结果 由于 PTEN IHC 评分有严格的截止值，5% 的患者 (n = 96) 治疗前和治疗后原发肿瘤之间 PTEN 表达不一致，9% (n = 33) 治疗后原发肿瘤和淋巴结转移之间 PTEN 表达不一致。不太严格的截止值产生了类似的不一致率。在 7% 的患者中观察到 PTEN 丢失的瘤内异质性。在治疗前的肿瘤中，与 IHC PTEN 缺失肿瘤相比，IHC 检测的 PTEN 阳性肿瘤中全外显子组测序 (n = 72) 的 PTEN 拷贝数显着更高 (p < 0.0001)。然而，通过 IHC 检测，PTEN 阳性和 PTEN 缺失肿瘤的拷贝数重叠：60 个 PTEN 阳性样本中的 14 个显示出 PTEN 缺失肿瘤拷贝数范围内的拷贝数减少。结论 在一小部分 TNBC 患者中，通过 IHC 检测不同标本可能会产生不同的 PTEN 结果；因此，在临床试验中测试一个样本还是多个样本的决定应在患者纳入标准中定义。尽管尚未确定 CNV 将 PTEN 阳性肿瘤与 PTEN 缺失肿瘤区分开来的明显界限，但较高的 PTEN 拷贝数可能会产生阳性 PTEN，而较低的 PTEN 拷贝数则需要通过 IHC 进行额外测试来评估 PTEN 缺失。试用注册NCT02276443。