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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.

Hormone replacement therapy (HRT) has increased in the United States over the past 2 decades in response to reports of long-term health benefits. A relationship between HRT and breast cancer risk has been observed in a number of epidemiological studies. In 2002, the Women's Health Initiative Randomized Controlled Trial reported an association between continuous combined HRT and breast cancer risk. The objective of this study was to examine the association between breast cancer risk and HRT according to regimen and duration and recency of use.A multicenter, population-based, case-control study was conducted in five United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823 postmenopausal white and black women (1870 cases and 1953 controls) aged 35-64 years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using standard, unconditional, multivariable logistic regression analysis. Potential confounders were included in the final model if they altered ORs by 10% or more. Two-sided P values for trend were computed from the likelihood ratio statistic. Continuous combined HRT was associated with increased breast cancer risk among current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17). Additionally, a statistically significant trend indicating increasing breast cancer risk with longer duration of continuous combined HRT was observed among current users (P =.01). There were no positive associations between breast cancer risk and other HRT regimens. Our data suggest a positive association between continuous combined HRT and breast cancer risk among current, longer term users. Progestin administered in an uninterrupted regimen may be a contributing factor. Risk dissipates once use is discontinued.

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.

BACKGROUND The association between method of detection and breast carcinoma histopathology has not been assessed adequately in a population-based setting. METHODS Among women who were included in a population-based, case-control study of breast cancer, patients who were newly diagnosed with invasive breast carcinoma were identified from Wisconsin's statewide tumor registry. Only women age ≥ 50 years were analyzed, because screening by mammography was not recommended before age 50 years at the time of the study. The breast tumors among these women (n = 2341 tumors) included the following histopathologies: lobular carcinoma (n = 206 tumors); ductal carcinoma, not otherwise specified (n = 1920 tumors); papillary carcinoma (n = 15 tumors); medullary carcinoma (n = 36 tumors); mucinous adenocarcinoma (n = 56 tumors); tubular adenocarcinoma (n = 41 tumors); invasive comedocarcinoma (n = 24 tumors); scirrhous adenocarcinoma (n = 15 tumors); and mixed ductal/lobular carcinoma (n = 28 tumors). RESULTS Overall, women reported that 41% of tumors were detected by mammography, 48% of tumors were self detected, and 11% of tumors were detected by clinical breast examination (CBE). Detection by mammography was significantly more likely for women who had tubular carcinoma (83%; P < 0.001) and invasive comedocarcinoma (67%; P = 0.23) compared with women who had ductal carcinoma (40%). Mammography was significantly less likely to detect medullary carcinoma (17%) than ductal carcinoma (40%; P = 0.01). Lobular carcinoma was the only histopathology that, compared with ductal carcinoma, was detected significantly more often by CBE than by self detection. Mammography detected lobular carcinoma (42%) as frequently as ductal carcinoma (40%). However, the use of postmenopausal hormones may have modified these detection patterns: Among current users, mammography discovered a greater percentage of ductal carcinomas (51%) and fewer lobular carcinomas (36%) than nonusers. CONCLUSIONS Among women age ≥ 50 years, breast cancer detection by mammography, self detection, and CBE varied according to tumor histopathology. Cancer 2002;95:470–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10695

PURPOSE: This paper presents methods and operational results of a population-based case-control study examining the effects of oral contraceptive use on breast cancer risk among white and black women aged 35–64 years in five U.S. locations. METHODS: Cases were women newly diagnosed with breast cancer during July 1994 through April 1998. Controls were identified through random digit dialing (RDD) using unclustered sampling with automated elimination of nonworking numbers. Sampling was density-based, with oversampling of black women. In-person interviews were conducted from August 1994 through December 1998. Blood samples were obtained from subsets of cases and controls, and tissue samples were obtained from subsets of cases. A computerized system tracked subjects through study activities. Special attention was devoted to minimizing exposure misclassification, because any exposure-disease associations were expected to be small. RESULTS: An estimated 82% of households were screened successfully through RDD. Interviews were completed for 4575 cases (2953 whites; 1622 blacks) and 4682 controls (3021 whites; 1661 blacks). Interview response rates for cases and controls were 76.5% and 78.6%, respectively, with lower rates for black women and older women. CONCLUSIONS: The methodologic details of this large collaboration may assist researchers conducting similar investigations.

OBJECTIVE: To examine the hypothesis that higher body weight increases the risk of oral contraceptive (OC) failure. METHODS: We conducted a retrospective cohort analysis of data from 755 randomly selected female enrollees of Group Health Cooperative of Puget Sound who completed an in-person interview and dietary questionnaire between 1990 and 1994 as control subjects for a case-control study of ovarian cysts. Among the 618 women who were OC ever-users, we used Cox proportional hazards regression models to estimate the relative risk (RR) of pregnancy while using OCs associated with body weight quartile. RESULTS: During 2822 person-years of OC use, 106 confirmed pregnancies occurred (3.8 per 100 person-years of exposure). After controlling for parity, women in the highest body weight quartile (70.5 kg or more) had a significantly increased risk of OC failure (RR 1.6, 95% confidence interval [CI] 1.1, 2.4) compared with women of lower weight. Higher elevations of risk associated with the highest weight quartile were seen among very low-dose OC users (RR 4.5, 95% CI 1.4, 14.4) and low-dose OC users (RR 2.6, 95% CI 1.2, 5.9), controlling for parity, race, religion, and menstrual cycle regularity. CONCLUSION: Our findings suggest that body habitus may affect metabolism sufficiently to compromise contraceptive effectiveness. Consideration of a woman’s weight may be an important element of OC prescription.

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.

Objectives: To evaluate the associations of dietary macronutrients, food groups, and eating patterns with risk of breast cancer in a population-based case–control study. Methods: In this study among women 20–44 years of age, 568 cases with breast cancer and 1451 population-based controls were included. They completed a detailed in-person interview, a self-administered food-frequency questionnaire and were measured for anthropometric indices. Logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) of breast cancer, adjusted for age, study site, race, education, alcohol consumption, oral contraceptive usage, smoking status, and body mass index. Results: There was no association between breast cancer risk and intake of calories, macronutrients, or types of fat. Risk of breast cancer was unrelated to intakes of a variety of food groups, including red meats, dairy, high-fat snacks and desserts, or foods high in animal fat. Increased risk was observed for high intake of a food group composed of sweet items, particularly sodas and desserts. Risk increased linearly with percent of calories from sweets and frequency of sweets intake. Consumption of sweets 9.8 or more times per week compared with

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: Recent studies have reported conflicting results on a possible relationship between hypertension, heart rate, and prostate cancer. A model has been developed suggesting that high blood pressure and high heart rate may both be markers for increased central sympathetic nervous activity, which may result in androgen-mediated stimulation of prostate cancer growth. METHODS: In this study we examined the associations between hypertension, heart rate, use of antihypertensive medications, and incident prostate cancer in a cohort of 2442 men. Data from the Cardiovascular Health Study (CHS), an NHLBI-sponsored observational study of adults age 65 or older in four U.S. communities, were analyzed using Cox proportional hazards regression. Seated systolic and diastolic blood pressures were measured using a standardized protocol at the initial clinical examination and annually at follow-up visits. Medications data were transcribed by trained interviewers from prescription medication containers brought into the clinic by participants. RESULTS: A total of 209 cases of incident prostate cancer were identified from either an ICD-9 code of 185 in hospital medical records (n = 130) or by self-report from annual surveillance interviews (n = 79). An average of 5.6 years of follow-up was available for analyses. No associations between blood pressure measures at entry into the study and prostate cancer were found, although these results may have been affected by subsequent treatment of hypertension. An association between resting heart rate (HR) equal to or greater than 80 beats per minute and incident prostate cancer was found compared to men with a rate of less than 60 beats per minute (HR: 1.6, 95% confidence interval [CI]: 1.03–2.5). An inverse association was found between risk of incident prostate cancer and use of any antihypertensive medication (HR: 0.7, 95% CI: 0.5–0.9). A test of heterogeneity found no difference between use of the specific classes of antihypertensive medication and the association with prostate cancer risk. CONCLUSIONS: These data tend to support the hypothesized causal pathway between vascular disease markers and prostate cancer.

Background: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. Methods: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. Results: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ERpositive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P

OBJECTIVE: To determine whether human papillomavirus (HPV) type 16 affects survival in oral squamous cell carcinoma.STUDY DESIGN: Two hundred fifty-four patients diagnosed with primary oral cancer were studied for survival in relation to tumor HPV type 16 status. Kaplan-Meier analysis and Cox proportional hazard models were used to assess survival and estimate hazard ratios adjusted for potential confounders.RESULTS: HPV type 16 DNA was detected in 15.1% of tumors. HPV 16 positive patients had significantly reduced all-cause mortality (hazard ratio [HR] estimates = 0.34, 95% CI = 0.14, 0.83) and disease-specific mortality (HR = 0.17, 95% CI = 0.04, 0.76) compared with HPV 16 negative patients after adjustment for age, stage, treatment, smoking, alcohol, education, and comorbid disease.CONCLUSIONS: The presence of HPV type 16 DNA is independently associated with a favorable prognosis in patients with oral squamous cell carcinoma.CLINICAL SIGNIFICANCE: Although HPV genotyping is currently not widely availab...

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.

BACKGROUND Obesity has been shown to affect breast carcinoma prognosis, with the heaviest women having a higher mortality due to breast carcinoma. Few studies have focused on premenopausal women or the correlation of body mass index (BMI) to tumor characteristics related to prognosis. METHODS The authors conducted a population-based follow-up study for mortality of 1177 women younger than 45 years of age who had invasive ductal breast carcinoma diagnosed from 1983 through 1992. Histologic slides and/or tumor tissue were collected for pathologic review, immunohistochemistry assays, and bivariate flow cytometric analysis. RESULTS Women with breast carcinoma who were in the highest quartile of BMI were 2.5 times as likely (95% confidence interval [CI], 1.6–3.9) to die of their disease within 5 years of diagnosis compared with women in the lowest quartile of BMI. The tumors of the women in the highest quartile of BMI were more likely to be estrogen receptor negative (odds ratio [OR], 1.5; 95% CI, 1.0–2.2) and to have a high S-phase fraction (OR, 1.9; 95% CI, 1.2–3.1), high histologic grade (OR, 1.7; 95% CI, 1.0–2.9), high mitotic cell count (OR, 2.0; 95% CI, 1.2–3.1), and large tumor size (2 to < 5 cm: OR, 2.3; 95% CI, 1.5–3.1; or ≥ 5 cm: OR, 2.7; 95% CI, 1.5–4.8) compared with the tumors of women whose BMI was in the first quartile. Relative to the large tumors (≥ 2 cm) in women in the lowest BMI quartile, the large tumors in women in the highest BMI quartile were more likely to express markers of high proliferation, indicating they may have grown faster than similar size tumors of the thinnest women. In a multivariate analysis including the tumor characteristics, obesity, as measured by being in the highest quartile of BMI, remained an independent prognostic factor for mortality (hazard ratio, 1.7; 95% CI, 1.0–2.9; P < 0.05. CONCLUSIONS Our study results indicated that being in the highest quartile of BMI was a strong predictor of mortality in women with breast carcinoma diagnosed at a young age. The tumors of the heavy women were larger and more likely to have markers of high cellular proliferation than those of thinner women. Cancer 2001;92:720–9. © 2001 American Cancer Society.

BACKGROUND An increased incidence of breast carcinoma has been reported among relatives of individuals who are affected with the rare recessive disorder, ataxia-telangiectasia (A-T), and who are heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. However, most studies of breast carcinoma cases from the general population have failed to find a higher incidence of ATM mutations in cases when compared with controls. METHODS Genomic DNA samples from 258 individuals were screened for mutations of all types in each of the 62 coding exons of the ATM gene; 142 of these were from breast carcinoma cases with a first-degree family history or early age at diagnosis, 35 were from cases selected for the presence of either known disease-related mutations (n = 25) or missense alterations of unknown consequences (n = 10) in BRCA1 or BRCA2, and 81 were from matched controls. RESULTS A total of 12 individuals with ATM mutations were identified, 11 among 142 breast carcinoma cases (7.7%; 95% CI, 3.9–13.4%) and 1 among 81 controls (1.2%; 95% CI, 0.0–6.7%) (P = 0.06). All mutations detected were of the missense type; none were predicted to truncate the ATM protein. Among cases, mutations were found exclusively in patients with a family history of breast carcinoma (12.1%; 95% CI, 6.2–20.6%) (P = 0.02). Similar frequencies of ATM mutations were found in 35 additional cases selected for the presence of BRCA1 or BRCA2 mutations when compared with cases overall. CONCLUSIONS ATM mutations, specifically missense mutations, are more common in breast carcinoma cases selected for first-degree family history and early age at diagnosis. Cancer 2001;92:479–87. © 2001 American Cancer Society.

Objective: Exercise has been hypothesized to influence cancer risk through a variety of mechanisms including hormonal, metabolic and immunologic effects, yet its relation with the risk of thyroid cancer has not been examined. We conducted a population-based case–control study in women aged 18–64 in three counties of western Washington State to assess the relation of recreational physical activity with risk of papillary thyroid cancer. Methods: Of 558 women with thyroid cancer of the follicular epithelium diagnosed during 1988–1994 who were identified as eligible, 468 (83.9%) were interviewed; this analysis was restricted to women with papillary histology (n = 410). Controls (n = 574) were identified by random digit dialing, with a response proportion of 73.6%. Logistic regression was used to calculate odds ratios (OR) and associated confidence intervals (CI) estimating the relative risk of papillary thyroid cancer associated with various aspects of recreational exercise. Results: Risk of thyroid cancer was reduced among women who reported that they engaged in regular recreational exercise during the 2 years before diagnosis relative to women who did not report exercise during that time period (OR = 0.76, 95% CI 0.59–0.98). A similar risk reduction was noted among women who reported having exercised regularly between ages 12 and 21 (OR = 0.83, 95% CI 0.64–1.1). However, no clear associations with aspects of recreational activity, including average hours exercised per week or weekly energy expenditure, were observed. Conclusions: These results provide some initial support for the hypothesis that physical activity may reduce risk of thyroid cancer.

OBJECTIVE: Postmenopausal women who receive sequential hormone replacement therapy with estrogen combined with progestogen for 10 to 24 d/mo for a prolonged period may have an elevated endometrial cancer risk relative to those who have never received hormone replacement therapy. We investigated whether daily use of estrogen and progestogen (continuous combined hormone replacement therapy) could diminish any excess endometrial cancer risk. STUDY DESIGN: A population-based study in Washington State obtained interview data from 969 women aged 45 to 74 years with endometrial cancer diagnosed during 1985 through 1991 or 1994 through 1995 and from 1325 age-matched control subjects selected primarily by random digit dialing. Women who had received only continuous combined hormone replacement therapy were compared with women who had only received another hormone replacement therapy regimen or who had never received hormone replacement therapy. RESULTS: The risk of endometrial cancer among users of continuous combined hormone replacement therapy (n = 9 case patients, n = 33 control subjects) relative to women who had never received hormone replacement therapy was 0.6 (95% confidence interval, 0.3-1.3); the risk relative to women who received hormone replacement that included progestogen for 10 to 24 d/mo was 0.4 (95% confidence interval, 0.2-1.1). Most continuous combined hormone replacement therapy use was short-term (

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.

BACKGROUND In 1998, an unusually large number of invasive lobular breast carcinoma cases were seen at the University of Washington. The purpose of this study was to assess whether the incidence rate of invasive lobular carcinoma has been increasing disproportionately compared with the incidence rate of invasive ductal carcinoma. METHODS Age specific and age-adjusted breast carcinoma incidence rates from 1977–1995 were obtained from the nine population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program. Three histologic groupings were used: lobular, ductal, and all invasive breast carcinomas. Overall incidence rates for each grouping, as well as for each stage (local, regional, and distant), were obtained. RESULTS The rate of incidence of lobular carcinoma increased steadily from 1977–1995 in women age ≥ 50 years whereas it remained stable in women age < 50 years. Alternatively, the rate of incidence of ductal carcinoma increased steadily from 1977–1987, but from 1987–1995 it remained relatively constant across all age groups. CONCLUSIONS The incidence rates of invasive lobular breast carcinomas increased steadily since 1977 whereas the incidence rates of invasive ductal carcinoma have plateaued since 1987. This rise occurred specifically among women age ≥ 50 years and may be related to postmenopausal status. Further epidemiologic, clinical, and laboratory research is required to assess what factors are contributing to this trend. Cancer 2000;88:2561–9. © 2000 American Cancer Society.

Background Many epidemiological studies have assessed the relationships between anthropometric variables and breast cancer risk. However, methodological approaches for analysing these factors differ appreciably. Also, age when maximum height is achieved has been identified as a potential risk factor for breast cancer in premenopausal women, but this issue has not been studied in postmenopausal women. Methods The participants in this population-based case-control study were postmenopausal women 50-64 years of age from the general female population of western Washington State. It included 479 women with incident primary breast cancer and 435 controls. Results This study found that: (i) women who gained over 70 pounds since age 18 had an increased risk of breast cancer relative to those who stayed within 10 pounds of their weight at age 18 (odds ratio [OR] = 2.7; 95% CI: 1.5-4.9), (ii) women with body mass indices (BMI) below what is considered healthy had a decreased risk (OR = 0.4; 95% CI: 0.2-1.1) while women with a BMI in the obese range had an increased risk of breast cancer (OR = 1.4; 95% CI: 1.0-2.1), and (iii) women who reached their maximum height at or after the age of 18 had a decreased risk of breast cancer compared to women who reached their maximum height at age 13 or younger (OR = 0.7; 95% CI: 0.5-1.0). Conclusions By examining various anthropometric variables using clinically relevant strata, a clearer picture of how these variables relate to postmenopausal breast cancer risk was developed. Similar to younger women, postmenopausal women who reached their maximum height at later ages had a decreased risk of breast cancer.

BACKGROUND There is a clear and growing need for data regarding BRCA1 and BRCA2 mutation frequencies among breast carcinoma cases not specifically ascertained on the basis of extreme family history profiles. Toward this end, the authors previously reported results with regard to BRCA1 in breast carcinoma patients drawn from a population-based study. In the current study the authors present new findings concerning BRCA2 mutation frequency in this same population, as well as summary data regarding the combined contribution of these two genes. METHODS Subjects were drawn from two population-based, case-control studies of breast carcinoma in young women conducted in western Washington State and focused on 1) women diagnosed with breast carcinoma before age 35 years (n = 203); and 2) women with a first-degree family history of breast carcinoma who were diagnosed before age 45 years (n = 225). Similarities and differences between BRCA2 carriers and BRCA1 carriers were analyzed in terms of age at diagnosis, family history status, and disease features. RESULTS Of cases diagnosed before age 35 years, all of whom were unselected for family history, 9.4% carried germline mutations (3.4% for BRCA2 and 5.9% for BRCA1). Of cases diagnosed before age 45 years who had a first-degree family history of breast carcinoma, 12.0% carried germline mutations (4.9% for BRCA2 and 7.1% for BRCA1). Increased frequencies of mutations were observed in cases with a personal or family history of early age at diagnosis and in those with four or more family members affected with breast carcinoma. BRCA2 mutations were less common than BRCA1 mutations in families with any history of ovarian carcinoma. CONCLUSIONS Overall, given current constraints on health care resources, these data suggest that screening for germline mutations in these breast carcinoma susceptibility genes may have the greatest impact on overall health care if it is prioritized toward high and moderate risk populations. Cancer 2000;88:1393–1402. © 2000 American Cancer Society.

Decreased age at onset in successive generations has been observed for a number of diseases. Two nonparametric matched and unmatched test statistics are proposed, taking into account not only current age or age at death for unaffected individuals and age at disease onset for affected individuals, but also possible correlations among family members. Both are asymptotically normal with readily estimated variances from the data. A simulation study is conducted to compare the proposed tests with the commonly used paired t-test and log-rank test. It has been shown that the proposed test statistics yield valid conclusions in assessing genetic anticipation under all situations considered. However, the paired t-test is valid only when the censoring distributions are comparable between two generations, whereas the log-rank test is valid when the correlation among family members is weak. As expected, the matched test is most powerful when the data are heterogeneous, and the unmatched and the log-rank tests are most powerful when the data are homogeneous and the correlation is weak. Lastly, a population-based family study of breast cancer conducted at the Fred Hutchinson Cancer Research Center is used for illustration of the proposed and the log-rank tests. The preliminary analysis suggests that there appears a decreased age at onset over the successive generations in breast cancer.

Background:Breast and thyroid cancer have been observed to occur more frequently than expected as multiple primary tumors in women. The study presented herein focuses on the effects of age at diagnosis and treatment for the first cancer on the development of the second cancer. Methods:This retrospective cohort study used a study population consisting of 38,632 women diagnosed with primary invasive breast cancer and 2189 women diagnosed with primary invasive thyroid cancer between 1974 and 1994. Cases were identified from records of the Cancer Surveillance System of western Washington and followed for subsequent cancer development through 1995. Results:Seventy-one women were diagnosed during their lives with both breast and thyroid cancers. Including cancers diagnosed during the same month as or after the initial cancer, the relative risk (RR) of breast cancer among women with thyroid cancer was 1.5 (95% confidence interval [CI] 1.1–2.0), and the RR of thyroid cancer among women with breast cancer was 1.5 (95% CI 1.1–2.2). Among women with thyroid cancer, risk of breast cancer was greatest when the latter cancer was diagnosed under 45 years of age (RR = 2.3, 95% CI 1.1–4.4). First course of treatment, including radiation or hormonal therapy to treat thyroid cancer, and radiation, chemotherapy, or hormonal therapy to treat breast cancer, did not alter a woman's risk of developing the second cancer. Conclusions:The data suggest that the incidence of breast and thyroid cancer may be related, and that in particular women with thyroid cancer may be at a moderately increased risk of developing breast cancer before age 45.

BACKGROUND To the authors' knowledge, no previous studies have identified an adverse effect of pregnancy on patient survival after breast carcinoma. However, results are difficult to interpret because of failure to control for stage of disease at the time the pregnancy occurred. METHODS Study participants were women diagnosed with invasive breast carcinoma between 1983–1992 who previously had participated in a population-based case–control study or, if deceased, proxy respondents. Information regarding subsequent pregnancies was obtained by self-administered questionnaire or telephone interview. Information regarding breast carcinoma recurrences was obtained by questionnaire and from cancer registry abstracts. Women who became pregnant after a diagnosis of breast carcinoma (n = 53) were matched with women without subsequent pregnancies based on stage of disease at diagnosis and a recurrence free survival time in the comparison women greater than or equal to the interval between breast carcinoma diagnosis and onset of pregnancy in the women with a subsequent pregnancy. RESULTS Sixty-eight percent of women who became pregnant after being diagnosed with breast carcinoma delivered one or more live-born infants. Miscarriages occurred in 24% of the patients who became pregnant compared with 18% of the controls (women without breast carcinoma) of similar ages from the case–control study. Five of the 53 women who had been pregnant after breast carcinoma died of the disease. The age-adjusted relative risk (RR) of death associated with any subsequent pregnancy was 0.8 (95% confidence interval [95% CI], 0.3–2.3). All five deaths occurred among the 36 women who had a live birth (age-adjusted RR = 1.1; 95% CI, 0.4–3.7). CONCLUSIONS The findings of the current study are based on a small number of deaths but do not suggest that pregnancy after a diagnosis of breast carcinoma has an adverse effect on survival. [See editorial on pages 2301–4, this issue.] Cancer 1999;85:2424–32. © 1999 American Cancer Society.

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.

Objectives: The reported mutagenic and carcinogenic effects of some chemicals present in hair dyes have raised concern that hair dye use could increase breast cancer risk. This case–control study evaluated how detailed aspects of hair coloring and hair spray application by reproductive-age women may affect breast cancer risk. Methods: Cases were white female residents of three counties of western Washington state 45 years of age or less, who were diagnosed with breast cancer between 1983 and 1990 (n = 844). A sample of similarly aged women residing in the same counties served as controls (n = 960). Information on hair coloring and hair spray use, as well as other exposures, was ascertained during in-person interviews. Results: Breast cancer cases were slightly more likely than controls to report ever having used some type of hair coloring application, including use of rinses, semi-permanent or permanent dyes, as well as bleaching then dyeing or frosting their hair (relative risk [RR] = 1.3, 95% CI = 1.0–1.6, adjusted for age, fullterm pregnancies, family history of breast cancer, and weight). In subgroup analyses, women with exclusive use of just one of these methods of hair coloring application had no elevation in risk (similarly adjusted RR = 1.1, 95% CI = 0.9–1.3), whereas women who used two or more of these methods did have an elevated risk (RR = 1.9, 95% CI = 1.4–2.5). Hair spray use was not related to the risk of breast cancer (ever versus never users: RR = 1.0, 95% CI = 0.8–1.3). Conclusion: The lack of an association between exclusive use of a single type of hair coloring application and breast cancer risk argues that hair coloring application does not influence breast cancer risk among reproductive-age women. Thus, the results of the present study, as well as negative ones from most (but not all) prior studies, are most consistent with the conclusion that neither hair coloring application nor hair spray application influences breast cancer risk.

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]

Objective: To examine demographic and behavioral factors related to perineal application of powders. Methods: Controls from three case-control studies ( N = 1206) were asked identical questions about the use of genital powders by direct perineal application. The relationship of perineal powder application with demographic factors, reproductive factors, body mass index (BMI), douching, and alcohol and tobacco use was assessed. Data were analyzed by multiple logistic regression. Results: Women who douched (prevalence odds ratio [prevalence OR] 2.0, 95% confidence interval [CI] 1.0, 3.9), drank alcohol (prevalence OR 1.8, 95% CI 1.2, 2.8), smoked cigarettes (prevalence OR 1.3, 95% CI 1.0, 1.8), or were in the highest BMI quartile were more likely to engage in perineal use of powder (prevalence OR 1.6, 95% CI 1.1, 2.6). There appeared to be a close response relationship between the number of perineal applications of powder and BMI ( P Conclusion: Body mass index might confound the relationship between perineal powder application and the development of ovarian cancer. Other factors, such as alcohol and tobacco use and douching, are related to perineal use of powder and may represent similar behavioral characteristics.

In a population-based case-control study of parous women less than 45 years of age, we evaluated the relations of various pregnancy characteristics to maternal breast cancer risk. Cases (N = 1,239) diagnosed with in situ or invasive breast cancer from 1990 to 1992 in Atlanta, GA, Seattle/Puget Sound, WA, and five counties in central New Jersey, and population controls (N = 1,166) identified by random-digit dialing, were interviewed regarding the details of their pregnancies. We used logistic regression to estimate relative risks (RR) and 95% confidence intervals (CI) and to adjust for breast cancer risk factors. Women who reported nausea or vomiting in their first pregnancy had a slightly lower risk of breast cancer (RR = 0.87; 95% CI = 0.72-1.0). We found no strong or consistent associations for maternal risk related to gestational length, pregnancy weight gain, gestational diabetes, pregnancy hypertension, or gender of the offspring, although we found some evidence for reductions in risk for toxemia (RR = 0.81; 95% CI = 0.61-1.1) and specific sex (RR for female twins vs singletons = 0.48; 95% CI = 0.20-1.3) and timing characteristics of twinning. Overall, these data provide little support for the hypothesis that pregnancy hormone levels are associated with subsequent maternal risk of breast cancer in young women.

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.

The authors used data from a population-based case-control study of breast cancer in women aged < or = 44 years (cases, n = 975; controls, n = 866) conducted between 1994 and 1996 in three counties of western Washington state to assess the validity and reliability of reported perinatal factors. For a sample of participants, exposure information from self-administered questionnaires was validated with information from birth certificates (cases, n = 378; controls, n = 283). Detailed information regarding perinatal characteristics of their daughters was also collected from subjects' mothers (case mothers, n = 510; control mothers, n = 436) to assess the reliability of subjects' reporting of these events. Although reporting of birth weight by subjects (cases, r = 0.83; controls, r = 0.80) and their mothers (case mothers, r = 0.89; control mothers, r = 0.84) was highly correlated with the birth certificates, there was differential measurement error by subjects; cases reported birth weight accurately on average, but controls tended to underestimate their birth weight. Agreement between the subject and mother report was excellent for birth weight (cases, r = 0.85; controls, r = 0.87) and good for other perinatal factors, but birth order and maternal diethylstilbestrol use were underreported among cases and reported accurately among controls. Differential measurement error of birth weight by case-control status resulted in biased odds ratios for breast cancer risk.

Objectives: Greater incidence of thyroid cancer in women than men, particularly evident during the reproductive years, has led to the suggestion that female hormones may increase risk of this disease. We conducted a population-based case-control study in women aged 18 to 64 years in three counties of western Washington State (United States) to assess the relation of use of exogenous hormones, including oral contraceptives (OC) and hormone replacement therapy (HRT), to risk of papillary thyroid cancer.

BACKGROUND The use of calcium channel blockers in an elderly population recently was reported to be associated with the incidence of cancer. The Cardiovascular Health Study, a multisite observational cohort study, provided the opportunity to investigate the epidemiologic association between the use of calcium channel blockers and breast carcinoma risk in 3198 women age ≥ 65 years. METHODS Standard questionnaires and clinical procedures were administered at four study sites annually from 1989-1990 to 1993-1994. Drug usage was assessed by a medication inventory and hospitalizations for 75 incident invasive breast carcinoma cases were identified using International Classification of Diseases-9 Clinical Modification codes. Time-dependent Cox proportional hazards regression models were used to assess associations between incident breast carcinoma and the use of specific antihypertensive medication including calcium channel blockers. RESULTS In adjusted Cox proportional hazards models, an elevated risk of breast carcinoma was associated with use of calcium channel blockers (hazard ratio [HR]: 2.57; 95% confidence interval [CI], 1.47-4.49). This association persisted when the comparison group was users of other antihypertensive medication. No associations between the use of other antihypertensive medication with incident breast carcinoma were found. Associations were enhanced by assessment of high dose at baseline (HR: 4.42; 95% CI, 1.37-14.27) and when calcium channel blockers were combined with estrogen use (HR: 4.48; 95% CI, 1.58-12.75). The association was found to be strongest for the use of estrogens with immediate release calcium channel blockers (HR: 8.48; 95% CI, 2.99-24.08). CONCLUSIONS Although the number of cases was limited in this observational study, associations found between the use of calcium channel blockers and incident invasive breast carcinoma warrant further investigation. Site specific carcinomas should be included as an outcome of ongoing and planned long term clinical trials using calcium channel blockers. Cancer 1997; 80:1438-47. © 1997 American Cancer Society.

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.

It has been hypothesized that women who participate in vigorous physical activity may have lower risk of breast cancer due to lower lifetime exposure to ovarian hormones. A population-based case-control study was conducted to investigate the association between leisure-time physical activity and risk of breast cancer among women aged 21 to 45 years. Cases were 747 women diagnosed with invasive breast cancer between 1983 and 1990 in three counties of western Washington state (United States), and were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) registry. Controls were 961 women selected from the same area by random-digit telephone dialing. Physical activity was assessed through personal interview, with questions on frequency and duration of each type of recreational activity during the two-year period immediately prior to reference date (date of diagnosis for cases and a comparable assigned date for controls) and between ages 12 and 21. For the two-year time period before diagnosis, there was no association with frequency of activity (age-adjusted odds ratio [OR]=0.93, 95 percent confidence interval [CI]=0.71-1.22 for four or more episodes per week cf none), total hours spent in physical activity (age-adjusted OR=0.92, CI=0.71-1.22 for four or more hours per week cf none) or MET (metabolic equivalent energy expenditure unit) (age-adjusted OR=0.95, CI=0.73-1.23 for 18 or more METs per week cf none), nor any trend in risk with increasing activity levels. Similarly, there was no association between leisure activity during adolescence and breast cancer risk. These results were not confounded further by body mass index (wt/ht2), age at menarche, age at first full-term pregnancy, parity, family history of breast cancer, or other measured health behaviors. Our findings do not support a protective effect of leisure-time physical activity either in the adolescent years or in adulthood on breast cancer in young women.

The Women’s Health Initiative (WHI) randomized trials found that use of combined estrogen and progestin menopausal hormone therapy (CHT) increases breast cancer risk, but use of unopposed estrogen hormone therapy (EHT) does not. However, several questions regarding the impact of hormone use on risk of different types of breast cancer and what thresholds of use confer elevations in risk remain. We conducted a population-based case–control study among women 55–74 years of age to assess the association between menopausal hormone use and risk of invasive ductal and invasive lobular breast carcinomas. Associations were evaluated using polytomous logistic regression and analyses included 880 ductal cases, 1,027 lobular cases, and 856 controls. Current EHT and CHT use were associated with 1.6-fold [95 % confidence interval (CI): 1.1–2.2] and 2.3-fold (95 % CI: 1.7–3.2) increased risks of lobular breast cancer, respectively, but neither was associated with risk of ductal cancer. Lobular cancer risk was increased after 9 years of EHT use, but after only 3 years of CHT use. Evidence across more than a dozen studies indicates that lobular carcinoma is the type of breast cancer most strongly influenced by menopausal hormones. Here, we characterize what thresholds of duration of use of both EHT and CHT that confer elevations in risk. Despite the rapid decline in hormone therapy use the WHI results were published, study of the hazards associated with these medications remains relevant given the estimated 38 million hormone therapy prescriptions that are still filled in the United States annually.

Background: Mechanistic studies largely support the chemopreventive potential of statins. However, results of epidemiologic studies investigating statin use and breast cancer risk have been inconsistent and lacked the ability to evaluate long-term statin use. Methods: We used data from a population-based case–control study of breast cancer conducted in the Seattle–Puget Sound region to investigate the relationship between long-term statin use and breast cancer risk. Nine hundred sixteen invasive ductal carcinoma (IDC) and 1,068 invasive lobular carcinoma (ILC) cases in patients 55 to 74 years of age diagnosed between 2000 and 2008 were compared with 902 control women. All participants were interviewed in-person and data on hypercholesterolemia and all episodes of lipid-lowering medication use were collected through a structured questionnaire. We assessed the relationship between statin use and IDC and ILC risk using polytomous logistic regression. Results: Current users of statins for 10 years or longer had a 1.83-fold increased risk of IDC [95% confidence interval (CI): 1.14–2.93] and a 1.97-fold increased risk of ILC (95% CI: 1.25–3.12) compared with never users of statins. Among women diagnosed with hypercholesterolemia, current users of statins for 10 years or longer had more than double the risk of both IDC (OR: 2.04, 95% CI: 1.17–3.57) and ILC (OR: 2.43, 95% CI: 1.40–4.21) compared with never users. Conclusion: In this contemporary population-based case–control study, long-term use of statins was associated with increased risks of both IDC and ILC. Impact: Additional studies with similarly high frequencies of statin use for various durations are needed to confirm this novel finding. Cancer Epidemiol Biomarkers Prev; 22(9); 1529–37. ©2013 AACR.

BACKGROUND This study investigates whether a positive family history of breast carcinoma is associated with improved survival after invasive breast carcinoma among women ages 21 through 45. METHODS Subjects were 733 nonadopted women born after 1944 who were diagnosed with primary invasive breast carcinoma between January 1983 and April 1990 while residing in the metropolitan Seattle area and who provided information on family history of breast carcinoma. Information on clinical characteristics and survival was obtained from a population-based cancer registry. Subjects were followed for survival through 1994. Cox proportional hazards models were used to estimate the relative risk (RR) of dying in relation to family history of breast carcinoma, adjusting for selected clinical characteristics, age and year of diagnosis, and prior mammograms. RESULTS The risk of dying among women with a first-degree family history of breast carcinoma was half that of women with no family history of breast carcinoma (RR = 0.5; 95% confidence interval [CI], 0.3–0.9). There was no evidence of a reduction in the risk of dying among women with only a second-degree family history of breast carcinoma (RR = 1; 95% CI, 0.6–1.4). These associations were adjusted for age and year of diagnosis, stage of disease, tumor size, bilaterality, and mammogram history. These findings were not further influenced by adjustment for initial treatment or the numbers and ages of relatives at risk for breast carcinoma. CONCLUSIONS Compared with women with neither a first- nor second-degree family history of breast carcinoma, the authors found that women who had a first-degree family history experienced increased survival. This finding did not appear to be attributable to differences in screening or treatment. To the extent that this difference is attributable to underlying biologic mechanisms, new insights into the natural history and treatment of breast carcinoma could result. Future studies should investigate whether specific susceptibility genes are associated with differential survival from breast carcinoma. Cancer 1996;78:1417-25.

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.

To evaluate predictors of contralateral breast cancer risk, we examined data from a nested case-control study of second primary cancers among a cohort of women in western Washington (United States) diagnosed with breast cancer during 1978 through 1990 and identified through a population-based cancer registry. Cases included all women in the cohort who subsequently developed contralateral breast cancer at least six months after the initial diagnosis, but prior to 1992 (n = 234). Controls were sampled randomly from the cohort, matched to cases on age, stage, and year of initial breast cancer diagnosis. Information on potential risk factors for second primary cancer was obtained through medical record abstractions and physician questionnaires. Women who were postmenopausal due to a bilateral oophorectomy (i.e., a surgical menopause) at initial breast cancer diagnosis had a reduction in contralateral breast cancer risk compared with premenopausal women (matched odds ratio [mOR] = 0.25, 95 percent confidence interval [CI] = 0.09-0.68), whereas no reduction in risk was noted among postmenopausal women who had had a natural menopause (mOR = 0.90, CI = 0.39-2.09). Among postmenopausal women, there was a suggestion of a lower risk associated with relatively high parity (2+). A family history of breast cancer was associated with an increased risk (mOR = 1.96, CI = 1.22-5.15) and varied little by menopausal status. Having an initial tumor with a lobular component (c.f. a ductal histology) was not related strongly to risk (mOR = 1.47, CI = 0.79-2.74). The results of the present and earlier studies argue that we have limited ability to predict the occurrence of a contralateral breast tumor. Better predictors will be required before diagnostic and preventive interventions can be targeted to subgroups of patients with unilateral breast cancer.

HPV infections have been previously observed in oral cancers, and inactivation of the p53 gene has been shown to be one of the most common genetic alterations in human tumors. We examined 179 oral specimens from 70 individuals with histologic findings of either normal mucosa (n = 6) or oral disease that ranged from mild dysplasia to invasive squamous-cell carcinoma (n = 64) to determine the occurrence of both HPV infection and p53 mutations and their relationship with several clinical factors. HPV infection was detected by PCR amplification of viral DNA, and the presence of p53 mutations was assayed using the single-strand conformation polymorphism (SSCP)-PCR technique. HPV infection was found in 31% of individuals with oral disease and was not seen in healthy individuals. Mutations in exons 5, 6, 7 or 8 of the p53 gene were detected in 37.5% of patients with oral lesions and in a biopsy from 1 healthy individual who was a heavy smoker. Approximately one-third of lesions classified as pre-malignant (dysplasia and carcinoma in situ) and 42% of invasive carcinomas contained p53 mutations. The majority of these mutations were G:T transversions located within exons 7 and 8. Tumor tissues from 6 patients with oral lesions were found both to be HPV-16-positive and to contain p53 mutations; of these, 4 were poorly differentiated carcinomas that were diagnosed as late-stage disease. In this study, p53 mutations were detected in the early stages of cancer development. © 1996 Wiley-Liss, Inc.

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.

BACKGROUND We analyzed data from a population-based, multi-center, case-control study to determine whether the occurrence of histologic types of uterine sarcoma is related to exogenous hormone use and/or to two correlates of endogenous estrogens: excess weight and cigarette smoking. METHODS One hundred sixty-seven women with newly-diagnosed uterine sarcoma (56 leiomyosarcoma, 85 mixed mullerian tumors, and 26 endometrial stromal sarcomas) were interviewed by telephone regarding possible risk factors for these neoplasms. For comparison, 208 women identified at random from the general population of the study areas were interviewed as controls. RESULTS Use of oral contraceptives was positively associated with the risk of leiomyosarcoma (odds ratios [OR] = 1.7, 95% confidence interval [CI] = 0.7, 4.1), primarily among women who last used these medications 15 or more years prior to diagnosis. Use of noncontraceptive estrogens was directly associated with the risk of mixed mullerian tumors, but only among recent and long-term users of these medications. Women in the highest quantile of body mass index (;ce 27.5 kg/m2) one year prior to diagnosis were at increased risk of each type of uterine sarcoma (leiomyosarcoma, OR = 2.5, 95% CI = 1.1, 5.7; mixed mullerian tumors, OR = 2.9, 95% CI = 1.3, 6.7; stromal sarcoma, OR = 3.5, 95% CI = 1.1, 10.9). Women who had ever smoked cigarettes were at reduced risk of leiomyosarcoma (OR = 0.6, 95% CI = 0.3, 1.1) and stromal sarcoma (OR = 0.5, 95% CI = 0.2, 1.2), but the relationship was not more pronounced among heavy smokers; no association with smoking was observed with mixed mullerian tumors. CONCLUSIONS Several of these findings parallel those from studies of endometrial carcinoma, and may indicate a role for unopposed estrogen in the etiology of histologic types of uterine sarcoma. Cancer 1996;77:717-24.