Chang Dwan-Ying, Ma Wei-Li, Lu Yen-Shen
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Ther Clin Risk Manag. 2021 Mar 5;17:193-207. doi: 10.2147/TCRM.S251668. eCollection 2021.
The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; mutation detection techniques; and adverse effect management. -mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2- advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies mutation testing upon diagnosing HR+/HER2- advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.
长期以来，人们一直认为PI3K/AKT/mTOR通路在癌细胞的生长和存活中起主要作用。乳腺肿瘤常常存在基因改变，因此构成了一个合理的药物靶点。然而，花了很多年才证明PI3K抑制具有临床相关疗效并最终获得监管批准。随着PI3K抑制剂数据的不断成熟，本综述更新并总结了当前的科学现状，包括PI3K改变在乳腺癌中的预后作用；PI3K抑制剂的演变；一流的口服选择性PI3Kα抑制剂阿培利司的临床应用；PIK3CA突变检测技术；以及不良反应管理。PIK3CA突变的乳腺癌预测PI3K抑制剂治疗可带来生存获益。泛PI3K抑制剂布帕利司和保留β异构体的PI3K抑制剂塔西利司在临床试验中达到了疗效终点，但pictilisib未达到；此外，这三种药物的耐受性差导致进一步的临床试验终止。阿培利司耐受性更好，毒性特征更易于管理；主要不良事件高血糖、皮疹和腹泻可通过加强监测和及时干预得到缓解，从而使患者能够坚持接受具有临床益处的治疗。阿培利司联合内分泌治疗在治疗HR+/HER2-晚期绝经后乳腺癌方面显示出有前景的疗效。支持在一线内分泌治疗（无论是否使用CDK4/6抑制剂）疾病进展后使用阿培利司的现有证据证明，在诊断HR+/HER₂-晚期乳腺癌时进行PIK3CA突变检测是合理的，这可以使用肿瘤组织或循环肿瘤DNA来完成。通过适当的毒性管理和使用经过验证的检测方法进行患者选择，所有符合条件的患者都可能从这种新治疗中获益。评估激素疗法与PI3K、AKT、mTOR或CDK 4/6抑制剂联合使用的进一步临床试验，或针对其他乳腺亚型的男性和女性的研究正在进行中。
