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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.

Supplementary Figure 1 from Array Comparative Genomic Hybridization Analysis of Genomic Alterations in Breast Cancer Subtypes

Supplementary Table 2 from Array Comparative Genomic Hybridization Analysis of Genomic Alterations in Breast Cancer Subtypes

Supplementary Table 1 from Array Comparative Genomic Hybridization Analysis of Genomic Alterations in Breast Cancer Subtypes

Squamous cell skin cancer (SCSC) disproportionately affects organ transplant recipients, and may be related to increased viral replication in the setting of immune suppression. We conducted a nested case–control study among transplant recipients to determine whether SCSC is associated with antibodies to cutaneous human papillomaviruses (HPV), to genes associated with a rare genetic susceptibility to HPV (TMC6/TMC8), or to human polyomaviruses (HPyV). Cases (n = 149) had histologically confirmed SCSC, and controls (n = 290) were individually matched to cases on time since transplant, type of transplant, gender, and race. All subjects had serum drawn immediately prior to transplant surgery. Antibodies to 25 cutaneous HPVs and six HPyVs were assayed by detection of binding to virus-like particles, and 11 TMC6/8 variants were genotyped. After correction for multiple comparisons, only antibodies to HPV37 were associated with SCSC (OR 2.0, 95% CI 1.2–3.4). Common genetic variants of TMC6/8 were not associated with SCSC, but three variants in TMC8 (rs12452890, rs412611, and rs7208422) were associated with greater seropositivity for species 2 betapapillomaviruses among controls. This study suggests that some betaHPVs, but not polyomaviruses, may play a role in the excess risk of SCSC among transplant recipients.

Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL-12/IL-10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case–parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3’ UTR SNP (OR=1.76, 95% CI=1.15–2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26–0.82; rs2229546, OR=0.43, 95% CI=0.21–0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26–3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12–2.05). Finally, the minor allele of the IL12B rs3181224 3’ UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12–0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.

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.

Background: Inherited predisposition may be associated with distinctive breast cancer phenotypes and/or mortality. Past studies have had inconsistent results and little is known about the contributions of screening and treatment. Methods: Within a population-based cohort of 1,260 women diagnosed with invasive breast cancer before age 46, we assessed how family history of breast cancer relates to mortality and tumor characteristics. Analyses were repeated excluding BRCA1/BRCA2 carriers. Medical records were reviewed for treatment history and tumors were centrally reviewed and tested. Cox proportional hazard modeling was used to assess the risk of dying in relation to family history; logistic regression was used to assess the association of family history to tumor characteristics. Results: Compared with women with no family history, women with first-degree family history of breast cancer had a 40% reduction (95% CI: 0.5–0.8) in the risk of dying. Mortality in women with only a second-degree family history was similar to those with no family history. The risk of dying was further reduced in those with a greater number of affected relatives. These relationships did not seem to be attributable to differences in screening, detection method, or treatment. Tumors in women with a first-degree family history had generally more favorable prognostic profiles. Conclusion: Our findings suggest that breast cancer patients with a first-degree family history, compared with their counterparts without such a profile, may have a better prognosis. Impact: These findings support the need for future research directed at replicating these results and identifying factors underlying this possible relationship. Cancer Epidemiol Biomarkers Prev; 20(12); 2560–71. ©2011 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

Background: The frequency of migraine headache changes at various times of a woman's reproductive cycle. Menarche, menses, pregnancy, and perimenopause may carry a different migraine risk conceivably because of fluctuating estrogen levels, and in general, migraine frequency is associated with falling estrogen levels. Given the strong relationship between endogenous estrogen levels and breast cancer risk, migraine sufferers may experience a reduced risk of breast cancer.Methods: We combined data from two population-based case-control studies to examine the relationship between migraine and risk of postmenopausal invasive breast cancer among 1,199 ductal carcinoma cases, 739 lobular carcinoma cases, and 1,474 controls 55 to 79 years of age. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI).Results: Women who reported a clinical diagnosis of migraine had reduced risks of ductal carcinoma (OR, 0.67; 95% CI, 0.54-0.82) and lobular carcinoma (OR, 0.68; 95% CI, 0.52-0.90). These associations were primarily limited to hormone receptor–positive tumors as migraine was associated with a 0.65-fold (95% CI, 0.51-0.83) reduced risk of estrogen receptor–positive (ER+)/progesterone receptor–positive (PR+) ductal carcinoma. The reductions in risk observed were seen among migraine sufferers who did and did not use prescription medications for their migraines.Conclusions: These data suggest that a history of migraine is associated with a decreased risk of breast cancer, particularly among ER+/PR+ ductal and lobular carcinomas. Because this is the first study to address an association between migraine history and breast cancer risk, additional studies are needed to confirm this finding. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3116–22)

Molecular profiling studies have identified subtypes of breast cancer that can be approximately classified by estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER-2) expression. These molecular subtypes are prognostically significant, but to the authors' knowledge, differences in their etiologic profiles have not been established. Reproductive factors may plausibly be differentially correlated with the risk of different breast cancer subtypes because these factors are presumed to impact exposure to endogenous sex hormones.The authors pooled 2 population-based, case-control studies of breast cancer in women ages 55 to 79 years for an analysis including 1476 controls and 1023 cases of luminal breast cancer, 39 cases of HER-2-overexpressing breast cancer, and 78 cases of triple-negative breast cancer. Polytomous logistic regression was used to compare each case group with controls.Associations varied by molecular subtype. Early age at menarche was only found to be associated with risk of HER-2-overexpressing disease (odds ratio [OR] of 2.7; 95% confidence interval [95% CI], 1.4-5.5), whereas breastfeeding foror =6 months was only found to be protective for luminal and triple-negative disease (OR of 0.8 [95% CI, 0.6-1.0] and OR of 0.5 [95% CI, 0.3-0.9], respectively). Both late age at menopause and the use of estrogen plus progestin hormone therapy were only found to be associated with risk of luminal disease (OR of 1.6 [95% CI, 1.1-2.2] and OR of 1.7 [95% CI, 1.3-2.1], respectively). No differences in risks associated with parity or age at first live birth were observed by subtype.Certain reproductive factors may have a greater impact on the risk of certain molecular subtypes of disease compared with others. Future studies that further define the etiology of breast cancer subtypes will add to the biologic understanding of this disease.

Although the clinical relevance of molecular subtypes of breast cancer has been documented, little is known about risk factors for different tumor subtypes, especially the HER2-overexpressing and the triple-negative subtypes that have poor prognoses. Obesity may be differentially related to the risk of different subtypes given the various potential mechanisms underlying its association with breast cancer. We pooled two population-based case-control studies of postmenopausal breast cancer for an analysis, including 1,447 controls and 1,008 luminal (hormone receptor positive), 39 HER2-overexpressing (hormone receptor negative, HER2 positive), and 77 triple-negative (hormone receptor and HER2 negative) cases. Associations between anthropometric factors and the risk of different breast cancer subtypes were evaluated using polytomous logistic regression. Among women not currently using menopausal hormone therapy, body mass index (BMI) and weight were associated with the risk of luminal tumors [odds ratio (OR) comparing highest versus lowest quartiles, 1.7; 95% confidence interval (95% CI), 1.2-2.4 and OR, 1.7; 95% CI, 1.2-2.4, respectively] and suggestively associated with risk of triple-negative tumors (OR, 2.7; 95% CI, 1.0-7.5 and OR, 5.1; 95% CI, 1.1-23.0, respectively). Neither BMI nor weight was associated with the risk of any tumor subtype among hormone therapy users. The positive relationship between BMI and luminal tumors among postmenopausal women not using hormone therapy is well characterized in the literature. Although our sample size was limited, body size may also be related to the risk of postmenopausal triple-negative breast cancer among nonusers of hormone therapy. Given the expanding obesity epidemic, the widespread cessation of hormone therapy use, and the poor prognosis of triple-negative tumors, this novel finding merits confirmation. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2078–86)

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)

Variation in human major histocompatibility genes may influence the risk of squamous cell cervical cancer (SCC) by altering the efficiency of the T-cell–mediated immune response to human papillomavirus (HPV) antigens. We used high-resolution methods to genotype human leukocyte antigen (HLA) class I (A, B, and Cw) and class II (DRB1 and DQB1) loci in 544 women with SCC and 542 controls. Recognizing that HLA molecules are codominantly expressed, we focused on co-occurring alleles. Among 137 allele combinations present at >5% in the case or control groups, 36 were significantly associated with SCC risk. All but one of the 30 combinations that increased risk included DQB1*0301, and 23 included subsets of A*0201-B*4402-Cw*0501-DRB1*0401-DQB1*0301. Another combination, B*4402-DRB1*1101-DQB1*0301, conferred a strong risk of SCC (odds ratio, 10.0; 95% confidence interval, 3.0–33.3). Among the six combinations that conferred a decreased risk of SCC, four included Cw*0701 or DQB1*02. Most multilocus results were similar for SCC that contained HPV16; a notable exception was A*0101-B*0801-Cw*0701-DRB1*0301-DQB1*0201 and its subsets, which were associated with HPV16-positive SCC (odds ratio, 0.5; 95% confidence interval, 0.3–0.9). The main multilocus associations were replicated in studies of cervical adenocarcinoma and vulvar cancer. These data confirm that T helper and cytotoxic T-cell responses are both important cofactors with HPV in cervical cancer etiology and indicate that co-occurring HLA alleles across loci seem to be more important than individual alleles. Thus, certain co-occurring alleles may be markers of disease risk that have clinical value as biomarkers for targeted screening or development of new therapies. [Cancer Res 2008;68(9):3532–9]

Background: Histamine2-receptor antagonist (H2 blocker) medications are used to treat heartburn, gastroesophageal reflux disease, and ulcers. Some H2 blockers, specifically cimetidine and ranitidine, also increase serum prolactin concentrations. Given the positive relationship between prolactin levels and postmenopausal breast cancer risk, use of H2 blockers is a potential breast cancer risk factor. The few previous studies evaluating this association have been null but have been limited by small sample sizes, and none have evaluated risk by either histologic type or estrogen receptor/progesterone receptor status. Methods: Combining data from two population-based case-control studies conducted in western Washington, we assessed the relationship between use of H2 blockers and risk of different types of breast cancer among 1,941 cases and 1,476 controls 55 to 79 years old. Odds ratios and 95% confidence intervals (95% CI) were calculated using polytomous logistic regression. Results: Current use of H2 blockers overall, cimetidine, and famotidine was not associated with an increased risk of either invasive ductal or invasive lobular breast cancer. Current users of ranitidine had a 2.2-fold (95% CI, 1.1-4.3) increased risk of ductal carcinoma that was confined to a 2.4-fold (95% CI, 1.2-4.9) increased risk of estrogen receptor–positive/progesterone receptor–positive ductal carcinoma. Conclusions: Use of H2 blockers in general is not associated with an increased risk of breast cancer, although current use of ranitidine may increase risk of hormone receptor–positive ductal carcinoma. Further studies to confirm this finding are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(1):67–72)

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)

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.

Objectives: To explore associated biological outcomes and clarify the role of timing of exposure in the alcohol-breast cancer relationship. Methods: In a population-based study of 4,575 women ages 35 to 64 years diagnosed with invasive breast cancer between 1994 and 1998 and 4,682 controls, we collected details of lifetime alcohol use and factors that could confound or modify the alcohol-breast cancer relationship. We used conditional logistic regression to compute the odds of breast cancer among drinkers relative to nondrinkers at all ages and at ages 35 to 49 and 50 to 64 years separately. Results: Recent consumption (at reference age minus two) of ≥7 drinks per week was associated with increased risk [odds ratio (OR), 1.2; 95% CI, 1.01-1.3] and evidence of dose response was observed. Most of the excess was observed among women ages 50-64 years (OR 1.3; 95% CI, 1.1-1.6), although the test for age interaction was not statistically significant. Exposure later in life seemed more important than early exposure. Excess breast cancer associated with recent consumption was restricted to localized disease. When outcome was examined according to tumor hormone receptor status, highest risks were observed for estrogen receptor–positive/progesterone receptor–negative tumors (OR 1.6; 95% CI, 1.2-2.3). Conclusions: The effect of timing of alcohol exposure on breast cancer risk is complicated and will require additional study focused on this one issue. Further work is needed to explain how alcohol exposure, sex hormones, and tumor receptor status interact.

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.

A validation study evaluated the accuracy of self-reported use of commonly used medications among older women. Within a case-control study of breast cancer, drug information was ascertained by interview. Pharmacy records from 1990 to 1999 were obtained from a Washington State health maintenance organization (66% of subjects) and retail pharmacies (34% of subjects) on a sample of subjects (212 cases, 191 controls) and used as the "gold standard." Recall accuracy was assessed for 6-month, 2-year, and 8-year time windows. Sensitivity of antihypertensive use was 92% (95% confidence interval (CI): 85, 96) for cases and controls in the 6-month period and slightly lower for the 2-year (90% (95% CI: 82, 94) and 87% (95% CI: 78, 92)) and 8-year (80% (95% CI: 69, 88) and 79% (95% CI: 68, 88)) periods. For statins, sensitivity was 83% (95% CI: 64, 93) for cases and 93% (95% CI: 69, 99) for controls in the 6-month period, 75% (95% CI: 55, 88) and 86% (95% CI: 60, 96) in the 2-year period, and 67% (95% CI: 42, 85) and 75% (95% CI: 41, 93) in the 8-year period. For self-report of antidepressants, sensitivities ranged from 66% (95% CI: 47, 80) in the 6-month period to 44% (95% CI: 30, 60) in the 8-year period. Specificity was high among all drug classes, ranging from 91% to 100%. Recall did not differ by case-control status. Trivial changes in estimates were observed when health maintenance organization records alone were used as the gold standard. Self-reported use of antihypertensives and statins appears to be relatively accurate among older women.

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. The incidence of anal cancer has increased among both men (160%) and women (78%) from 1973 to 2000 in the U.S. The authors conducted a population-based case– control study of anal cancer to examine factors that may account for this increase. METHODS. Men (n 119 patients) and women (n 187 patients) who were diagnosed with anal cancer between 1986 and 1998 in the Seattle area were ascertained through the local Surveillance, Epidemiology, and End Results registry. Control participants (n 1700) were ascertained through random-digit telephone dialing. Participants were interviewed in person and provided blood samples. Archival tumor tissue was tested for human papilloma virus (HPV) DNA, and serum samples were tested for HPV type 16 (HPV-16). RESULTS. Overall, 88% of tumors (all histologies) in the study were found to be positive for HPV. HPV-16 was the most frequent HPV type detected (73% of all tumors), followed by HPV-18 (6.9%), regardless of gender. However, 97.7% of tumors from men who were not exclusively heterosexual contained HPV DNA. The risk of anal cancer increased among men (odds ratio [OR], 5.3; 95% confidence interval [95% CI], 2.4 –12.0) and women (OR, 11.0; 95% CI, 5.5–22.1) who had 15 sexual partners during their lifetime. Among men who were not exclusively heterosexual and women, receptive anal intercourse was related strongly to the risk of anal cancer (OR, 6.8 [95% CI, 1.4 –33.8] and OR, 2.2 [95% CI, 1.4 –3.3], respectively). Current smokers among men and women were at particularly high risk for anal cancer, independent of age and other risk factors (OR, 3.9 [95% CI, 1.9 – 8.0] and OR, 3.8 [95% CI, 2.4 – 6.2], respectively). CONCLUSIONS. The high proportion of tumors with detectable HPV suggests that infection with HPV is a necessary cause of anal cancer, similar to that of cervical cancer. Increases in the prevalence of exposures, such as cigarette smoking, anal intercourse, HPV infection, and the number of lifetime sexual partners, may account for the increasing incidence of anal cancer in men and women. Cancer 2004;101:270 – 80. © 2004 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.

Use of combined estrogen-progestin hormone replacement therapy appears to be associated with an increased risk of invasive lobular breast carcinomas (ILC) and, to a lesser degree, with risk of invasive ductal carcinoma (IDC). Conceivably, ILCs are more hormonally responsive and so may be more strongly associated than IDCs with reproductive and anthropometric characteristics that can influence hormone levels. However, few epidemiologic studies of breast cancer have evaluated these factors by histologic type. We conducted a population-based case-control study of women aged 65–79 years in western Washington State. Responses from 975 women diagnosed with breast cancer during 1997–1999 were compared to those of 1,007 controls. Associations between various reproductive and anthropometric factors and risks of IDC (n = 656) and ILC (n = 196) were evaluated using polytomous logistic regression. Earlier age at menarche, later age at menopause and obesity were more strongly associated with elevated risks of IDC than ILC. Alternatively, oral contraceptive use was associated with an increased risk of ILC but not IDC. Thus, the pattern of results that we observed suggest that factors influencing endogenous hormones and duration of ovarian function may be more strongly associated with IDC risk, while exogenous hormones may be more strongly associated with ILC risk. © 2003 Wiley-Liss, Inc.

BACKGROUND Limited data are available regarding the incidence of breast carcinoma among users of relatively recently introduced forms of antihypertensive therapy. Although it has been suggested that women who have taken calcium channel blockers (CCBs) have an increased risk and that women who have taken angiotensin-I-converting enzyme (ACE) inhibitors have a decreased risk, currently, no conclusions can be drawn. METHODS A population-based case–control study of women ages 65–79 years was conducted in western Washington State. The responses of 975 women who were diagnosed with invasive breast carcinoma during 1997–1999 were compared with the responses of 1007 women in a control group. Associations between use of different types of antihypertensive medications and breast carcinoma incidence were evaluated using logistic regression. RESULTS Overall, women who had ever used CCBs, β-blockers, or ACE inhibitors did not have an altered risk of breast carcinoma relative to women who had never used antihypertensive medications. Although the use of immediate-release CCBs, thiazide diuretics, and potassium-sparing diuretics was associated with modestly increased risks of breast carcinoma (odds ratio [OR], 1.5; 95% confidence interval [95% CI], 1.0–2.1; OR, 1.4; 95% CI, 1.1–1.8; and OR, 1.6; 95% CI, 1.2–2.1, respectively), the absence of any trend in the size of excess risk with increasing duration or with current versus former use of these agents argues for a cautious interpretation. CONCLUSIONS The use of particular types of antihypertensive medications, including immediate-release CCBs and certain diuretics, may increase the risk of breast carcinoma among older women. Additional studies are warranted to clarify these potential associations. Cancer 2003;98:1504–13. © 2003 American Cancer Society. DOI 10.1002/cncr.11663

Objective: To investigate the relationship between allergy and risk of breast cancer in women 45 years of age and younger. Methods: Data were analyzed from a population-based case–control study of breast cancer in western Washington. Cases were women born after 1944 who were diagnosed with invasive breast cancer (n = 747) between January 1983 and April 1990. Controls (n = 958) were similarly aged women ascertained through random-digit dialing. Cases and controls were interviewed about their history of doctor diagnosed allergies, including detailed information on the specific types of allergies and the age of onset. Using logistic regression we examined the associations between allergy history and breast cancer. Results: A history of allergies was associated with a reduced risk of breast cancer for women older than 35 (odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.60–0.99), but not for women 35 years or younger (OR = 1.30; 95% CI = 0.94–1.81). There was little difference in effect when age of first allergy onset was examined. No specific type of allergy was associated with breast cancer risk. Conclusion: Our results provide some evidence that a history of allergy may be associated with a reduced risk of breast cancer for women who develop breast cancer between 35 and 45 years of age. Future studies are needed to verify the relationship between immune responses and breast cancer risk.

Objective: Postmenopausal hormone use and risk of breast cancer by histopathology was examined in a large multi-centered population-based case–control study. Methods: Women younger than 75 years newly diagnosed with invasive breast cancer between 1988 and 1991 were identified from statewide tumour registries in Wisconsin, Massachusetts, New Hampshire, and Maine. Only postmenopausal women were included in this analysis. Breast cancer cases (lobular (n = 219), ductal, NOS (n = 2172), and specific ductal subtypes (n = 242)) were compared with randomly selected population controls (n = 3179) using adjusted multi-variable polytomous logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for each histology. Results: Lobular carcinoma was associated with recent (within 2 years) estrogen therapy (OR:1.8, 95%CI: 1.0–3.4) and recent use of combined estrogen-plus-progestin therapy (OR:3.6, 95%CI: 1.8–7.6). Risk of ductal carcinoma was not associated with recent use of either estrogen alone (OR: 0.9, 95%CI: 0.7–1.2) or combined therapy (OR:0.9, 95%CI: 0.6–1.3). No associations were found with ductal subtypes. Conclusions: The association between postmenopausal hormone use and risk of breast cancer may depend on histopathology. Of particular interest is the association between combined hormone therapy and increased risk of lobular carcinoma. This lesion is increasingly common but, nonetheless, comprises fewer than 10% of invasive breast cancers.

Objective: To assess risk factors for breast cancer among very young compared to older premenopausal women. Methods: Between 1990 and 1992 a population-based case–control study conducted in Atlanta, GA, Seattle/Puget Sound, WA, and central NJ interviewed 3307 premenopausal women aged 20–54 years. Logistic regression models estimated adjusted relative risks (RR) and 95% confidence intervals (CI) for each of three 10-year age groups. Results: Among the youngest age group (

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)

Objective: To examine the relation between breast cancer risk and job history among women 20–44 years of age who participated in a multi-center, population-based, case–control study. Methods: Participants consisted of women newly diagnosed with breast cancer (1642) and controls identified by random-digit dialing (1494). Details about the three longest jobs were collected and coded by an industrial hygienist. Odds ratios and 95% confidence intervals were calculated and adjusted for age, study site, and other breast cancer risk factors. Results: Several occupational and industrial categories were found to influence breast cancer risk. Stratification of the study population by parity revealed differences in breast cancer risk between the two groups for several occupational categories, including teachers, librarians or counselors (increased risk only among parous women) and natural scientists and mathematicians (decreased risk only among nulliparous women). Conclusions: This is among the first population-based case–control studies to examine occupational history and breast cancer risk in young women, with the ability to consider a wide array of potential confounders, including reproductive characteristics. This study provides further evidence of an increased breast cancer risk for several occupations and industries. Other findings were not as strongly supported by previous investigations.

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.

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

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.

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

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.

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.