Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer.

PURPOSE: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. DESIGN: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. RESULTS: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82-1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). CONCLUSION: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

The risk of breast cancer in BRCA1 and BRCA2 mutation carriers without a first-degree relative with breast cancer.

The objective of this study was to estimate the lifetime risk of breast cancer in women with a BRCA1 or BRCA2 mutation with and without at least 1 first-degree relative with breast cancer. A total of 2835 women with a BRCA1 or BRCA2 mutation were followed. Age- and gene-specific breast cancer rates were calculated. The relative risks of breast cancer for subjects with a family history of breast cancer, compared to no family history were calculated. The mean age at baseline was 41.1 years, and they were followed for a mean of 6.0 years. The estimated penetrance of breast cancer to age 80 years was 60.8% for BRCA1 and 63.1% for BRCA2. For all BRCA carriers, the penetrance of breast cancer to age 80 for those with no first-degree relative with breast cancer was 60.4% and 63.3% for those with at least 1 first-degree relative with breast cancer. The risk of breast cancer for BRCA carriers with no first-degree relative with breast cancer is substantial, and as a result, clinical management for these women should be the same as those for women with an affected relative.

Cyclin E as a potential therapeutic target in high grade serous ovarian cancer.

Cyclin E1 (CCNE1) gene amplification occurs in approximately 20% of ovarian high grade serous carcinoma (HGSC) and is associated with chemotherapy resistance and, in some studies, overall poor prognosis. The role of cyclin E1 in inducing S phase entry relies upon its interactions with cyclin dependent kinases (CDK), specifically CDK2. Therapies to target cyclin E1-related functions have centered on CDK inhibitors and proteasome inhibitors. While many studies have helped elucidate the functions and regulatory mechanisms of cyclin E1, further research utilizing cyclin E1 as a therapeutic target in ovarian cancer is warranted. This review serves to present the scientific background describing the role and function of cyclin E1 in cancer development and progression, to distinguish cyclin E1-amplified HGSC as a unique subset of ovarian cancer deserving of further therapeutic investigation, and to provide an updated overview on the studies which have utilized cyclin E1 as a target for therapy in ovarian cancer.

Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy.

OBJECTIVES: The reported incidence of neoplasia identified at the time of risk-reducing salpingo-oophorectomy (RRSO) in germline BRCA1/2 mutation carriers ranges from 4 to 12% but long-term outcomes have not been described. We evaluated recurrence and survival outcomes of mutation carriers with neoplastic lesions identified at RRSO. METHODS: We identified BRCA1/2 mutation carriers with neoplasia at RRSO at three institutions. Data was collected on clinical variables, adjuvant treatment and follow-up. RESULTS: We identified 32 mutation carriers with invasive carcinomas (n=15) or high-grade intraepithelial neoplasia (n=17) that were not suspected prior to surgery. 26 occurred in BRCA1 and 6 in BRCA2 mutation carriers. Median and mean age for carcinomas were 50 years and 49.3 respectively, significantly younger than for intraepithelial neoplasm, median 53 years, and mean 55 years (p=0.04). For the 15 invasive carcinomas, median follow up was 88 months (range 45-172 months), 7 recurred (47%), median time to recurrence was 32.5 months and 3 have died of disease; 1 additional patient died of breast cancer. Overall survival was 73%, disease specific overall survival was 80% and disease free survival was 66%. For the 17 high-grade intraepithelial neoplasms, median follow up was 80 months (range 40-150), 4 were treated with chemotherapy. One recurred at 43 months and is currently not on therapy with a normal CA125, 16 months later. All patients with noninvasive neoplasia are alive. CONCLUSIONS: BRCA1 and BRCA2 mutation carriers with unsuspected invasive carcinoma at RRSO have a relatively high rate of recurrence despite predominantly early stage, small volume disease. High-grade intraepithelial neoplasms rarely recur as carcinoma and may not require adjuvant chemotherapy.

Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.

Although the link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established, the role, if any, of BRCA1 in non-familial cancers is unclear. BRCA1 mutations are rare in sporadic cancers, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non-familial breast and ovarian cancers. Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear, to conditionally nuclear, to the ER/golgi, to cytoplasmic invaginations into the nucleus. In an attempt to resolve this issue, we have comprehensively characterized 19 anti-BRCA1 antibodies. These reagents detect a 220-kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies. Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers.

Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment.

BACKGROUND: Bortezomib is a proteasome inhibitor with minimal clinical activity as a monotherapy in solid tumours, but its combination with other targeted therapies is being actively investigated as a way to increase its anticarcinogenic properties. Here, we evaluate the therapeutic potential of co-treatment with bortezomib and indole-3-carbinol (I3C), a natural compound found in cruciferous vegetables, in human ovarian cancer. METHODS: We examined the effects of I3C, bortezomib and cisplatin in several human ovarian cancer cell lines. Synergy was determined using proliferation assays and isobologram analysis. Cell cycle and apoptotic effects were assessed by flow cytometry. The mechanism of I3C and bortezomib action was determined by RNA microarray studies, quantitative RT-PCR and western blotting. Antitumour activity of I3C and bortezomib was evaluated using an OVCAR5 xenograft mouse model. RESULTS: I3C sensitised ovarian cancer cell lines to bortezomib treatment through potent synergistic mechanisms. Combination treatment with bortezomib and I3C led to profound cell cycle arrest and apoptosis as well as disruptions to multiple pathways, including those regulating endoplasmic reticulum stress, cytoskeleton, chemoresistance and carcinogen metabolism. Moreover, I3C and bortezomib co-treatment sensitised ovarian cancer cells to the standard chemotherapeutic agents, cisplatin and carboplatin. Importantly, in vivo studies demonstrated that co-treatment with I3C and bortezomib significantly inhibited tumour growth and reduced tumour weight compared with either drug alone. CONCLUSION: Together, these data provide a novel rationale for the clinical application of I3C and bortezomib in the treatment of ovarian cancer.

Vaginal high-grade sarcoma in pregnancy.

BACKGROUND: Vaginal cancer is a rare malignancy making up 1-2% of all female genital tract cancers. Among vaginal cancers, sarcomas constitute 2% of malignant vaginal lesions, with leiomyosarcomas being the most common type of sarcoma. There is a paucity of data to guide treatment of vaginal sarcomas. This case report details a patient diagnosed with a gynecologic sarcoma during pregnancy who is subsequently treated for residual vaginal disease in the postpartum period with local resection and adjuvant vaginal brachytherapy. CASE: A 31-year-old gravida 4 para 0 who presented at 22-weeks gestation with vaginal bleeding to an outside hospital and expelled a mass 11 cm in diameter from the vagina during her admission. Findings were consistent with a high grade gynecologic sarcoma. She underwent planned cesarean section at 36 weeks gestational age with uterine pathology showing no sarcoma. At her 3 month postpartum visit she was found to have a 1 cm posterior vaginal wall lesion which was resected and consistent with vaginal sarcoma. She underwent adjuvant brachytherapy. CONCLUSION: This case demonstrates the challenges with obtaining a correct pathological diagnosis for pregnant patients with vaginal sarcoma during pregnancy. Surgical resection with negative margins remains an important treatment component. Given the low incidence of disease occurrence in pregnancy and rare number of cases reported in literature, further elucidation of timing of delivery and adjuvant treatment is warranted.

Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles.

OBJECTIVES.: The utility of hormone therapy in the management of uterine sarcomas is poorly defined. We hypothesize that estrogen receptor (ER) expression is common in uterine sarcomas, and carries prognostic significance. Further, we hypothesize that ER-positive uterine sarcomas respond to hormone therapy. METHODS.: We retrospectively reviewed charts of patients with uterine sarcomas. Stepwise Cox proportional hazards regression model was used to evaluate variables related to the risk of death: age, histology, stage, use of pelvic radiotherapy, and ER expression. In addition, we examined clinical outcomes in patients treated with aromatase inhibitors, megestrol acetate, depot medroxyprogesterone acetate, and tamoxifen. RESULTS.: Fifty-four patients underwent immunohistochemical staining, and 34 (63%) were ER-positive. Kaplan-Meier survival analysis and log-rank test indicated that patients with ER-positive sarcomas demonstrated improved overall survival when compared with ER-negative patients (median OS 36 vs. 16 months, p=0.004). Upon multivariate analysis, ER positivity retained significance as an independent predictor of survival (HR=0.32, CI 0.12-0.89, p=0.03). Four patients received hormonal treatment in the adjuvant setting and remained in remission (range of follow up: 18-68 months). Eighteen patients received hormone therapy in the setting of recurrent or progressive disease: fourteen (78%) demonstrated stable disease or complete or partial response (range of follow up: 6-124 months). CONCLUSIONS.: ER expression is common and is associated with improved overall survival in uterine sarcomas. Conducting immunohistochemical staining to ascertain ER status may aid with prognostication in this disease. Hormone therapy should be considered in patients with primary and recurrent ER-positive uterine sarcomas.

Contemporary progress in ovarian cancer screening.

Our limited understanding of the natural biology of ovarian cancer, along with its low prevalence in the general population make early detection especially challenging. To be successful at the population level, an ovarian cancer screening test must prove its beneficial effect on ovarian cancer-specific mortality while achieving near-perfect specificity in order to minimize the harms resulting from false-positive results. No current screening tests for ovarian cancer fulfill these expectations. We review the current status and the challenges of ovarian cancer screening in the context of evidence-based principles that define a valuable cancer screening program.

Glucocorticoid sensitivity of OVCA 433 human ovarian carcinoma cells: inhibition of plasminogen activators, cell growth, and morphological alterations.

OVCA 433 human ovarian carcinoma cells secrete large amounts of plasminogen activator (PA), which consists of immunologically identifiable urokinase (UK) and tissue-type PA (tPA). Total extracellular PA activity is 95% inhibited by treatment of cells with 1 X 10(-7) M dexamethasone (Dex) for 3 days. This inhibition is both time and concentration dependent, with half-maximal inhibition occurring after 1.5 days with 1 X 10(-7) M Dex, or with 1 X 10(-9) M Dex for 3 days, respectively. Interestingly, the loss of UK activity precedes the loss of tPA activity, such that half-maximal inhibition of the two PA types occurs at 1 and 2 days, respectively. Dex treatment leads to approximately 50% inhibition of cell growth and pronounced morphological alterations, including marked enlargement, flattening, and multinucleation. Treatment of the cells with other classes of steroid hormones, i.e., estrogens, progestins, androgens, and mineralocorticoids, is without effect on UK and tPA activities, cell growth, or morphology. OVCA 433 cells contain about 14,000 nuclear glucocorticoid receptors (GR) per cell (measured at 37 degrees C), with an average affinity (Kd) for [3H]Dex of 6.6 X 10(-9) M. Only active glucocorticoids compete with [3H]Dex for nuclear GR binding sites. Our results demonstrate steroid-specific glucocorticoid responsiveness of ovarian carcinoma cells, a tumor cell type not usually considered hormonally responsive. Since almost 90% of ovarian carcinoma tumor biopsies contain GR (M. C. Galli, et al., Cancer (Phila.), 47: 1297-1302, 1981), it is possible that glucocorticoid sensitivity could be exploited clinically, particularly following the almost universal development of resistance to the chemotherapeutic drugs commonly used in this disease.

Hormonal regulation of CA125 tumor marker expression in human ovarian carcinoma cells: inhibition by glucocorticoids.

The CA125 tumor marker is an antigenic determinant present on a high-molecular-weight glycoprotein expressed by more than 80% of newly diagnosed nonmucinous epithelial ovarian cancers. OVCA 433 human ovarian carcinoma cells express the CA125 marker at the cell surface and release large quantities of this antigen into culture medium. Here we show that release of CA125 by OVCA 433 cells is 90 to 95% inhibited by treatment with 1 x 10(-7) M dexamethasone, as determined using a biotin-based enzyme-linked immunosorbent assay utilizing OC125 monoclonal antibodies to CA125. The relative cell surface density of CA125 is also decreased following dexamethasone treatment as determined by immunofluorescence techniques using OC125 monoclonal antibodies. Inhibition of CA125 expression is specific for glucocorticoids, such as cortisol and dexamethasone, and does not occur with estrogens, progestins, androgens, or mineralocorticoids. CA125 inhibition is also dependent on the concentration of steroid used, with half-maximal and maximal inhibition by dexamethasone occurring at about 3 x 10(-9) M and 1 x 10(-7) M, respectively. Previous work has shown that OVCA 433 cells are growth inhibited by glucocorticoids and contain 14,000 glucocorticoid receptors per cell with an affinity for dexamethasone (Kd = 6.6 x 10(-9) M) which corresponds well with the concentration required for half-maximal CA125 inhibition. This correspondence, together with the specificity of CA125 inhibition for glucocorticoids, suggests that this effect is mediated by glucocorticoid receptors and is a specific biological effect of glucocorticoids on this cell type. Our results demonstrate glucocorticoid inhibition of CA125 expression by ovarian carcinoma cells and suggest that endogenous or therapeutically administered glucocorticoids can influence CA125 production by tumors in vivo.

BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.

There is a clear association between germ-line BRCA1 mutations and inherited ovarian cancer; however, the association between BRCA1 mutations and sporadic ovarian cancer remains ambiguous. The frequency of BRCA1 promoter hypermethylation as an epigenetic means of BRCA1 inactivation was determined for a large, population-based cohort of ovarian cancer patients. BRCA1 promoter hypermethylation was determined by methylation-specific restriction digestion of tumor DNA, followed by Southern blot analysis and confirmed by methylation-specific PCR. BRCA1 promoter hypermethylation was observed in 12 of 98 ovarian tumors. BRCA1 methylation status of the primary tumor was conserved in six recurrent tumors after interim chemotherapy. None of the 12 tumors with BRCA1 promoter hypermethylation demonstrated BRCA1 protein expression by immunohistochemistry. BRCA1 methylation was only seen in ovarian cancer patients without a family history suggestive of a breast/ ovarian cancer syndrome. Therefore, the 12 BRCA1 methylated tumors represented 15% (12 of 81) of the sporadic cancers analyzed in this study. Although the clinical significance of BRCA1 promoter hypermethylation is yet to be determined, promoter hypermethylation may be an alternative to mutation in causing the inactivation of the BRCA1 tumor suppressor gene in sporadic ovarian cancer.

No association of the I1307K APC allele with ovarian cancer risk in Ashkenazi Jews.

Familial adenomatous polyposis is a dominantly inherited colon cancer syndrome associated with germ-line mutations in the APC tumor suppressor gene. An APC gene sequence alteration, the I1307K allele, occurs in 6% of the Ashkenazi Jewish population and is reported to double the risk for colorectal cancer. We screened a population of 190 Ashkenazi women who were diagnosed with epithelial ovarian carcinoma for the I1307K variant and measured the effect of this allele on the risk for cancer development in their first-degree relatives. We identified the I1307K allele in 7.9% (15 of 190) of our ovarian cancer cases. The average age of ovarian cancer diagnosis in carriers of the I1307K allele (57.5 years) was not statistically different than the age for noncarriers (56.4 years; P = 0.70). Among the 1087 first-degree relatives, there were 23 cases of colorectal cancer; 3 of 100 relatives of probands with the I1307K allele (3.0%) had a history of colorectal cancer versus 20 of 987 relatives of probands without the I1307K allele (2.1%; relative risk, 1.48; 95% confidence interval, 0.45-4.88; P = 0.462). Relatives of the I1307K carriers had a risk of 38.0% for developing any cancer to age 80, similar to the risk for relatives of noncarriers of the I1307K allele (42.1%; P = 0.86). The average age of diagnosis of cancer of any type was not different between relatives of carriers (59.0 years) and noncarriers (60.4 years). In the Ashkenazi Jewish population, the I1307K allele is unlikely to increase the risk of ovarian cancer or of cancer in general.

Differential gene expression between normal and tumor-derived ovarian epithelial cells.

The majority of ovarian tumors arise from the transformation of the ovarian surface epithelial cells, a single layer of cells surrounding the ovary. To identify genes that may contribute to the malignant phenotype of ovarian cancers, cDNA representational difference analysis was used to compare expressed genes in primary cultures of normal human ovarian surface epithelium (HOSE) and ovarian tumor-derived epithelial cells from the Cedars-Sinai Ovarian Cancer (CSOC) repository. A total of 255 differentially expressed genes were identified, of which 160 and 95 were specifically expressed in HOSE and CSOC cells, respectively. Using cDNA array hybridization, the expression profiles of the genes identified by cDNA-representational difference analysis were examined in an additional 5 HOSE and 10 CSOC lines. The comparison of average signal of each gene revealed 44 HOSE-specific and 16 CSOC-specific genes that exhibited at least a 2.5-fold difference in expression. A large number of genes identified in this study encode membrane-associated or secreted proteins and, hence, may be useful as targets in the development of serum-based diagnostic markers for ovarian cancer. Very few genes associated with protein synthesis or metabolism were identified in this study, reflecting the lack of observable differences in phenotypic or growth characteristics between HOSE and CSOC cells. Northern blot analysis on a subset of these genes demonstrated comparable levels of gene expression as observed in the cDNA array hybridization.

DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies.

p53 mutations are the most common genetic alterations found in human malignancies. However current estimates of p53 alterations in cancers may be inaccurate because there is evidence that current approaches do not detect all p53 alterations. In this study we determine the status of the p53 gene by complete DNA sequencing of exons 2 through 11 as well as immunohistochemical staining in cohorts of primary human breast, ovarian and non small cell lung cancer. Overall, 24 of 93 (26%) breast cancers, 62 of 108 (57%) ovarian cancers and 88 of 154 (57%) non small cell lung cancers contained DNA sequence mutations, whereas positive immunohistochemical staining was detected in 15 of 64 (23%) breast, 35 of 94 (37%) ovarian, and 63 of 137 (46%) lung cancers. Of those tumors that contained mutations, the mutation occurred outside the 'hot-spot' region in 19% of breast, 18% of ovarian and 17% of lung tumors, indicating that a substantial number of mutations remain undetected in studies that are restricted to exons 5 through 9. We observed a high concordance between the presence of p53 missense mutations and positive immunohistochemical staining, but a poor concordance between other types of mutations and staining in all three types of malignancies. We conclude that a combination of DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known alterations in the p53 gene in human malignancies.

Different mechanisms contribute to simultaneous inhibition of urokinase and tissue-type plasminogen activators by glucocorticoids in human ovarian carcinoma cells.

Previous studies from our laboratory have demonstrated that OVCA 433 human ovarian carcinoma cells are glucocorticoid responsive by several criteria and contain high affinity, saturable, steroid-specific glucocorticoid receptors. These cells secrete both mammalian plasminogen activators (PAs), urokinase (uPA) and tissue-type PA (tPA). Treatment of OVCA 433 cells with 1 x 10(-7) M dexamethasone (Dex) for 4 days led to 77% and 83% reductions in the extracellular activities of uPA and tPA, respectively, released into serum-free conditioned medium during a 1-h period. Dex treatment led to a 71% decrease in the rate of extracellular uPA antigen accumulation, as determined by enzyme-linked immunosorbent assay, as well as a 73% reduction in steady state uPA mRNA levels. In contrast, Dex treatment led to only a 42% decrease in the rate of extracellular tPA antigen accumulation and a 48% decrease in tPA mRNA levels; such decreases were insufficient to account for the 83% reduction in tPA activity. Thus, while Dex-induced decreases in uPA antigen and mRNA levels accounted for all but 6% of the decrease in uPA activity, a large discrepancy existed between the magnitudes of decreased tPA activity and decreased tPA antigen and mRNA levels. OVCA 433 cells produce both PAI-1 and PAI-2, two specific PA inhibitors. Treatment of cells with 1 x 10(-7) M Dex for 4 days led to a 3.3-fold increase in the rate of extracellular PAI-1 accumulation, with little or no effect on PAI-2 accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.

Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas.

Comparative hybridization of cDNA arrays is a powerful tool for the measurement of differences in gene expression between two or more tissues. We optimized this technique and employed it to discover genes with potential for the diagnosis of ovarian cancer. This cancer is rarely identified in time for a good prognosis after diagnosis. An array of 21,500 unknown ovarian cDNAs was hybridized with labeled first-strand cDNA from 10 ovarian tumors and six normal tissues. One hundred and thirty-four clones are overexpressed in at least five of the 10 tumors. These cDNAs were sequenced and compared to public sequence databases. One of these, the gene HE4, was found to be expressed primarily in some ovarian cancers, and is thus a potential marker of ovarian carcinoma.

Ovarian cancer tumor marker behavior in asymptomatic healthy women: implications for screening.

Ovarian cancer screening protocols generally have been limited by inadequate recognition of the normal behavior of tumor markers in women at risk of ovarian cancer. We have characterized the behavior of five serum tumor markers in a large cohort of healthy women and examined the implications for screening. Serial measurements of CA125, HER-2/neu, urinary gonadotropin peptide, lipid-associated sialic acid, and Dianon marker 70/K were obtained during 6 years of follow-up of 1257 healthy women at high risk of ovarian cancer. We analyzed individual-specific tumor marker behavior and explored methods that can exploit this information to develop individual-specific screening rules. These five tumor markers behaved approximately independently. Substantial heterogeneity was observed among women in the behavior of each tumor marker, particularly CA125. Intraclass correlation (ICC), or the proportion of total variability that occurs between individuals, was approximately 0.6 for log-transformed CA125 and urinary gonadotropin peptide, and less than 0.4 for the other markers. This degree of tumor marker heterogeneity among healthy women, and the relative independence of these markers, has important implications for screening and diagnostic tests. Independence of markers results in the clinically useful fact that the combined false positive rate from screening with multiple markers may be estimated by the sum of individual false positive rates. Heterogeneity of tumor marker patterns in healthy women implies that a fixed screening cutoff level is suboptimal to a degree that depends strongly on ICC. Using information on longitudinal measurements and ICC, individual-specific screening rules may be developed with the potential to improve early detection of ovarian cancer.