Patricia G. Moorman

BREAST CANCER: HORMONES AND OTHER RISK FACTORS

UNLABELLED In North America and Northern Europe, breast cancer incidence rates begin increasing in the early reproductive years and continue climbing into the late seventies, whereas rates plateau after menopause in Japan and less developed countries. Female gender, age and country of birth are the strongest determinants of disease risk. Family history and mutations in the BRCA1 and BRCA2 genes are important correlates of lifetime risk. Genetic polymorphisms associated with estrogen synthesis and metabolism are currently under study. Atypical hyperplasia and molecular alterations in benign breast lesions appear to be involved in the pathogenesis of invasive carcinoma. In postmenopausal women, increased breast density on mammograms increases risk. Bone density and breast cancer are associated, presumably through the mechanism of endogenous estrogen levels. Serum estrogen levels are higher in breast cancer cases than controls. Many established risk factors for breast cancer may function through and endocrine mechanism. Current use of oral contraceptives and prolonged, current or recent use of hormone replacement therapy moderately increase risk. Tamoxifen and possibly other selective estrogen receptor modulators reduce breast cancer risk in high risk women. Relationships between various dietary micro and macronutrients and breast cancer have been suggested but require evaluation in clinical trials. Whereas alcohol consumption is associated with increased risk, most environmental factors, including polychlorinated compounds and electromagnetic fields, are not. CONCLUSION Breast cancer etiology is becoming clearer through the study of molecular alterations in germline and somatic cell genes, and the interaction of these genes with steroid hormones and relevant growth factors. This knowledge should be useful for breast cancer prevention.

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).

The Carolina Breast Cancer Study: integrating population-based epidemiology and molecular biology

SummaryThe integration of epidemiology and molecular biology provides a new strategy to identify additional risk factors for breast cancer and to better understand the role played by traditionally recognized risk factors. The Carolina Breast Cancer Study (CBCS) is a population-based, case-control study designed to identify causes of breast cancer among Caucasian and African-American women who are residents of a 24-county area of central and eastern North Carolina. Information on established and potential breast cancer risk factors is obtained by personal interviews. Blood samples are collected from all consenting participants. Medical record documentation and paraffin-embedded tumor specimens are obtained for all breast cancer patients. DNA from tumor tissue is tested for a variety of molecular alterations characteristic of breast cancer. Germline DNA from blood lymphocytes is evaluated for presence of alleles increasing susceptibility to breast cancer. Statistical analyses evaluate gene-environment interaction by exploring the associations between environmental/behavioral factors and breast cancer in relation to specific molecular alterations (germline and tumor). Results will help identify high-risk women, clarify causal pathways, and hopefully contribute to the prevention of breast cancer.

Benefits and Harms of Breast Cancer Screening A Systematic Review

IMPORTANCE Patients need to consider both benefits and harms of breast cancer screening. OBJECTIVE To systematically synthesize available evidence on the association of mammographic screening and clinical breast examination (CBE) at different ages and intervals with breast cancer mortality, overdiagnosis, false-positive biopsy findings, life expectancy, and quality-adjusted life expectancy. EVIDENCE REVIEW We searched PubMed (to March 6, 2014), CINAHL (to September 10, 2013), and PsycINFO (to September 10, 2013) for systematic reviews, randomized clinical trials (RCTs) (with no limit to publication date), and observational and modeling studies published after January 1, 2000, as well as systematic reviews of all study designs. Included studies (7 reviews, 10 RCTs, 72 observational, 1 modeling) provided evidence on the association between screening with mammography, CBE, or both and prespecified critical outcomes among women at average risk of breast cancer (no known genetic susceptibility, family history, previous breast neoplasia, or chest irradiation). We used summary estimates from existing reviews, supplemented by qualitative synthesis of studies not included in those reviews. FINDINGS Across all ages of women at average risk, pooled estimates of association between mammography screening and mortality reduction after 13 years of follow-up were similar for 3 meta-analyses of clinical trials (UK Independent Panel: relative risk [RR], 0.80 [95% CI, 0.73-0.89]; Canadian Task Force: RR, 0.82 [95% CI, 0.74-0.94]; Cochrane: RR, 0.81 [95% CI, 0.74-0.87]); were greater in a meta-analysis of cohort studies (RR, 0.75 [95% CI, 0.69 to 0.81]); and were comparable in a modeling study (CISNET; median RR equivalent among 7 models, 0.85 [range, 0.77-0.93]). Uncertainty remains about the magnitude of associated mortality reduction in the entire US population, among women 40 to 49 years, and with annual screening compared with biennial screening. There is uncertainty about the magnitude of overdiagnosis associated with different screening strategies, attributable in part to lack of consensus on methods of estimation and the importance of ductal carcinoma in situ in overdiagnosis. For women with a first mammography screening at age 40 years, estimated 10-year cumulative risk of a false-positive biopsy result was higher (7.0% [95% CI, 6.1%-7.8%]) for annual compared with biennial (4.8% [95% CI, 4.4%-5.2%]) screening. Although 10-year probabilities of false-positive biopsy results were similar for women beginning screening at age 50 years, indirect estimates of lifetime probability of false-positive results were lower. Evidence for the relationship between screening and life expectancy and quality-adjusted life expectancy was low in quality. There was no direct evidence for any additional mortality benefit associated with the addition of CBE to mammography, but observational evidence from the United States and Canada suggested an increase in false-positive findings compared with mammography alone, with both studies finding an estimated 55 additional false-positive findings per extra breast cancer detected with the addition of CBE. CONCLUSIONS AND RELEVANCE For women of all ages at average risk, screening was associated with a reduction in breast cancer mortality of approximately 20%, although there was uncertainty about quantitative estimates of outcomes for different breast cancer screening strategies in the United States. These findings and the related uncertainty should be considered when making recommendations based on judgments about the balance of benefits and harms of breast cancer screening.

Oral Contraceptive Use and Risk of Breast, Cervical, Colorectal, and Endometrial Cancers: A Systematic Review

Oral contraceptives may influence the risk of certain cancers. As part of the AHRQ Evidence Report, Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer, we conducted a systematic review to estimate associations between oral contraceptive use and breast, cervical, colorectal, and endometrial cancer incidence. We searched PubMed, Embase, and Cochrane Database of Systematic Reviews. Study inclusion criteria were women taking oral contraceptives for contraception or ovarian cancer prevention; includes comparison group with no oral contraceptive use; study reports quantitative associations between oral contraceptive exposure and relevant cancers; controlled study or pooled patient-level meta-analyses; sample size for nonrandomized studies ≥100; peer-reviewed, English-language; published from January 1, 2000 forward. Random-effects meta-analyses were conducted by estimating pooled ORs with 95% confidence intervals (CIs). We included 44 breast, 12 cervical, 11 colorectal, and 9 endometrial cancers studies. Breast cancer incidence was slightly but significantly increased in users (OR, 1.08; CI, 1.00–1.17); results show a higher risk associated with more recent use of oral contraceptives. Risk of cervical cancer was increased with duration of oral contraceptive use in women with human papillomavirus infection; heterogeneity prevented meta-analysis. Colorectal cancer (OR, 0.86; CI, 0.79–0.95) and endometrial cancer incidences (OR, 0.57; CI, 0.43–0.77) were significantly reduced by oral contraceptive use. Compared with never use, ever use of oral contraceptives is significantly associated with decreases in colorectal and endometrial cancers and increases in breast cancers. Although elevated breast cancer risk was small, relatively high incidence of breast cancers means that oral contraceptives may contribute to a substantial number of cases. Cancer Epidemiol Biomarkers Prev; 22(11); 1931–43. ©2013 AACR.

Oral Contraceptives and Risk of Ovarian Cancer and Breast Cancer Among High-Risk Women: A Systematic Review and Meta-Analysis

PURPOSE To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history. METHODS We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer. RESULTS From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned. CONCLUSION Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.

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.

Hormonal Risk Factors for Ovarian Cancer in Premenopausal and Postmenopausal Women

Ovarian cancer is most frequently diagnosed in postmenopausal women; however, the strongest risk predictors, pregnancy and oral contraceptive use, occur in most women in their twenties and thirties. Relatively few studies have examined how reproductive risk factors vary between pre- and postmenopausal ovarian cancer. The authors used data from a population-based, case-control study of ovarian cancer (896 cases, 967 controls) conducted in North Carolina from 1999 to 2006. Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Inverse associations with ovarian cancer were observed with duration of oral contraceptive use, later age at last use, and more recent use among premenopausal women; no significant associations were found for postmenopausal women. Analyses limited to oral contraceptive users showed that duration was a more significant predictor of risk than was timing of use. Parity was inversely associated with premenopausal but not postmenopausal ovarian cancer. Later age at pregnancy was associated with reduced risk for both pre- and postmenopausal women. Analyses among parous women showed that pregnancy timing was a stronger risk predictor than number of pregnancies. Findings suggest that associations between ovarian cancer and reproductive characteristics vary by menopausal status. Additional research is needed to further elucidate risk factors for postmenopausal disease.

Effect of Hysterectomy With Ovarian Preservation on Ovarian Function

OBJECTIVE: To prospectively estimate the risk for earlier ovarian failure among women undergoing hysterectomy with ovarian preservation, as compared with women of similar age without hysterectomy. METHODS: A prospective cohort study was conducted among women aged 30 to 47 years undergoing hysterectomy without bilateral oophorectomy (n=406) and women with intact uteri (n=465). Blood samples and questionnaire data were obtained at baseline and annually for up to 5 years. Hazard ratios (HR) for ovarian failure, defined as follicle-stimulating hormone levels 40 international units/L or higher, were calculated using Cox proportional hazards models. RESULTS: Ovarian failure occurred among 60 of the women with hysterectomy and 46 of the women in the control group. Women undergoing hysterectomy were at nearly a twofold increased risk for ovarian failure as compared with women with intact uteri (HR 1.92, 95% confidence interval [CI] 1.29–2.86). The proportional hazards model further estimated that 14.8% of women with hysterectomies experienced ovarian failure after 4 years of follow-up compared with 8.0% of the women in the control group. Risk for ovarian failure was greater for women who had a unilateral oophorectomy along with their hysterectomy (HR 2.93, 95% CI 1.57–5.49), but also it was significantly increased for women who retained both ovaries (HR 1.74, 95% CI 1.14–2.65). CONCLUSION: Increased risk of earlier ovarian failure is a possible consequence of premenopausal hysterectomy. Although it is unresolved whether it is the surgery itself or the underlying condition leading to hysterectomy that is the cause of earlier ovarian failure, physicians and patients should take into account this possible sequela when considering options for treatment of benign conditions of the uterus. LEVEL OF EVIDENCE: II

Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis.

OBJECTIVE: To estimate the overall reduction in ovarian cancer risk associated with the use of oral contraceptive pills (OCPs) and whether reduction in risk is affected by specifics of OCP use, such as formulation or duration of use. DATA SOURCES: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1990 to June 2012, with primary analysis of studies published since January 2000. METHODS OF STUDY SELECTION: We reviewed 6,476 citations. We included English-language controlled studies with human participants reporting a quantitative association between exposure to OCPs (in which the explicit or implicit indication for OCP use was prevention of pregnancy or ovarian cancer) compared with no use of OCPs. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were resolved by team review and consensus. TABULATION, INTEGRATION, AND RESULTS: Fifty-five studies met inclusion criteria. A random-effects meta-analysis of 24 case-control and cohort studies showed significant reduction in ovarian cancer incidence in ever-users compared with never-users (odds ratio 0.73, 95% confidence interval 0.66–0.81). There was a significant duration–response relationship, with reduction in incidence of more than 50% among women using OCPs for 10 or more years. The lifetime reduction in ovarian cancer attributable to the use of OCPs is approximately 0.54% for a number-needed-to-treat of approximately 185 for a use period of 5 years. CONCLUSION: Significant duration-dependent reductions in ovarian cancer incidence in the general population are associated with OCP use.