Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives.
Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives.
复制标题
Alpelisib在PIK3CA突变乳腺癌治疗中的作用：患者选择和临床前景。
DOI：
10.2147/tcrm.s251668
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发表时间：
2021
影响因子：
2.8
通讯作者：
Lu YS
中科院分区：
文献类型：
--
作者：
Chang DY;Ma WL;Lu YS
PI 3 K/AKT/mTOR通路长期以来一直被认为在癌细胞的生长和存活中起重要作用。乳腺肿瘤通常具有PIK 3CA基因改变，因此构成了合理的药物靶点。然而，已经花了很多年来证明PI 3 K抑制的临床相关功效并最终获得监管批准。随着PI 3 K抑制剂的数据不断成熟，本文综述了当前的科学状况，包括PIK 3CA改变在乳腺癌中的预后作用; PI 3 K抑制剂的演变;第一类口服选择性PI 3 K α抑制剂alpelisib的临床效用; PIK 3CA突变检测技术;和不良反应管理。PIK 3CA突变的乳腺癌预测PI 3 K抑制剂治疗的生存获益。泛PI 3 K抑制剂buparlisib和β-亚型保留PI 3 K抑制剂taselisib在临床试验中达到了疗效终点，但pictilisib没有;此外，这三种药物的耐受性差，取消了进一步的临床试验。Alpelisib的耐受性更好，毒性特征更易于管理;主要不良事件高血糖症、皮疹和腹泻可以通过强化监测和及时干预来缓解，从而使患者能够坚持临床有益的治疗。Alpelisib联合内分泌治疗显示出治疗绝经后HR+/HER 2-晚期乳腺癌女性的良好疗效。支持在一线内分泌治疗伴或不伴CDK 4/6抑制剂的疾病进展后使用alpelisib的现有证据证明了在诊断HR+/HER 2-晚期乳腺癌时进行PIK 3CA突变检测的合理性，这可以使用肿瘤组织或循环肿瘤DNA进行。通过使用经验证的测试方法进行适当的毒性管理和患者选择，所有符合条件的患者都可能从这种新治疗中受益。正在进行进一步的临床试验，以评估激素治疗与PI 3 K，AKT，mTOR或CDK 4/6抑制剂的组合，或在患有其他乳腺亚型的男性和女性中进行的研究。
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 PIK3CA 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 PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA-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 PIK3CA 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.