Alpelisib

点击蓝字，关注我们大家好 我是广东省人民医院廖宁医生，欢迎大家来到《Liao ning’s Insight与宁同行，乳腺癌精准基因靶点GENEfield》专栏，今天我将为大家解读乳腺癌经典信号通路——PAM通路。PAM通路是指PI3K-AKT-mTOR信号通路，最先由美国科学家Lewis C. Cantley教授于 1988 年发现[1]。经过科学家们不断探索和研究，PAM通路的异常激活被证实在乳腺癌的发生、发展中起到了重要作用[2]。PAM 通路的信号转导，主要是由PIK3CA、AKT1、PTEN和mTOR基因编码的蛋白完成。PAM 信号通路的激活首先由胞外配体，与跨膜蛋白RTK结合或趋化因子与GPCR受体结合，从而激活PI3K蛋白，激活的PI3K催化PIP2磷酸化为PIP3，PIP3再招募AKT到细胞膜上，并进一步激活AKT。激活后的AKT作用于mTOR等下游底物，mTOR被激活后可增强原癌基因的转录，促进血管形成并影响代谢，促进肿瘤细胞的增殖与生存。PTEN是PAM通路的负调节因子，通过将PIP3去磷酸化，实现PI3K/PIP3信号传导的阻断，当 PIK3CA、PTEN、AKT1等关键驱动基因异常，PAM 通路调节机制失调会导致细胞异常增殖[3,4]。有研究显示，PAM信号通路的异常激活与早期乳腺癌的病理完全缓解率低[5]、复发风险高、总生存期短相关[6]，与晚期乳腺癌生存预后差相关[7]。此外，PAM信号通路的异常激活还与HR+/HER2-乳腺癌内分泌治疗耐药、CDK4/6抑制剂耐药相关[8]。根据广东省人民医院的数据，62.6%的乳腺癌患者存在至少一个PAM通路基因突变[9]。其中最常见的3个基因为PIK3CA发生率可达45%、PTEN发生率可达7.5%、AKT1发生率可达5.9%[9]。PIK3CA突变是PAM通路最常见的基因突变，在总体乳腺癌的发生率约为30%-40%[7]。相较高加索人，中国乳腺癌患者PIK3CA突变发生率更高，可达45.6%[10]。ER阳性和ER低表达转移性乳腺癌中，PIK3CA突变均是发生率最高的基因突变。而在ER阴性转移性乳腺癌中，PIK3CA突变发生率也可达13%[11]。PIK3CA突变与预后不良相关。一项纳入3219例HR+/HER2-转移性乳腺癌病例的回顾性分析显示，无论进行何种治疗方案，相较 PIK3CA未突变组，PIK3CA突变组患者中位PFS更短[7]。目前，乳腺癌治疗领域靶向PIK3CA的药物包括PI3K抑制剂伊那利塞、阿培利司，其中阿培利司尚未在国内获批。PTEN蛋白功能缺陷是导致 PAM 信号通路持续激活，从而使细胞持续增殖的因素之一。在TNBC 中，PTEN蛋白功能缺陷发生率可达67%，而在Luminal型乳腺癌中发生率为29%~44%，在HER2阳性乳腺癌中发生率可达22%[2]。由于PTEN蛋白功能缺陷，可能由基因突变、启动子甲基化异常、RNA 调控异常或翻译后修饰异常等多种原因导致[12]，PTEN基因突变和PTEN蛋白功能缺陷的发生率存在较大差异。一项纳入4895例乳腺癌组织样本的回顾性研究显示，PTEN蛋白功能缺失的发生率高达54.8%。其中7.0%的样本中，携带PTEN基因突变和/或51.4%的样本存在PTEN蛋白功能缺陷[13]。根据CAPItello-291研究的探索性分析结果，内分泌治疗后进展或复发HR+/HER2-晚期乳腺癌患者中，免疫组化检测的PTEN蛋白功能缺陷发生率达19%，而这些PTEN蛋白功能缺陷患者也可从卡匹色替联合氟维司群疗法中获益[14]。因而 PTEN蛋白功能缺陷，也可能是筛选优势患者的生物标志物之一。一项回顾性研究纳入了4111例 PTEN缺失或突变的乳腺癌患者，结果显示PTEN蛋白功能缺陷与乳腺癌预后更差有关[15]。AKT处于PAM通路的关键中心环节，可激活下游因子调控细胞周期。AKT1主要突变在各亚型乳腺癌中发生率相似，为2.6%~7.4%[2]。在中国乳腺癌患者中，AKT1的突变率约为 6.4%，尤其是Luminal A型乳腺癌患者的突变率可达12.1%[16]。目前靶向AKT抑制剂卡匹色替已被证实，可为内分泌治疗经治且存在PIK3CA/AKT1/PTEN任意突变的HR+/HER2-转移性乳腺癌带来PFS获益[17]。总的来说PAM 通路相关基因突变在乳腺癌中发生率高，且目前已有相关药物可以靶向这一信号通路，从而延缓肿瘤发展、转移的进程。相信随着基因检测的普及，越来越多的乳腺癌患者可以接受个性化、精准化治疗策略，从靶向PAM通路的治疗中获益。感谢收看，我们下期再见！廖宁 教授广东省人民医院外科乳腺科行政主任，医学博士，教授，博士生导师国际肿瘤学预防和治疗学会（ISOPT）公共教育主任美国肿瘤外科学会（SSO）国际理事会理事国际前哨淋巴结学会（ISNS）国际理事会理事文章发表:Zhang W, Ning L (Corresponding author) et al. An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses. Nat Commun 2024; 15: 5470. (IF=16.6)Ning L (First author), Charles Balch et al. Accuracy and Reproducibility of ChatGPT Responses to 362 Breast Cancer Tumor Board Cases. JCO Clinical Cancer Informatics 2025.Ning L (First author & corresponding author), Li C, Cao L et al. Single-cell profile of tumor and immune cells in primary breast cancer, sentinel lymph node, and metastatic lymph node. Breast Cancer 2023; 30: 77-87 etc.Hello everyone, I am Dr. Liao Ning from Guangdong Provincial People's Hospital. Welcome to the "Liao Ning's Insight & Journey with Ning – Breast Cancer Precision Gene Target GENEfield" column,where today we'll delve into a pivotal signaling pathway in breast cancer: the PAM pathway.The PAM pathway refers to the PI3K-AKT-mTOR signaling pathway, first discovered by American scientist Prof. Lewis C. Cantley in 1988[1]. Through continuous exploration and research by scientists, the abnormal activation of the PAM pathway has been confirmed to play a crucial role in the initiation and progression of breast cancer[2].Signal transduction within the PAM pathway is primarily mediated by proteins encoded by the PIK3CA, AKT1 , PTEN , and mTOR genes. Activation of the PAM signaling pathway is initiated by the binding of extracellular ligands to transmembrane receptor tyrosine kinases or by the interaction of chemokines with G protein-coupled receptors, leading to the activation of PI3K protein. Activated PI3K catalyzes the phosphorylation of PIP2 to PIP3, which subsequently recruits AKT to the cell membrane, resulting in its further activation. Activated AKT then acts on downstream substrates, including mTOR. Upon activation, mTOR enhances oncogene transcription, promotes angiogenesis, and influences metabolism, thereby facilitating tumor cell proliferation and survival. PTEN functions as a negative regulator of the PAM pathway by dephosphorylating PIP3, thereby blocking PI3K/PIP3 signal transduction. Dysregulation of the PAM pathway's regulatory mechanisms, often due to abnormalities in key driver genes such as PIK3CA, PTEN, and AKT1, contributes to aberrant cellular proliferation [3,4].Studies have demonstrated that the dysregulation and subsequent hyperactivation of the PAM signaling pathway are associated with a diminished pathological complete response rate [5], elevated recurrence risk, and reduced overall survival in patients with early-stage breast cancer [6]. Moreover, this aberrant activation is correlated with an unfavorable survival prognosis in advanced breast cancer[7].Beyond these associations, the abnormal activation of the PAM pathway has also been implicated in mediating resistance to endocrine therapy and CDK4/6 inhibitors in individuals with HR+/HER2- breast cancer [8].Data from Guangdong Provincial People's Hospital indicate that 62.6% of breast cancer patients possess at least one mutation in a PAM pathway gene [9]. Among these, the three most common mutated genes are PIK3CA, with an incidence of up to 45%, PTEN, at up to 7.5%, and AKT1, at up to 5.9% [9].PIK3CA mutations represent the most prevalent genetic alteration within the PAM pathway, with an overall incidence of approximately 30-40% in breast cancer [7]. Notably, the incidence of PIK3CA mutations is higher in Chinese breast cancer patients compared to Caucasians, reaching up to 45.6% [10]. PIK3CA mutations are the most frequent genetic alterations observed in both ER-positive and ER-low-expressing metastatic breast cancer. Even in ER-negative metastatic breast cancer, the incidence of PIK3CA mutations can reach 13% [11]. PIK3CA mutations are associated with a poor prognosis. A retrospective analysis of 3219 cases of HR+/HER2- metastatic breast cancer revealed that patients with PIK3CA mutations had a shorter median progression-free survival  compared to those without the mutation, regardless of the treatment regimen [7]. Currently, drugs targeting PIK3CA in breast cancer treatment include the PI3K inhibitors Inavolisib and alpelisib. Of these, alpelisib is not yet approved in China.PTEN protein dysfunction is a contributing factor to the sustained activation of the PAM signaling pathway, which in turn drives continuous cell proliferation. The incidence of PTEN protein dysfunction can reach up to 67% in Triple-Negative Breast Cancer, while it ranges from 29% to 44% in Luminal breast cancer and up to 22% in HER2-positive breast cancer [2].Since PTEN protein dysfunction can stem from various causes, including gene mutations, abnormal promoter methylation, aberrant RNA regulation, or post-translational modifications   [12], there's a significant disparity between the incidence of PTEN gene mutations and PTEN protein dysfunction. A retrospective study of 4895 breast cancer tissue samples revealed that PTEN protein loss occurred in a high proportion of cases, reaching 54.8%. Within this group, 7.0% of samples carried PTEN gene mutations and/or 51.4% exhibited PTEN  protein dysfunction [13].According to exploratory analysis results from the CAPItello-291 study, the incidence of PTEN protein dysfunction, as detected by immunohistochemistry, was 19% in HR+/HER2- advanced breast cancer patients who had progressed or relapsed after endocrine therapy. Patients with this PTEN protein dysfunction also benefited from capivasertib combined with fulvestrant therapy [14]. Consequently, PTEN protein dysfunction could serve as a biomarker for selecting patients who would most benefit from targeted therapies. A retrospective study involving 4111 breast cancer patients with PTEN deletion or mutation demonstrated that PTEN protein dysfunction was associated with a poorer breast cancer prognosis [15].AKT occupies a central, pivotal position within the PAM pathway, capable of activating downstream effectors and regulating the cell cycle. The incidence of AKT1 mutations is relatively consistent across various breast cancer subtypes, ranging from 2.6% to 7.4% [2]. In Chinese breast cancer patients, the AKT1 mutation rate is approximately 6.4%, with a notably higher incidence of up to 12.1% observed specifically in Luminal A subtype breast cancer patients [16]. Currently, the AKT inhibitor capivasertib has demonstrated progression-free survival benefits in HR+/HER2- metastatic breast cancer patients who have previously undergone endocrine therapy and harbor any PIK3CA, AKT1, or PTEN mutation [17].In summary, PAM pathway-related gene mutations are highly prevalent in breast cancer, and existing targeted therapies are capable of modulating this signaling pathway to impede tumor progression and metastasis. As genetic testing becomes more widespread, it is anticipated that an increasing number of breast cancer patients will receive personalized and precision treatment strategies, thereby benefiting from PAM pathway-targeted therapies.Thank you for watching, and we'll see you next time! See you!Prof. Ning LiaoAdministrative Director, Department of Breast Surgery, Guangdong Provincial People's Hospital; MD, Professor, Doctoral SupervisorDirector of Public Education, International Society of Oncology Prevention and Treatments (ISOPT)International Board Member, Society of Surgical Oncology (SSO), USAInternational Board Member, International Society of Sentinel Node (ISNS)Publications:Zhang W, Ning L (Corresponding author) et al. An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses. Nat Commun 2024; 15: 5470. (IF=16.6)Ning L (First author), Charles Balch et al. Accuracy and Reproducibility of ChatGPT Responses to 362 Breast Cancer Tumor Board Cases. JCO Clinical Cancer Informatics 2025.Ning L (First author & corresponding author), Li C, Cao L et al. Single-cell profile of tumor and immune cells in primary breast cancer, sentinel lymph node, and metastatic lymph node. Breast Cancer 2023; 30: 77-87 etc.参考文献：（滑动查看）[1] Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332(6165):644-646. doi:10.1038/332644a0[2] Zhu, Kunrui et al. PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer. Cells vol. 11,16 2508. 12 Aug. 2022, doi:10.3390/cells11162508[3] Rasti, Aryana R et al. PIK3CA Mutations Drive Therapeutic Resistance in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. JCO precision oncology vol. 6 (2022): e2100370.[4] Browne IM, André F, Chandarlapaty S, Carey LA, Turner NC. Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer. Lancet Oncol. 2024 Apr;25(4):e139-e151.[5] Jank P, Karn T, van Mackelenbergh M, et al. An analysis of PIK3CA hotspot mutations and response to neoadjuvant therapy in breast cancer patients from four prospective clinical trials. Clin Cancer Res. Published online June 5, 2024. doi:10.1158/1078-0432.CCR-24-0459[6] Zagami P, Fernandez-Martinez A, Rashid NU, et al. Association of PIK3CA Mutation With Pathologic Complete Response and Outcome by Hormone Receptor Status and Intrinsic Subtype in Early-Stage ERBB2/HER2-Positive Breast Cancer. JAMA Netw Open. 2023;6(12):e2348814. Published 2023 Dec 1. doi:10.1001/jamanetworkopen.2023.48814[7] 赵佳宁,刘月平. 乳腺癌PIK3CA突变的临床意义及其检测研究进展[J]. 临床与实验病理学杂志,2024,40(9):973-978. DOI:10.13315/j.cnki.cjcep.2024.09.014.[8] Schagerholm, C., Robertson, S., Toosi, H. et al. PIK3CA mutations in endocrine-resistant breast cancer. Sci Rep 14, 12542 (2024).[9] Weikai Xiao, et al. J Cancer. 2021 May 27;12(14):4408-4417. [10] Jia M,Liao N,Chen B,et al. PIK3CA somatic alterations in invasive breast cancers:different spectrum from Caucasians to Chinese detected by next generation sequencing[J].Breast Cancer,2021,28(3):644-652. [11] Chiara Corti, et al. Differential genomic landscape of estrogen receptor (ER)-low versus ER-positive (ER+) and ER-negative (ER-) metastatic breast cancer (MBC).2025 ASCO 1071.[12] Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018 Sep;19(9):547-562. doi: 10.1038/s41580-018-0015-0. PMID: 29858604. [13] Khoury K, et al. Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer. Front Oncol. 2020 Aug 31;10:1475.[14] Capivasertib–fulvestrant for patients with HRpositive/HER2-negative advanced breast cancer who had relapsed or progressed during or after aromatase inhibitor treatment: exploratory analysis of PTEN deficiency by IHC from the Phase III CAPItello-291 trial.2024 SABCS P2-03-19.[15] Wang T,et al. Loss of PTEN Expression, PIK3CA Mutations, and Breast Cancer Survival in the Nurses' Health Studies. Cancer Epidemiol Biomarkers Prev. 2022 Oct 4;31(10):1926-1934. [16] Jiang YZ, Ma D, Jin X, et al. Integrated multiomic profiling of breast cancer in the Chinese population reveals patient stratification and therapeutic vulnerabilities. Nat Cancer 2024;5(4):673-690.[17] Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070.（来源：良医汇肿瘤资讯）声 明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。