ERCC5 is a novel biomarker of ovarian cancer prognosis.

PURPOSE: To identify a biomarker of ovarian cancer response to chemotherapy. PATIENTS AND METHODS Study: participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. RESULTS: Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation. CONCLUSION: ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.

Hereditary ovarian cancer--assessing risk and prevention strategies.

Hereditary ovarian cancers are almost entirely attributable to mutations in BRCA1/2 or the genes of DNA mismatch repair. Identifying individuals at risk requires a complete family history and evidence-guided genetic testing. Screening of women at increased risk for ovarian cancer can be considered in those not wishing prophylactic surgery and typically should include a twice-annual pelvic examination, serum CA-125 measurement, and transvaginal sonography. Patients must understand that these measures have not been conclusively proven to improve early detection or long-term survival. In all mutation carriers who have completed or do not desire childbearing, prophylactic bilateral salpingo-oophorectomy must be strongly considered.

Hyperandrogenism, mediated by obesity and receptor polymorphisms, promotes aggressive epithelial ovarian cancer biology.

OBJECTIVE: Epidemiologic data suggest that aberrant androgen homeostasis may promote aggressive epithelial ovarian cancer biology. Hyperandrogenism results from both obesity and expression of polymorphic androgen receptor (AR) allelotypes harboring short cytosine-adenine-guanine (CAG) repeat sequences; both have been shown to independently correlate with poor overall survival in ovarian cancer. We have hypothesized that the combination of these factors further manifests an aggressive ovarian cancer phenotype. METHODS: Genotype analysis of the AR CAG polymorphism was performed on 81 patients with papillary serous epithelial ovarian cancer. Medical records were reviewed for body mass index (BMI), clinico-pathologic factors, and survival. Data were examined using the Fishers exact test, Kaplan-Meier survival, and Cox regression analyses. RESULTS: Overweight or obese women (BMI > or = 25) with a short AR allele (< or = 19 CAG repeats) demonstrated statistically shorter progression-free survival (9 months) when compared to underweight or ideal body weight women (BMI < 25) and a long AR allele (> 19 CAG repeats; 26 months, p=0.0002). Overweight/obese women with a short AR allele also demonstrated shorter overall survival (34 months) when compared to underweight/ideal body weight women with a long AR allele (59 months, p=0.036). On multivariate analyses, the combination of a short AR allele and BMI > 25 was an independent poor prognostic factor after controlling for age, stage, grade, optimal cytoreduction, and AR allele length and BMI independently (p=0.05). CONCLUSION: These data provide further evidence that suggest that hyperandrogenism promotes an aggressive epithelial ovarian cancer phenotype.

Effect of obesity on survival in epithelial ovarian cancer.

BACKGROUND: Epidemiologic studies suggest that obese women are more likely to die of ovarian cancer than those of ideal body weight, but it is not known whether increased incidence, comorbidities common to obese women, or altered tumor biology is responsible for this difference. The current study attempted to determine the influence of excess body weight on ovarian cancer survival, disease progression, and clinicopathologic factors. METHODS: The records of patients undergoing surgery for epithelial ovarian cancer at Cedars Sinai Medical Center between January 1, 1996 and June 30, 2003 were reviewed for height, weight, age, comorbidities, and treatment-specific details. Statistical analyses included the Fisher exact test, Kaplan-Meier survival, and Cox regression analyses. RESULTS: In all, 216 patients were identified. Eight percent were underweight (body mass index [BMI] < 18.5), 50% were ideal body weight (18.5 /= 30). Age, comorbidities including coronary artery disease and venous thromboembolism, and rates of optimal surgical cytoreduction were similar among BMI strata. Diabetes and hypertension were more common in obese women. Ten (29%) of the obese patients had International Federation of Gynecology and Obstetrics (FIGO) Stage I disease, compared with 19 (10%) of the patients with BMI < 30 (P = .01). In a subcohort of 149 patients with Stage III or IV disease, a significant trend was identified favoring increased BMI as an independent negative factor for disease-free (P = .02) and overall (P = .02) survival. CONCLUSIONS: Obese patients were more likely to have disease limited to the ovaries. For patients with advanced stage disease, obesity was independently associated with both shorter time to recurrence and shorter overall survival. These findings suggest an effect of excess body weight on tumor biology, and studies are under way to elucidate the molecular and hormonal mechanisms underlying these clinical observations.

Adenocarcinoma of the uterine cervix with choriocarcinomatous metastasis.

BACKGROUND: Nongestational choriocarcinoma, in very rare instances, has been described as a component of other malignancies with a tendency for a very poor prognosis. CASE: A 55 year old woman was diagnosed with adenocarcinoma of the cervix, and incompletely treated with only external beam radiation. Adjuvant radical hysterectomy demonstrated no residual tumor, but the patient developed a tumor metastasis mimicking a pulmonary artery thrombus which by histology and immunohistochemistry was pure choriocarcinoma. While chemotherapy was successful in achieving a complete remission, the patient succumbed to complications of her pulmonary metastasis. CONCLUSION: Choriocarcinomatous dedifferentiation of cervical adenocarcinoma is extremely rare, with only one other case reported in the literature. While the prognosis for patients with such a tumor is generally poor, aggressive combination chemotherapy may be of benefit in some.

Morbid obesity and endometrial cancer: surgical, clinical, and pathologic outcomes in surgically managed patients.

OBJECTIVE: To evaluate surgical, clinical, and pathologic outcomes of patients with endometrial cancer managed with primary surgery when stratified by body mass index (BMI). METHODS: A review of 356 consecutive patients undergoing primary surgical management of endometrial carcinoma by a single gynecologic oncology service from 1997 to 2003 was undertaken. Patients were divided into three groups based on preoperative BMI. Data regarding surgical and pathologic outcomes were compared. RESULTS: Twenty-two percent of patients had a BMI >40, 38% were 30-40, and 40% were <30. Overall, 90% underwent some surgical staging, including 93%, 92%, and 81% of those with a BMI <30, 30-40, and >40, respectively. In fully staged patients, a median 23 lymph nodes were removed in all groups, without a significant difference in the number of aortic nodes recovered between the heaviest and lightest groups. Aortic lymphadenectomy was performed in 48% patients with BMI >40 compared with 74% of patients with BMI <30. Intraoperative and postoperative complications were rare and similar between groups. Patients with BMI >40 were more commonly diagnosed with grade 1 tumor than patients with BMI <30. Rates of nodal metastasis were similar between groups and occurred in 11% of patients overall. In those with a BMI >40, extrauterine disease was encountered in 12% of patients. CONCLUSIONS: While surgical staging of morbidly obese patients is difficult, adequate lymphadenectomy can be performed safely; although aortic nodes are less commonly resected in this population. Staging remains important in obese women, as the risk of extrauterine disease, including lymph node metastasis, is similar to that in women with ideal body weight.