Rayna K. Matsuno

Type I and II Endometrial Cancers: Have They Different Risk Factors?

PURPOSE Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. PATIENTS AND METHODS Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

BACKGROUND Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING Carraresi Foundation and others.

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.

Estimating age-specific breast cancer risks: A descriptive tool to identify age interactions

ObjectiveClarifying age-specific female breast cancer risks and interactions may provide important etiologic clues.MethodUsing a population-based case–control study in Poland (2000–2003) of 2,386 incident breast cancer cases and 2,502 control subjects aged 25–74 years, we estimated age-specific breast cancer incidence rates according to risk factors.ResultsBreast cancer risks were elevated among women with positive family history (FH), younger age at menarche, older age at first full-term birth, nulliparity, exogenous hormonal usage, and reduced physical activity (PA). Notwithstanding overall risks, we observed statistically significant quantitative (non-crossover) and qualitative (crossover) age interactions for all risk factors except for FH and PA. For example, nulliparity compared to parity reduced breast cancer risk among women ages 25–39 years then rates crossed or reversed, after which nulliparity increased relative risks among women ages 40–74 years.ConclusionThough quantitative age interactions could be expected, qualitative interactions were somewhat counterintuitive. If confirmed in other populations, qualitative interactions for a continuous covariate such as age will be difficult to reconcile in a sequential (multistep or monolithic) ‘stochastic’ breast cancer model. Alternatively, the reversal of relative risks among younger and older women suggests subgroup heterogeneity with different etiologic mechanisms for early-onset and late-onset breast cancer types.

Early- and Late-Onset Breast Cancer Types Among Women in the United States and Japan

Background: Although differences in breast cancer incidence among Occidental and Asian populations are often attributed to variations in environmental exposures and/or lifestyle, fewer studies have systematically examined the effect of age-related variations. Methods: To further explore age-related geographic breast cancer variations, we compared age-specific incidence patterns among cases of female invasive breast cancer from the Surveillance, Epidemiology, and End Results (SEER) program and the Osaka Cancer Registry (1978-1997). Results: In SEER, there were 236,130 Whites, 21,137 Blacks, and 3,304 Japanese-Americans in Hawaii with invasive breast cancer. In Osaka, there were 25,350 cases. Incidence rates per 100,000 woman-years ranged from 87.6 among Whites to 21.8 in Osaka. Age-specific incidence rates increased rapidly until age 50 years for all race/ethnicity groups, and then continued to increase more slowly for Whites, Blacks, and Japanese-Americans in Hawaii but plateaud for Osaka. Age-specific incidence rates in SEER reflected bimodal (early-onset and late-onset) breast cancer populations, whereas Osaka had only an early-onset age distribution. These age-specific differences in incidence among SEER and Osaka persisted after adjustment for calendar-period and birth-cohort effects using age-period-cohort models. Conclusions: Results confirm striking age-specific differences among Occidental and native Japanese breast cancer populations, probably due to complex age-related biological and/or environmental variations among Occidental and Asian breast cancer populations. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1437–42)

The Obesity-Associated Polymorphisms FTO rs9939609 and MC4R rs17782313 and Endometrial Cancer Risk in Non-Hispanic White Women

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR)  = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

Shifting Breast Cancer Trends in the United States

PURPOSE United States breast cancer incidence rates declined during the years 1999 to 2003, and then reached a plateau. These recent trends are impressive and may indicate an end to decades of increasing incidence. METHODS To put emerging incidence trends into a broader context, we examined age incidence patterns (frequency and rates) during five decades. We used age density plots, two-component mixture models, and age-period-cohort (APC) models to analyze changes in the United States breast cancer population over time. RESULTS The National Cancer Institutes Connecticut Historical Database and Surveillance, Epidemiology, and End Results program collected 600,000+ in situ and invasive female breast cancers during the years 1950 to 2003. Before widespread screening mammography in the early 1980s, breast cancer age-at-onset distributions were bimodal, with dominant peak frequency (or mode) near age 50 years and smaller mode near age 70 years. With widespread screening mammography, bimodal age distributions shifted to predominant older ages at diagnosis. From 2000 to 2003, the bimodal age distribution returned to dominant younger ages at onset, similar to patterns before mammography screening. APC models confirmed statistically significant calendar-period (screening) effects before and after 1983 to 1987. CONCLUSION Breast cancer in the general United States population has a bimodal age at onset distribution, with modal ages near 50 and 70 years. Amid a background of previously increasing and recently decreasing incidence rates, breast cancer populations shifted from younger to older ages at diagnosis, and then back again. These dynamic fluctuations between early-onset and late-onset breast cancer types probably reflect a complex interaction between age-related biologic, risk factor, and screening phenomena.

Functional Polymorphisms in the TERT Promoter Are Associated with Risk of Serous Epithelial Ovarian and Breast Cancers

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.

Modern Radiation Therapy and Cardiac Outcomes in Breast Cancer

PURPOSE Adjuvant radiation therapy, which has proven benefit against breast cancer, has historically been associated with an increased incidence of ischemic heart disease. Modern techniques have reduced this risk, but a detailed evaluation has not recently been conducted. The present study evaluated the effect of current radiation practices on ischemia-related cardiac events and procedures in a population-based study of older women with nonmetastatic breast cancer. METHODS AND MATERIALS A total of 29,102 patients diagnosed from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Medicare claims were used to identify the radiation therapy and cardiac outcomes. Competing risk models were used to assess the effect of radiation on these outcomes. RESULTS Patients with left-sided breast cancer had a small increase in their risk of percutaneous coronary intervention (PCI) after radiation therapy-the 10-year cumulative incidence for these patients was 5.5% (95% confidence interval [CI] 4.9%-6.2%) and 4.5% (95% CI 4.0%-5.0%) for right-sided patients. This risk was limited to women with previous cardiac disease. For patients who underwent PCI, those with left-sided breast cancer had a significantly increased risk of cardiac mortality with a subdistribution hazard ratio of 2.02 (95% CI 1.23-3.34). No other outcome, including cardiac mortality for the entire cohort, showed a significant relationship with tumor laterality. CONCLUSIONS For women with a history of cardiac disease, those with left-sided breast cancer who underwent radiation therapy had increased rates of PCI and a survival decrement if treated with PCI. The results of the present study could help cardiologists and radiation oncologists better stratify patients who need more aggressive cardioprotective techniques.

Use of Nonsteroidal Anti-inflammatory Drugs and Risk of Ovarian and Endometrial Cancer: The Multiethnic Cohort

Background: Chronic inflammation may play an etiologic role in ovarian and endometrial cancer, and it is hypothesized that nonsteroidal anti-inflammatory drugs (NSAID) decrease the risk of developing these malignancies. No prospective study with a large multiethnic population has explored this hypothesis. Methods: We investigated whether NSAID use was associated with risks of ovarian and endometrial cancer in the Multiethnic Cohort Study. Medication use of at least twice a week for ≥1 month was assessed at baseline. Multivariable relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Results: During 13.3 years of follow-up, 275 ovarian and 620 endometrial incident cases were identified among approximately 64,000 women included in this analysis (16.5% African Americans, 30.8% Japanese, 7.7% Native Hawaiians, 18.9%, Latinas, and 26.0% whites). The RR (95% CI) for ovarian cancer associated with aspirin, non-aspirin NSAIDs, and acetaminophen were 0.87 (0.68–1.14), 0.97 (0.74–1.26), and 0.86 (0.67–1.12), respectively. The RR (95% CI) for endometrial cancer associated with aspirin, non-aspirin NSAIDs, and acetaminophen were 0.93 (0.79–1.10), 0.88 (0.74–1.05), and 0.96 (0.81–1.13), respectively. No heterogeneity across ethnic groups (P ≥ 0.29) or dose–response relation with increased duration of use (Ptrend ≥ 0.16) was observed. The results did not differ by tumor histology. Conclusions: We found no compelling evidence to support an association between the use of NSAIDs and risk of ovarian and endometrial cancers in a multiethnic population. Impact: It is unlikely that NSAID is involved in the etiology of endometrial and ovarian cancer. Cancer Epidemiol Biomarkers Prev; 21(9); 1441–9. ©2012 AACR.