Comparison between serous and non-serous ovarian cancer as a prognostic factor in advanced epithelial ovarian carcinoma after primary debulking surgery

Background  

Residual tumor size after primary surgery is the most important prognostic factor in advanced ovarian cancer. We conducted a retrospective study in Japanese women to evaluate the association of various residual disease diameters and histological subtypes with overall survival (OS) in patients with residual disease ≥1 cm.     

Breast cancer 1 (BRCA1) protein expression as a prognostic marker in sporadic epithelial ovarian carcinoma: an NCIC CTG OV.16 correlative study

BackgroundBreast cancer 1 (BRCA1) protein inactivation in sporadic ovarian carcinoma (OC) is common and low BRCA1 expression is linked with platinum sensitivity. The clinical validation of BRCA1 as a prognostic marker in OC remains unresolved.Patients and methodsIn 251 patient samples from the NCIC CTG clinical trial, OV.16, BRCA1 protein expression was determined by immunohistochemistry.ResultsFor all patients, when BRCA1 score was analyzed as a continuous variable, there was no significant correlation between BRCA1 protein expression and progression-free survival (PFS) [adjusted hazard ratio (HR) = 1.15 (0.96–1.37), P = 0.12] or response rate [HR = 0.89 (0.70–1.12), P = 0.32]. In the 116 patients with minimal residual disease (RD), higher BRCA1 expression correlated significantly with worse PFS [HR = 1.40 (1.04–1.89), P = 0.03]. Subgroup analysis divided patients with minimal RD into low (BRCA1 ≤2.5) and high (BRCA1 >2.5) expression groups. Patients with low BRCA1 expression had a more favorable outcome [median PFS was 24.7 and 16.6 months in patients with low and high BRCA1, respectively; HR = 0.56 (0.35–0.89), P = 0.01].ConclusionsThis study suggests that BRCA1 protein is a prognostic marker in sporadic OC patients with minimal RD. Further research is needed to evaluate BRCA1 as a predictive biomarker and to target BRCA1 expression to enhance chemotherapeutic sensitivity.     

Granulin-epithelin precursor is a novel prognostic marker in epithelial ovarian carcinoma

BACKGROUND: The granulin-epithelin precursor (GEP) was preferentially expressed in invasive ovarian tumor epithelium specimens compared with specimens of borderline ovarian tumors. The objective of the current study was to evaluate the anatomic site-related and cellular expression of GEP and its association with clinicopathologic parameters and survival in patients with advanced-stage ovarian carcinoma. METHODS: Effusions (n = 190), corresponding primary tumor specimens (n = 64), and specimens of metastatic lesions (n = 125) were analyzed using immunohistochemistry with a specific polyclonal antipeptide antibody. In addition, 36 effusions were analyzed using immunoblotting. RESULTS: GEP was detected in tumor cells in 171 of 190 (90%) effusions and demonstrated both focal membrane and cytoplasmic localization. Mesothelial cells were often GEP positive (81%). GEP was found in carcinoma cells in 180 of 189 (95%) tumor biopsy specimens, with stromal and endothelial cell expression in 93 of 180 (52%) and 124 of 185 (67%) specimens, respectively. Lower GEP expression in stromal cells was observed in metastases sampled during or after chemotherapy (P = 0.034). The presence of GEP-positive stromal cells in untreated primary tumor specimens correlated with worse overall survival (P = 0.014). Significantly more frequent GEP expression was observed in tumor cells of both primary (P = 0.002) and metastatic (P < 0.001) tissue specimens compared with malignant effusions. CONCLUSIONS: GEP expression was observed in primary and metastatic epithelial ovarian carcinoma specimens, with down-regulated expression in tumor cells of malignant effusions. The poor outcome associated with stromal GEP expression suggests a prognostic role for this growth factor in ovarian carcinoma.     

BubR1 as a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers

Background:

Epithelial ovarian cancer is one of the most lethal malignancies, and has a high recurrence rate. Thus, prognostic markers for recurrence are crucial for the care of ovarian cancer. As ovarian cancers frequently exhibit chromosome instability, we aimed at assessing the prognostic significance of two key mitotic kinases, BubR1 and Aurora A.

Methods:

We analysed paraffin-embedded tissue sections from 160 ovarian cancer patients whose clinical outcomes had been tracked after first-line treatment.

Results:

The median recurrence-free survival in patients with a positive and negative expression of BubR1 was 27 and 83 months, respectively (P<0.001). A positive BubR1 expression was also associated with advanced stage, serous histology and high grade. In contrast, Aurora A immunostaining did not correlate with any of the clinical parameters analysed.

Conclusion:

BubR1, but not Aurora A, is a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers.     

Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1alpha) expression in serous ovarian cancer: an immunohistochemical study

Background  

The hypoxia-inducible factor (HIF) has emerged as an attractive target for cancer therapy. The few publications addressing the prognostic significance of Hypoxia-Inducible Factor 1α (HIF-1α) cellular expression in ovarian cancer produced contradictory findings which are not permissible to widely acceptable conclusions and clinical applications. Our study was designed to investigate this by including a comparatively large number of cases and by using a combination of antibodies to analyze immunohistochemically the expression of HIF-1α.     

Circulating serum STN antigen as a prognostic marker in epithelial ovarian cancer]

Circulating serum sialyl Tn (STN) antigen levels were measured in 89 patients with epithelial ovarian cancer. Survival at 5 years for patients with STN-negative (serum STN levels less than 50 U/ml) versus STN-positive tumors (serum STN levels greater than or equal to 50 U/ml) was 76.9% versus 10.8%, respectively (p less than 0.05). The overall survival probability was worse in patients with STN-positive sera. Percent progression-free survival at 5 years for patients with STN-negative versus STN-positive tumors was 51.9% versus 5.4%, respectively (p less than 0.05). The overall progression-free survival was shorter in patients with STN-positive sera. Multivariate regression analysis revealed that positive STN antigen level in sera is an independent predictor of poor prognosis in epithelial ovarian cancer.     

Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study.

The eukaryotic cell cycle is controlled by protein complexes consisting of cyclin-dependent kinases and cyclins. The cyclin-dependent kinases are in turn negatively regulated by a family of cyclin-dependent kinase inhibitors, comprising, among others, the p21 and p27 proteins. p21 and p27 have been shown to be of prognostic significance in a broad array of human tumors. Using immunohistochemistry, the frequency of expression and the possible prognostic and predictive significance of these proteins were examined in a series of 185 uniformly treated patients with stage III ovarian cancer. We found p21 to be overexpressed in 48% of cases. No significant correlation was found between the expression of p21 and p53 proteins (P = 0.273). A low level of p27 was demonstrated in 48.5% of cases. p21 overexpression correlated with lower Fédération Internationale des Gynaecologistes et Obstetristes substage, lower patient age, and absence of ascites, but neither p21 nor p27 expression was of prognostic significance for the whole group of patients. Only a trend toward reduced survival (P = 0.092) was noticed for the small subgroup of patients (6%), whose tumors lacked p27 expression completely. A clear positive correlation could be found between p21 and p27 protein expression (P = 0.012). Despite the suggested role of the 21 and p27 proteins in determining drug sensitivity, they were not found to be predictive for response to chemotherapy, as assessed by second-look laparotomy in this large group of patients with advanced ovarian cancer.     

WT1 expression as an independent marker of poor prognosis in colorectal cancers

WT1 has been proven to be a prognostic marker and molecular target in various human cancers. In this study, we aimed to investigate the prognostic role of WT1 in colorectal cancers (CRCs). Archival tissue samples from 157 CRC cases who underwent curative surgery in our institute from February 1999 to May 2004 were subjected to WT1 expression studies using an immunohistochemistry technique. Number of positive staining per 500 tumor cells and staining intensities were analyzed against overall survival. Of 157 CRCs, 83 were colonic and 74 were rectal cancers. The mean follow-up period was 116 (range 77-145) months. Five-year and seven-year OS rates were 60.9% and 52.8%, respectively. WT1 immunostaining was positive in 143 cases (91%). The median number of positive cells was 120 (range 0-420). Univariate analysis by Log-rank test showed that AJCC stage, tumor site (rectal cancer), number of positive cells > 120 and high staining intensity (score ++/+++) were significantly associated with poorer survival (p-value < 0.01). Five-year survival rates in cases with positive cells of ? 120 cells and > 120 cells were 72.2% and 49.4%, respectively. Five-year survival in cases with staining intensity of ++ or more was 45.3%, compared with 69% in cases with intensity of less than ++. Multivariate regression analysis demonstrated that the staining intensity, high tumor stage and rectal site were independent factors indicating poorer survival. Our findings indicate that WT1 expression is a marker of poor prognosis in CRCs, independent of AJCC staging.     

卵巢上皮癌组织中HMGA1的表达及其意义

目的：探索卵巢上皮癌组织中HMGA1的表达及其对卵巢癌诊断与预后的意义.方法：通过半定量RT-PCR法分析36例卵巢癌和36例正常卵巢上皮组织中HMGA1的表达情况.结果：36例正常卵巢上皮组织中均未检测到HMGA1的转录产物;36例卵巢上皮癌组织中,有26（72.0%）例HMGA1呈阳性表达;HMGA1在原发性卵巢上皮浸润癌中的表达与病理分级相关,21例G3的卵巢癌组织中有18例（86.0%）呈阳性表达,而10例G1和G2的卵巢癌组织中仅有4（40.0%）例呈阳性表达（P＜0.001）,与临床分期及病理分型无关（P＞0.05）.结论：HMGA1在卵巢癌组织中呈过度表达状态,与卵巢上皮浸润癌病理分级相关,可作为卵巢癌诊断与良恶性鉴别诊断指标.     

Prognostic significance of Notch 3 gene expression in ovarian serous carcinoma

The Notch signaling pathway is an important cell signaling system, which regulates cell differentiation, proliferation, and apoptosis, and is aberrantly activated in a wide range of cancer, including ovarian cancers. However, it remains unclear as to whether Notch signaling plays a role in the progression and prognosis of ovarian cancer. We examined the mRNA and protein expression of Notch 3, Jagged 1, and Jagged 2 in 98 ovarian epithelial tumors via real‐time PCR and in 175 tumors with immunohistochemical analysis, and then correlated their expression levels with clinicopathological parameters and patient survival. In this study, we detected high levels of Notch3 mRNA and protein expression especially in serous ovarian carcinomas compared to their benign counterparts, accompanied by a positive correlation with the expressions of Jagged 1 and Jagged 2. High levels of Notch 3 mRNA expression (>2‐fold than that of benign tumor) were noted in 63% of the serous carcinomas (mean level: 17‐fold, P = 0.032). Additionally, Notch 3 protein overexpression was significantly associated with advanced stage (P = 0.0008), lymph node (P = 0.001), and distant metastasis (P = 0.003). Notably, high Notch 3 mRNA and protein expressions were correlated with chemoresistance (P = 0.033) and poor overall survival (P = 0.027, P = 0.042) in these patients. Our results indicate that the Notch 3 signaling pathway is involved in the tumor progression of ovarian serous carcinoma, and higher Notch 3 expression may be an independent poor prognostic factor in this subset of tumors. (Cancer Sci 2010)     

RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer

Treatment of epithelial ovarian cancer consists of surgery plus platinum‐taxane based chemotherapy. Neither prognostic nor predictive serum or tissue markers except BRCA1/2 mutations are available thus precluding individualized treatment. Aim of this study is the identification and validation of DNA‐methylation markers with prognostic value. Genome‐wide array analyses were used to determine methylation patterns in groups of serous EOC with different outcome (PFS < vs. > 3 years, each n = 6) but comparable clinical parameters. Two hundred and twenty differentially methylated regions in tumor tissue of patients with short vs. long PFS (106 hypo‐ and 114 hypermethylated regions) were identified. Thirty‐five of 37 selected CpG islands were validated by MSP using the same samples as for microarray analyses. Six of these regions were analyzed by targeted next‐generation bisulfite‐sequencing confirming array and MSP results. Validation experiments with an enlarged patient group of Type II EOC samples (PFS <3 years n = 30; >3 years n = 18) revealed the CpG island of RUNX3 as significantly more often methylated in patients with short PFS (10/30 vs. 0/18; p < 0.01). Marker combinations with significantly different methylation frequencies in patient groups reached an increased sensitivity with equal specificity (RUNX3+CAMK2N1; sens 40%; spec 100%; p < 0.01). RUNX3/CAMK2N1 methylation‐positive patients of the array‐independent subset (n = 36) showed a significantly lower PFS (p < 0.01) but no other difference in clinical parameters compared to methylation‐negative patients. Genome‐wide methylation analyses reliably identified markers of potentially prognostic value. Hypermethylation of RUNX3/CAMK2N1 is associated with poor clinical outcome in Type II EOC, also after macroscopic complete resection.     

BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells

Several angiogenesis-promoting factors have prognostic significance in ovarian cancer. The objective of this study was to evaluate whether traditional chemotherapy affects angiogenesis-related factors in ovarian carcinoma and to assess the clinical significance of these effects. To screen for angiogenesis-related factors of possible relevance, OVCAR-3 and A2780 ovarian cancer cells were treated with IC₅₀ doses of cisplatin (CDDP) or docetaxel, or with bevacizumab, and mRNA expression of several angiogenesis-related factors was analyzed. Thrombospondin-1 (TSP-1), bone morphogenetic protein-4 (BMP-4), endothelin-1, and placental growth factor-2 were statistically significantly induced by CDDP. At protein level, CDDP also induced hypoxia-inducible factor-1α but not vascular endothelial growth factor. In carcinoma samples taken before and after platinum-based neoadjuvant chemotherapy from 28 patients with advanced, high-grade serous ovarian carcinoma, CD105 and factors most induced by CDDP (TSP-1 and BMP-4) were analyzed by immunohistochemistry. Strong expression of BMP-4 before chemotherapy was an independent prognostic factor of longer progression-free time (p = 0.002) and overall survival (p = 0.02), but it was not associated with neovascularization (as evaluated by CD105). However, changes in BMP-4 expression in samples analyzed before and after chemotherapy (observed in 22/28 patients) were not associated with prognosis. TSP-1 expression was not associated with clinical parameters. Our results indicate that in serous ovarian carcinoma, BMP-4 has prognostic significance, which is not angiogenesis-related. We also show that CDDP induces several angiogenesis-related growth factors in vitro and future studies are warranted to clarify the clinical significance of this phenomenon.     

p63 expression as a new prognostic marker in Merkel cell carcinoma

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumor, mostly affecting elderly individuals. The histogenesis of this rare tumor as well as its prognostic criteria are a matter of dispute. METHODS: An immunohistochemical analysis of markers of proliferation (Ki-67/MIB-1), neuroendocrine differentiation (chromogranin A and synaptophysin), and basal cell differentiation (p63) was performed in a series of 47 cases of MCC. The significance of pathologic data and of immunoreactivity with different markers was evaluated using the chi-square test. Survival curves were calculated using the Kaplan-Meyer method. The survival difference was estimated using the Wilcoxon or Mantel-Cox test. RESULTS: Immunohistochemical evidence of neuroendocrine differentiation and immunopositivity for cytokeratin 20 were observed in all cases, whereas positivity for p63 was detected in approximately half of the cases (25 of 47 cases; 53.2%). Cases that were positive for p63 demonstrated a more aggressive clinical course than those that were negative (Z value of 2.93; P = .0003; hazards ratio of 22.22). CONCLUSIONS: Data from the current study indicate that p63 expression is associated with a worse prognosis in patients with MCC and represents a new independent marker of clinical evolution.     

Nin one binding protein expression as a prognostic marker in prostate carcinoma

Background

To investigate the prognostic value of expression levels of nin one binding protein (Nob1) in prostate carcinoma.

Methods

Nob1 protein levels were evaluated by Western blot in samples from 40 prostate carcinomas and matched adjacent non-neoplastic prostate tissues. Nob1 expression was also assessed by immunohistochemistry in samples from 300 prostate carcinoma and matched adjacent non-neoplastic prostate tissues, as well as 20 benign prostatic hyperplasia samples. The findings were compared with clinical and pathologic parameters and patient outcome.

Results

Nob1 protein analysis showed significant differences between the prostate carcinomas and control groups tested. Immunohistochemical analysis showed that Nob1 positivity was higher in prostate carcinoma than that in paired adjacent non-cancerous tissues (58 vs 7 %, P < 0.001). Nob1 positivity was significantly associated with high Gleason scores and metastasis in patients. Nob1 expression was significantly associated with shorter biochemical recurrence-free survival (BCRFS). Multivariate analysis revealed that Nob1 is an independent marker for BCRFS.

Conclusions

These findings provide evidence that Nob1 is an indicator of poor prognosis in prostate carcinoma.     

Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma

The search for molecular markers to improve diagnosis, individualize treatment and predict behavior of tumors has been the focus of several studies. This study aimed to analyze homeobox gene expression profile in oral squamous cell carcinoma (OSCC) as well as to investigate whether some of these genes are relevant molecular markers of prognosis and/or tumor aggressiveness. Homeobox gene expression levels were assessed by microarrays and qRT-PCR in OSCC tissues and adjacent non-cancerous matched tissues (margin), as well as in OSCC cell lines. Analysis of microarray data revealed the expression of 147 homeobox genes, including one set of six at least 2-fold up-regulated, and another set of 34 at least 2-fold down-regulated homeobox genes in OSCC. After qRT-PCR assays, the three most up-regulated homeobox genes (HOXA5, HOXD10 and HOXD11) revealed higher and statistically significant expression levels in OSCC samples when compared to margins. Patients presenting lower expression of HOXA5 had poorer prognosis compared to those with higher expression (P=0.03). Additionally, the status of HOXA5, HOXD10 and HOXD11 expression levels in OSCC cell lines also showed a significant up-regulation when compared to normal oral keratinocytes. Results confirm the presence of three significantly upregulated (>4-fold) homeobox genes (HOXA5, HOXD10 and HOXD11) in OSCC that may play a significant role in the pathogenesis of these tumors. Moreover, since lower levels of HOXA5 predict poor prognosis, this gene may be a novel candidate for development of therapeutic strategies in OSCC.     

M-CAM expression as marker of poor prognosis in epithelial ovarian cancer

Currently available clinico-pathologic criteria provide an imperfect assessment of outcome for patients with advanced epithelial ovarian cancer (EOC). Identification of prognostic factors related to tumor biology might improve this assessment. We investigated the prognostic significance of the melanoma cell adhesion molecule (M-CAM) in EOC. Using the same antibody, M-CAM expression was tested by Western blotting in protein extracts and by immunohistochemestry in tissue microarrays generated from 133 consecutively resected, well characterized EOC samples. Fisher test, Kaplan-Meier method and Cox proportional hazards analysis were used to relate M-CAM expression to clinico-pathological variables and to time to progression (TTP) and overall survival (OS). In vitro biochemical analysis showed a progressively increased M-CAM expression from normal to malignant cells. M-CAM protein, detected immunohistochemically, was significantly associated with advanced tumor stage, serous and undifferentiated histotype, extent of residual disease and p53 accumulation. Presence or absence of M-CAM significantly divided patients according to their TTP (median, 22 vs. 79 months, respectively; log-rank p = 0.001) and OS (median, 42 vs. 131 months, respectively; log-rank p = 0.0003). In the subgroup of advanced stage patients who achieved complete response after front-line treatment, M-CAM expression and absence of residual disease were significantly associated with shorter TTP (p = 0.003, HR 5.25, 95% Cl 1.79-15.41 and p = 0.011, HR 3.77, 95% Cl 1.36-10.49 respectively) at the multivariate level. In the same sub-group of patients, M-CAM expression remained the only parameter significantly associated with OS (p = 0.005, HR 3.35, 95% Cl 1.42-6.88). M-CAM is a marker of early relapse and poorer outcome in EOC. In particular, M-CAM expression identifies a subgroup of front-line therapy-responding patients who undergo dramatic relapses, thus helping to better select patients who might benefit from new/alternative therapeutic modalities.