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Advances in Clinical Medicine
Vol. 13  No. 02 ( 2023 ), Article ID: 61770 , 5 pages
10.12677/ACM.2023.132384

PIK3CA基因突变与HR阳性且HER2阴性 乳腺癌的关系

依合里曼·买买提，梁丽萍，江志民，马晓梅*

新疆医科大学第三临床医学院(附属肿瘤医院)病理科，新疆 乌鲁木齐

收稿日期：2023年1月21日；录用日期：2023年2月16日；发布日期：2023年2月23日

摘要

PIK3CA靶向药物也在临床上得到开发和试验验证。PI3K抑制剂已批准用于PIK3CA突变、激素受体阳性且HER2阴性(HR+/HER2−)晚期乳腺癌患者。然而并非所有患者都能从靶向治疗获益且大多数患者不可避免地会出现内分泌抵抗。PIK3CA突变状态作为HR+/HER2−乳腺癌生物标志物的预后和预测价值，作为分子靶点用于乳腺癌的常规治疗等方面仍存在争议。

关键词

乳腺癌，ER，HR，HR+/HER2−，PIK3CA

The Relationship between PIK3CA Mutation and Hormone Receptor Positive and HER2 Negative Breast Cancer

Yiheliman·Maimaiti, Liping Liang, Zhimin Jiang, Xiaomei Ma*

Department of Pathology, Third Clinical Medical College (Affiliated Cancer Hospital), Xinjiang Medical University, Urumqi Xinjiang

Received: Jan. 21st, 2023; accepted: Feb. 16th, 2023; published: Feb. 23rd, 2023

ABSTRACT

PIK3CA targeted drugs have also been developed and tested clinically. PI3K inhibitor has been approved for use in patients with PIK3CA mutation, hormone receptor positive and HER2 negative (HR+/HER2−) advanced breast cancer. However, not all patients can benefit from targeted therapy and most patients will inevitably develop endocrine resistance. The PIK3CA mutation status as a biomarker of HR+/HER2 breast cancer and its predictive value, as a molecular target for routine treatment of breast cancer, is still controversial.

Keywords:Breast Cancer, ER, HR, HR+/HER2−, PIK3CA

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

乳腺癌(Breast Cancer)是最常见的女性恶性肿瘤之一。2020年全球新增230万新病例，这占所有癌症病例的11.7%，有685,000死亡病例 [1] [2] 。PIK3CA是近年来发现的乳腺癌又一常见突变基因，PIK3CA突变存在于高达40%的HR+/HER2−乳腺癌患者中 [3] [4] 。

2. PIK3CA基因的分子病理特征

磷脂酰肌醇-3-激酶(PI3K)在细胞内介导不同的过程，包括生长、增殖和存活，并且经常参与癌发生、肿瘤进展和转移 [5] 。PI3K的失调会在许多癌症中启动丝氨酸/苏氨酸激酶AKT的活性，从而调节一系列下游蛋白质从而导致肿瘤的发生和发展 [6] 。三十年前Arafeh和Samules [7] 发现并总结PI3K/AKT/mTOR 信号通路与致癌和癌症进展相关 [8] 。PI3激酶将磷脂酰肌醇(4,5)-二磷酸(PIP2)转化为磷脂酰肌醇(3,4,5)-三磷酸(PIP3)，随后激活AKT并调控细胞生长和存活所需的下流信号通路。PI3K激活在生理上被肿瘤抑制磷酸酶和张力蛋白同系物(PTEN)消除，后者将PIP3转化回PIP2 [9] 。PIP3肽水平取决于PI3K和PTEN之间的竞争。PI3K的过度激活以及PTEN表达的降低导致AKT的激活和表达水平升高，从而在病理上促进细胞周期进程 [9] 。已确定存在三类 PI3K：I类(Ia、Ib)、II类和III类。与细胞调节相关性最强的是Ia类PI3K，它们充当调节和催化亚基的异源二聚体 [10] 。I类PI3激酶p110α的催化亚基由PIK3CA基因编码，总基因组大小为86,190个碱基对，包含21个外显子，最终转录本为3207个碱基对，编码1068个氨基酸的蛋白质。p110α蛋白有五个结构域：连接调节亚基的衔接子结合结构域、Ras结合结构域、结合PIP2和PIP3的C2结构域、螺旋结构域和激酶结构域 [11] 。PIK3CA基因的体细胞突变在人类癌症中最为普遍，在原发性乳腺癌中的突变率高达40% [12] [13] 。最常见的三个位点：Exon9中的COSMIC 760 (发生率为17%)和E545K突变，Exon19中的COSMIC 763 (发生率17%)影响E545，Exon20中的COSMIC 775 (发生率35%)改变H1047 [14] 。PIK3CA高频率突变具有激酶活性，当野生型和突变型克隆通过尾静脉注射到裸鼠体内，野生型没有肿瘤形成，而突变型克隆在不同部位形成肿瘤，并伴有微转移和浸润 [15] [16] 。此外，PIK3CA突变被认为是乳腺癌发展的早期事件，即使在较小体积的肿瘤和非浸润性前驱病变(如DCIS)中也能检测到其突变 [17] 。研究发现PIK3CA基因突变患者有更高的生存率(Dumont 等人、Pang 等人 [18] [19] )，而Sobhani等人及Fan等人的研究结果则支持PIK3CA突变与较低的生存率 [20] [21] 之间存在关联。这些相矛盾的结果可能是由于人群差异、样本含量大小、亚组分布和治疗类型方面的异质性所致。

3. PIK3CA基因在HR+/HER2−乳腺癌中的突变及临床意义

根据免疫组织化学(IHC)，大多数乳腺癌呈激素受体(HR)阳性，并且缺乏皮生长因子受体2 (HER2)扩增(HR+/HER2−)，占50岁以下女性的病例的65%和50岁以上女性病例的75% [22] 。HR+/HER2−乳腺癌是一个异质性亚群，大多数HR+/HER2−肿瘤属于Luminal亚型 [23] 。低级别(高分化)肿瘤通常具有较高的HR表达以及较低的增殖率，而中级别和高级肿瘤可能具有较低水平的ER并且可能缺乏PR表达，具有较高的细胞增殖率 [24] 。肿瘤在雌激素受体(ER)和孕激素受体(PR)表达水平(由ER驱动)、组织学分级、增殖程度(通过Ki-67或其他指标测量)、基因表达模式以及分子类型方面各不相同 [23] [24] 。PIK3CA基因突变存在于大约40% HR+/HER2−乳腺癌患者中 [12] [13] 且与这些特征高度相关，研究PIK3CA基因突变与乳腺癌潜在联系具有重要的临床意义。最近，TEAM以摘要形式发表的研究发现，进行了辅助内分泌治疗的绝经后ER+乳腺癌患者中PIK3CA基因突变发生率为39.8% (1702/4272) [25] 。也有研究发现有PIK3CA基因突变并未接受PI3K抑制剂治疗的HR+/HER2−乳腺癌患者无转移生存率较接受PI3K抑制剂治疗者低 [26] 。一项涉及278名女性的四项新辅助内分泌治疗乳腺癌试验的回顾性汇总分析发现PIK3CA突变与内分泌治疗耐药性相关 [27] 。内分泌治疗耐药是临床治疗乳腺癌患者时常见的治疗挑战，且其机制尚未被完全解读。PIK3CA基因在HR+/HER2−乳腺癌中的临床意义研究前景广阔，可为临床制定治疗策略提供理论基础。

4. PIK3CA基因与HR+/HER2−乳腺癌靶向治疗及预后的关系

晚期HR+/HER2−阴性乳腺癌的标准化治疗包括内分泌治疗、联合或不联合使用细胞周期蛋白依赖性激酶4和6 (CDK4/6)抑制剂 [28] 。PI3K抑制剂与内分泌治疗联合使用的原理是协同抑制PI3K和ER通路 [29] 。早期原发性乳腺癌发生PIK3CA基因突变，就可以在其微转移的腋窝淋巴结中发现同样的突变基因，并用特定的方法检查出微量的突变DNA分子，这可能成为早期检测乳腺癌微转移结节的一种分子诊断手段 [30] [31] 。PIK3CA的突变是与HR+/HER2−转移性乳腺癌标准辅助化疗的结局高度相关的预后指标 [32] 。最近的一项研究也发现不仅在PI3K抑制剂治疗组中PIK3CA突变可能作为HR+/HER2−乳腺癌不良预后的重要预测因子，而且在非PI3K抑制治疗组也有同样的结果 [33] 。数据表明PIK3CA突变是具有PI3K通路依赖性的晚期或转移性HR+/HER2−乳腺癌的相关治疗靶点。2020年5月28日，欧洲药品管理局批准了alpelisib联合氟维司群用于治疗HR+/HER2−的绝经后女性患者和男性患者 [34] 。SOLAR-1 III期临床试验调查了alpelisib (一种特异性I类PI3K抑制剂加氟维司组对比安慰剂加氟维司组对转移性HR+/HER2乳腺癌患者的疗效和安全性)接受内分泌治疗的癌患者中，约85.6%的患者出现了内分泌抵抗 [35] 。Ramirez-Ardila等人也描述了晚期HR+/HER2−乳腺癌对不同治疗的反应 [36] ，研究结果指出。Stemke-Hale等的研究中没有发现PIK3CA突变与辅助他莫昔芬的作用之间存在关联 [37] 。也有一些作者描述了PIK3CA突变HR+/HER2−乳腺癌对他莫昔芬的耐药性之间的正向联系，此类晚期患者生存率更低，产生耐药的周期更短 [38] [39] ，而其他作者发现如果检测到PIK3CA突变表示肿瘤对他莫昔芬的敏感性偏高 [40] 。必须承认，这些联系复杂且涉及多重机制，且仍缺乏更加有力的前瞻性研究。同时这也表示了PIK3CA基因组畸变可预测HR+/HER2−乳腺癌疾病进展及肿瘤对药物治疗的反应，这也意味着PIK3CA基因突变的检测可作为预测患者预后的辅助因子、可以识别可能受益于PI3K靶向治疗的目标患者。

文章引用

依合里曼·买买提,梁丽萍,江志民,马晓梅. PIK3CA基因突变与HR阳性且HER2阴性乳腺癌的关系
The Relationship between PIK3CA Mutation and Hormone Receptor Positive and HER2 Negative Breast Cancer[J]. 临床医学进展, 2023, 13(02): 2724-2728. https://doi.org/10.12677/ACM.2023.132384

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    41. NOTES

    *通讯作者。

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