Differences in risk for type 1 and type 2 ovarian cancer in a large cancer screening trial.

OBJECTIVE: To investigate the role of previous gynecologic surgery, hormone use, and use of non-steroidal anti-inflammatory drugs on the risk of type 1 and type 2 ovarian cancer. METHODS: We utilized data collected for the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. All diagnosed ovarian cancers were divided into three groups: type 1, endometrioid, clear cell, mucinous, low grade serous, and low grade adenocarcinoma/not otherwise specified (NOS); type 2, high grade serous, undifferentiated, carcinosarcoma, and high grade adenocarcinoma/NOS; and other: adenocarcinoma with grade or histology not specified, borderline tumors, granulosa cell tumors. The odds ratios for type 1, type 2, and other ovarian cancers were assessed with regard to historical information for specific risk factors. RESULTS: Ibuprofen use was associated with a decrease in risk for type 1 ovarian cancer. Tubal ligation and oral contraceptive use were associated with a decrease in risk for type 2 ovarian cancer. A history of ectopic pregnancy was associated with a decreased risk for all ovarian cancers by almost 70%. CONCLUSION: These findings support the hypothesis that carcinogenic pathways for type 1 and type 2 ovarian cancer are different and distinct. The marked reduction in all ovarian cancer risk noted with a history of ectopic pregnancy and salpingectomy implies that the fallopian tube plays a key role in carcinogenesis for both type 1 and type 2 ovarian cancer.

Ovarian cancer screening in menopausal females with a family history of breast or ovarian cancer.

OBJECTIVE: To determine whether annual screening reduces ovarian cancer mortality in women with a family history of breast or ovarian cancer. METHODS: Data was obtained from the Prostate, Lung, Colorectal, and Ovarian cancer trial, a randomized multi-center trial conducted to determine if screening could reduce mortality in these cancers. The trial enrolled 78,216 women, randomized into either a screening arm with annual serum cancer antigen 125 and pelvic ultrasounds, or usual care arm. This study identified a subgroup that reported a first degree relative with breast or ovarian cancer. Analysis was performed to compare overall mortality and disease specific mortality in the screening versus usual care arm. In patients diagnosed with ovarian cancer, stage distribution, and survival were analyzed as a secondary endpoint. RESULTS: There was no significant difference in overall mortality or disease specific mortality between the two arms. Ovarian cancer was diagnosed in 48 patients in the screening arm and 44 patients in the usual care arm. Screened patients were more likely to be diagnosed at an earlier stage than usual care patients. Patients in the screening arm diagnosed with ovarian cancer experienced a significantly improved survival compared to patients in the usual care arm; relative risk 0.66 (95% CI, 0.47 to 0.93). CONCLUSION: Screening did not appear to decrease ovarian cancer mortality in participants with a family history of breast or ovarian cancer. Secondary endpoints, however, showed notable differences. Significantly fewer patients were diagnosed with advanced stage disease in the screening arm; and survival was significantly improved. Further investigation is warranted to assess screening efficacy in women at increased risk.

Loss of Mismatch Repair Protein Expression in Unselected Endometrial Adenocarcinoma Precursor Lesions.

OBJECTIVE: The benefit of evaluating the precursor of endometrial carcinoma, endometrial hyperplasia (intraepithelial neoplasia [EIN]), for loss of mismatch repair (MMR) protein expression and Lynch syndrome has yet to be determined. The present study aims to establish the incidence and type of loss of MMR protein expression in unselected premalignant lesions of endometrial adenocarcinoma, as well as the agreement of immunohistochemical staining in pretreatment endometrial biopsy (EMB) specimens with subsequent uterine resections. METHODS: A retrospective review identified 112 endometrial biopsies meeting criteria for endometrial EIN. Slides made from tissue microarray blocks were evaluated using antibodies against MLH1, PMS2, MSH2, and MSH6. Cases with a deficit in MLH1 were evaluated for gene promoter hypermethylation by polymerase chain reaction analysis. Fifty-four subsequent hysterectomy specimens were retrieved and assessed for MMR protein expression. RESULTS: Of the 112 endometrial biopsies with EIN, 4.5% (5/112) exhibited loss of MMR protein expression. The majority (4/5) demonstrated a deficit of MLH1, of which all exhibited inactivation via promoter hypermethylation. A single case displayed an absence of MSH6. Age was not significantly associated with MMR deficiency. There was no significant association between MMR status in the EMB and a subsequent diagnosis of cancer. Immunohistochemical staining in all successive hysterectomy cases was concordant with the pattern observed in the EMB specimen. CONCLUSIONS: Sporadic hypermethylation of MLH1 seems to be the primary mechanism underlying defective MMR protein expression in EIN. Among our cohort, only 1 patient (<1%) had a mutation suggestive of a hereditary inheritance. Hence, the utility of evaluating EIN for MMR protein expression as a screen for Lynch syndrome is limited, regardless of age.

Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary.

OBJECTIVE: Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma. METHODS: A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed. RESULTS: Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p=0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p<0.001). CONCLUSION: Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.

Abnormal CA-125 levels in menopausal women without ovarian cancer.

OBJECTIVE: To determine if an abnormal CA-125 level in a menopausal female without ovarian cancer is associated with an increase in mortality. METHODS: The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Randomized Controlled (PLCO) Trial is a large multicenter prospective trial conducted by the National Cancer Institute (NCI). Over 78,000 healthy women aged 55-74 were randomized to a screening arm versus a usual medical care arm to evaluate the efficacy of screening in reducing mortality due to ovarian cancer. Women in the screening arm underwent annual screening for ovarian cancer with transvaginal ultrasound and CA-125 levels. There were 38,818 patients without ovarian cancer that had at least one CA-125 level drawn; 1201 (3.09%) had at least one abnormal level. The current study compares mortality in patients that had one or more abnormal CA-125 levels without ovarian cancer versus those with all normal levels. RESULTS: Patients with one or more abnormal CA-125 levels, without ovarian cancer, had a significantly higher mortality than patients with all normal CA-125 levels in the PLCO screening trial (p<0.0001). This increased risk extended throughout the follow-up period. Analysis of cause of death listed on the death certificate showed an excess mortality attributable to lung cancer, digestive disease, and endocrine, nutritional, and metabolic disease. CONCLUSION: Menopausal females with an elevated CA-125 and without ovarian cancer are exposed to an increased risk of premature mortality.

Non-islet cell tumor hypoglycemia associated with recurrent carcinosarcoma of the ovary.

OBJECTIVE: To describe the first reported case of non-islet cell tumor hypoglycemia (NICTH) associated with carcinosarcoma of the ovary. METHODS: We report the clinical course, imaging, and pathologic findings of our patient and review relevant literature. RESULTS: A 48-year-old woman had a surgery to remove ovarian masses, which turned out to be carcinosarcoma of the ovary, stage IIIc; however, she declined postoperative adjuvant chemotherapy. Six months later, she became unconscious with severe hypoglycemia. A large pelvic mass was found and thought to represent a recurrence. Serum insulin and C-peptide were undetectable. Morning cortisol was mildly elevated. Thyroid stimulating hormone, amylase, lipase, and renal and hepatic functions were normal. While insulin-like growth factor (IGF)-I was low, IGF-II was inappropriately elevated. Increased IGF-II/IGF-I ratio was suggestive of NICTH in light of the large pelvic tumor. She required frequent meals, dextrose boluses, and continuous infusions, oral prednisone, and glucagon continuous infusion to prevent recurrent hypoglycemic attacks. Chemotherapy with carboplatin and paclitaxel was initiated, and glucose control started to improve. After 4 cycles of the chemotherapy, the tumor regressed substantially and was surgically removed. She had 3 more cycles of postoperative chemotherapy. Although the reported median survival of this aggressive neoplasm is less than 2 years, this patient has been free of recurrent disease and hypoglycemia for 6 years. CONCLUSION: This is the first study to report NICTH in a patient with carcinosarcoma of the ovary. Clinicians should be aware of NICTH as a cause of hypoglycemia especially in a patient with a tumor or history of tumor.

Survival of endometrial cancer patients with lymphatic invasion and deficient mismatch repair expression.

OBJECTIVE: This study examines patients under the age of 70 with endometrial cancer and lymphatic invasion or lymph node metastases. Survival of patients with loss of tumor mismatch repair expression is compared to survival of patients with normal mismatch repair expression. METHODS: This is a retrospective review of patients treated from 1998-2009 for carcinoma of the endometrium. All patients with lymphatic invasion, including lymph node metastases, had immunohistochemical staining of the primary tumor for loss of expression of the mismatch repair genes MLH1, PMS2, MSH6, and MSH2. Overall survival and disease specific survival were compared using Kaplan-Meier plots. RESULTS: Sixty-six patients were identified for inclusion; 26 demonstrated loss of mismatch repair expression and 40 demonstrated normal mismatch repair expression. Overall survival and disease specific survival were significantly better in the group with defective mismatch repair expression. Subgroup analysis of FIGO stage 3C patients also showed significantly better survival in patients with deficient mismatch repair expression. CONCLUSION: For patients with endometrial cancer and lymphatic invasion, patients demonstrating loss of mismatch repair expression in the primary tumor appear to have a significantly better survival than patients with normal mismatch repair expression. Further investigation appears warranted to examine a possible role of mismatch repair expression as a prognostic marker for high risk patients with endometrial cancer.

Clinical and pathologic features of young endometrial cancer patients with loss of mismatch repair expression.

OBJECTIVE: This study examines premenopausal and early menopause patients in a unique population with endometrial cancer and loss of mismatch repair (MMR) gene expression. The purpose is to compare clinical and pathologic differences in patients with loss of expression (LOE) to those with normal expression (NE). METHODS: Endometrial cancer patients under age 60 in-between 1998 and 2008 were identified from a single tumor registry. Clinical and pathologic data were abstracted from records. Staining for expression of MSH6, MSH2, MLH1, and PMS2 were performed on archived tissue blocks. Statistical analysis was performed. RESULTS: 158 patients were analyzed; 58% Asian, 34% Pacific Islander, and 8% Caucasian. 31 demonstrated LOE of at least one MMR gene; 127 retained NE. 50% Caucasian, 21.9% Asian, and 12.5% Pacific Island populations had LOE of one or more MMR genes. LOE was found to have a higher incidence of Grade III (p=0.0013) and stage 3-4 tumors (p=0.0079), mean depth of myometrial invasion (p=0.0019), lymphovascular space invasion (p=0.0020), nodal metastases (p=0.0157), and a lower incidence of Grade I (p=0.0020) and stage 1A tumors (p=0.0085). LOE had a significantly lower mean BMI (p=0.0001). 35% of patients in the NE vs zero in the LOE group had a BMI greater than 40. CONCLUSION: Younger patients with LOE endometrial cancer appear to represent a clinically significant subgroup of patients without features characteristically found in classic type 1 endometrial cancer generally demonstrating lower BMI and tumors associated with poor prognostic characteristics. It is unclear if the distinctive ethnicity found in Hawaii has a significant impact on outcome. Further investigation is necessary to identify appropriate treatment strategies.

Genetic polymorphisms in the estrogen receptor beta (ESR2) gene and the risk of epithelial ovarian carcinoma.

Ovarian cancer is influenced by exogenous and endogenous estrogens as suggested by experimental and epidemiological evidence. Estrogen receptor beta is a predominant estrogen receptor in the normal ovary. Polymorphisms in the estrogen receptor beta gene (ESR2) might influence epithelial ovarian risk through regulation of cell proliferation and apoptosis. This population-based case-control study included 313 women with epithelial ovarian carcinoma and 574 controls, frequency-matched on age and ethnicity. Unconditional logistic regression was used to test associations of rs1271572, rs1256030, rs1256031, and rs3020450 ESR2 genotypes with ovarian cancer risk. Compared to homozygous common allele carriers, homozygous carriers of variant alleles for rs1271572 [odds ratio (OR) = 1.79, 95% confidence interval (CI):1.15-2.79, p global = 0.01] and rs1256030 [OR = 1.67, CI: 1.08-2.59, p global = 0.04], and women with haplotypes, including variant alleles of rs1271572, rs1256030, and rs1256031 SNPs [OR = 1.75, CI: 1.17-2.63, p global = 0.007], had significantly increased risk of ovarian carcinoma. The association of the rs1271572 genotype was strongest among women who had never used contraceptive steroids (p for interaction = 0.04). Our data suggest that ESR2 might be a susceptibility marker for epithelial ovarian cancer.

Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women.

Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567-72).

Genetic polymorphisms in the Paraoxonase 1 gene and risk of ovarian epithelial carcinoma.

Oxidative stress during successive ovulations increases the opportunity for DNA damage to ovarian epithelial cells and the potential for malignant transformation. Paraoxonase 1 (PON1) is an endogenous free radical scavenger that reduces oxidative stress. The association of two common functional single nucleotide polymorphisms (SNP), rs854560 T>A and rs662 A>G, with the risk of epithelial ovarian cancer was examined in a population-based case-control study in Hawaii. A personal interview and blood specimens were collected from 274 women with histologically confirmed, primary ovarian cancer and 452 controls frequency matched on age and ethnicity. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. Both PON1 SNPs were significantly associated with ovarian cancer risk. The ORs were 0.53 (95% CI, 0.35-0.79; P for allele-dose effect = 0.01) for women carrying the rs854560 T allele compared with women with the AA genotype and 0.65 (95% CI, 0.44-0.95; P for allele-dose effect = 0.03) for women carrying the rs662 A allele compared with women with the GG genotype. The association of the rs854560 T genotype with risk was stronger among smokers (OR, 0.33; 95% CI, 0.17-0.64; P for allele-dose effect = 0.0007) than among nonsmokers (OR, 0.68; 95% CI, 0.40-1.18; P for allele-dose effect = 0.53). The decreased risk associated with the rs854560 T allele was also stronger among obese women (OR, 0.19; 95% CI, 0.06-0.55; P for allele-dose effect = 0.007) than among nonobese women (OR, 0.62; 95% CI, 0.40-0.98; P for allele-dose effect = 0.16). Our study provides evidence for an association of two PON1 SNPs with the risk of epithelial ovarian cancer. Possible effect modification of these associations by tobacco smoking and obesity needs confirmation in other studies.

Combined oral contraceptive use and epithelial ovarian cancer risk: time-related effects.

BACKGROUND: Although the protective effect of oral contraceptives (OCs) use against epithelial ovarian cancer is well-established, there remain gaps in our understanding of the contributions of time-related characteristics of OC use to risk. METHODS: This population-based case-control study, carried out in Hawaii and Los Angeles 1993-2006, included 813 cases of epithelial ovarian cancer and 992 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. RESULTS: Epithelial ovarian cancer risk was reduced 5 or more years after initiation of OC use (OR = 0.18; CI = 0.08-0.39). Each year of use provided a 5% reduction (CI = 2%-8%) in risk. A positive gradient in risk with time since first OC use was independent of duration of OC use. The inverse association of OCs with risk was attenuated decades after last use, but was not affected by age at first or last use. OC use for <1 year was associated with decreased ovarian cancer risk (OR = 0.45; CI = 0.26-0.79) only among recent users (< or =20 years from diagnosis/interview). Women who used OCs for a year or more were protected for at least 3 decades after they stopped use. CONCLUSIONS: Reduction in epithelial ovarian cancer risk associated with OC use became apparent after a short latency period and short duration of use, and was long-lasting. Time since first use and time since last use seem to modify the association of OCs with ovarian cancer risk independently of duration of use.

Vitamin D receptor gene polymorphisms and epithelial ovarian cancer risk.

Epidemiologic and laboratory studies support a role for the vitamin D endocrine system in ovarian carcinogenesis. The association of ovarian cancer risk with polymorphisms in the vitamin D receptor (VDR) gene, including rs10735810 (FokI), rs11568820 (Cdx-2), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI), and BsmI-ApaI-TaqI combined genotypes, was examined among 313 women with epithelial ovarian carcinoma and 574 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. The associations of VDR polymorphisms with risk were generally inconsistent across ethnic groups. Among Caucasian women (72 cases, 148 controls), heterozygous and homozygous ApaI A allele carriers were at increased ovarian carcinoma risk compared with homozygous carriers of the ApaI a allele (OR 2.8, 95% CI 1.2-7.0 and OR 3.4, 95% CI 1.3-9.1; P(trend) = 0.02). Caucasian heterozygous carriers of FokI f allele were also at increased risk of ovarian carcinoma compared with homozygous carriers of the common allele (OR 2.5, 95% CI 1.3-4.8; P(trend) = 0.04). Among Japanese women (94 cases, 173 controls), ovarian cancer risk was significantly decreased (OR 0.5, 95% CI 0.3-0.9) among Cdx-2 A allele heterozygotes compared with homozygote G allele carriers (P(trend) = 0.03). Compared with the bbaaTT BsmI-ApaI-TaqI genotype, bbaATT and BBAAtt genotypes were associated with increased ovarian cancer risk in Caucasian women (OR 4.2, 95% CI 1.3-13.1 and OR 5.2, 95% CI 1.6-17.5), but not in Japanese women (OR 1.1, 95% CI 0.6-1.9 and OR 2.3, 95% CI:0.4-12.3). This investigation provides some evidence that polymorphisms in the VDR gene might influence ovarian cancer susceptibility.

Association of estrogen and progestin potency of oral contraceptives with ovarian carcinoma risk.

OBJECTIVE: To estimate the association of the estrogen and progestin potency of combined oral contraceptive pills (OCPs) with epithelial ovarian carcinoma risk. METHODS: This population-based case-control study included 745 women with incident, histologically confirmed epithelial ovarian carcinoma and 943 controls, matched on age and ethnicity. Data were collected using a standard questionnaire, picture albums, and calendars. The association of OCP potency with epithelial ovarian carcinoma risk was modeled using unconditional logistic regression. RESULTS: When compared with women who never used hormonal contraception, users of OCPs with low estrogen (equal to or less than 0.035 mg ethinyl estradiol) and low progestin (less than 0.3 mg norgestrel) were at significantly reduced risk of ovarian carcinoma (odds ratio 0.19; 95% confidence interval 0.05-0.75). The risk among these women was lower than among users of estrogen or progestin of high potency, but the difference was not statistically significant. However, in a subset of 205 women who reported exclusive use of norethindrone, users of 0.5 mg or less, had a significantly reduced risk of ovarian cancer compared with women using 10 mg of this progestin. Increased norethindrone dose resulted in a significant increase in ovarian carcinoma risk, indicating a dose-response association. CONCLUSION: Combined OCPs were effective at decreasing the risk of epithelial ovarian carcinoma, with the strongest risk reduction associated with low-potency formulations. LEVEL OF EVIDENCE: II.

Sentinel node dissection in vulvar cancer.

Vulvar cancer is an uncommon but devastating disease. In addition to radical vulvectomy, most patients require inguinofemoral lymphadenectomy, which often results in wound infection, wound breakdown, and chronic lymphedema. In the past, the gold standard for early lesions was radical vulvectomy with complete bilateral inguinal-femoral lymphadenectomy. This resulted in a low rate of recurrence but devastating disfigurement and high complication rates. Because only approximately 20% of patients with vulvar cancer have positive lymph nodes upon presentation, the traditional approach of inguinal-femoral lymphadenectomy for all patients resulted in many patients undergoing a morbid procedure without any real benefit. Sentinel node dissection, by removing only the nodes with the highest risk of containing metastases, offers a much less morbid alternative. In addition, because only one or two lymph nodes are removed, these can be subjected to a more thorough histopathologic analysis than conventional complete lymphadenectomy. This involves serial sectioning and immunohistochemical staining for cytokeratin antigen. Very small metastases, termed micrometastases, can be detected in this fashion. Therefore, sentinel node dissection with serial sectioning and immunohistochemical staining potentially offers a more accurate assessment of the regional nodes with less morbidity. Patients with positive sentinel nodes may then undergo additional therapy. Patients with negative sentinel nodes are theoretically at very low risk for metastases and should not require any additional treatment.

Outcomes for patients with T1 squamous cell cancer of the vulva undergoing sentinel node biopsy.

OBJECTIVE: This retrospective review was undertaken to evaluate survival in patients with T1 squamous cell carcinoma of the vulva treated with radical local excision and sentinel node dissection. METHODS: Patients with T1 cancers underwent pre-operative lymphoscintigraphy and sentinel lymph node dissection using technetium sulfur colloid and isosulfan blue dye. The primary tumor was removed with radical local excision. Patients with negative sentinel nodes did not receive any additional treatment. Survival was calculated using life table analysis. RESULTS: There were 21 patients who underwent 27 sentinel node dissections. Three patients were found to have positive sentinel nodes. At a median follow-up of 4.6 years, two patients have died of cancer, and three patients have died of intercurrent illness. None of the patients with negative sentinel nodes has died of cancer. There were no groin or distant recurrences in patients with negative sentinel nodes. Three-year disease-free survival for all patients and for patients with negative sentinel nodes were 90% and 100% respectively. CONCLUSION: The survival for patients with early vulvar cancer treated with sentinel node dissection and radical local excision appears excellent.

Effect of anovulation factors on pre- and postmenopausal ovarian cancer risk: revisiting the incessant ovulation hypothesis.

Risk factors for ovarian cancer may differ between pre- and postmenopausal women. The authors used data from a multiethnic, population-based, case-control study, conducted between 1993 and 1999 in Hawaii and Los Angeles, California, to examine whether menopause modified the effect of ovulation on ovarian cancer risk. A structured questionnaire was administered to 558 histologically confirmed epithelial ovarian cancer cases and 607 population controls. Lifetime ovulatory (log)years were significantly associated with an increased risk of ovarian cancer (odds ratio = 1.78, 95% confidence interval: 1.24, 2.57), particularly among premenopausal women (odds ratio = 2.49) but not among postmenopausal women (odds ratio = 0.88) (p(interaction) = 0.006). Factors that induced anovulation, including oral contraceptives, pregnancy, and breastfeeding, were associated with a reduced risk of ovarian cancer. Among anovulation factors, prolonged oral contraceptive pill use provided a greater protective effect against premenopausal ovarian cancer than against postmenopausal ovarian cancer (for > or =5.4 years of use vs. never use: odds ratio = 0.28, 95% confidence interval: 0.15, 0.52 vs. odds ratio = 0.58, 95% confidence interval: 0.31, 1.08, respectively), but the difference was not significant (p(interaction) = 0.20). Association of breastfeeding and pregnancy with ovarian cancer risk was also similar between pre- and postmenopausal women (respective p(interaction) = 0.72 and 0.43). The authors' data support the hypothesis that lifetime ovulation is involved in the pathogenesis of pre- but not postmenopausal ovarian cancer, while the protective effects of anovulation factors persist from pre- to postmenopausal women.

Polymorphisms of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, and IL-18 and the risk of ovarian cancer.

OBJECTIVE: Recent studies of ovarian cancer have suggested a role for inflammation in carcinogenesis. Data from a population-based case-control study in Hawaii were examined to assess the relation between polymorphisms in cytokines involved with the inflammatory response, specifically members of the interleukin (IL) family and the incidence of ovarian cancer. PATIENTS AND METHODS: The analysis of 182 epithelial ovarian cancer cases and 219 controls focused on the polymorphisms in the following genes: IL-1alpha, IL-1beta, IL-6, IL-10, and IL-18. Genotype data were obtained from blood samples collected in participants' homes, and reproductive, demographic, and lifestyle histories were collected during interview. RESULTS: There were no significant odds ratios (ORs) for ovarian cancer by allelic variants in any of the IL genes after adjusting for age, ethnicity, education, oral contraceptive pill use, pregnancy, and history of tubal ligation. Although there was a significantly reduced risk of ovarian cancer risk among women with an IL-1alpha (-4845) T allele compared to women with two G alleles (OR: 0.59; 95% confidence interval: 0.37-0.97) after adjustment for age and ethnicity, the trend was not significant (p = 0.10). Further examination of the data suggested that women with at least one IL-18 variant allele (a G to C transition at position -137) were at significantly decreased risk of advanced ovarian cancer (OR: 0.51; 95% confidence interval: 0.28-0.90) compared to women with the IL-18 GG genotype. There was a significant difference in the risk of ovarian cancer associated with the IL-18 C allele by stage at diagnosis (p = 0.04 for homogeneity in the ORs): cases with IL-18 GC or CC genotypes were less likely to be diagnosed at regional/distant stages. Analysis of the data within ethnic subgroups revealed a significant positive association of the heterozygous IL-18 GC genotype with ovarian cancer risk among Native Hawaiian women (OR: 9.96; 95% CI: 1.88-52.90). The OR for ovarian cancer was not significant for Native Hawaiian women homozygous for the IL-18 C allele, but only one case and control had the IL-18 CC genotype. CONCLUSIONS: Overall, this study does not support an association of selected IL-1alpha, IL-1beta, IL-6, IL-10, or IL-18 polymorphisms with the risk for ovarian cancer. However, the IL-18 G137C variant may be a marker for ovarian cancer progression or metastasis.

Reproductive factors and epithelial ovarian cancer risk by histologic type: a multiethnic case-control study.

Associations of reproductive factors with ovarian cancer may differ by histologic type. Data from a multiethnic, population-based, case-control study, conducted in Hawaii and Los Angeles, California, between 1993 and 1999, were used to assess this hypothesis. A structured questionnaire was administered to 558 histologically confirmed epithelial ovarian cancer cases and 607 population controls. Factors suppressing ovulation, including pregnancy and oral contraceptive use, were inversely associated with the risk of all histologic types. Nonmucinous but not mucinous tumors were significantly associated with menstruation years (odds ratio = 1.5 for the highest vs. the lowest quartile) and lifetime ovulatory cycles (odds ratio = 2.8 for the highest vs. the lowest quartile). Duration of breastfeeding (odds ratio = 0.4 for the highest vs. the lowest quartile) was significantly and inversely related to nonmucinous tumors but not to mucinous tumors. Among all tumor types, endometrioid tumors were the most strongly related to pregnancy and tubal ligation, while clear cell tumors were the only type that was associated with noncontraceptive hormone use. The risk factors were similar for borderline and invasive tumors, except for age at diagnosis. Mucinous tumors, both borderline and invasive, were more common in Asian women than in Caucasian and other women. Our data suggest that histologic types of epithelial ovarian cancer are etiologically distinct.