Kristin K. Zorn

Gene Expression Profiles of Serous, Endometrioid, and Clear Cell Subtypes of Ovarian and Endometrial Cancer

Purpose: The presence of similar histologic subtypes of epithelial ovarian and endometrial cancers has long been noted, although the relevance of this finding to pathogenesis and clinical management is unclear. Despite similar clinical characteristics, histologic subtypes of cancers of the ovary and endometrium are treated according to organ of origin. This study compares the gene expression profiles of analogous histologic subtypes of cancers of the ovary and endometrium using the same genomic platform to determine the similarities and differences between these tumors. Experimental Design: Gene expression profiles of 75 cancers (endometrioid, serous, and clear cell) of the ovary and endometrium, five renal clear cell cancers, and seven normal epithelial brushings were determined using a 11,000-element cDNA array. All images were analyzed using BRB ArrayTools. Validation was done using real-time PCR on select genes and immunohistochemical staining. Results: Comparison across endometrial and ovarian cancers and serous and endometrioid tumors showed expression patterns reflecting their organ of origin. Clear cell tumors, however, showed remarkably similar expression patterns regardless of their origin, even when compared with renal clear cell samples. A set of 43 genes was common to comparisons of each of the three histologic subtypes of ovarian cancer with normal ovarian surface epithelium. Conclusions: The comparison of the gene expression profiles of endometrioid and serous subtypes of ovarian and endometrial cancer are largely unique to the combination of a particular subtype in a specific organ. In contrast, clear cell cancers show a remarkable similarity in gene expression profiles across organs (including kidney) and could not be statistically distinguished.

Gene Expression Profiles Associated with Response to Chemotherapy in Epithelial Ovarian Cancers

Purpose: The goal of this study was to determine whether distinct gene expression profiles are associated with intrinsic and/or acquired chemoresistance in epithelial ovarian carcinoma. Experimental Design: Gene expression profiles were generated from 21 primary chemosensitive tumors and 24 primary chemoresistant tumors using cDNA-based microarrays. Gene expression profiles of both groups of primary tumors were then compared with those of 15 ovarian carcinomas obtained following platinum-based chemotherapy (“postchemotherapy” tumors). A theme discovery tool was used to identify functional categories of genes involved in drug resistance. Results: Comparison of primary chemosensitive and chemoresistant tumors revealed differential expression of 85 genes (P < 0.001). Comparison of gene expression profiles of primary chemosensitive tumors and postchemotherapy tumors revealed more robust differences with 760 genes differentiating the two groups (P < 0.001). In contrast, only 230 genes were differentially expressed between primary chemoresistant and postchemotherapy groups (P < 0.001). Common to both gene lists were 178 genes representing transcripts differentially expressed between postchemotherapy tumors and all primary tumors irrespective of intrinsic chemosensitivity. The gene expression profile of postchemotherapy tumors compared with that of primary tumors revealed statistically significant overrepresentation of genes encoding extracellular matrix–related proteins. Conclusions: These data show that gene expression profiling can discriminate primary chemoresistant from primary chemosensitive ovarian cancers. Gene expression profiles were also identified that correlate with states of intrinsic and acquired chemoresistance and that represent targets for future investigation and potential therapeutic interventions.

BRCA1/2 mutations and expression: Response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer

OBJECTIVE Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect patients with advanced epithelial ovarian cancer (EOH). METHODS BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24 patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers when normal tissue was available. BRCA expression was ascertained by quantitative rt-PCR. Associations between BRCA mutation status and expression levels and parameters of platinum response were analyzed. RESULTS Fifteen of 53 (28.3%) EOC tumors had BRCA1/2 mutations. Twelve mutations were in BRCA1, while 3 involved BRCA2. Of the 12 mutation-carriers with normal tissue available for DNA analyses, 33.3% of the mutations were found to be somatic. Three mutations were novel. The majority of BRCA mutations (73%) were identified in patients with platinum-sensitive disease. In total, 38% of platinum-sensitive tumors were found to have a BRCA mutation, compared to 17% of the platinum-resistant patients. A statistical trend toward platinum-sensitive disease was seen in BRCA mutation carriers (p=0.079). Nineteen (36%) study patients had some form of BRCA deficiency, and these patients were less likely to have platinum-resistant tumors (OR=0.29; p value=0.048). CONCLUSIONS BRCA mutations occurred more frequently in platinum-sensitive EOC than platinum-resistant disease. The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting the DNA repair pathway are being investigated.

Preoperative intensity-modulated radiotherapy and chemotherapy for locally advanced vulvar carcinoma

OBJECTIVE Intensity-modulated radiation therapy (IMRT) is a rapidly maturing technology that allows delivery of radiation dose in a more conformal manner by varying the radiation beams spatially or temporally. The purpose of the study was to assess the clinical outcome in patients with locally-advanced vulvar cancers treated using preoperative chemotherapy with IMRT. METHODS Eighteen patients with stage II-IVA cancer were treated with a modified GOG schema using 5-fluorouracil (5-FU) and cisplatin with twice-daily (BID) IMRT during the first and last weeks of treatment. Surgery was planned for 6-8 weeks post-treatment. RESULTS The median follow-up time was 22 months (2-60 months). Fourteen patients had surgery performed with pathological complete response (pCR) in 9 (64%) patients and partial response (pPR) in 5 patients. There were no recurrences in the 9 patients who achieved pCR whereas 3/5 with pPR had local recurrence (p=0.027). Four patients did not have surgery: one patient died a week after treatment while 2 of the remaining 3 patients had local recurrences. Acute desquamative skin reactions in the vulva and perineum were seen in all patients. Three of the 14 patients who had surgery had prolonged wound complications requiring debridement. No patients had radiation-related acute or late toxicity of grade = 3. The 2-year cause specific and overall survivals were 75% and 70% respectively. CONCLUSION Preoperative chemotherapy and IMRT were well tolerated with good clinical response and early clinical outcome. Pathological complete response predicts better outcomes. Prospective clinical trials with sufficient patient numbers and follow-up are needed to determine the true impact of IMRT in these patients.

Venous thromboembolism in obstetrics and gynecology.

The diagnosis of venous thromboembolism can present a clinical challenge. Using D-dimer testing and spiral or helical computed tomography scans has simplified the diagnosis of venous thromboembolism. In addition, the use of low molecular weight heparin has become widely accepted in the prevention and treatment of venous thromboembolism. However, further studies are needed to determine optimal prevention and treatment strategies, particularly in the obstetric population.

The prognostic value of pretreatment CA 125 in patients with advanced ovarian carcinoma: a Gynecologic Oncology Group study.

The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen.

PROGNOSTIC VALUE OF PRETREATMENT CA-125 IN ADVANCED OVARIAN CARCINOMA: A GYNECOLOGIC ONCOLOGY GROUP STUDY

The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen.

Completion of intraperitoneal chemotherapy in advanced ovarian cancer and catheter-related complications

OBJECTIVE Combination intravenous/intraperitoneal (IV/IP) chemotherapy has been shown in three randomized trials to be superior to IV therapy alone in the treatment of advanced ovarian cancer with respect to overall survival (OS). We sought to evaluate the effect of dose modification of IP therapy on completion rates. METHODS From November 1999 until August 2008, all optimally debulked, advanced stage ovarian cancer patients who received adjuvant IP chemotherapy at a single institution were reviewed. The primary endpoint was completion of 6 cycles of IP chemotherapy. This rate was compared to published results from GOG 172. A secondary analysis evaluated completion of chemotherapy based on IP catheter type. Statistical analysis was performed with a chi square test with a significance level of p<0.05. RESULTS One hundred and three patients received IP chemotherapy during this period. Seventy-five patients received the modified IV/IP chemotherapy regimen. Sixty-two patients (83%) completed all 6 cycles in our cohort compared to 119 patients (42%) reported in GOG 172 (p=0.0001). Fifty-five patients had a fenestrated catheter (F) and 48 had a non-fenestrated (NF) catheter. Eight patients in each cohort discontinued treatment, for a completion rate of 85.5% in NF and 82.3% in F (p=0.79). CONCLUSIONS The dose modifications utilized in this study allowed for completion of 6 cycles of adjuvant IP chemotherapy in 83% of patients. Choice of catheter type did not affect completion rates. Continued monitoring of outcomes is planned to compare PFS and OS. The high completion rate may increase acceptance of IP chemotherapy in the community setting.

Does the number of nodes removed impact survival in vulvar cancer patients with node-negative disease?

OBJECTIVE To determine if the extent of lymphadenectomy as determined by lymph node count from an inguinal-femoral lymph node dissection for vulvar cancer impacts overall survival (OS) and disease-specific survival (DSS) in patients with node-negative disease. METHODS Patients with stage I, II and III squamous cell carcinoma of the vulva who underwent primary inguinal-femoral nodal dissection were identified from the Surveillance, Epidemiology and End Results Program between 1988 and 2003. Patients were divided into 2 groups, those with <or=10 nodes and those with >10 nodes removed, and analyzed according to stage. All patients with histologically positive nodes were excluded. Log-rank test was done for univariate analysis. Cox regression method was used for multivariate analysis. RESULTS Squamous cell vulvar cancer was identified in 1030 patients. Statistically significant differences were seen on univariate analysis of OS between stage II and III patients with <or=10 and >10 nodes removed. The difference in 5-year DSS survival was statistically significant only for patients with stage III disease. On multivariate analysis age, stage and number of lymph nodes removed were all found to be significant variables affecting OS and DSS. CONCLUSIONS The removal of greater than 10 lymph nodes was associated with a significant improvement in DSS in patients with stage III vulvar carcinoma. This improvement in survival may be due to removal of micrometastatic disease in the inguinal lymph nodes. These data suggest that a thorough inguinal-femoral lymph node dissection should be performed in patients with advanced-stage node-negative vulvar carcinoma.

Surgery versus radiation therapy for stage IB2 cervical carcinoma: a population-based analysis.

Objective The objective of the study was to examine outcomes in stage IB2 cervical cancer patients undergoing primary surgery versus radiation. Methods Stage IB2 cervical cancer patients were identified from the Surveillance, Epidemiology and End Results Public-Use Database from 2000 to 2006. Patients were divided into those receiving radiation (radiation first) or surgery (surgery first) as initial treatment. Overall survival was calculated by Kaplan-Meier method and compared using log-rank test. Results In total, 770 patients were identified with stage IB2 cervical cancer; 369 received radiation, and 401 received surgery initially. The radiation-first group had larger mean tumor size than the surgery-first group (6.0 vs 5.5 cm, respectively; P < 0.0001). The overall survival was longer in the surgery-first group compared with the radiation-first group (72.0 vs 61.4 months, respectively; P < 0.0001). Conclusions Patients undergoing surgery as initial treatment for stage IB2 cervical cancer appear to have improved outcomes in the current era of chemoradiation; however, given the lack of chemotherapy information, a randomized trial will be necessary to see if these results remain valid.