Anatomic, Geographic, and Taxon-Specific Relative Risks of Carbapenem Resistance in the Health Care System of the U.S. Department of Defense.

Carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter spp., and Enterobacteriaceae pose urgent public health threats. The differential burden, relative risks, associations with antimicrobial consumption, and temporal trends of those taxa in large, geographically diverse U.S. health systems remain under reported. Electronic records of all patients in a geographically dispersed 280-hospital managed-care system from 2005 to 2014 were reviewed. Carbapenem-resistant strains were identified based on Clinical and Laboratory Standards Institute guidelines and breakpoints. A total of 360,000 potentially carbapenem-resistant strains were identified from 14.7 million cultures (80% infecting and 20% surveillance). Isolation of bacteria overseas or isolation from the bloodstream was associated with a higher relative risks of carbapenem resistance (CR; P < 0.0001). Enterobacteriaceae were isolated 11 times more frequently than P. aeruginosa and Acinetobacter spp. However, compared to Enterobacteriaceae, the CR levels were 73-fold and 210-fold higher in P. aeruginosa and Acinetobacter spp., respectively. Significant differences in the relative risk of CR between taxa, anatomic, and geographic locations persisted after adjustment for other variables, the biggest differences occurring between taxa. Overall, CR rates increased for Enterobacteriaceae (P = 0.03) and decreased for Acinetobacter spp. and P. aeruginosa (P < 0.0001). These data provide a useful baseline for resistance trending and have implications for surveillance. Infections acquired overseas and bloodstream infections are particularly important areas for continued monitoring.

Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan.

Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.

Incarceration predicts virologic failure for HIV-infected injection drug users receiving antiretroviral therapy.

BACKGROUND: Incarceration may lead to interruptions in antiretroviral therapy (ART) for persons receiving treatment for human immunodeficiency virus (HIV) infection. We assessed whether incarceration and subsequent release were associated with virologic failure for injection drug users (IDUs) who were previously successfully treated with ART. METHODS: ALIVE is a prospective, community-based cohort study of IDUs in Baltimore, Maryland. IDUs receiving ART during 1998-2009 who successfully achieved an HIV RNA level below the limit of detection (<400 copies/mL) were followed up for development of virologic failure at the subsequent semiannual study visit. Logistic regression with generalized estimating equations was used to assess whether incarceration was independently associated with virologic failure. RESULTS: Of 437 HIV-infected IDUs who achieved undetectable HIV RNA for at least one study visit, 69% were male, 95% were African-American, and 40% reported at least one incarceration during follow-up. Virologic failure occurred at 26.3% of visits after a median of 6 months since achieving undetectable HIV RNA. In multivariate analysis accounting for demographic characteristics, drug use, and HIV disease stage, brief incarceration was strongly associated with virologic failure (adjusted odds ratio, 7.7; 95% confidence interval, 3.0-19.7), although incarceration lasting >30 days was not (odds ratio, 1.4; 95% confidence interval, .8-2.6). CONCLUSIONS: Among IDUs achieving viral suppression while receiving ART, virologic failure occurred with high frequency and was strongly associated with brief incarceration. Efforts should be made to ensure continuity of care both during and after incarceration to improve treatment outcomes and prevent viral resistance in this vulnerable population.

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

Reproductive factors, exogenous hormone use and risk of lymphoid neoplasms among women in the National Institutes of Health-AARP Diet and Health Study Cohort.

Reasons for higher incidence of lymphoid neoplasms among men than women are unknown. Because female sex hormones have immunomodulatory effects, reproductive factors and exogenous hormone use may affect risk for lymphoid malignancies. Previous epidemiologic studies on this topic have yielded conflicting results. Within the National Institutes of Health-AARP Diet and Health Study cohort, we prospectively analyzed detailed, questionnaire-derived information on menstrual and reproductive factors and use of oral contraceptives and menopausal hormone therapy among 134,074 US women. Using multivariable proportional hazards regression models, we estimated relative risks (RRs) for 85 plasma cell neoplasms and 417 non-Hodgkin lymphomas (NHLs) identified during follow-up from 1996 to 2002. We observed no statistically significant associations between plasma cell neoplasms, NHL, or the 3 most common NHL subtypes and age at menarche, parity, age at first birth, oral contraceptive use or menopausal status at baseline. For menopausal hormone therapy use, overall associations between NHL and unopposed estrogen and estrogen plus progestin were null, with the potential exception of an inverse association (RR = 0.49, 95% CI, 0.25-0.96) between use of unopposed estrogen and diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype, among women with a hysterectomy. These data do not support an important role for reproductive factors or exogenous hormones in modulating lymphomagenesis.

Nonsteroidal anti-inflammatory drugs and breast cancer risk in the National Institutes of Health-AARP Diet and Health Study.

INTRODUCTION: By inhibiting cyclooxygenase-2, nonsteroidal anti-inflammatory drugs (NSAIDs) decrease aromatase activity and might reduce breast cancer risk by suppressing estrogen synthesis. Epidemiologic evidence for a protective role of NSAIDs in breast cancer, however, is equivocal. METHODS: We tested NSAID use for its association with breast cancer incidence in the National Institutes of Health-AARP Diet and Health Study, where 127,383 female AARP (formerly known as the American Association of Retired Persons) members with no history of cancer, aged 51 to 72 years, completed a mailed questionnaire (1996 to 1997). We estimated relative risks of breast cancer for NSAID exposures using multivariate Cox proportional hazards regression models. The state cancer registry and mortality index linkage identified 4,501 primary incident breast cancers through 31 December 2003, including 1,439 estrogen receptor (ER)-positive cancers and 280 ER-negative cancers. RESULTS: Proportional hazards models revealed no statistically significant association between overall NSAIDs and total breast cancer. As cyclooxygenase inhibition by aspirin (but not other NSAIDs) is irreversible, we tested associations by NSAID type. Although we observed no significant differences in risk for daily use (versus nonuse) of aspirin (relative risk = 0.93, 95% confidence interval = 0.85 to 1.01) or nonaspirin NSAIDS (relative risk = 0.96, 95% confidence interval = 0.87 to 1.05), risk of ER-positive breast cancer was significantly reduced with daily aspirin use (relative risk = 0.84, 95% confidence interval = 0.71 to 0.98)--a relationship not observed for nonaspirin NSAIDS. Neither aspirin nor nonaspirin NSAIDs were associated with risk of ER-negative breast cancer. CONCLUSION: Breast cancer risk was not significantly associated with NSAID use, but daily aspirin use was associated with a modest reduction in ER-positive breast cancer. Our results provide support for further evaluating relationships by NSAID type and breast cancer subtype.

Menopausal hormone therapy and breast cancer risk in the NIH-AARP Diet and Health Study Cohort.

BACKGROUND: Results from the Women's Health Initiative trial raise new questions regarding the effects of estrogen therapy (ET) and estrogen plus progestin therapy (EPT) on breast cancer risk. METHODS: We analyzed data from 126,638 females, ages 50 to 71 years at baseline, who completed two questionnaires (1995--1996 and 1996--1997) as part of the NIH-AARP Diet and Health Cohort Study and in whom 3,657 incident breast cancers were identified through June 30, 2002. Hormone-associated relative risks (RR) and 95% confidence intervals (CI) of breast cancer were estimated via multivariable regression models. RESULTS: Among thin women (body mass index < 25 kg/m2), ET use was associated with a significant 60% excess risk after 10 years of use. EPT was associated with a significantly increased risk among women with intact uteri, with the highest risk among current, long-term (> or = 10 years) users (RR, 2.44; 95% CI, 2.13-2.79). These risks were slightly higher when progestins were prescribed continuously than sequentially (< 15 days/mo; respective RRs of 2.76 versus 2.01). EPT associations were strongest in thin women, but elevated risks persisted among heavy women. EPT use was strongly related to estrogen receptor (ER)-positive tumors, requiring consideration of this variable when assessing relationships according to other clinical features. For instance, ER- ductal tumors were unaffected by EPT use, but all histologic subgroups of ER+ tumors were increased, especially low-grade and mixed ductal-lobular tumors. CONCLUSIONS: Both ET and EPT were associated with breast cancer risks with the magnitude of increase varying according to body mass and clinical characteristics of the tumors.

Reproducibility of biopsy diagnoses of endometrial hyperplasia: evidence supporting a simplified classification.

BACKGROUND: Identifying which categories in the World Health Organization classification of endometrial hyperplasia contribute to suboptimal reproducibility is clinically important. METHODS: A 2-member panel reviewed 209 endometrial biopsy/curettage specimens originally diagnosed as incident endometrial hyperplasia as part of a progression study. Original diagnoses included the following: disordered proliferative endometrium, simple hyperplasia, complex hyperplasia, and atypical hyperplasia; panel diagnoses also included negative and carcinoma. We assessed percentage agreement and kappa statistics+/-standard errors (K+/-SE). RESULTS: Original and panel diagnoses (combining negative with disordered proliferative endometrium; atypical hyperplasia with carcinoma) agreed for 34.9% of biopsies (K-unweighted+/-SE=0.18+/-0.03; K-weighted+/-SE=0.27+/-0.04). Panelists' diagnoses agreed (using 6 categories) for 51.7% of biopsies, corresponding to K-unweighted+/-SE=0.37+/-0.03, improving with weighting to K-weighted+/-SE=0.63+/-0.05. Reproducibility based on a 2-tier classification ([negative, disordered proliferative endometrium, simple hyperplasia, or complex hyperplasia] versus [atypical hyperplasia or carcinoma]) increased agreement between original and panel diagnoses to 82.8%, K-unweighted+/-SE=0.37+/-0.06, and between panelists to 87.0%, K-unweighted+/-SE=0.63+/-0.07. Agreement between panelists at a cutpoint of complex hyperplasia and more severe versus simple hyperplasia or less severe was 88.0%, K-unweighted+/-SE=0.72+/-0.07. CONCLUSIONS: Developing and prospectively testing a binary system of classifying endometrial hyperplasia on endometrial biopsy may aid efforts to improve interobserver reproducibility.

Semi-Automated Visualization and ANalysis of Trends: A "SAVANT" for Facilitating Antimicrobial Stewardship Using Antistaphylococcal Resistance and Consumption as a Prototype.

BACKGROUND: Governments and health care regulators now require hospitals and nursing homes to establish programs to monitor and report antimicrobial consumption and resistance. However, additional resources were not provided. We sought to develop an approach for monitoring antimicrobial resistance and consumption that health care systems can implement with minimal added costs or modifications to existing diagnostic and informatics infrastructure. METHODS: Using (1) the electronic laboratory information system of a nationwide managed care network, (2) the 3 most widely used commercial microbiology diagnostic platforms, and (3) Staphylococcus aureus, one of the most common causes of infections worldwide, as a prototype, we validated the approach dubbed "SAVANT" for Semi-Automated Visualization and ANalysis of Trends. SAVANT leverages 3 analytical methods (time series analysis, the autoregressive integrated moving average, and generalized linear regression) on either commercial or open source software to report trends in antistaphylococcal use and resistance. RESULTS: All laboratory results from January 2010 through December 2015 from an annual average of 9.2 million health care beneficiaries were queried. Inpatient and outpatient prescription rates were calculated for 8 key antistaphylococcal compounds. Trends and relationships of antistaphylococcal consumption and resistance among 81 840 unique S. aureus isolates from >6.5 million cultures were revealed. CONCLUSIONS: Using existing or freely available resources, SAVANT was successfully implemented across a complex and geographically dispersed 280-hospital network, bridging a critical gap between medical informatics, large-scale data analytics, and mandatory reporting of health care quality metrics.

Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study.

BACKGROUND: The sex hormone-binding globulin (SHBG) is a carrier protein that modulates the bio-availability of serum sex steroid hormones, which may be involved in ovarian cancer. We evaluated whether common genetic variation in SHBG and its 3' neighbor ATP1B2, in linkage disequilibrium, is associated with the risk of epithelial ovarian cancer. METHODS: The study population included 264 women with ovarian carcinoma and 625 controls participating in a population-based case-control study in Poland. Five common single nucleotide polymorphisms (SNPs) in SHGB and five in ATP1B2 were selected to capture most common variation in this region. RESULTS: None of the SNPs evaluated was significantly associated with ovarian cancer risk, including the putative functional SNPs SHBG D356N (rs6259) and -67G>A 5'UTR (rs1799941). However, our data were consistent with a decreased ovarian cancer risk associated with the variant alleles for these two SNPs, which have been previously associated with increased circulating levels of SHBG. CONCLUSION: These data do not support a substantial association between common genetic variation in SHBG and ovarian cancer risk.

Correlating Cleaning Thoroughness with Effectiveness and Briefly Intervening to Affect Cleaning Outcomes: How Clean Is Cleaned?

OBJECTIVES: The most efficient approach to monitoring and improving cleaning outcomes remains unresolved. We sought to extend the findings of a previous study by determining whether cleaning thoroughness (dye removal) correlates with cleaning efficacy (absence of molecular or cultivable biomaterial) and whether one brief educational intervention improves cleaning outcomes. DESIGN: Before-after trial. SETTING: Newly built community hospital. INTERVENTION: 90 minute training refresher with surface-specific performance results. METHODS: Dye removal, measured by fluorescence, and biomaterial removal and acquisition, measured with culture and culture-independent PCR-based assays, were clandestinely assessed for eight consecutive months. At this midpoint, results were presented to the cleaning staff (intervention) and assessments continued for another eight consecutive months. RESULTS: 1273 surfaces were sampled before and after terminal room cleaning. In the short-term, dye removal increased from 40.3% to 50.0% (not significant). For the entire study period, dye removal also improved but not significantly. After the intervention, the number of rooms testing positive for specific pathogenic species by culturing decreased from 55.6% to 36.6% (not significant), and those testing positive by PCR fell from 80.6% to 53.7% (P = 0.016). For nonspecific biomaterial on surfaces: a) removal of cultivable Gram-negatives (GN) trended toward improvement (P = 0.056); b) removal of any cultivable growth was unchanged but acquisition (detection of biomaterial on post-cleaned surfaces that were contaminant-free before cleaning) worsened (P = 0.017); c) removal of PCR-based detection of bacterial DNA improved (P = 0.046), but acquisition worsened (P = 0.003); d) cleaning thoroughness and efficacy were not correlated. CONCLUSION: At this facility, a minor intervention or minimally more aggressive cleaning may reduce pathogen-specific contamination, but not without unintended consequences.

Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia.

PURPOSE The severity of endometrial hyperplasia (EH)-simple (SH), complex (CH), or atypical (AH)-influences clinical management, but valid estimates of absolute risk of clinical progression to carcinoma are lacking. Materials and METHODS We conducted a case-control study nested in a cohort of 7,947 women diagnosed with EH (1970-2002) at one prepaid health plan who remained at risk for at least 1 year. Patient cases (N = 138) were diagnosed with carcinoma, on average, 6 years later (range, 1 to 24 years). Patient controls (N = 241) were matched to patient cases on age at EH, date of EH, and duration of follow-up, and they were counter-matched to patient cases on EH severity. After we independently reviewed original slides and medical records of patient controls and patient cases, we combined progression relative risks (AH v SH, CH, or disordered proliferative endometrium [ie, equivocal EH]) from the case-control analysis with clinical censoring information (ie, hysterectomy, death, or left the health plan) on all cohort members to estimate interval-specific (ie, 1 to 4, 5 to 9, and 10 to 19 years) and cumulative (ie, through 4, 9, and 19 years) progression risks. Results For nonatypical EH, cumulative progression risk increased from 1.2% (95% CI, 0.6% to 1.9%) through 4 years to 1.9% (95% CI, 1.2% to 2.6%) through 9 years to 4.6% (95% CI, 3.3% to 5.8%) through 19 years after EH diagnosis. For AH, cumulative risk increased from 8.2% (95% CI, 1.3% to 14.6%) through 4 years to 12.4% (95% CI, 3.0% to 20.8%) through 9 years to 27.5% (95% CI, 8.6% to 42.5%) through 19 years after AH. CONCLUSION Cumulative 20-year progression risk among women who remain at risk for at least 1 year is less than 5% for nonatypical EH but is 28% for AH.

Prospective evaluation of risk factors for male breast cancer.

Most risk factors for male breast cancer have been derived from retrospective studies that may reflect selective recall. In the prospective National Institutes of Health-AARP Diet and Health Study, we studied 324 920 men, among whom 121 developed breast cancer. Men who reported a first-degree relative with breast cancer had an increased risk of breast cancer (relative risk [RR] = 1.92, 95% confidence interval [CI] = 1.19 to 3.09). Among the medical conditions examined, a new finding emerged regarding increased male breast cancer risk associated with a history of a bone fracture (RR = 2.20, 95% CI = 1.24 to 3.91). Obesity was positively related to risk (RR = 1.79, 95% CI = 1.10 to 2.91, for body mass indices of >or=30 vs <25 kg/m2) and physical activity inversely related, even after adjustment for body mass index. Smokers were at somewhat elevated risk, although trends with smoking characteristics were inconsistent. Alcohol consumption was not related to risk. The identified risk factors show some commonalities with female breast cancer and indicate the importance of hormonal mechanisms. Differences in risk factors may reflect unique mechanisms associated with androgens and their ratio to bioavailable estrogens.

PTEN expression in endometrial biopsies as a marker of progression to endometrial carcinoma.

Inactivation of PTEN tumor suppressor gene is common in endometrial carcinoma and its precursor, atypical endometrial hyperplasia (EH). We compared PTEN expression via immunohistochemistry in endometrial biopsies diagnosed as EH in 138 cases, who were diagnosed with EH and then endometrial carcinoma at least 1 year later (median, 6 years), and 241 individually matched controls, who were diagnosed with EH but did not progress to carcinoma during equivalent follow-up. We assessed PTEN status (normal versus null) in index biopsies containing EH to estimate the relative risk (RR) of developing endometrial carcinoma up to 25 years later. Analysis of 115 cases and 193 controls with satisfactory assays revealed PTEN-null glands in index biopsies of 44% of cases and 49% of controls [P = 0.85; RR, 1.51; 95% confidence interval (CI), 0.73-3.13]. For predicting progression to carcinoma, PTEN-null status had low sensitivity (44%; 95% CI, 45-54%) and specificity (51%; 95% CI, 44-58%). Among 105 cases with PTEN results for both index biopsy and carcinoma, 16% had a PTEN-null index biopsy, 23% had PTEN-null carcinoma, and 26% had both a PTEN-null index biopsy and carcinoma. Loss of PTEN expression in endometrial biopsies was neither associated with nor a sensitive and specific marker of subsequent progression to endometrial carcinoma.

Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies.

BACKGROUND: Histopathologic diagnosis of endometrial biopsies is used to estimate the risk of progression to carcinoma and guide clinical management. Problems with the widely used World Health Organization (WHO) system for classifying endometrial hyperplasia (EH) have prompted the development of an alternative system based on endometrial intraepithelial neoplasia (EIN). The authors estimated progression risk associated with EIN among endometrial biopsies in a nested case-control study of EH progression. METHODS: Index biopsies with original community pathology diagnoses of disordered proliferative endometrium (DPEM) or EH that were independently confirmed by a panel of pathologists were independently reviewed and assigned EIN classifications (inadequate, benign, EIN, or cancer) by a second panel of pathologists. Cases (N = 138) progressed to carcinoma at least 1 year (median, 6 years) after their index biopsy. Controls (N = 241) also had EH, did not progress to carcinoma, and were individually matched to cases based on age at EH, date of EH, and length of follow-up. By using conditional logistic regression, the authors estimated relative risks (RRs) with 95% confidence intervals (95% CIs) for progression to carcinoma for EIN versus benign. RESULTS: In the EIN system, 71 (52.6%) cases and 159 (66.8%) controls were classified as benign and 42 (31.1%) cases and 65 (27.3%) controls were classified as EIN. The RR for EIN versus benign was 7.76 (95% CI, 3.36-17.91). In the WHO system, the RR for atypical hyperplasia (AH) versus DPEM, simple hyperplasia, or complex hyperplasia was 9.19 (95% CI, 3.87-21.83). CONCLUSIONS: Among women observed for at least 1 year after receiving a biopsy-based EH diagnosis, EIN and AH were both found to have similarly increased risks of progression to carcinoma.

Variation in breast cancer hormone receptor and HER2 levels by etiologic factors: a population-based analysis.

Evidence suggests that breast cancer hormone receptor status varies by etiologic factors, but studies have been inconsistent. In a population-based case-control study in Poland that included 2,386 cases and 2,502 controls, we assessed ER-alpha and PR status of tumors based on clinical records according to etiologic exposure data collected via interview. For 842 cancers, we evaluated ER-alpha, ER-beta, PR and HER2 levels by semiquantitative microscopic scoring of immunostained tissue microarrays and a quantitative immunofluorescence method, automated quantitative analysis (AQUAtrade mark). We related marker levels in tumors to etiologic factors, using standard regression models and novel statistical methods, permitting adjustment for both correlated tumor features and exposures. Results obtained with different assays were generally consistent. Receptor levels varied most significantly with body mass index (BMI), a factor that was inversely related to risk among premenopausal women and directly related to risk among postmenopausal women with larger tumors. After adjustment for correlated markers, exposures and pathologic characteristics, PR and HER2 AQUA levels were inversely related to BMI among premenopausal women (p-trend = 0.01, both comparisons), whereas among postmenopausal women, PR levels were associated directly with BMI (p-trend = 0.002). Among postmenopausal women, analyses demonstrated that BMI was related to an interaction of PR and HER2: odds ratio (OR) = 0.86 (95% CI = 0.69-1.07) for low PR and HER2 expression vs. OR = 1.78 (95% CI = 1.25-2.55) for high expression (p-heterogeneity = 0.001). PR and HER2 levels in breast cancer vary by BMI, suggesting a heterogeneous etiology for tumors related to these markers.