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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.

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 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)

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

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

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.

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.

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

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

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

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

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

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

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.

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.

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.

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 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 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.

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]

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.

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: 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.

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.