Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study

Objective

To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors.

Prognostic value of p53 accumulation in epithelial ovarian carcinomas

Aim: To evaluate the prognostic significance of p53 expression in epithelial ovarian carcinomas (EOC), and to look for correlations between p53 and other disease parameters. Material and methods: Immunohistochemical techniques were used to evaluate p53 expression in paraffin-embedded tissue specimens of 50 EOC cases. Results: p53 immunoreactivity was present in 33 of the 50 cases (66%). The expression of the p53 did not show any association with the tumor histologic type, grade or with the disease stage. However, p53 accumulation was significantly more prevalent among tumors with high mitotic index (p<0.01). Although median survival was low in the p53 negative cases, this biologic marker did not reveal as an independent prognostic factor in Cox’s regression analysis. Conclusion: Abnormalities of p53 expression which is an inducer of apoptosis occur commonly in EOC. Although we could not find it as an independent prognostic factor, p53 expression should be studied in larger series to reveal its accurate prognostic significance. Received: 14 May 2001 / Accepted: 16 July 2001     

Pre-treatment tumor expression of ERCC1 in women with advanced stage epithelial ovarian cancer is not predictive of clinical outcomes: a Gynecologic Oncology Group study

Objective

Excision repair cross-complementation group 1 (ERCC1) is required for the repair of platinum-induced DNA damage. This study sought to assess the prognostic value of ERCC1 expression, measured by immunohistochemistry (IHC) using a highly specific antibody, in advanced epithelial ovarian cancer (EOC) patients treated with platinum-based chemotherapy.

Methods

Formalin-fixed, paraffin-embedded tumors were collected from two GOG phase III trials (GOG-172 and GOG-182) of patients with stage III/IV EOC treated with platinum-based chemotherapy. ERCC1 was detected by (IHC) using FL297 polyclonal antibody and tumors were categorized as negative or positive, based on nuclear staining of tumor cells. ERCC1 genotyping was performed as previously reported. Associations between ERCC1 expression and clinical characteristics, platinum responsiveness, progression-free survival (PFS) or overall survival (OS) were evaluated.

Results

Of 408 eligible patients, 27% had tumors that were ERCC1 positive. ERCC1 expression was not associated with clinical characteristics or platinum-responsiveness. Women with ERCC1-positive versus -negative tumors had similar median PFS (17.9 months versus 17.5 months, respectively, p = 0.59), median OS (52.0 months versus 47.0 months, respectively, p = 0.30), risk of disease progression (adjusted hazard ratio [HR] = 0.90, 95% confidence interval (CI): 0.71-1.15, p = 0.41), and risk of death (adjusted HR = 0.81, 95% CI: 0.61-1.07, p = 0.14). ERCC1 expression, as measured by IHC, was not associated with single nucleotide polymorphisms (SNPs), in codon 118 and C8092A, of the ERCC1 gene.

Conclusions

ERCC1 expression, measured by IHC in pre-treatment tumor specimens, using a highly specific antibody, has limited clinical value in patients with advanced EOC treated with platinum and taxane based chemotherapy.     

Phase II evaluation of dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study

Objective

To determine whether CA-125 velocity is a statistically significant predictor of ovarian cancer and develop a classification rule to screen for ovarian cancer.

Methods

In the ovarian component of the PLCO cancer screening trial, 28,038 women aged 55-74 had at least two CA-125 screening tests. Ovarian cancer was diagnosed in 72 (0.26%) women. A multiple logistic regression model was developed to evaluate CA-125 velocity and other related covariates as predictors of ovarian cancer. Predictive accuracy was assessed by the concordance index and measures of discrimination and calibration while the fit of the model was assessed by the Hosmer and Lemeshow's goodness-of-fit χ² test.

Results

CA-125 velocity decreased as the number of CA-125 measurements increased but was unaffected by age at baseline screen and family history of ovarian cancer. The average velocity (19.749 U/ml per month) of the cancer group was more than 500 times the average velocity (0.035 U/ml per month) of the non-cancer group.

Conclusion

Among six covariates used in the model, CA-125 velocity and time intervals between baseline and second to last screening test and between last two screening tests were statistically significant predictors of ovarian cancer. The chance of having ovarian cancer increased as velocity increased, and the chance decreased when the time intervals between baseline and the second to last screening test and between last two screening tests of an individual increased.     

Prognostic significance of p53, Her-2, and EGFR overexpression in borderline and epithelial ovarian cancer

The objective of the study was to evaluate the prognostic effect of p53, Her-2, and EGFR in borderline and epithelial ovarian cancer. Tumor tissue from 85 patients with borderline and 783 patients with epithelial ovarian cancer stage I-IV were analyzed immunohistochemically for p53 positivity and over-expression of Her-2 and EGFR. In the ovarian cancer (OC) group 415 patients (53%) had p53-positive tumors, 272 (35%) had tumors with Her-2 over-expression, and 483 (62%) had over-expression of EGFR. In the OC group the classical prognostic factors (older age, higher FIGO stage, and poorer differentiated stage) had significant prognostic value in both uni- and multivariate analyses. Multivariate analyses in the OC group proved p53 positivity to increase mortality significantly depending on the grade of the tumor. Her-2 likewise increased the risk of mortality significantly in this group depending on the grade of the tumor. EGFR on the other hand did not have any additional prognostic effect in the OC group after adjustment for the classical prognostic and molecular factors was made. In the borderline group Her-2 and EGFR over-expression in combination, adjusted for age and p53, significantly improved the prognosis.     

Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: An exploratory study of the Gynecologic Oncology Group

Objective

To determine whether chemotherapy-induced neutropenia (C-iN) is associated with improved survival in a population of primary advanced ovarian cancer and peritoneal carcinoma patients treated with a carboplatin plus paclitaxel chemotherapy backbone.

Methods

A post-hoc exploratory analysis of Gynecologic Oncology Group (GOG) protocol 182 was performed. Landmark analysis was conducted on all patients with progression-free survival > 18 weeks from the time of study entry. Neutropenia was defined as the absolute neutrophil count < 1000 mm³. The occurrence of C-iN was analyzed according to demographic, clinicopathologic, and therapeutic intent, including age, body surface area, and treatment arm. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The Cox proportional hazards model was used to evaluate independent prognostic factors and to estimate their effects on PFS and OS.

Results

Neutropenic data was available for 3447 patients. Neutropenic (n = 3196) and non-neutropenic groups (n = 251) were similar in demographic and clinicopathologic characteristics. Neutropenic patients experienced significantly improved survival compared to non-neutropenic patients with the adjusted hazard ratio (HR) for death being 0.86 (95% confidence interval 0.74–0.99; p = 0.041). There was no survival benefit associated with any of the treatment arms among patients with C-iN.

Conclusion

These data suggest that C-iN may represent a clinical biomarker associated with a survival advantage for patients with untreated advanced ovarian cancer. The absence of C-iN may indicate under-dosing and ultimately attenuated anti-neoplastic effect in vulnerable populations.     

A phase II study of a urokinase-derived peptide (A6) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study

Purpose

This multi-institutional phase II trial assessed the activity and tolerability of the anti-metastatic A6 peptide that binds CD44 in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (EOC/FTC/PPC).

Patients and methods

Women with persistent or recurrent EOC/FTC/PPC were eligible for participation if they had measurable disease defined by RECIST criteria, good performance status, and good overall organ function. Patients must have received one prior platinum-based chemotherapeutic regimen and were allowed to have received one additional cytotoxic regimen for the management of recurrent or persistent disease. Women received a 150 mg twice daily subcutaneous dose of A6 and continued on treatment until disease progression or unacceptable toxicity. Primary measures of clinical efficacy were objective tumor response and progression-free survival (PFS) at 6 months. The association of CD44 in archival tissue specimens with clinical outcome was investigated.

Results

Thirty-one eligible patients were evaluated. No responses were observed. Two patients (6.5%) were progression free for at least 6 months. The median PFS was 2.0 months, and median overall survival has not yet been reached. One patient died of hemorrhage which was possibly study related. There were no grade 4 toxicities. The most common grade 3 toxicities were constitutional (2/31; 6.5%). Archival specimens were available for 27 patients, and 5 (18.5%) were CD44 positive by immunohistochemistry. CD44 expression was not associated with the 6-month PFS (p = 0.342).

Conclusion

A6 was well tolerated but had minimal activity in patients with persistent or recurrent EOC/FTC/PPC.     

Single nucleotide polypmorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; a Gynecologic Oncology Group study

Objective

This study evaluated common polymorphisms in excision repair cross-complementation group 1 (ERCC1) involved in repair of platinum-induced DNA damage in advanced-stage, epithelial ovarian/peritoneal/tubal cancer (EOC/PPC/FTC) patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy.

Methods

Pyrosequencing was performed to examine single nucleotide polymorphisms (SNPs) in codon 118 and C8092A in ERCC1 in leukocyte DNA from the Gynecologic Oncology Group phase III protocol, GOG-182. Kaplan-Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphisms and progression-free survival (PFS) and overall survival (OS).

Results

The genotype distribution at codon 118 (n = 278) in ERCC1 for CC, CT, and TT was 23%, 45% and 32%, and the median OS was 32, 47 and 43 months, respectively. Patients with the CT + TT versus CC genotype in codon 118 in ERCC1 were at a reduced risk of death (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.49-0.95, p = 0.025). The genotype distribution for C8092A in ERCC1 (N = 280) was 50%, 42% and 8%, and the median OS was 45, 40 or 30 months for CC, CA and AA, respectively. Women with the CA + AA versus CC genotype in C8092A in ERCC1 had a trend suggesting an increased risk of death (HR = 1.29, 95% CI = 0.97-1.72, p = 0.077).

Conclusions

The polymorphism in codon 118 in the DNA repair gene ERCC1 was an independent predictor for better survival in EOC/PPC/FTC patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. The relationship between the C8092A polymorphisms in ERCC1 and survival was modest with an effect size that was not always statistically significant.     

A phase I study of paclitaxel, topotecan, cisplatin and Filgrastim in patients with newly diagnosed advanced ovarian epithelial malignancies: a Gynecologic Oncology Group study

OBJECTIVES: To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. METHODS: Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m2/3 h, followed 2 h later by cisplatin 50 mg/m2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m2 (cohort 1), or 3 days beginning at 0.5 mg/m2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. RESULTS: Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.5 mg/m2 daily x 5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.75 mg/m2 daily x 3 with Filgrastim. CONCLUSION: In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.     

BRCA1 and p53 protein expression in cultured ovarian surface epithelial cells derived from women with and without a BRCA1 germline mutation

Aim Mutations in the BRCA1 and TP53 genes are early genetic events leading to (hereditary) ovarian carcinoma. The human ovarian surface epithelium (OSE) is considered the tissue of origin of at least a subset of these tumours. Therefore, OSE cell cultures derived from women harbouring BRCA1 germline mutations can be a potential model to study hereditary ovarian carcinogenesis. In fact, previous in vitro studies indicate phenotypical differences between OSE from women with and without such germline mutations. Therefore, we have assessed whether differences in the expression of BRCA1 and p53 proteins in cultured OSE cells could contribute to these observations.Study design Thirty-two OSE cultures derived from women harbouring a BRCA1 mutation (Predisposed OSE [POSE]) and ten cultures from women without a cancer predisposition (Non predisposed OSE [NPOSE]) were grown under standard conditions. Immunocytochemistry was performed to assess the expression of the BRCA1- and p53 proteins. Ki67 immunocytochemical expression was assessed to determine possible differences in cell cycle status between the two groups. In addition, to study whether wild type p53 was expressed, induction of p53 by cis-platinum was assessed by Western blot.Results On the basis of Ki67 expression, three different groups were analyzed. In the group with all cultures that expressed Ki67 no significant difference was observed in BRCA1 (P = 0.19) and p53 expression (P = 0.09). In the group with moderate to high Ki67 expression no difference in BRCA1 expression (P = 0.50) was observed. However, p53 expression was significantly lower in the case group (P = 0.01). The same observation for p53 was made in the group with only high Ki67 expression (P = 0.02). Furthermore, the expression of both BRCA1 and p53 positively correlates with Ki67 expression. In POSE and NPOSE, p53 was induced by cis-platinum to a similar extent.Conclusion Our study indicates differences in the expression of p53, but not in the expression of BRCA1 between POSE and NPOSE. In addition, our findings do suggest the absence of losses of the wild type BRCA1 and p53 genes in the studied OSE cultures. This indicates that losses in these genes cannot account for observed differences in phenotypical traits between POSE and NPOSE, but that differences in levels of p53 might contribute.     

Independent radiologic review of the Gynecologic Oncology Group Study 0218, a phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian,primary peritoneal,or fallopian tube cancer

Objectives

Gynecologic Oncology Group Study 0218 (GOG-0218), a phase III, placebo-controlled trial in newly diagnosed stage III/IV ovarian cancer (OC), demonstrated a benefit in investigator (INV)-assessed progression-free survival (PFS) with bevacizumab (BEV) administered with and following carboplatin/paclitaxel (CP) for up to 15 months vs. CP alone. To determine the reliability of Response Evaluation Criteria in Solid Tumors (RECIST) in assessing disease progression (PD) in GOG-0218, an independent review of radiologic and clinical data (IRC) was conducted.

Methods

Blinded reviews followed RECIST 1.0 in accordance with the study protocol; PFS was analyzed in the intent-to-treat population.

Results

CP + BEV → BEV achieved a significant PFS improvement in both assessments. Hazard ratios for PFS (IRC: 0.623; 95% confidence interval [CI]: 0.503–0.772; p < 0.0001 vs. INV: 0.624; 95% CI: 0.520–0.749; p < 0.0001) and the improvement in median PFS (IRC: 19.1 and 13.1 months vs. INV: 18.2 and 12 months) were similar between IRC and INV assessments. There was high concordance between IRC- and INV-determined PD status (77%) and date (73%). Subgroup analyses were consistent with the primary IRC findings. Early and late discontinuation discordance measures showed no evidence of INV bias.

Conclusion

IRC analysis confirmed a significant PFS improvement with CP + BEV → BEV vs. CP alone. Concordance was not influenced by extent of residual disease after cytoreductive surgery or initial stage. The IRC size, high participation rate, and strong concordance between IRC and INV assessments suggest that RECIST can be applied objectively in OC studies.