Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor-Positive, HER2-Negative Early Breast Cancer.
Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor-Positive, HER2-Negative Early Breast Cancer.
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DOI：
10.1016/j.tranon.2016.01.001
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发表时间：
2016-04
影响因子：
5
通讯作者：
Bachelot T
中科院分区：
文献类型：
--
作者：
Azim HA;Kassem L;Treilleux I;Wang Q;El Enein MA;Anis SE;Bachelot T
背景技术背景：PI 3 K/AKT/mTOR通路的改变在乳腺癌的发生、发展和转移扩散中起重要作用。此外，它们还涉及耐药性的过程，特别是内分泌疗法。在这项研究中，我们的目的是确定在开罗大学医院治疗的雌激素受体（ER）阳性，人表皮生长因子受体2阴性（管腔）早期乳腺癌妇女的PI 3 K突变和不同下游分子的磷酸化形式的表达之间的相关性。方法：使用下一代测序检测PIK 3CA热点（外显子9和20）中的突变。对从Centre Léon Bérard（CLB）病理学部门的35名埃及管腔乳腺癌患者的样本制备的组织微阵列块进行免疫组织化学。对染色肿瘤细胞的强度和百分比进行积分，以定义高与低生物标志物表达。细胞质和细胞核染色分别分级。患者的中位随访时间为4.7年（2.1 - 6.9年）。分析PI 3 K基因突变和pAKT、LKB 1、p4 EBP 1、pS 6核糖体蛋白（pS 6 RP）的免疫组化表达与患者临床病理特征及无病生存期（DFS）的关系。结果：诊断时的中位年龄为51.3岁（范围：25 - 82岁）。79.2%的病例肿瘤大于20 mm，57.9%的病例有腋窝淋巴结沉积。只有12.3%的患者为SBR I级肿瘤，50.8%为II级，36.8%为III级。6例（17%）经病理检查ER为阴性。32例可评估LKB 1和pAKT，33例可评估p4 EBP 1和pS 6 RP，24例可评估PI 3 K突变。细胞核LKB 1、细胞质LKB 1、细胞核pAKT、细胞质pAKT、细胞核p4 EBP 1和细胞质pS 6 RP的高表达率分别为65.6%、62.5%、62.5%、68.8%、42.4%和57.6%。PIK 3CA突变7例（29.2%）。PI 3 K突变与pAKT的核定位相关（即，胞浆pAKT降低，P = 0.04;核pAKT增加，P = 0.10）。PI 3 K突变与pS 6 RP（P = 0.10）和p4 EBP 1（P = 0.19）的表达呈负相关。核LKB 1表达是预后良好的标志。它与较小的肿瘤（P = 0.05），更多的ER（P = 0.08）和孕酮受体（PgR）阳性（P = 0.002）相关。在Kaplan Meier（KM）模型中，核LKB 1高的患者DFS较长（风险比= 0.36; 95%置信区间，0.15-1.10; P = 0.08）。核pAKT高表达也有延长DFS的趋势（风险比= 0.51; 95%置信区间，0.11-1.16; P = 0.13）。p4 EBP 1、pS 6 RP的表达和PI 3 K突变状态在我们的队列中没有显示出任何预后意义。结论：在所研究的生物标志物中，只有LKB 1和pAKT的核表达倾向于预测乳腺癌患者的生存率。PI 3 K突变与核内pAKT的表达相关，而与pS 6 RP和p4 EBP 1的表达无关。
BACKGROUND: The PI3K/AKT/mTOR pathway alterations have been shown to play significant roles in the development, progression, and metastatic spread of breast cancer. Furthermore, they have been implicated in the process of drug resistance, especially endocrinal therapies. In this study, we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules in women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative (luminal) early breast cancer treated at Cairo university hospitals. METHODS: Next-generation sequencing was used to detect mutations in the PIK3CA hotspots (in exons 9 and 20). Immunohistochemistry was performed on tissue microarray blocks prepared from samples of 35 Egyptian luminal breast cancer patients in the pathology department of Centre Léon Bérard (CLB). The intensity and the percentage of stained tumor cells were integrated to define high versus low biomarker expression. The cytoplasmic and nuclear stainings were graded separately. Patients were followed for a median of 4.7 years (2.1 to 6.9 years). Correlation was done between PI3K mutations and the immunohistochemistry expression of pAKT, LKB1, p4EBP1, and pS6 ribosomal protein (pS6RP) with the clinicopathologic features and disease free survival (DFS) of the patients. RESULTS: Median age at diagnosis was 51.3 years (range, 25 to 82 years). Tumors were larger than 20 mm in 79.2% of the cases, whereas 57.9% had axillary lymph node deposits. Only 12.3% of the patients had SBR grade I tumors, 50.8% had grade II, and 36.8% had grade III. ERs were negative in 6 patients (17%) after pathology review. Thirty-two cases were assessable for LKB1 and pAKT, 33 for p4EBP1 and pS6RP, and 24 for PI3K mutations. Nuclear LKB1, cytoplasmic LKB1, nuclear pAKT, cytoplasmic pAKT, nuclear p4EBP1, and cytoplasmic pS6RP expression was high in 65.6%, 62.5%, 62.5%, 68.8%, 42.4%, and 57.6%, respectively. PIK3CA mutations were found in 7 patients (29.2%). PI3K mutations were correlated with nuclear localization of pAKT (i.e., decreased cytoplasmic pAKT, P = .04; and increased nuclear pAKT, P = .10). There was a tendency toward an inverse correlation between PI3K mutations and the expression of pS6RP (P = .10) and p4EBP1 (P = .19). Nuclear LKB1 expression was a marker of good prognosis. It was associated with smaller tumors (P = .05), more ER (P = .08) and progesteron receptor (PgR) positivity (P = .002). In the Kaplan Meier (KM) model, patients with high nuclear LKB1 had longer DFS (hazard ratio = 0.36; 95% confidence interval, 0.15-1.10; P = .08). Nuclear pAKT high expression also carried a tendency toward longer DFS (hazard ratio = 0.51; 95% confidence interval, 0.11-1.16; P = .13). The expression of p4EBP1, pS6RP, and the PI3K mutational status did not show any prognostic significance in our cohort. CONCLUSION: Among the studied biomarkers, only nuclear expression of LKB1 and pAKT tended to predict better survival in breast cancer patients. PI3K mutation was correlated with the expression of nuclear pAKT but not pS6RP or p4EBP1.