PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib.
PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib.
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DOI：
10.1186/1471-2407-11-248
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发表时间：
2011-06-15
期刊：
影响因子：
3.8
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Wang L;Zhang Q;Zhang J;Sun S;Guo H;Jia Z;Wang B;Shao Z;Wang Z;Hu X
人表皮生长因子受体 2 (HER2) 是 HER2 阳性（称为 HER2 过表达）乳腺癌中最重要的 ErbB 受体酪氨酸激酶 (RTK) 家族成员，其依赖于或“成瘾”于磷脂酰肌醇 3 激酶 (PI3K) 途径。 HER2相关靶向药物曲妥珠单抗和拉帕替尼已成为治疗HER2阳性乳腺癌的基础。本研究旨在探讨接受蒽环类药物、紫杉烷类药物和曲妥珠单抗治疗的 HER2 阳性转移性乳腺癌患者中 PI3K 通路激活与拉帕替尼敏感性之间的关系。全球拉帕替尼扩大使用计划招募了 67 名 HER2 阳性转移性乳腺癌患者，其中 57 名患者拥有可用于确定 PI3K 通路状态的原发肿瘤标本。通过免疫组织化学染色测定 PTEN 状态，并通过 PCR 测序检测 PIK3CA 突变。所有患者均连续接受拉帕替尼 1250 mg/天和卡培他滨 1000 mg/m2 每日两次治疗，疗程为 2 周，停药 1 周，直至疾病进展、死亡、撤回知情同意书或出现无法耐受的毒性。 PIK3CA 突变和 PTEN 缺失分别在 12.3% (7/57) 和 31.6% (18/57) 的患者中检测到。与 35 名未激活的患者相比，22 名 PI3K 通路激活（定义为 PIK3CA 突变和/或 PTEN 表达缺失）的患者的临床获益率较低（36.4% 对比 68.6%，P = 0.017），总体缓解率较低（9.1% 对比 31.4%，P = 0.05）。对首次含曲妥珠单抗方案治疗数据的回顾性分析表明，PI3K 通路激活与较短的中位无进展生存期相关（4.5 个月与 9.0 个月，P = 0.013）。 PIK3CA 突变在老年 HER2 阳性乳腺癌患者中更常见。 PIK3CA 突变和 PTEN 缺失并不相互排斥。 PTEN 缺失或 PIK3CA 突变导致的 PI3K 通路激活可能导致对拉帕替尼和曲妥珠单抗的耐药性（http://ClinicalTrials.gov 编号，NCT00338247）。
Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or "addictive" to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab. Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity. PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013). PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting from PTEN loss or PIK3CA mutations may lead to drug resistance to lapatinib and trastuzumab (http://ClinicalTrials.gov number, NCT00338247).
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影响因子：
45.3
作者：
Dave, Bhuvanesh;Migliaccio, Ilenia;Chang, Jenny C.
通讯作者：
Chang, Jenny C.
影响因子：
7.3
作者：
Buttitta, F;Felicioni, L;Marchetti, A
通讯作者：
Marchetti, A
磷脂酰肌醇3-激酶过度激活导致拉帕替尼的抗性，这是由mTOR/磷脂酰/磷脂酰肌醇3-激酶抑制剂NVP-BEZ235逆转的。
影响因子：
11.2
作者：
Eichhorn PJ;Gili M;Scaltriti M;Serra V;Guzman M;Nijkamp W;Beijersbergen RL;Valero V;Seoane J;Bernards R;Baselga J
通讯作者：
Baselga J
影响因子：
45.3
作者：
Di Leo, Angelo;Gomez, Henry L.;Press, Michael F.
通讯作者：
Press, Michael F.
影响因子：
11.5
作者：
Kalinsky, Kevin;Jacks, Lindsay M.;Moynahan, Mary Ellen
通讯作者：
Moynahan, Mary Ellen