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Aspects of reproductive history are among the most well-established breast cancer risk factors. However, relatively little is known about how they influence risk of different molecular subtypes of breast cancer, particularly among younger women. Using data from a population-based case–control study of women 20–44 years of age, we assessed the relationships between various reproductive factors and risk of estrogen receptor positive (ER+), triple-negative, and HER2-overexpressing breast cancers. Detailed reproductive histories were obtained through structured interviewer administered in-person questionnaires. Reproductive histories among control women (n = 941) were compared to those of ER+ cases (n = 781), triple-negative cases (n = 180), and HER2-overexpressing cases (n = 60) using polytomous logistic regression. Age at menarche, parity, and number of full-term pregnancies were similarly associated with risk of all three breast cancer subtypes. In contrast, age at first live birth, the interval between age at menarche and age at first birth, and breastfeeding were inversely associated with risk of triple-negative breast cancer (P values for trend 0.002, 0.006 and 0.018, respectively), but were not associated with risk of ER+ or HER2-overexpressing cancers. A strong inverse association between breastfeeding and risk of triple-negative breast cancer has now been consistently observed across numerous studies, and at present it is the most well-established protective factor for this aggressive and lethal form of breast cancer. Further studies clarifying the biological mechanisms underlying this relationship and confirming our results with respect to age at first birth and the interval between age at menarche and age at first birth are needed.

The Skin Cancer after Organ Transplant (SCOT) study was designed to investigate the link between genus beta human papillomavirus (HPV) and squamous cell skin cancer (SCSC). We focused on a population receiving immunosuppressive therapy for extended periods, transplant patients, as they are at extremely high risk for developing SCSC. Two complementary projects were conducted in the Seattle area: (i) a retrospective cohort with interview data from 2004 recipients of renal or cardiac transplants between 1995 and 2010 and (ii) a prospective cohort with interview data from 328 people on the transplant waiting lists between 2009 and 2011. Within the retrospective cohort, we developed a nested case-control study (172 cases and 337 control subjects) to assess risk of SCSC associated with markers of HPV in SCSC tumour tissue and eyebrow hair bulb DNA (HPV genotypes) and blood (HPV antibodies). In the prospective cohort, 135 participants had a 1-year post-transplant visit and 71 completed a 2-year post-transplant visit. In both arms of the cohort, we collected samples to assess markers of HPV infection such as acquisition of new types, proportion positive for each type, persistence of types at consecutive visits and number of HPV types detected. In the prospective cohort, we will also examine these HPV markers in relation to levels of cell-mediated immunity. The goal of the SCOT study is to use the data we collected to gain a more complete understanding of the role of immune suppression in HPV kinetics and of genus beta HPV types in SCSC. For more information, please contact the principal investigator through the study website: http://www.fhcrc.org/science/phs/cerc/The_SCOT_Study.html.

Depo-medroxyprogesterone acetate (DMPA) is an injectable contraceptive that contains the same progestin as the menopausal hormone therapy regimen found to increase breast cancer risk among postmenopausal women in the Women's Health Initiative clinical trial. However, few studies have evaluated the relationship between DMPA use and breast cancer risk. Here, we conducted a population-based case–control study among 1,028 women ages 20 to 44 years to assess the association between DMPA use and breast cancer risk. Detailed information on DMPA use and other relevant covariates was obtained through structured interviewer-administered in-person questionnaires, and unconditional logistic regression was used to evaluate associations between various aspects of DMPA use and breast cancer risk. We found that recent DMPA use for 12 months or longer was associated with a 2.2-fold [95% confidence interval (CI), 1.2–4.2] increased risk of invasive breast cancer. This risk did not vary appreciably by tumor stage, size, hormone receptor expression, or histologic subtype. Although breast cancer is rare among young women and the elevated risk of breast cancer associated with DMPA appears to dissipate after discontinuation of use, our findings emphasize the importance of identifying the potential risks associated with specific forms of contraceptives given the number of available alternatives. Cancer Res; 72(8); 2028–35. ©2012 AACR.

As part of a prospective case-control study of newly diagnosed rheumatoid arthritis (RA) in women, we identified all cases of probable, definite, or classic RA diagnosed in 1987-1989 in 18-64-year-old women who were members of a health maintenance organization based in the Seattle, Washington area. Using both the 1958 and the 1987 American Rheumatism Association criteria for the diagnosis of RA and enrollment data from the health maintenance organization, we calculated the incidence by age and diagnostic class. Rates of RA incidence in women increased steadily with age. The incidence of probable, definite, or classic RA ranged from 13.1 per 100,000 person-years at risk for 18-29-year-old women to 82.1 per 100,000 person-years for 60-64-year-old women. The overall incidence rate, age-adjusted to the 1980 US female population, was 27.9/100,000 person-years. The overall incidence rate for definite/classic RA, age-adjusted to the 1980 US female population, was 23.9 per 100,000 person-years. When compared with adjusted rates of incidence of definite RA in Rochester, Minnesota, in 1950-1974, the incidence rates we found were 44.7% lower. Methodologic differences, changes in diagnostic criteria, and a declining incidence of RA among women over time may all be partial explanations for these results. The possible effects of reproductive factors, including oral contraceptives use, are discussed.

Both migraine and breast cancer are hormonally mediated diseases, and it is biologically plausible that women with a history of migraine may have a reduced breast cancer risk. However, this relationship has only been assessed in a single relatively small study that was unable to assess the effect of migraine triggers, which are also well-established breast cancer risk factors (e.g., use of alcohol and exogenous hormones), on the inverse association observed. Utilizing data on 4,568 breast cancer cases and 4,678 controls who participated in a multicenter population-based case-control study in the United States, we evaluated the association between migraine history and breast cancer risk using unconditional logistic regression. Migraine history data were obtained from structured in-person interviews. Women with a history of migraine had a reduced risk of breast cancer [odds ratio, 0.74; 95% confidence interval (CI), 0.66-0.82]. This risk did not differ by menopausal status, age at migraine diagnosis, use of prescription migraine medications, or when analyses were restricted to women who avoided various migraine triggers (including alcohol, exogenous hormones, and smoking). These data support a previous finding that a history of migraine may be associated with a reduced risk of breast cancer. It extends the prior report in observing that this relationship holds for both premenopausal and postmenopausal women and is independent of exposure to common migraine triggers. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2030–4)

BACKGROUND: The incidence of testicular germ cell tumors (TGCTs) has been increasing the past 4 to 6 decades; however, exposures that account for this rise have not been identified. Marijuana use also grew during the same period, and it has been established that chronic marijuana use produces adverse effects on the human endocrine and reproductive systems. In this study, the authors tested the hypothesis that marijuana use is a risk factor for TGCT. METHODS: A population-based, case-control study of 369 men ages 18 to 44 years who were diagnosed with TGCT from January 1999 through January 2006 was conducted in King, Pierce and Snohomish Counties in Washington State. The responses of these men to questions on their lifetime marijuana use were compared with the responses of 979 age-matched controls who resided in the same 3 counties during the case diagnosis period. RESULTS: Men with a TGCT were more likely to be current marijuana smokers at the reference date compared with controls (odds ratio [OR], 1.7; 95% confidence interval [95% CI], 1.1-2.5). In analyses according to histologic type, most of the association between current marijuana use and TGCT was observed in men who had nonseminomas/mixed histology tumors (current use: OR, 2.3; 95% CI, 1.3-4.0). Age at first use among current users (age

Cigarette smoking is an established cofactor to human papillomavirus (HPV) in the development of cervical and vulvar squamous cell carcinoma (SCC), and may influence risk through an immunosuppressive pathway. Genetic variation in interleukin 2 (IL2), associated in some studies with the inhibition of HPV-targeted immunity, may modify the effect of smoking on the risk of HPV-related anogenital cancers. We conducted a population-based case-only study to measure the departure from a multiplicative joint effect of cigarette smoking and IL2 variation on cervical and vulvar SCC. Genotyping of the four IL2 tagSNPs (rs2069762, rs2069763, rs2069777, and rs2069778) was done in 399 cervical and 486 vulvar SCC cases who had been interviewed regarding their smoking history. Compared with cases carrying the rs2069762 TT genotype, we observed significant departures from multiplicativity for smoking and carriership of the TG or GG genotypes in vulvar SCC risk [interaction odds ratio (IOR), 1.67; 95% confidence interval (CI), 1.16-2.41]. Carriership of one of three diplotypes, together with cigarette smoking, was associated with either a supramultiplicative (TGCT/GGCC; IOR, 2.09; 95% CI, 0.98-4.46) or submultiplicative (TTCC/TGTC; IOR, 0.37; 95% CI, 0.16-0.85 or TGCT/TGCC; IOR, 0.37; 95% CI, 0.15-0.87) joint effect in vulvar cancer risk. For cervical SCC, departure from multiplicativity was observed for smokers homozygous for the rs2069763 variant allele (TT versus GG or GT genotypes; IOR, 1.87; 95% CI, 1.00-3.48), and for carriership of the TTCC/TTCC diplotype (IOR, 2.08; 95% CI, 1.01-4.30). These results suggest that cervical and vulvar SCC risk among cigarette smokers is modified by genetic variation in IL2. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1790–9)

Ages at menarche and first birth are established risk factors for breast cancer. The interval between these ages may also affect risk, since the breast is more susceptible to carcinogenic insults during this period than during the parous period. However, few investigators have studied this relation. Using logistic regression, the authors evaluated associations between the timing of reproductive events and breast cancer risk among 4,013 cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White and African-American women (1994-1998). For White, parous premenopausal and postmenopausal women, those who had an interval of > or =16 years between the ages of menarche and first birth had 1.5-fold (95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer, respectively, in comparison with those who had < or =5 years between these ages. Adjusting for age at first birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95% CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positive tumors but were absent among premenopausal African-American women. The authors conclude that the interval between age at menarche and age at first birth is associated with the risk of hormonally sensitive types of breast cancer, particularly among White women.

Differences in cervical cancer incidence rates by race/ethnicity persist in the United States. We examined these differences by histologic type and by various patient and socioeconomic characteristics. Thirteen U.S. cancer registries were used to identify women 20–79 years of age diagnosed from 1992 to 2003 with invasive cervical cancer. Age-adjusted incidence rates and annual percent changes were calculated for four different races/ethnicities (Non-Hispanic whites, Hispanic whites, African-Americans, and Asians/Pacific Islanders) for cervical cancer overall, squamous cell carcinoma (SCC), and adenocarcinoma (AC). Hispanic whites had the highest incidence rate of cervical cancer overall (24.2/100,000), SCC (18.3/100,000), and AC (4.6/100,000). Non-Hispanic whites had the lowest rates of cervical cancer overall (10.8/100,000) and SCC (7.2/100,000), while African-Americans had the lowest rate of AC (2.3/100,000). Incidence rates of cervical cancer overall and SCC declined across all racial/ethnic groups. Numerous variations in incidence rates and annual percent changes were observed when analyses were stratified by county level socioeconomic characteristics. Variations in screening utilization and socioeconomic status may account for the majority of racial/ethnic disparities in cervical cancer incidence. Targeting groups with the greatest burdens of cervical cancer is of public health importance, particularly as we enter the human papillomavirus vaccine era.

Background: Important differences in the contributions of certain exposures to the risks of ductal versus lobular breast carcinomas have been observed, but few studies have evaluated the relationships between established breast cancer risk factors and other histologic types.Methods: Information on family history of cancer and reproductive, hormonal, anthropometric, and lifestyle characteristics were collected in a multicenter population-based case-control study consisting of 3,463 ductal, 274 lobular, 261 ductal-lobular, 91 medullary, 77 tubular, 70 comedo, and 61 mucinous invasive breast carcinoma cases (ages 35-64 years, newly diagnosed 1994-1998) and 4,682 controls. Associations between each of these histologic types and various exposures were evaluated using polytomous regression.Results: Heterogeneity in the risks of different histologic types of breast cancer was observed for three exposures: menopausal hormone use, body mass index (BMI), and alcohol consumption. Specifically, current use of unopposed estrogen was associated with a reduced risk of ductal carcinoma and increased risk of comedocarcinoma, and current use of estrogen and progestin was associated with elevated risks of ductal-lobular and tubular carcinomas. Among postmenopausal women, BMI was only inversely related to risk of ductal-lobular carcinoma, and alcohol use was only positively related to risk of lobular carcinoma.Conclusions: Variations in the associations between known breast cancer risk factors and risk of different breast cancer histologies were observed. Although these findings require confirmation, and the analyses of some histologic groups were limited by small sample sizes, they provide some insight into the different etiologies of various histologic subtypes of breast cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(5):946–54)

Epidemiologic evidence suggests obese premenopausal women experience a reduced risk of breast cancer. The mechanism underlying this protection is not fully understood although it is well documented that abdominal obesity may impair ovulatory function and reduce gonadal steroidogenesis. We measured levels of several metabolic markers that are modified by obesity [measured by body mass index (BMI, (weight (kg)/height (m2)))] and play a role in the reproductive axis, including, leptin, insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP3), C-peptide and prolactin in 233 cases and 251 controls participating in a retrospective study of breast cancer in young women conducted in the Seattle/Puget Sound region between 1990 and 1992. Consistent with the finding of a reduced risk with increasing BMI, risks declined with leptin levels, although to a lesser degree with odds ratios (OR) for the highest vs. lowest quartile of BMI=0.34 (95% C.I. 0.3-0.8) and for leptin=0.71 (95% C.I. 0.5-1.3). IGF-I, IGFBP3, C-peptide and prolactin were not related to breast cancer risk in a dose-dependent manner. With the possible exception of leptin, our findings do not suggest that these markers explain the breast cancer protection provided by obesity in premenopausal women.

Human papillomavirus (HPV) is the central etiologic factor for cervical cancer, and prior studies suggested C. trachomatis may act as an HPV cofactor. We examined the C. trachomatis-cervical cancer association by serotype, histology, HPV type in the tumor, and other HPV cofactors. We conducted a population-based study in the Seattle-Puget Sound area of 302 women with invasive squamous cell carcinomas (SCC), 185 women with adenocarcinomas of the cervix (AC), and 318 HPV seropositive control women. The risk of SCC associated with antibodies to C. trachomatis was increased (OR 1.6, 95% CI 1.1-2.2) but not for AC (OR 1.0, 95% CI 0.6-1.5). This association was independent of HPV type in the SCC tumor tissue. There was an association between specific serotypes of C. trachomatis and SCC for 6 of the 10 serotypes: B (OR 3.6, 95% CI 1.5-8.4), D (OR 2.1, 95% CI, 1.2-3.5), E (OR 2.4, 95% CI, 1.4-3.9), G (OR 3.0, 95% CI, 1.1-7.9), I (OR 4.2, 95% CI, 1.5-11.7), and J (OR 2.3, 95% CI, 1.0-5.1), but not for the 4 types (C, F, H, and K) that were present at very low prevalence in this population. There was an increased risk of SCC, but not AC, associated with antibodies to C. trachomatis that was not serotype specific.

BACKGROUND Incidence rates of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have been rising, but little is known about which patients will develop invasive breast cancer or what types of tumors these patients may develop. METHODS By using Surveillance, Epidemiology and End Results (SEER) data, the authors evaluated how types of invasive breast cancers diagnosed among 37,692 DCIS and 4490 LCIS patients differed and how clinical characteristics influenced subsequent breast cancer risk. RESULTS Among DCIS patients, incidence rates of ipsilateral and contralateral invasive breast cancer were 5.4/1000 person-years and 4.5/1000 person-years, respectively; and among LCIS patients, incidence rates were 7.3/1000 person-years and 5.2/1000 person-years, respectively. LCIS patients were 5.3-fold more likely than DCIS patients to develop invasive lobular carcinomas. Women whose DCIS had comedo histologic features or was poorly differentiated had 1.4-fold and 2.0-fold elevations in ipsilateral invasive breast cancer risk. Furthermore, among DCIS patients, 20-49 year-olds and black women and Hispanic white women had 1.6, 2.7, and 2.3-fold elevated risks of Stage III/IV breast cancer compared with 50-59 year-olds and non-Hispanic whites, respectively. CONCLUSIONS Screening young DCIS patients more frequently and improving the follow-up care of blacks and Hispanic whites with DCIS may reduce their risk of advanced-stage breast cancer. In addition, LCIS may be a precursor rather than just an ambiguous risk factor for invasive breast cancer, and, therefore, localized treatment for LCIS may be warranted. Given that incidence rates of DCIS and LCIS have been rising, investigations of these tumors should be continued to better understand their etiology and appropriate clinical management. Cancer 2006. © 2006 American Cancer Society.

Background: Physical inactivity is a potentially modifi able breast cancer risk factor. Because few data on this rela tionship exist for black women, we examined the relationship between breast cancer risk and lifetime and time- or age- specifi c measures of recreational exercise activity among white women and among black women. Methods: The Women’s Contraceptive and Reproductive Experiences Study was a multicenter populationbased case – control study of black women and white women aged 35 – 64 years with newly diagnosed invasive breast cancer. We collected detailed histories of lifetime recreational exercise activity during in-person interviews with 4538 case patients with breast cancer (1605 black and 2933 white) and 4649 control subjects (1646 black and 3033 white). Control subjects were frequency-matched to case patients on age, race, and study site. We examined associations between exercise activity measures (metabolic equivalents of energy expenditure [MET]-hours per week per year) and breast cancer risk overall and among subgroups defi ned by race, other breast cancer risk factors, and tumor characteristics by use of unconditional logistic regression. All statistical tests were two-sided. Results: Among all women, decreased breast cancer risk was associated with increased levels of lifetime exercise activity (e.g., average MET-hours per week per year, P trend = .002). An average annual lifetime exercise activity that was greater than the median level for active control subjects was associated with an approximately 20% lower risk of breast cancer, compared with that for inactivity (for 6.7 – 15.1 MET-hours/week/year, odds ratio [OR] = 0.82, 95% confi dence interval [CI] = 0.71 to 0.93; for ≥ 15.2 MET-hours/week/year, OR = 0.80, 95% CI = 0.70 to 0.92). The inverse associations did not differ between black and white women (for MET-hours/week/year, P trend = .003 and P trend = .09, respectively; homogeneity of trends P = .16). No modifi cation of risk was observed by disease stage, estrogen receptor status, or any breast cancer risk factor other than fi rst-degree family history of breast cancer. Conclusions: This study supports an inverse association between physical activity and breast cancer among black women and among white women. [J Natl Cancer Inst 2005;97:1671 – 9]

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case–control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER − PR − tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Smoking is one of the few risk factors that have been identified for functional ovarian cysts, and results of one epidemiologic study suggest that body mass index (BMI; weight (kg)/height (m)(2)) may modify the effect of this exposure. The current study assessed the association of cigarette smoking and marijuana use with functional ovarian cyst risk by using data from a population-based 1990-1995 case-control study of 586 incident functional ovarian cyst cases and 757 age-matched controls in a large health maintenance organization in Washington State. In multivariate analyses controlling for age, education, and reference year, the authors found an increase in risk associated with current cigarette smoking among women whose BMI was20 (odds ratio (OR) = 2.48, 95% confidence interval (CI): 1.32, 4.64) or 20-25 (OR = 1.60, 95% CI: 1.04, 2.46) but not25 (OR = 0.85, 95% CI: 0.53, 1.37). Corresponding risks associated with current marijuana use were BMI20, OR = 2.05 (95% CI: 0.89, 4.75); BMI 20-25, OR = 1.78 (95% CI: 1.00, 3.17); and BMI25, OR = 0.72 (95% CI: 0.36, 1.42). Study results indicate that increased BMI may attenuate the adverse effect of smoking on the risk of functional ovarian cyst.

In this study, we performed high-resolution array comparative genomic hybridization with an array of 4153 bacterial artificial chromosome clones to assess copy number changes in 44 archival breast cancers. The tumors were flow sorted to exclude non-tumor DNA and increase our ability to detect gene copy number changes. In these tumors, losses were more frequent than gains, and gains in 1q and loss in 16q were the most frequent alterations. We compared gene copy number changes in the tumors based on histologic subtype and estrogen receptor (ER) status, i.e., ER-negative infiltrating ductal carcinoma, ER-positive infiltrating ductal carcinoma, and ER-positive infiltrating lobular carcinoma. We observed a consistent association between loss in regions of 5q and ER-negative infiltrating ductal carcinoma, as well as more frequent loss in 4p16, 8p23, 8p21, 10q25, and 17p11.2 in ER-negative infiltrating ductal carcinoma compared with ER-positive infiltrating ductal carcinoma (adjusted P values ≤ 0.05). We also observed high-level amplifications in ER-negative infiltrating ductal carcinoma in regions of 8q24 and 17q12 encompassing the c-myc and c-erbB-2 genes and apparent homozygous deletions in 3p21, 5q33, 8p23, 8p21, 9q34, 16q24, and 19q13. ER-positive infiltrating ductal carcinoma showed a higher frequency of gain in 16p13 and loss in 16q21 than ER-negative infiltrating ductal carcinoma. Correlation analysis highlighted regions of change commonly seen together in ER-negative infiltrating ductal carcinoma. ER-positive infiltrating lobular carcinoma differed from ER-positive infiltrating ductal carcinoma in the frequency of gain in 1q and loss in 11q and showed high-level amplifications in 1q32, 8p23, 11q13, and 11q14. These results indicate that array comparative genomic hybridization can identify significant differences in the genomic alterations between subtypes of breast cancer.

Previous laboratory investigations, case reports, and a hospital-based case-control study have suggested that marijuana use may be a risk factor for squamous cell head and neck cancer. We conducted a population-based case-control study to determine whether marijuana use is associated with the development of oral squamous cell carcinoma (OSCC). Case subjects (n = 407) were 18–65-year-old residents of three counties in western Washington State who were newly diagnosed with OSCC from 1985 through 1995. Control subjects (n = 615), who were similar to the cases with respect to age and sex, were selected from the general population using random-digit telephone dialing. Lifetime histories of marijuana use and exposure to known OSCC risk factors were ascertained using a structured questionnaire. Information on genetic polymorphisms in glutathione S-transferase enzymes was obtained from assays on participant DNA. Odds ratios for associations with features of marijuana use were adjusted for sex, education, birth year, alcohol consumption, and cigarette smoking. A similar proportion of case subjects (25.6%) and control subjects (24.4%) reported ever use of marijuana (adjusted odds ratio, 0.9; 95% confidence interval, 0.6–1.3). There were no trends in risk observed with increasing duration or average frequency of use or time since first or last use. No subgroup defined by known or suspected OSCC risk factors (age, cigarette smoking, alcohol consumption, and genetic polymorphisms) showed an increased risk. Marijuana use was not associated with OSCC risk in this large, population-based study.

Animal data indicate that both estrogens and progestins could be carcinogenic and that progestins could serve as tumor promoters. Human studies have not confirmed an increased risk of breast cancer from long-term use of oral contraceptives, but have shown an increased risk from hormone replacement therapy including progestins. The present study analyzed the relationship between breast cancer and use of injectable and implantable progestin-only contraceptives. Analyses were performed on data collected in a population-based, multicenter, case-control study, the Women's Contraceptive and Reproductive Experiences Study of the National Institute of Child Health and Human Development. The study involved 4575 randomly sampled cases with invasive breast cancer diagnosed between 1994 and 1998, and 4682 controls, identified using random digit dialing. We assessed the association between exposure to injectable contraceptives and risk of breast cancer. The use of injectable contraceptives was not associated with an increased risk of breast cancer [odds ratio (OR) = 0.9, 95% confidence interval (CI): 0.7, 1.2]. Risk was not increased among current users, defined as women who used injectable contraceptives within 1 year of the reference date (OR = 0.7, 95% CI: 0.4, 1.3) or those who initiated use in the 5 years immediately preceding the reference date (OR = 0.9, 95% CI: 0.5, 1.4), or with use beginning before age 35 (OR = 0.9, 95% CI: 0.6, 1.3). Among users, risk increased with increasing duration of use (p = 0.03). However, short-term users (

Objective Leiomyomas are common benign neoplasms. Although hormone therapy is the most common and effective treatment for menopausal symptoms, little is known about its effect on leiomyomas. We examined the risk of a first diagnosis of leiomyomas in peri- and postmenopausal women associated with prior use of estrogen and progestogen therapy (EPT). Design A case-control study was conducted among enrollees from a nonprofit health plan. Cases had a first diagnosis of leiomyomas confirmed by surgery or ultrasound. Controls were women of the same age range without a diagnosis of leiomyomas selected at random from membership and outpatient files. Participants were interviewed regarding prior use of exogenous hormones, medical history, and reproductive history. This analysis was restricted to cases (n = 256) and controls (n = 276) who were peri- or postmenopausal and more than 40 years of age. Adjusted odds ratios (OR) and 95% CIs were estimated using logistic regression models. Results EPT use for more than 5 years was associated with a 1.7-fold increased risk of leiomyomas (95% CI, 0.9-3.3). Associations with EPT use were only present among women with a body mass index less than 24 kg/m; OR (ever-use), 2.3 (95% CI, 1.2-4.3); and OR (>or= 5 years use), 4.0 (95% CI, 1.6-10.3). Conclusion Among peri- and postmenopausal women, prior EPT use was associated with an increased risk of a subsequent leiomyomas. This association seemed limited to the subset of women with low body mass index. Exogenous sources of estrogen and progestin in the setting of low adiposity may contribute to the development of leiomyomas.

High levels of serum estrogens and androgens have been convincingly linked with an increased risk of breast cancer among postmenopausal women. By contrast, the role of blood levels of these hormones in the etiology of premenopausal breast cancer is not well understood. In a case-control study, we sought to examine associations between levels of serum estradiol, sex-hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), testosterone, androstenedione and progesterone and risk of premenopausal breast cancer. Cases of breast cancer under age 45 were identified using rapid ascertainment systems in Seattle/Puget Sound, Washington and control subjects were identified from the same area through random digit dialing methods. A total of 169 eligible breast cancer cases and 195 control subjects donated blood (either before or six or more weeks after surgery) and were interviewed using a standardized questionnaire. The fully adjusted risk ratios and 95% confidence intervals for the highest versus lowest tertiles of estradiol, according to menstrual cycle phase, were 3.10 (0.8-12.7) for early follicular, 0.54 (0.2-1.7) for late follicular and 0.60 (0.3-1.4) for luteal. Risks for highest versus lowest quartiles of SHBG and androgens were 0.81 (0.4-1.6) for SHBG, 2.42 (1.1-5.2) for DHEA, 1.12 (0.6-2.5) for testosterone, and 1.33 (0.6-2.8) for androstenedione. For luteal progesterone, the RR for the highest versus lowest tertile was 0.55 (0.2-1.4). In summary, we did not find a convincing association between serum SHBG, estradiol, testosterone or androstenedione and premenopausal breast cancer risk. Observed differences between cases and controls subjects in serum levels of DHEA and luteal phase progesterone should be investigated further in large prospective studies.

BACKGROUND. Anal cancer is a rare malignancy of the anogenital tract that historically has affected women at a greater rate than men. METHODS. The authors analyzed changing trends in incidence rates and 5-year relative survival percentages for patients with anal cancer. The publicly available data used in the current study were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program, a system of population-based tumor registries in the United States. RESULTS. The incidence of anal cancer was similar for men and women between 1994 and 2000 (2.04 per 100,000 and 2.06 per 100,000, respectively), the most recent period for which data were available, whereas men had lower rates than did women between 1973 and 1979 (1.06 per 100,000, compared with 1.39 per 100,000), the earliest period for which data were available. In addition, recently, black men had higher incidence rates than did other race-specific and gender-specific groups (2.71 per 100,000). From the earliest period for which data were available to the most recent period, relative 5-year survival improved from 59% to 73% among women, was unchanged among men (60%), and decreased from 45% to 27% among black men. Eighteen percent of patients who had distant disease were alive at 5 years, compared with 78% of patients who had localized disease. CONCLUSIONS. The incidence of anal cancer in the United States increased between 1973 and 2000, particularly among men. There were higher incidence rates and lower survival rates for black men compared with other race-specific and gender-specific groups. Later disease stage was inversely associated with the survival rate, indicating that earlier detection may improve the survival of patients with anal cancer. Cancer 2004;101:281– 8. © 2004 American Cancer Society.

BACKGROUND Few studies have investigated the association between reproductive factors and the risk of breast carcinoma among African-American women. The authors assessed whether the number of full-term pregnancies, age at first full-term pregnancy, and total duration of breastfeeding were associated with similar relative risk estimates in white and African-American women in a large multicenter, population-based case–control study of breast carcinoma. METHODS Case patients were 4567 women (2950 white women and 1617 African-American women) ages 35–64 years with newly diagnosed invasive breast carcinoma between 1994 and 1998. Control patients were 4668 women (3012 white women and 1656 African-American women) who were identified by random-digit dialing and were frequency matched to case patients according to study center, race, and age. Adjusted odds ratios and 95% confidence intervals were estimated using unconditional logistic regression. RESULTS For white women, the reduction in risk of breast carcinoma per full-term pregnancy was 13% among younger women (ages 35–49 years) and 10% among older women (ages 50–64 years). The corresponding risk reductions for African-American women were 10% and 6%, respectively. Risk decreased significantly with increasing number of full-term pregnancies for both races and both age categories. Duration of lactation was inversely associated with breast carcinoma risk among younger parous white (trend P = 0.0001) and African-American (trend P = 0.01) women. African-American women tended to have more children compared with white women, but parity rates were lower in younger women than in older women in both racial groups. However, breastfeeding was substantially more common in young white women than in young African-American women. CONCLUSIONS Overall, parity and lactation had similar effects on breast carcinoma risk in white and African-American women. If younger African-American women now are giving birth to fewer children than in the past, without a substantial increase in breastfeeding, breast carcinoma rates may continue to increase at a more rapid rate among these women compared with white women. Cancer 2004. Published 2004 by the American Cancer Society.

Objective: We examined breast cancer risk related to lifetime exposure to oral contraceptives (OCs) and hormone replacement therapy (HRT) in postmenopausal women. Methods: The Women's Contraceptive and Reproductive Experiences (CARE) Study was a population-based case–control study that included 1847 postmenopausal women with incident invasive breast cancer, and 1932 control subjects, identified using random digit dialing. Results: 45% of cases and 49% of controls used both OCs and HRT. OC users were not at increased risk regardless of subsequent HRT exposure. HRT users who had used OCs previously did not have a higher risk of breast cancer than women with no exposure to OCs. We observed a negative interaction (p-value: 0.032) of combined hormone replacement therapy (CHRT) and past OC use. The increase in risk with CHRT was stronger in women who had never used OCs in the past (odds ratio: 1.05; 95% confidence interval: 1.01–1.10 per year of exclusive CHRT use) than in women who had used OCs (odds ratio: 1.00; 95% confidence interval: 0.97–1.03). Conclusions: We found no indication that adverse effects of exposure to OCs or HRT appeared only in the presence of the other hormone or were exacerbated by exposure to the other hormone.

Objective To determine whether current contraceptive method affects functional ovarian cyst risk, with emphasis on oral contraceptives (OCs) and tubal sterilization. Methods We conducted a case–control study of 18–39-year-old health maintenance organization enrollees with a functional ovarian cyst diagnosed between January 1, and June 30, 1994, and age-matched female controls randomly selected from enrollment files. In-person interviews as well as medical and pharmacy records were obtained for 78% of cases and 82% of controls; these analyses were based on 392 cases and 623 controls. Odds ratios (ORs) calculated with unconditional logistic regression were used to estimate the risk of a functional ovarian cyst diagnosis associated with current contraceptive method. Results In multivariable analyses adjusting for age, education, number of live births, and reference year, the overall OR was 0.72 (95% confidence interval [CI] 0.53, 0.99) for current OC use, compared with use of nonsurgical nonhormonal contraception or no contraception. The risk associated with use of 35 μg ethinyl estradiol monophasic OCs (OR 0.69; 95% CI 0.44, 1.10) was slightly lower than that associated with less than 35 μg ethinyl estradiol monophasic (OR 0.79; 95% CI 0.43, 1.47) or multiphasic OCs (OR 0.76; 95% CI 0.49, 1.19). Women with tubal sterilization had a substantially increased risk of a functional ovarian cyst diagnosis (OR 1.70; 95% CI 1.05, 2.75) compared with women using nonhormonal or no contraception. Conclusion Our findings suggest that low-dose OC use has little or no effect on functional ovarian cyst likelihood. The increased risks we found associated with tubal sterilization merit further investigation.

Early life events have important short- and long-term consequences. It is clear from previous studies that birthweight is associated with infant mortality and with childhood and adult morbidities. However, few studies have focused on the relationship between birthweight and childhood mortality. To assess this relationship, we conducted a population-based case-control study of children born during 1968-96 in Washington state. Cases consisted of 6247 children who died at 1-19 years of age. A total of 31 074 controls were matched five to one to cases by birth year. Compared with children with a birthweight of 3000-3499 g, children with lower birthweights had a greater risk of childhood mortality. These lower birthweight children had increased risks of childhood deaths from infectious diseases, congenital anomalies, central nervous system diseases and heart disease, but not of deaths resulting from accidents, cancer, suicide or homicide. The magnitude of these risks differed somewhat by age. Our results suggest that birthweight exerts important influences on children's risk of age-specific and cause-specific mortalities, particularly those with a strong biological component. Language: en

Recent use of oral contraceptive pills is associated with a modest risk of breast cancer among very young women. In this US population-based case-control study, we evaluated whether the excess risk associated with recent oral contraceptive use is ubiquitous for all pill types or attributable to specific oral contraceptive preparations. Hormonal content and potency of combination oral contraceptives used for the longest duration within 5 years of interview for breast cancer cases aged 20-44 years (N=1640) were compared with age-matched community controls (N=1492). Women who recently used oral contraceptives containing more than 35 microg of ethinyl oestradiol per pill were at higher risk of breast cancer than users of lower dose preparations when compared to never users (respective relative risks of 1.99 and 1.27, P(trend)

The critical role of the human leukocyte antigen (HLA) system in presenting peptides to antigen-specific T cell receptors may explain why only some human papillomavirus (HPV)-infected women progress to cervical cancer. HLA class II DRB1 and DQB1 genes were examined in 315 women with invasive squamous cell cervical cancer (SCC) and 381 control subjects. Increased risks of SCC were associated with DRB1*1001, DRB1*1101, and DQB1*0301, and decreased risks were associated with DRB1*0301 and DRB1*13. Of squamous cell tumors, those containing HPV-16 were different from those not containing HPV-16 for 3 alleles: DRB1*0401, DRB1*07, and DQB1*06. Increased risks of SCC were associated with DRB1*0401-DQB1*0301 (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.1-2.7) and DRB1*1101-DQB1*0301 (OR, 2.5; 95% CI, 1.4-4.5), and decreased risks were associated with DRB1*0301-DQB1*02 (OR, 0.7; 95% CI, 0.5-1.0) and DRB1*13-DQB1*06 (OR, 0.6; 95% CI, 0.4-0.9) haplotypes. These results add to the evidence that certain HLA class II alleles or allele combinations, or genes linked to them, make some women more susceptible to SCC.

Estimating the incidence of lobular carcinoma in situ (LCIS) of the breast is challenging because it lacks both clinical and mammographic signs and is usually an incidental finding in breast biopsies performed for other reasons. In general, population-based studies are believed to provide the most accurate measures, but few documenting changes in LCIS incidence rates over time have been reported. Age-adjusted age-specific LCIS incidence rates among women with no prior history of in situ or invasive breast carcinoma from 1978 to 1998 were obtained from nine population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program. Linear trends were evaluated using negative binomial regression. Overall, LCIS incidence rates increased fourfold (95% confidence interval, 2.9-5.6) over the study period. Specifically, they rose from 0.90/100,000 person-years in 1978-80 to 2.83/100,000 person-years in 1987-89, but then increased only modestly up to 1996-98 where the incidence rate was 3.19/100,000 person-years. However, among women 50-79 years of age, LCIS incidence rates increased continuously over the study's duration. In 1996-98, 50-59 year-olds had the highest incidence rate (11.47/100,000 person-years) and experienced the greatest absolute increase in incidence over the study period (9.48/100,000 person-years). LCIS incidence rates have steadily increased from 1978 to 1998 only among postmenopausal women. Further research is required to assess what factors are contributing to these trends.

Little is known about the etiology of in situ or invasive squamous cell cancer of the vagina. It is thought that some vaginal cancers may have the same etiology as cervical cancer. It is also not known whether in situ and invasive vaginal cancer share the same etiologic factors. We conducted a study to evaluate risk factors for in situ and invasive vaginal cancer and their potential relationship to prior exposure to human papillomaviruses (HPV).A population-based case-control study included 156 women with squamous cell in situ or invasive vaginal cancer diagnosed between January 1981 and June 1998 and 2041 control women identified through random-digit dialing in western Washington state. Cases and controls were interviewed in person and provided blood samples; archival tumor tissue was retrieved for cases. Blood samples were tested for antibodies to HPV, and tumor tissue was tested for HPV DNA.Women with vaginal cancer were more likely to have five or more lifetime sexual partners (OR = 3.1, 95% CI 1.9 to 4.9), to have an early age at first intercourse (17 years OR = 2.0, 95% CI 1.2 to 3.5), and to be current smokers at diagnosis (OR = 2.1, 95% CI 1.4 to 3.1) than control women. Approximately 30% of all cases had been treated for a prior anogenital tumor, most often of the cervix. Prior hysterectomy was a risk factor only among women who had no history of prior anogenital cancer (OR = 3.9 95% CI 2.5 to 6.1). Antibodies to HPV16 L1 were strongly related to risk of vaginal cancer (OR = 4.3, 95% CI 3.0 to 6.2). We detected HPV DNA in tumor blocks from over 80% of the patients with in situ and 60% of the patients with invasive cancers.In situ and invasive vaginal neoplasia have many of the same risk factors as cervical cancer, including a strong relationship to HPV infection. Women who have been treated for a prior anogenital cancer, particularly of the cervix, have a high relative risk, although low absolute risk, of being diagnosed with vaginal cancer.

Background: Evidence suggests that recent oral contraceptive (OC) use is associated with a small increased breast cancer risk; yet risks associated with contemporary OC preparations and by molecular subtype are not well characterized. Methods: We conducted a population-based case–control study of invasive breast cancer among women ages 20 to 44 residing in the Seattle–Puget Sound area from 2004 to 2010 (985 cases and 882 controls). We collected information on contraceptive use and participant characteristics via an in-person interview. Multivariable-adjusted logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results: Lifetime duration of OC use for ≥15 years was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.1–2.2). Current OC use (within 1 year of reference date) for ≥5 years was associated with an increased risk (OR, 1.6; 95% CI, 1.1–2.5) and there were no statistically significant differences in risk by OC preparation. Risk magnitudes were generally greater among women ages 20 to 39, and for estrogen receptor–negative (ER−) and triple-negative breast cancer (current use for ≥5 years among ages 20–39: ER− OR, 3.5; 95% CI, 1.3–9.0; triple-negative OR, 3.7; 95% CI, 1.2–11.8), although differences between groups were not statistically significant. Conclusions: Long-term use of contemporary OCs and current use for ≥5 years was associated with an increased breast cancer risk among women ages 20 to 44. Risk may be greater among younger women and for ER− and triple-negative breast cancer, but these findings require confirmation. Impact: Continued surveillance and pooled analyses of OC use and breast cancer risk by molecular subtype are needed as OC preparations evolve. Cancer Epidemiol Biomarkers Prev; 23(5); 755–64. ©2014 AACR.

PURPOSE: To determine the association between human papillomavirus (HPV) type and prognosis of patients with invasive cervical carcinoma. PATIENTS AND METHODS: Patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB to IV cervical cancer between 1986 and 1997 while residents of three Washington State counties were included (n = 399). HPV typing was performed on paraffin-embedded tumor tissue using polymerase chain reaction methods. Patients were observed for a median of 50.8 months. Total mortality (TM) and cervical cancer–specific mortality (CCSM) were determined. Hazards ratios (HR) adjusted for age, stage, and histologic type were estimated using multivariable models. RESULTS: Eighty-six patients had HPV 18–related tumors and 210 patients had HPV 16–related tumors. Cumulative TM among patients with HPV 18–related tumors and among patients with HPV 16–related tumors were 33.7% and 27.6%, respectively; cumulative CCSM in these two groups were 26.7% and 18.1%, respectively. Compared with patients with HPV 16–related cancers, patients with HPV 18–related cancers were at increased risk for TM (HRTM, 2.2; 95% confidence interval [CI], 1.3 to 3.6) and CCSM (HRCCSM, 2.5; 95% CI, 1.4 to 4.4). The HPV18 associations were strongest for patients with FIGO stage IB or IIA disease (HRTM, 3.1; 95% CI, 2.3 to 4.2; and HRCCSM, 5.8; 95% CI, 3.9 to 8.7), whereas no associations were observed among patients with FIGO stage IIB to IV disease. Virtually identical associations were found in the subset of patients with squamous cell carcinoma (n = 219). CONCLUSION: HPV 18–related cervical carcinomas, particularly those diagnosed at an early stage, are associated with a poor prognosis. Elucidating the mechanism or mechanisms underlying this association could lead to new treatment approaches for patients with invasive cervical carcinoma.

The authors investigated the possibility that, in interview-based case-control studies, controls are more likely than cases to underreport a history of induced abortion. A case-control study was conducted in White women under 45 years of age who had given birth in Washington State during 1984-1994. The cases were women in three metropolitan counties of Washington State diagnosed with invasive breast cancer during 1984-1994; controls were selected through random digit dialing. A history of induced abortion among study participants was compared between interview data and information collected on the birth record of the last child to whom they gave birth (225 cases, 303 controls). Among women with a prior induced abortion recorded on the birth record, 14.0% of the 43 cases and 14.9% of the 47 controls did not report an induced abortion at interview (difference = -0.9%, 95% confidence interval of the difference: -15, 14). The authors' data do not suggest that controls are more reluctant to report a history of induced abortion than are women with breast cancer.

Objective: To assess the effect of cervical carcinoma in situ (CIS) and its management on subsequent pregnancy outcome. Methods: We used a population-based retrospective cohort design that included record linkage between cancer data and birth records. The Cancer Surveillance System records of women with CIS ( n = 1851, 312 diagnosed during pregnancy) diagnosed between 1984 and 1992, were linked to birth certificates of their first subsequent deliveries after CIS diagnosis. The comparison group ( n = 9201) was a random sample of women without CIS who gave birth during the same years. The outcome measures were preterm and low birth weight infants subsequent to CIS diagnosis and treatment. Treatments included no therapy, dilation and curettage or endocervical curettage, cryosurgery or laser vaporization, and conization. Results: Women with CIS who were not treated with conization had a small increased risk of preterm delivery (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.0, 2.0) and no increased risk of low birth weight infant (OR 1.0, 95% CI 0.7, 1.6), compared with women without CIS, after adjusting for maternal smoking, race, parity, marital status, and history of induced pregnancy termination. Women with CIS who had conization were more likely to deliver premature infants (OR 1.6, 95% CI 1.2, 2.0) than women without CIS, after adjusting for the same confounding factors. The apparently increased risk of low birth weight (OR 1.8, 95% CI 1.4, 2.4) seemed to be a reflection of premature delivery. Conclusion: The risk of prematurity increased after conization for CIS and did not increase when women with CIS had other procedures.

Background: Experimental models and analyses of human tumors suggest that oncogenic, sexually transmittable human papillomaviruses (HPVs) are etiologic factors in the development of oral squamous cell carcinoma (SCC). We conducted a population-based, case‐control study to determine whether the risk of this cancer is related to HPV infection and sexual history factors. Methods: Case subjects (n = 284) were 18‐65-year-old residents of three counties in western Washington State who were newly diagnosed with oral SCC from 1990 through 1995. Control subjects (n = 477) similar in age and sex were selected from the general population. Serum samples were tested for HPV type 16 capsid antibodies. Exfoliated oral tissue collected from case and control subjects and tumor tissue from case subjects were tested for HPV DNA. Odds ratios (ORs) were calculated after adjusting for age, sex, cigarette smoking, and alcohol consumption. Results: Among males only, oral SCC risk increased with self-reported decreasing age at first intercourse, increasing number of sex partners, and a history of genital warts. Approximately 26% of the tumors in case subjects contained HPV DNA; 16.5% of the tumors contained HPV type 16 DNA. The prevalence of oncogenic HPV types in exfoliated oral tissue was similar in case and control subjects. The ORs for HPV type 16 capsid seropositivity were 2.3 (95% confidence interval [CI] = 1.6‐3.3) for all oral SCCs and 6.8 (95% CI = 3.0‐15.2) for oral SCCs containing HPV type 16 DNA. The joint association of cigarette smoking and HPV type 16 capsid seropositivity with oral SCC (OR = 8.5; 95% CI = 5.1‐14.4) was stronger than predicted from the sum of individual associations with current smoking (OR = 3.2; 95% CI = 2.0‐5.2) and seropositivity (OR = 1.7; 95% CI = 1.1‐2.6). Conclusions: HPV type 16 infection may contribute to the development of a small proportion of oral SCCs in this population, most likely in combination with cigarette smoking. [J Natl Cancer Inst 1998;90:1626‐36]

Condylomata acuminata is one of the most common sexually transmitted diseases (STDs) diagnosed in the United States, yet relatively little research has been conducted on the determinants of this disease in well-defined populations.To determine the exposures that predispose a woman to the development of condylomata acuminata or genital warts.A population-based case-control study was conducted among enrollees of Group Health Cooperative of Puget Sound. Patients (94 women with incident and 55 women with recurrent condyloma) were diagnosed between April 1, 1987 and September 30, 1991. Control subjects were 133 women without a history of genital warts. An in-person interview was conducted to collect information on subject characteristics, exposures, and on all episodes of genital warts.Women with five or more partners within the 5 years before reference date were over seven times more likely to have incident condyloma (relative risk [RR], 7.5; 95% confidence interval [CI], 3.1-18.1) and over 12 times more likely to have recurrent condyloma (RR, 12.8; 95% CI, 4.2-38.9) compared with women with only one sexual partner during this time period. An increased risk of incident condyloma was also associated with a history of any STD (RR, 2.6; 95% CI, 1.1-5.8), a history of oral herpes (RR, 2.2; 95% CI, 1.1-4.4), and a history of allergies (RR, 2.0 95% CI, 1.0-3.8). Our data did not support a strong association between risk of condyloma and smoking or recent use of oral contraceptives.Our results suggest that risk of condyloma is primarily related to sexual behavior. We did not observe a strong association between risk of condyloma and many of the exposures considered to be potential cofactors for anogenital cancers associated with other types of human papillomaviruses.

To evaluate whether recreational physical activity is associated with breast cancer among young women, the authors analyzed data from a population-based case-control study. Cases (n = 1,668) were women under age 45 years who had been newly diagnosed with breast cancer between 1990 and 1992 in Atlanta, Georgia, central New Jersey, or Seattle, Washington. Controls (n = 1,505) were frequency-matched to cases by 5-year age group and geographic area of residence. Breast cancer was not associated with recreational activity in any of the three time periods assessed (highest quartile of activity vs. lowest: age- and center-adjusted odds ratio (OR) = 0.94 (95% confidence interval (CI) 0.77-1.15) at ages 12-13 years, OR = 1.08 (95% CI 0.88-1.32) at age 20 years, and OR = 1.18 (95% CI 0.97-1.44) during the past year), with the average of the three time periods (OR = 1.02, 95% CI 0.84-1.25), or with daily climbing of at least two flights of stairs (without stopping) during the past year (daily climbing vs. never climbing: OR = 1.03, 95% CI 0.86-1.23). Estimates were not modified or confounded by body mass index, menopausal status, or caloric intake during the past year. These results do not support a protective role for physical activity in the risk of breast cancer among young women.

Background: Human papillomavirus (HPV) has been previously associated with vulvar cancer. In a population-based study, we examined whether exposure to HPV, cigarette smoking, or herpes simplex virus 2 (HSV2) increases the risk of this cancer. Methods: Incident cases of in situ (n = 400) and invasive (n = 110) squamous cell vulvar cancer diagnosed among women living in the Seattle area from 1980 through 1994 were identified. Serum samples were analyzed for antibodies against specific HPV types and HSV2. HPV DNA in tumor tissue was detected by means of the polymerase chain reaction. In most analyses, case subjects were compared with population-based control subjects (n = 1403). Relative risks of developing vulvar cancer were estimated by use of adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Increased risks of in situ or invasive vulvar cancer were associated with HPV16 seropositivity (ORs = 3.6 [95% CI = 2.6‐4.8] and 2.8 [95% CI = 1.7‐4.7], respectively), current cigarette smoking (ORs = 6.4 [95% CI = 4.4‐9.3] and 3.0 [95% CI = 1.7‐5.3], respectively), and HSV2 seropositivity (ORs = 1.9 [95% CI = 1.4‐2.6] and 1.5 [95% CI = 0.9‐2.6], respectively). When the analysis was restricted to HPV16 DNA-positive tumors (in situ or invasive), the OR associated with HPV16 seropositivity was 4.5 (95% CI = 3.0‐6.8). The OR for vulvar cancer was 18.8 (95% CI = 11.9‐29.8) among current smokers who were HPV16 seropositive in comparison with never smokers who were HPV16 seronegative. Conclusions: Current smoking, infection with HPV16, and infection with HSV2 are risk factors for vulvar cancer. Risk appears particularly strong among women who are both current smokers and HPV16 seropositive. [J Natl Cancer Inst 1997;89:1516‐23]

In a case-control study of 1647 breast cancer cases and 1501 population controls under 45 years of age, potential modifying effects of other risk factors on the relationship of oral contraceptives to breast cancer were examined. Among the total series of study subjects, the relationship of extended pill usage was greater in non-white than white women. Oral contraceptive associations, however, did not appear to be substantially modified by other risk factors, including parity, body size, or family history of breast cancer (apart from a somewhat enhanced relationship among subjects who reported a sister with breast cancer. Further, oral contraceptive relationships did not vary by a history of benign breast disease, although the majority of subjects began pill usage prior to the development of benign breast disease. Among the women under the age of 35, in whom oral contraceptive relationships were heightened (over a twofold excess risk for use of 5 years or longer), pill relationships were less modified by race than in the total series. Although among these younger subjects there was no effect of pill usage in heavy women, and an enhanced relationship among heavier consumers of alcoholic beverages, these interactive effects were not statistically significant. The findings of this study generally support no substantial variation in oral contraceptive relationships by other breast cancer risk factors, although some further attention might be warranted regarding possible modifying effects of race, body size, type of relative with breast cancer, and alcohol consumption.To assess the possible interactive effects of oral contraceptives (OCs) with selected breast cancer risk factors, a case-control study involving US women diagnosed with breast cancer before 45 years of age was conducted. All incident cases of breast cancer diagnosed among younger women during 1990-92 in Atlanta, Georgia, Seattle/Puget Sound, Washington, and five counties of central New Jersey were eligible. Controls were identified through random-digit dialing. The final sample consisted of 1647 cases and 1501 controls. Ever-use of OCs for 6 months or more was associated with a slightly elevated breast cancer risk (relative risk (RR), 1.3; 95% confidence interval (CI), 1.1-1.5), with a stronger association for women whose breast cancer was diagnosed prior to age 35 years (RR, 1.8; 95% CI, 1.2-2.7). Among women under age 35 years, the risk was highest among women who had used OCs for 5 or more years and for those who used them within the past 5 years. In general, study findings did not support extensive variations in the risk associated with OC use across most risk factors. However, there were some noteworthy variations. At ages 35-44 years, long-term OC use exerted stronger effects in African-American women (RR, 1.5; 95% CI, 0.9-2.6) and other non-White women (RR, 2.8; 95% CI, 1.2-6.6) than among White women (RR, 1.0; 95% CI, 0.8-1.3). Although there was no interaction between OC use and a family history of breast cancer, OC use by a woman with a sister with breast cancer elevated the cancer risk. Body size was inversely associated with breast cancer risk in OC users, while weekly consumption of 7 or more alcoholic drinks slightly raised this risk.

Mutations in certain genes that regulate the cell cycle, such as p16 and p53, are frequently found in human cancers1. However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression2–8. It is now known that levels of both cyclin E and p27 can be controlled by posttranscriptional mechanisms, indicating that expression of these proteins can be altered by means other than simply mutation of their respective genes9,10. Thus, changes in p27 and cyclin E protein levels in tumors might be more common than previously anticipated and may be indicators of tumor behavior.

BACKGROUND: Information is limited on the risk of contralateral breast cancer after a diagnosis of breast carcinoma in situ (BCIS). METHODS: In western Washington, between 1974 and 1993, 1929 women with a first primary ductal carcinoma in situ (DCIS) and 282 women with a first primary lobular carcinoma in situ (LCIS) were followed for contralateral breast cancer. Rates of contralateral invasive breast cancer and BCIS were compared with population rates of first primary breast cancer using Poisson regression to adjust for age and calendar year. RESULTS: The rate of contralateral invasive disease after BCIS was approximately twice the population rate for women with DCIS and three times the population rate for women with LCIS; relative rates decreased somewhat with increasing time since diagnosis of LCIS, but were fairly stable after DCIS. The relative rate of contralateral DCIS after BCIS was substantially higher than for contralateral invasive disease, but dropped dramatically after the first year after the initial BCIS, especially among women with LCIS. Contralateral BCIS usually was of the same histologic type as the initial BCIS; histologic concordance of BCIS was 71% for women with an initial LCIS and 78% for women with DCIS. CONCLUSIONS: Data suggest that the rate of contralateral invasive breast cancer is elevated for at least 5 years after a diagnosis of BCIS compared with the rate of first primary breast cancer in the population, and that the rate is only slightly higher for women with LCIS than for women with DCIS. The markedly elevated rate of contralateral DCIS may result in large part from increased medical surveillance of women diagnosed with BCIS, especially during the first year after the initial diagnosis.

A population-based case-control study was conducted to assess the relation between physical activity and colon cancer among men and women aged 30-62 years. Cases were 251 men and 193 women diagnosed with colon cancer in 1985-1989 in three countries in the Seattle metropolitan area who were identified from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results registry. Controls were 233 men 194 women identified by random digit telephone dialing who were selected by stratified random sampling to approximate the age, sex, and county distribution of cases. Physical activity was assessed by questions on frequency and duration of types of recreational and occupational activities during the 10-year period ending 2 years before diagnosis. Each activity was classified as low intensity (4.5 METs ) or moderate to high intensity (or = 4.5 METs). For men and women combined, moderate or high intensity recreational activity was associated with a decreased risk of colon cancer (relative risk (RR) for two or more times per week vs. none = 0.70, 95% confidence interval (CI) 0.49-1.00). This relation was stronger for men than women. Occupational activity was not associated with colon cancer, except among men younger than 55 (RR foror = 14.5 hours per week of moderate activity vs. none = 0.29, 95% CI 0.12-0.69). Among men and women combined, total moderate or high intensity activity (occupational plus recreational) was marginally related to colon cancer (RR foror = 5 hours per week vs. none = 0.78, 95% CI 0.55-1.10). These results were adjusted for age (and sex in the combined sex analyses) and were not confounded by body mass index, dietary factors, or other measured health behaviors. The results of this study provide modest support to the growing number of studies showing that recreational and/or occupational physical activity is associated with a reduced risk of colon cancer.

Background and Objectives: Few published data describe the seroprevalence of antibodies to herpes viruses and hepatitis viruses among Southwestern minority women. Goals: To determine the prevalence of antibodies to herpes simplex virus type-1 and type-2, hepatitis B, and hepatitis C among 595 southwestern Hispanic and non-Hispanic white patients seeking gynecologic care; and to investigate risk factors associated with seropositivity. Study Design: Analysis of serologic and interview data. Antibody assays were based on purified glycoprotein assays (herpes simplex virus), and commercial assays for hepatitis B virus and hepatitis C virus. Results: Hispanic ethnicity was a risk factor for herpes simplex virus type-1 (age-adjusted odds ratio, 3.1; 95% confidence interval, 1.8-5.3) but was not associated with antibodies to herpes simplex virus type-2, hepatitis B virus, or hepatitis C virus. Risks associated with seropositivity to herpes simplex virus type-2 included a high lifetime number of sex partners, history of any sexually transmitted disease, and increasing age. Among all patients with herpes simplex virus type-2 antibodies, only 11.1% gave histories of genital herpes infection. For women with antibodies to hepatitis B virus, 31.1% gave histories of hepatitis during adulthood. Conclusions: The seroprevalence of antibodies to herpes simplex virus type-1 and herpes simplex virus type-2 was high in this clinic population; the prevalence of antibodies to herpes simplex virus type-1 was significantly higher in Hispanics than in non-Hispanic whites. Antibodies to herpes simplex virus type-2 and hepatitis B virus were associated with most indicators of sexual behavior. The high prevalence of antibodies to herpes simplex virus type-2 and the infrequent reporting of histories of genital herpes suggest that asymptomatic infection with herpes is common among these clinic patients.

To study maternal smoking during pregnancy and the risk of congenital urinary tract anomalies, we interviewed mothers of 118 affected infants born to residents of western Washington State during 1990 and 1991 and mothers of 369 control infants randomly selected from those without birth defects delivered during those years in five hospitals in King County, Washington. Maternal smoking was associated with an increased risk of congenital urinary tract anomalies in offspring (adjusted odds ratio [OR] = 2.3; 95% confidence interval [CI] = 1.2, 4.5). This risk was higher among light smokers (1-1000 cigarettes during the pregnancy) (OR = 3.7; 95% CI = 1.7, 8.6) than among heavy smokers (OR = 1.4; 95% CI = 0.6, 3.3). Our results corroborate previous findings and support the hypothesis of a causal relation.

In a population-based case-control study of breast cancer that included 2174 cases and 2009 population controls under 55 years of age, prior breast implants were reported by 36 cases versus 44 controls. After adjustment for the matching factors as well as variables associated with both breast cancer risk and breast enlargement (race, family history of breast cancer, body size, screening history), the relative risk of breast cancer associated with a prior implant was 0.6 (95% CI 0.4-1.0). The reduced risk persisted with increasing interval since surgery, arguing against selection bias as an explanation. Further, although a deficit of in situ tumors was seen among women with implants (RR = 0.2), the risk associated with implants remained reduced for both localized and distant tumors (RR = 0.8 for both stages). In a smaller group of women who had prior breast reduction surgery (10 cases, 13 controls), a reduced risk of breast cancer also was observed (RR = 0.7, 95% CI 0.3-1.6). The results of this study must be interpreted cautiously because of the small number of women involved and reliance on patient reports of prior operations. In not showing any elevation in breast cancer risk following a breast implant, our results confirm several record linkage studies but contradict some clinical studies that suggest an adverse effect. Additional investigations are needed in relation to specific types of breast implants, including the polyurethane-coated implants, which have been linked to high cancer rates in laboratory animals. (Plast. Reconstr. Surg. 97: 269. 1996.)

Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families. However, little is known about the contribution of BRCA1 mutations to breast cancer in the general population. We analyzed DNA samples from women enrolled in a population-based study of early-onset breast cancer to assess the spectrum and frequency of germ-line BRCA1 mutations in young women with breast cancer.We studied 80 women in whom breast cancer was diagnosed before the age of 35, and who were not selected on the basis of family history. Genomic DNA was studied for BRCA1 mutations by analysis involving single-strand conformation polymorphisms and with allele-specific assays. Alterations were defined by DNA sequencing.Germ-line BRCA1 mutations were identified in 6 of the 80 women. Four additional rare sequence variants of unknown functional importance were also identified. Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects.Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer. The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer. These results represent a minimal estimate of the frequency of BRCA1 mutations in this population. Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken.

The purpose of this study was to assess: (1) the risk of breast cancer associated with use of ovulation-inducing agents (such as clomiphene citrate) as treatment for infertility; and (2) the risk associated with ovulatory abnormalities that result in infertility. We performed a case-cohort study among 3837 women evaluated for infertility at clinics in Seattle, Washington, at some time during 1974–1985. Computer linkage with a population-based tumor registry was used to identify women diagnosed with breast cancer before January 1, 1992. Data regarding infertility testing and treatment were abstracted from the infertility clinic medical records for women who developed breast cancer and a randomly selected subcohort. Twenty-seven women in the cohort developed in situ or invasive breast cancer, in comparison with an expected number of 28.8 cases (standardized incidence ratio, 0.9; 95% confidence interval (CI), 0.6–1.4). Infertile women with evidence of an ovulatory abnormality were at a risk of breast cancer similar to that of women whose infertility was believed to be due to other causes. The risk among women who had taken clomiphene was reduced relative to infertile women who had not used this drug (adjusted relative risk, 0.5; 95% CI, 0.2–1.2), but the reduction in risk did not increase with duration of use. The possibility that use of clomiphene as treatment for infertility lowers the risk of breast cancer should be examined in other, larger studies.

A high level of endogenous estrogen in utero has been hypothesized to be a possible risk factor for breast cancer. We used information from two population-based case-control studies to investigate the relation between perinatal factors and risk of invasive breast cancer among women age 21-45 years (746 cases, 960 controls) and women age 50-64 years (401 cases, 439 controls). Breast cancer cases were ascertained through a population-based cancer registry, and controls were selected by random digit dialing. After adjustment for age, menopausal status, and maternal smoking, the birthweight-breast cancer association in women age 21-45 years followed a J-shaped curve, with women whose birthweight was less than 2,500 gm [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.9-2.0] and 4,000 gm or more (OR = 1.7; 95% CI = 1.1-2.5) at increased risk. Women age 50-64 years who were 4,000 gm or more at birth appeared to be at slightly reduced risk of breast cancer (OR = 0.6; 95% CI = 0.3-1.1). With the exception of maternal smoking, there was little effect of other perinatal factors on breast cancer risk in either group. These results support the hypothesized association between intrauterine estrogen exposure and subsequent risk of breast cancer.

To determine the risk of developing high grade anal squamous intraepithelial neoplasia (HG-AIN) in relation to HIV infection and immunosuppression, after controlling for the effects of human papillomavirus (HPV) infection.Prospective cohort study of 158 HIV-seropositive and 147 HIV-seronegative homosexual men presenting to a community-based clinic with initially negative anal cytologic and colposcopic findings.Subjects completed self-administered questionnaires, underwent cytologic screening, and standardized unaided and colposcopic examination of the proximal anal canal for presence of abnormalities suggestive of AIN. Anal specimens were screened for HPV DNA.HG-AIN developed in eight (5.4%) and 24 (15.2%) HIV-seronegative and -seropositive men, respectively. Risk of HG-AIN among HIV-seronegative men was associated with detection of anal HPV types 16 or 18 by Southern transfer hybridization (STH), detection of HPV 16 or 18 at the lower levels by polymerase chain reaction but not by STH, and with number of positive HPV tests; HG-AIN risk among HIV-seropositive men was associated with detection of HPV 16 or 18 only by STH, detection of HPV types other than 16 or 18, CD4 countor = 500 x 10(6)/l, and number of positive HPV tests. HIV-induced immunosuppression remained an independent predictor of HG-AIN after adjusting for type and level of detection of HPV; HIV infection predicted HG-AIN risk after adjustment for number of positive HPV tests.The association of HG-AIN with HIV, independent of HPV type, level of HPV detection and number of positive HPV tests, suggests that this increased risk cannot be entirely explained by an effect of HIV on HPV detection. Future studies focusing on factors more specific to the local microenvironment in the anal canal should help clarify these issues.

Background : The success of tamoxifen in reducing the occurrence of contralateral breast cancer among breast cancer patients in clinical trials has prompted the study of its use in the primary prevention of breast cancer. Long-term risks associated with tamoxifen therapy, however, are still being evaluated, particularly with respect to subsequent cancer occurrence at sites other than the breast. Purpose : This population-based, nested case-control study investigated the risks of second primary cancers of the ovary, endometrium, and contralateral breast among women receiving tamoxifen for breast cancer in conventional medical practice. Methods : A cohort of women diagnosed with breast cancer during 1978 through 1990 was identified from a population-based cancer registry. Case subjects included all women in the cohort who subsequently developed second primary ovarian (n = 39), endometrial (n = 42), or contralateral breast (n = 234) cancer prior to 1992. Control subjects were a random sample of the cohort who did not develop a second primary malignancy ; they were matched to the case subjects on age, disease stage, and year of initial breast cancer diagnosis (approximately two control subjects per case subject). Information on tamoxifen use as well as on potential risk factors for the second primary cancers was obtained through medical record abstractions and physician questionnaires. Results : The percentage of women who had received tamoxifen was 18% and 20%, respectively, among ovarian cancer case subjects and control subjects ; 26% and 31%, respectively, among endometrial cancer case subjects and control subjects; and 10% and 18%, respectively, among contralateral breast cancer case subjects and control subjects. The mean duration of tamoxifen use was less than 2 years for all groups. The relative risks for ovarian and endometrial cancers in women who took tamoxifen were relatively low but were consistent with no association (for ovarian cancer, matched odds ratio [mOR] = 0.6 and 95% confidence interval [CI] = 0.2-1.8 ; for endometrial cancer, mOR = 0.6 and 95% CI = 0.2-1.9). Tamoxifen therapy was associated with a decreased risk of contralateral breast cancer (mOR = 0.5 ; 95% CI = 0.3-0.9), especially if the drug had been taken for more than 1 year (mOR = 0.4 ; 95% CI = 0.2-0.9) or if the women were postmenopausal at initial breast cancer diagnosis (mOR = 0.4 ; 95% CI = 0.2-0.8). Conclusions and Implications: These data suggest that short durations of tamoxifen therapy are not associated with an increased risk of endometrial or ovarian cancer but are associated with a reduction in contralateral breast cancer risk. It would not be appropriate, however, to generalize these results to women who receive tamoxifen for longer periods.