Overexpression of HER2/HER3 and clinical feature of ovarian cancer.

OBJECTIVES: Human epidermal growth factor receptor-2 (HER2) and 3 (HER3) belong to the epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases. In this study, we assessed HER2/HER3 expression levels in specimens of epithelial ovarian cancer and determined their correlation with clinical features of ovarian cancer. METHODS: Tissue microarrays (TMAs) were prepared from paraffin blocks of 105 ovarian tumour samples. HER2, HER3, PI3K, Akt, p-Akt, mTOR, p-mTOR, S6, and p-S6 expression levels were investigated using immunohistochemistry (IHC). HER2 and HER3 amplifications were determined using in situ hybridization (ISH). The correlation between HER2/3 expression and disease outcome of the patients including surgical outcome, progression-free survival (PFS) and overall survival (OS) was analysed. RESULTS: HER2 positivity was 3.8% by IHC and 5.7% by ISH, whereas that of HER3 was 12.4% and 8.6%, respectively. HER2 status by either IHC or ISH was not related to PFS (p=0.128, 0.168, respectively) and OS (p=0.245, 0.164, respectively). However, the HER3 status determined using fluorescence ISH was associated with poor PFS (p=0.035 on log rank test), which was a significant risk factor even after adjusting other possible risk factors in multivariate analysis (hazard ratio=2.377 [1.18-7.49], p=0.021). Expressions of Akt, p-mTOR, and S6 were also related with poor progression (p=0.008, 0.049, 0.014, respectively). CONCLUSION: HER3 is possibly an independent marker for poor prognosis in individuals with ovarian cancer, as the HER3 signalling pathway is distinct from that of HER2. The possibility of targeted therapy for patients with HER3 alteration in ovarian cancer should be evaluated.

Circulating endothelial progenitor cells in gynaecological cancer.

OBJECTIVES: To compare the frequency and absolute numbers of circulating endothelial progenitor cells (EPCs) in healthy control subjects and patients with gynaecological cancer, and to test the hypothesis that cancer treatment lowers EPC numbers. METHODS: Patients with cervical or ovarian cancer and healthy control subjects provided peripheral blood samples for the isolation of mononuclear cells. EPCs were identified by quadruple immunofluorescence staining and flow cytometry as CD45(-)/CD34(+)/CD133(+)/vascular endothelial growth factor receptor 2 (VEGFR2)(+) cells. RESULTS: In total, 28 participants were enrolled. Circulating EPCs were present at higher frequencies (and in greater absolute numbers) in patients with cervical or ovarian cancer (n = 14) than in controls (n = 14). Concurrent chemoradiation therapy or surgery significantly reduced the frequency and number of EPCs in patients with gynaecological cancer, compared with pretreatment levels. CONCLUSIONS: EPC levels decline throughout cancer treatment; their measurement may therefore be a useful surrogate marker to monitor treatment response.

Detection of microRNA as novel biomarkers of epithelial ovarian cancer from the serum of ovarian cancer patients.

OBJECTIVE: MicroRNA (miRNA) is an abundant class of small noncoding RNAs that act as gene regulators. Recent studies have suggested that miRNA deregulation is associated with the initiation and progression of human cancer. However, information about cancer-related miRNA is mostly limited to tissue miRNA. The aim of this study was to find specific profiles of serum-derived miRNAs of ovarian cancer based on a comparative study using a miRNA microarray of serum, tissue, and ascites. METHODS: From 2 ovarian cancer patients and a healthy control, total RNA was isolated from their serum, tissue, and ascites, respectively, and analyzed by a microarray. Under the comparative study of each miRNA microarray, we sorted out several miRNAs showing a consistent regulation tendency throughout all 3 specimens and the greatest range of alteration in serum as potential biomarkers. The availability of biomarkers was confirmed by qRT-PCR of 18 patients and 12 controls. RESULTS: Out of 2222 kinds of total miRNAs that were identified in the microarray analysis, 95 miRNAs were down-regulated and 88 miRNAs were up-regulated, in the serum, tissue, and ascites of cancer patients. Among the miRNAs that showed a consistent regulation tendency through all specimens and showed more than a 2-fold difference in serum, 5 miRNAs (miR-132, miR-26a, let-7b, miR-145, and miR-143) were determined as the 5 most markedly down-regulated miRNAs in the serum from ovarian cancer patients with respect to those of controls. Four miRNAs (miR-132, miR-26a, let-7b, and miR-145) out of 5 selected miRNAs were significantly underexpressed in the serum of ovarian cancer patients in qRT-PCR. CONCLUSIONS: Serum miR-132, miR-26a, let-7b, and miR-145 could be considered as potential candidates as novel biomarkers in serous ovarian cancer. Also, serum miRNAs is a promising and useful tool for discriminating between controls and patients with serous ovarian cancer.

The appropriate cone depth to avoid endocervical margin involvement is dependent on age and disease severity.

OBJECTIVE: To analyse factors associated with endocervical cone margin involvement and suggest appropriate cone depth for the conization procedure. DESIGN: Retrospective cohort study. SETTING: Gynecological oncology center. POPULATION: One thousand two hundred and twenty women undergoing conization for cervical intraepithelial neoplasia (CIN) II or III or stage IA1 microinvasive cervical carcinoma. METHODS: The following factors were analysed: age, parity, gravida, conization type, margin status, disease severity and specimen depth. Receiver operating characteristic curve analyses were used to determine the best cut-off points to define appropriate cone depth. MAIN OUTCOME MEASURES: Cone depth to avoid endecervical margin involvement. RESULTS: Ninety-one women had endocervical margin involvement (7.5%). This was positively associated with disease severity and age and inversely related to cone depth. In women under 50 years of age, the cut-off value was achieved at 1.8 cm cone depth, with high sensitivity and relatively low specificity [area under the curve (AUC) 0.64, sensitivity 0.86, specificity 0.27, p= 0.005]. For a subset of CIN II patients aged ≤50 years, the cut-off value was 1.2 cm (AUC 0.75, sensitivity 0.90, specificity 0.47, p= 0.008). In women <40 years of age, the cut-off value was 1.8 cm (AUC 0.60, sensitivity 0.88, specificity 0.25, p= 0.036). In a subset of CIN II, the cut-off value was 0.9 cm (AUC 0.87, sensitivity 0.83, specificity 0.69, p= 0.002). CONCLUSIONS: Age, disease severity and cone depth are predictive factors for endocervical margin involvement. In women of reproductive age, the appropriate cone depth to avoid endocervical margin involvement can be changed depending on age and disease severity.

Endometrial mullerian adenosarcoma after toremifene treatment in breast cancer patients: a case report.

Toremifene is an anti-estrogen which has been shown to be effective in the treatment of breast cancer, and is thought to be a less uterotrophic agent than tamoxifen. The risk assessment concerning endometrial cancer has been inconclusive because of its rare use up to the mid-1990s. We report a case of an adenosarcoma, which is a very rare type of uterine malignancy, after toremifene treatment for 5 years in a breast cancer patient. After 1 year of toremifene use, the patient had a benign Mullerian adenofibroma. After an additional 4 years of toremifene treatment, the endometrial polypoid lesion was transformed into a Mullerian adenosarcoma. Although toremifene is a promising anti-estrogenic agent in the treatment of breast cancer patients, clinicians should not neglect the possibility of a uterine malignancy.