Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer
Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer
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DOI：
10.1007/s10549-011-1572-5
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发表时间：
2011-07-01
影响因子：
3.8
通讯作者：
Fountzilas, G.
中科院分区：
文献类型：
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作者：
Razis, E.;Bobos, M.;Fountzilas, G.
曲妥珠单抗（T）在HER 2过表达和/或扩增的转移性乳腺癌（MBC）中有效，但在大量HER 2阳性患者中对T产生耐药性。了解耐药机制对这些患者的护理至关重要。福尔马林固定的石蜡包埋的肿瘤组织样本收集自256例接受T治疗的MBC患者。临床信息从患者的病历中回顾性收集。通过荧光原位杂交（FISH）和/或免疫组织化学（IHC）对HER 2状态进行的中心审查显示，在227例合格患者中，仅139例（61%）为真正的HER 2阳性。通过IHC评估PTEN、ER、PgR和Ki 67，同时通过FISH评估PTEN状态。采用单核苷酸多态性（SNP）基因分型鉴定PIK 3CA突变。HER 2阳性患者的中位至进展时间（TTP）为14.4个月，HER 2阴性患者为10.3个月（对数秩，P = 0.22）。HER 2阳性和HER 2阴性亚组从T开始的生存期（survivalT）分别为50.4个月和35.3个月（P = 0.006）。更高的进展风险与HER 2阳性状态和PIK 3CA突变的存在相关（P = 0.014）。在整个人群（P = 0.029）和HER 2阳性人群（P = 0.017）中，通过IHC确定的PTEN缺失与较低的存活率T相关。将PIK 3CA突变和/或PTEN缺失状态作为单一参数一起评估，以估计PI 3 K/AKT分子途径活化的影响，并且其与TTP降低和PIK 3CA突变和/或PTEN缺失状态显著相关。（总人群P = 0.003，HER 2阳性患者P = 0.004）和生存期（生存T，总人群P = 0.011，HER 2阳性患者P = 0.006）。在该曲妥珠单抗治疗的乳腺癌人群中，PIK 3CA激活突变与TTP缩短和PTEN丢失以及生存期降低相关。PI 3 K/AKT通路的激活与TTP和生存率相关，表明该通路的状态对曲妥珠单抗疗效有不良影响。
Trastuzumab (T) is effective in metastatic breast cancer (MBC) with HER2 overexpression and/or amplification, but resistance to T develops in a significant number of HER2-positive patients. Understanding the mechanisms of resistance is critical to the care of these patients. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 256 patients with T-treated MBC. Clinical information was collected retrospectively from the patients' medical records. Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) revealed that of the 227 eligible patients only 139 (61%) were truly HER2-positive. PTEN, ER, PgR, and Ki67 were evaluated by IHC, while PTEN status was evaluated by FISH as well. PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping. Median time to progression (TTP) was 14.4 months for the HER2-positive and 10.3 for the HER2-negative patients (log-rank, P = 0.22). Survival from the initiation of T (survivalT) was 50.4 months for the HER2-positive and 35.3 for the HER2-negative subgroups (P = 0.006). Higher risk of progression was associated with HER2-positive status and the presence of PIK3CA mutations (P = 0.014). PTEN loss, as determined by IHC, was associated with lower survivalT in the whole population (P = 0.029) and in the HER2-positive population (P = 0.017). PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased TTP (P = 0.003 in the total population, P = 0.004 in HER2-positive patients) and survival (survivalT, P = 0.011 in total, P = 0.006 in HER2-positive). In this trastuzumab-treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival. The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway's status on trastuzumab efficacy.