Mary Anne Rossing

Ovarian Tumors in a Cohort of Infertile Women

BACKGROUND Case reports and the results of a recent case-control study have raised questions about the potential neoplastic effects of medications used as treatment for infertility. METHODS We examined the risk of ovarian tumors in a cohort of 3837 women evaluated for infertility between 1974 and 1985 in Seattle. Computer linkage with a population-based tumor registry was used to identify women in whom tumors were diagnosed before January 1, 1992. Data on infertility testing and treatment were abstracted from the medical records of women who had ovarian cancer and those of a randomly selected comparison group. The risk of ovarian tumors associated with exposure to ovulation-inducing medications was assessed through an age-standardized comparison with the rate of ovarian tumors in the general population, and Cox regression analysis was used to compare the risk of cancer among women who received these medications with the risk among infertile women who did not receive them. RESULTS There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4 (standardized incidence ratio, 2.5; 95 percent confidence interval, 1.3 to 4.5). Nine of the women in whom ovarian tumors developed had taken clomiphene; the adjusted relative risk among these women, as compared with that among infertile women who had not taken this drug, was 2.3 (95 percent confidence interval, 0.5 to 11.4). Five of the nine women had taken the drug during 12 or more monthly cycles. This period of treatment was associated with an increased risk of ovarian tumors among both women with ovarian abnormalities and those without apparent abnormalities (relative risk, 11.1; 95 percent confidence interval, 1.5 to 82.3), whereas treatment with the drug for less than one year was not associated with an increased risk. CONCLUSIONS Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.

Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients

BackgroundBreast cancer patients with tumors that are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive have lower risks of mortality after their diagnosis compared to women with ER- and/or PR-negative disease. However, few studies have evaluated variations in the risks of breast cancer-specific mortality across ER/PR status by either demographic or clinical characteristics.MethodsUsing data from 11 population-based cancer registries that participate in the SEER (Surveillance, Epidemiology, and End Results) program, 155,175 women at least 30 years old with a primary diagnosis of invasive breast carcinoma from 1990 to 2001 were included in the study. Associations between joint hormone receptor status and breast cancer mortality risk within categories of diagnosis age, diagnosis year, race/ethnicity, histologic tumor type, stage, grade, size, and axillary lymph node status were evaluated using the Cox proportional hazards model.ResultsCompared to ER+/PR+ cases, elevations in risk of mortality were observed across all subcategories of age at diagnosis, ranging from 1.2- to 1.5-fold differences for ER+/PR- cases, 1.5- to 2.1-fold differences for ER-/PR+ cases, and 2.1- to 2.6-fold differences for ER-/PR- cases. Greater differences were observed in analyses stratified by grade; among women with low-grade lesions, ER-/PR- patients had a 2.6-fold (95% confidence interval [CI] 1.7 to 3.9) to 3.1-fold (95% CI 2.8 to 3.4) increased risk of mortality compared to ER+/PR+ patients, but among women with high-grade lesions, they had a 2.1-fold (95% CI 1.9 to 2.2) to 2.3-fold (95% CI 1.8 to 2.8) increased risk.ConclusionCompared to women with ER+/PR+ tumors, women with ER+/PR-, ER-/PR+, or ER-/PR- tumors experienced higher risks of mortality, which were largely independent of the various demographic and clinical tumor characteristics assessed in this study. The higher relative mortality risks identified among ER-/PR- patients with small or low-grade tumors raise the question of whether there may be a beneficial role for adjuvant chemotherapy in this population.

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ∼2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 × 10−21).

Thyroid cancer incidence in Asian migrants to the United States and their descendants

We compared incidence rates of primary cancer of the thyroid among United States-born and foreign-born Chinese, Japanese, and Filipino residents of the US with rates among US-born Whites. Thyroid cancers diagnosed between 1973 and 1986 occurring among individuals 15 to 84 years of age residing in western Washington state, the San Francisco-Oakland (California) area, or the state of Hawaii were included in the analysis. Population estimates by age, gender, ethnicity, and country of birth were obtained for these areas from the US Bureau of the Census. Filipino women born in the Philippines had 3.2 (95 percent confidence interval=2.7–3.8) times the rate of thyroid cancer of US-born White women, while US-born Filipino women were not at any increased risk. Philippine-born Filipino men also had a relatively high rate of thyroid cancer (relative risk [RR]=2.6), more so than US-born Filipino men (RR=1.5). Among Japanese, risk of thyroid cancer varied by birthplace, but the direction of the association differed by gender and by histologic type of cancer. No clear association with birthplace was noted among Chinese men or women. These data suggest that persons residing in one or more regions from which Filipino-Americans migrated have been exposed to environmental influences that have increased their subsequent risk of thyroid cancer.

Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21.

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (alpha=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (alpha=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21.

Re: Predictive Value of Symptoms for Early Detection of Ovarian Cancer

BACKGROUND A recent consensus statement encouraged use of certain symptoms to diagnose ovarian cancer earlier. We assessed the sensitivity, specificity, and positive predictive value of a proposed symptom index and of symptoms included in the consensus recommendation. METHODS In-person interviews were conducted with 812 case patients, aged 35-74 years, who had epithelial ovarian cancer that was diagnosed from January 1, 2002, through December 31, 2005, and with 1313 population-based control subjects. The symptom index was considered positive when pelvic or abdominal pain or bloating or feeling full was reported at least daily for at least 1 week, with an onset of less than 12 months before diagnosis or a reference date (for control subjects). The consensus criteria were considered fulfilled when any symptom above or urinary urgency or frequency was reported for at least 1 month, with an onset of less than 12 months before diagnosis or a reference date. Positive predictive value was calculated by use of external estimates of cancer prevalence. RESULTS Most case patients who had a positive index or met consensus criteria did so only within 5 months before diagnosis. Symptoms (except nausea) were somewhat less likely to have occurred among women diagnosed with early-stage than late-stage ovarian cancer. The estimated positive predictive value of the symptom index or symptoms meeting the consensus criteria was 0.6%-1.1% overall and less than 0.5% for early-stage disease. CONCLUSION Use of symptoms to trigger medical evaluation for ovarian cancer is likely to result in diagnosis of the disease in only one of 100 women in the general population with such symptoms.

Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies

BACKGROUND Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes. METHODS We pooled primary data from 13 population-based case-control studies, including 10,157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13,904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births. RESULTS Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours. CONCLUSIONS We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.

Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium

BACKGROUND Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. RESULTS Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). CONCLUSIONS Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.

Menopausal Hormone Therapy and Risk of Epithelial Ovarian Cancer

Substantial increase in the use of menopausal hormone therapy (HT) throughout the 1990s, followed by widespread discontinuation after the 2002 publication of the Womens Health Initiative findings, has resulted in large numbers of former HT users among U.S. women. However, few studies have examined whether ovarian cancer risk varies according to recency and duration of specific HT regimens. We assessed risk of epithelial ovarian cancer among users of unopposed estrogen (ET) and combined estrogen/progestogen (EPT). In a population-based study in Washington state, 812 women with ovarian cancer diagnosed in 2002 to 2005 and 1,313 controls were interviewed in person about the use of HT and other characteristics. Women who used a single form of therapy (ET or EPT) were compared with women who never used HT using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). Risk was increased among current or recent (within the last 3 years) users of ET with ≥5 years of use (ORs, 95% CIs: 1.6, 1.1-2.5 and 1.8, 0.8-3.7, respectively). Little increase in risk was noted among long-term ET users who discontinued use in the more distant past (OR, 1.2; 95% CI, 0.6-2.6). No increase in risk was noted among women who used only EPT, regardless of duration. Compared with women who never used HT, current users of EPT had an OR of 1.1 (95% CI, 0.8-1.5), and risk declined with increasing time since stopping; the OR was 0.7 (95% CI, 0.4-1.0) among women who had discontinued EPT within the last 3 years and 0.5 (95% CI, 0.3-0.7) among women who stopped at an earlier point. Long-term ET may be associated with an increased ovarian cancer risk that wanes after use ceases. We did not observe an increased risk with EPT, and with increasing time after stopping, a reduction in risk became increasingly evident. The progestogen component of HT may confer a risk reduction that is masked by an opposing effect of estrogen until, among former users, estrogenic influences have diminished. These findings, if replicated, may have implications both for public health and development of chemoprevention strategies. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2548–56)

Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium

Whilst previous studies have reported that higher BMI increases a womans risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13 548 cases and 17 913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5 kg/m(2); 95% CI 1.18-1.30), invasive endometrioid (1.17; 1.11-1.23) and invasive mucinous (1.19; 1.06-1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94-1.02), but increased risks for low-grade serous invasive tumours (1.13, 1.03-1.25) and in pre-menopausal women (1.11; 1.04-1.18). Among post-menopausal women, the associations did not differ between hormone replacement therapy users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high-grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.