Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

Objective

A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC).

Methods

Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced.

Results

Three patients of 30 evaluable had PFS ≥ 6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months.

Conclusion

While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.     

Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance

Objectives

The identification of novel molecular biomarkers, predicting outcome of ovarian cancer, is highly desirable. Considering that angiogenesis is a critical factor for ascites development and peritoneal dissemination in ovarian cancer and given that the vascular endothelial growth factor (VEGF) receptor signaling axis is a major driver of angiogenesis, we sought to analyze expression and compartmental distribution of VEGF-receptor family in ovarian cancer and to assess its clinical relevance with regard to established clinicopathological parameters, tumor cell dissemination to the bone marrow (BM) and the patient's survival.

Methods

A total of 73 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGF-R1, VEGF-R2 and VEGF-R3 by immunohistochemistry. The presence of disseminated tumor cells (DTC) in the BM was analyzed by immunocytochemistry using the pancytokeratin antibody A45B/B3 and subsequent automatic detection based on staining and cytomorphology.

Results

In primary ovarian cancer tissue, VEGF-receptor expression, detected with an overall frequency of 44%, was mostly located in the vascular wall and across the stroma; positivity rates for VEGF-R1, VEGF-R2 and VEGF-R3 were 34%, 18% and 26%, respectively. Total VEGF-receptor expression correlated with residual tumor after primary debulking surgery and the presence of DTC at primary diagnosis (p = 0.035, p = 0.023, respectively). Interestingly, VEGF-R1 positivity significantly correlated with decreased progression-free survival (p = 0.026).

Conclusions

This is the first report, suggesting total VEGF-receptor status as a molecular biomarker for monitoring tumor cell spread to the BM and, particularly, revealing prognostic significance of VEGF-R1.     

VEGF和SDF-1/CXCR4在促进卵巢癌细胞侵袭与增殖中的相关作用

目的:研究血管内皮生长因子(VEGF)和趋化因子受体(Cys-X-Cysreceptor4,CXCR4)/配体基质细胞衍生因子-1(stromalcell-derivedfactor1,SDF-1)在卵巢上皮性癌细胞中的表达及其在促进卵巢癌细胞侵袭和增殖中的相关作用,进而探讨SDF-1/CX-CR4信号参与卵巢癌发生发展的相关机制。方法:(1)用Real-timeRT-PCR检测卵巢癌细胞株SKOV3中VEGF及其单克隆抗体anti-VEGF作用前后SDF-1/CXCR4mRNA表达水平的变化;(2)通过transwell小室体外侵袭实验检测VEGF和SDF-1以及anti-VEGF和CXCR4特异性抗体(AMD3100)对SKOV3细胞趋化活性的影响;(3)用MTT法测定VEGF和SDF-1以及anti-VEGF和AMD3100作用前后SKOV3细胞增殖率的变化。结果:(1)VEGF可以上调SDF-1和CXCR4的表达且有明显的剂量依赖性。(2)VEGF和SDF-1均有促进卵巢癌细胞侵袭的作用。VEGF的促侵袭作用具有一定的剂量依赖性且可以被40μg/mlanti-VEGF阻断,SDF-1的作用没有明显剂量依赖性;CXCR4的特异性受体抑制剂AMD3100有阻断VEGF和SDF-1的促侵袭作用。(3)VEGF和SDF-1均有促进卵巢癌细胞增殖的作用。VEGF的作用具有剂量依赖性,其效应可被anti-VEGF阻断,但不被AMD3100阻断,SDF-1的促增殖作用无明显剂量依赖性,其效应可被AMD3100阻断。结论:VEGF和SDF-1对卵巢癌细胞的侵袭和增殖有直接促进作用,并且VEGF可以上调SDF-1/CXCR4的表达。两者与卵巢癌的发生和生物学行为关系密切并协同促进卵巢癌细胞的转移。     

卵巢上皮性癌患者术前血清血管内皮生长因子与CA125水平的相关性及其预测预后的价值

目的分析卵巢上皮性癌（卵巢癌）患者术前血清血管内皮生长因子（VEGF）与CA125水平的相关性,探讨术前血清VEGF水平在卵巢癌患者预后判断中的价值。方法采用酶联免疫吸附试验（EHSA）测定41例卵巢癌患者（研究组）库存的术前血清中VEGF的水平,采用化学发光法测定同一份血清的CA125水平;以同期20例盆腔检查正常的妇女作为对照组。结合随诊资料,分析卵巢癌患者术前血清VEGF水平与CA125水平的相关性,并分析术前血清VEGF水平与患者复发和生存时间的关系。结果（1）研究组术前血清VEGF和CA125水平均明显高于对照组（VEGF中位数分别为415和165ng／L,CA125分别为611和16kU／L）,差异均有统计学意义（P〈0．01）;（2）Spearman等级相关分析显示,卵巢癌患者术前血清VEGF水平与血清CA125水平间无明显相关性（P=0．989）;（3）卵巢癌患者术前血清VEGF水平与其复发相关,复发者术前VEGF水平明显高于无复发者（中位数分别为490和315ng／L,P=0．035）;（4）单因素Kaplan-Meier法分析显示,卵巢癌患者术前血清VEGF水平与其生存时间呈负相关,高血清VEGF水平者的生存时间明显短于低血清VEGF水平者（中位数生存时间分别为18个月和〉35个月,P=0．010）;（5）多因素Cox回归模型分析显示,卵巢癌患者术前血清VEGF水平是与其生存时间有关的独立预后因素（P=0．042）。结论卵巢癌患者术前血清VEGF水平与CA125水平无明显相关性,VEGF水平变化是影响患者预后的独立因素。