三阴乳腺癌中的PTEN：治疗前和治疗后标本中的蛋白表达与基因组改变

PTEN in triple-negative breast carcinoma: protein expression and genomic alteration in pretreatment and posttreatment specimens.

作者信息

Chen Hui, Ding Qingqing, Khazai Laila, Zhao Li, Damodaran Senthil, Litton Jennifer K, Rauch Gaiane M, Yam Clinton, Chang Jeffrey T, Seth Sahil, Lim Bora, Thompson Alastair M, Mittendorf Elizabeth A, Adrada Beatriz, Virani Kiran, White Jason B, Ravenberg Elizabeth, Song Xingzhi, Candelaria Rosalind, Arun Banu, Ueno Naoto T, Santiago Lumarie, Saleem Sadia, Abouharb Sausan, Murthy Rashmi K, Ibrahim Nuhad, Routbort Mark J, Sahin Aysegul, Valero Vicente, Symmans William Fraser, Tripathy Debu, Wang Wei-Lien, Moulder Stacy, Huo Lei

机构信息

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

出版信息

Ther Adv Med Oncol. 2023 Aug 2;15:17588359231189422. doi: 10.1177/17588359231189422. eCollection 2023.

DOI:10.1177/17588359231189422

PMID:37547448

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10399250/

Abstract

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 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 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 ( = 96) and between posttreatment primary tumors and lymph node metastases in 9% ( = 33). A less stringent cutoff yielded similar discordance rates. Intratumoral heterogeneity for PTEN loss was observed in 7% of the patients. Among pretreatment tumors, copy numbers by whole exome sequencing ( = 72) were significantly higher in the PTEN-positive tumors by IHC compared with the IHC PTEN-loss tumors ( < 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 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 may confer positive PTEN, whereas lower copy number of would necessitate additional testing by IHC to assess PTEN loss.

TRIAL REGISTRATION

NCT02276443.

摘要

背景

在乳腺癌中，针对磷酸肌醇3激酶通路的研究取得了新进展。磷酸酶和张力蛋白同源物（PTEN）是该通路的关键组成部分。

目的

了解三阴性乳腺癌（TNBC）患者疾病进程中PTEN表达的变化，以及通过新一代测序（NGS）检测拷贝数变异（CNV）是否可作为免疫组织化学（IHC）检测PTEN缺失的替代方法。

方法

我们比较了96例参与TNBC临床试验患者新辅助化疗前肿瘤组织与乳腺及淋巴结残余肿瘤组织中PTEN的IHC表达情况。同时，对PTEN蛋白表达与NGS检测的CNV进行了相关性分析。

结果

采用严格的PTEN IHC评分标准，5%（n = 96）的患者新辅助化疗前与化疗后原发肿瘤组织中PTEN表达不一致，9%（n = 33）的患者化疗后原发肿瘤组织与淋巴结转移灶中PTEN表达不一致。采用较宽松的评分标准，不一致率相似。7%的患者存在PTEN缺失的瘤内异质性。在新辅助化疗前肿瘤组织中，通过全外显子测序检测（n = 72），IHC检测为PTEN阳性的肿瘤组织拷贝数显著高于PTEN缺失的肿瘤组织（P < 0.0001）。然而，IHC检测为PTEN阳性和PTEN缺失的肿瘤组织在拷贝数上存在重叠：60例PTEN阳性样本中有14例拷贝数下降，其范围与PTEN缺失肿瘤组织的拷贝数范围相同。

结论

在一小部分TNBC患者中，通过IHC检测不同标本可能会得出不同的PTEN检测结果；因此，在临床试验中决定检测单个或多个标本应在患者纳入标准中明确规定。虽然未确定CNV区分PTEN阳性肿瘤与PTEN缺失肿瘤的明确临界值，但较高的PTEN拷贝数可能提示PTEN阳性，而较低的PTEN拷贝数则需要通过IHC进行额外检测以评估PTEN缺失情况。