近年来，针对磷酸肌醇3-激酶通路在乳腺癌治疗方面取得了新的进展。磷酸酸化肽酶和张力同源物（PTEN）是该通路的关键组成部分。为了了解三阴性乳腺癌（TNBC）患者疾病过程中PTEN表达的变化，并探讨下一代测序（NGS）中的PTEN拷贝数变异（CNV）是否可以作为免疫组化学（IHC）识别PTEN丢失的替代方法，本研究比较了参与TNBC临床试验的96名患者新辅助化疗前后的乳腺和淋巴结残留肿瘤的PTEN IHC表达，并进行了PTEN蛋白表达与PTEN CNV的相关分析。 在严格的PTEN IHC评分截断值下，96名患者（n=96）预治疗和治疗后原发肿瘤的PTEN表达不一致比例为5%，而治疗后原发肿瘤和淋巴结转移的不一致比例为9%（n=33）。更宽松的截断值产生了类似的不一致率。我们观察到7%的患者中存在PTEN丢失的肿瘤内异质性。在预治疗肿瘤中，全外显子测序（n=72）显示PTEN阳性肿瘤的拷贝数显著高于IHC PTEN丢失肿瘤（p<0.0001）。然而，IHC诊断为PTEN阳性和PTEN丢失的肿瘤在拷贝数上有重叠：60个PTEN阳性样本中有14个显示拷贝数降低，与PTEN丢失肿瘤的范围相当。 在TNBC患者中，通过IHC测试不同标本可能会产生不同的PTEN结果，因此，在临床试验中选择测试一个还是多个标本的决定应根据患者纳入标准进行定义。虽然我们未找到一个明确的截断值来区分PTEN阳性肿瘤和PTEN丢失肿瘤的CNV差异，但更高的PTEN拷贝数可能表明PTEN阳性，而较低的PTEN拷贝数则需要通过IHC进行进一步的检测以评估PTEN丢失。 NCT02276443. © 作者，2023年。

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.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.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.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.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.NCT02276443.© The Author(s), 2023.