Nixon Mellissa J, Formisano Luigi, Mayer Ingrid A, Estrada M Valeria, González-Ericsson Paula I, Isakoff Steven J, Forero-Torres Andrés, Won Helen, Sanders Melinda E, Solit David B, Berger Michael F, Cantley Lewis C, Winer Eric P, Arteaga Carlos L, Balko Justin M
1Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN USA.
2Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN USA.
NPJ Breast Cancer. 2019 Sep 23;5:31. doi: 10.1038/s41523-019-0126-6. eCollection 2019.
Clinical trials have demonstrated the efficacy of combining phosphoinositide 3-kinase (PI3K) inhibitors with endocrine therapies in hormone therapy-refractory breast cancer. However, biomarkers of PI3K pathway dependence in ER+ breast cancer have not been fully established. Hotspot mutations in the alpha isoform of PI3K () are frequent in ER+ disease and may identify tumors that respond to PI3K inhibitors. It is unclear whether PIK3CA mutations are the only biomarker to suggest pathway dependence and response to therapy. We performed correlative molecular characterization of primary and metastatic tissue from patients enrolled in a phase Ib study combining buparlisib (NVP-BKM-120), a pan-PI3K inhibitor, with letrozole in ER+, human epidermal growth factor-2 (HER2)-negative, metastatic breast cancer. Activating mutations in and inactivating mutations marked tumors from patients with clinical benefit (≥6 months of stable disease). Patients harboring mutations in both genes exhibited the greatest likelihood of clinical benefit. In ER+ breast cancer cell lines, siRNA-mediated knockdown of MAP3K1 did not affect the response to buparlisib. In a subset of patients treated with buparlisib or the PI3Kα inhibitor alpelisib each with letrozole where PAM50 analysis was performed, nearly all tumors from patients with clinical benefit had a luminal A subtype. Mutations in MAP3K1 in ER+ breast cancer may be associated with clinical benefit from combined inhibition of PI3K and ER, but we could not ascribe direct biological function therein, suggesting they may be a surrogate for luminal A status. We posit that luminal A tumors may be a target population for this therapeutic combination.
临床试验已证明，在激素治疗难治性乳腺癌中，将磷酸肌醇3激酶（PI3K）抑制剂与内分泌疗法联合使用具有疗效。然而，雌激素受体阳性（ER+）乳腺癌中PI3K通路依赖性的生物标志物尚未完全确立。PI3Kα异构体的热点突变在ER+疾病中很常见，可能识别出对PI3K抑制剂有反应的肿瘤。尚不清楚PIK3CA突变是否是表明通路依赖性和对治疗反应的唯一生物标志物。我们对参加一项Ib期研究的患者的原发和转移组织进行了相关分子特征分析，该研究将泛PI3K抑制剂布帕利西布（NVP-BKM-120）与来曲唑联合用于ER+、人表皮生长因子2（HER2）阴性的转移性乳腺癌。PIK3CA的激活突变和PTEN的失活突变标志着具有临床获益（疾病稳定≥6个月）患者的肿瘤。两个基因均发生突变的患者临床获益可能性最大。在ER+乳腺癌细胞系中，siRNA介导的MAP3K1敲低不影响对布帕利西布的反应。在接受布帕利西布或PI3Kα抑制剂阿培利司与来曲唑联合治疗且进行了PAM50分析的部分患者中，几乎所有具有临床获益的患者的肿瘤均为管腔A型亚型。ER+乳腺癌中MAP3K1的突变可能与PI3K和ER联合抑制的临床获益相关，但我们无法确定其中的直接生物学功能，这表明它们可能是管腔A型状态的替代指标。我们认为管腔A型肿瘤可能是这种治疗组合的目标人群。
