Bryan Langholz

A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients

IntroductionThe Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting.MethodsA case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score.ResultsAfter adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values.ConclusionIn this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.

Maternal and Grandmaternal Smoking Patterns Are Associated With Early Childhood Asthma

OBJECTIVE To investigate the associations of maternal and grandmaternal smoking before, during, and after pregnancy with childhood asthma. DESIGN, SETTING, AND PARTICIPANTS We conducted a case-control study nested within the Childrens Health Study in southern California. The case patients consisted of 338 children with asthma that had been diagnosed in the first 5 years of life, and 570 control subjects were countermatched on in utero exposure to maternal smoking within grade, sex, and community of residence. MEASUREMENTS Detailed maternal and household smoking histories and other asthma risk factor information was obtained by telephone interview. RESULTS The participation rates were 72.3% and 82.5%, respectively, for control subjects and case patients. In utero exposure to maternal smoking was associated with increased risk for asthma diagnosed in the first 5 years of life (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0 to 2.3), and for persistent asthma (OR, 1.5; 95% CI, 1.0 to 2.3). The associations did not differ in children with early transient asthma compared to those with early persistent asthma. Relative to never-smokers, children whose mothers smoked throughout the pregnancy had an elevated risk of asthma in the first 5 years of life (OR, 1.6; 95% CI, 1.0 to 2.6). Children of mothers who quit smoking prior to the pregnancy showed no increased risk (OR, 0.9; 95% CI, 0.5 to 1.5). We were unable to assess the association of smoking cessation during pregnancy because very few mothers were reported to have done so (15%). Asthma risk did not increase in a monotonic pattern with smoking intensity during pregnancy. Postnatal secondhand smoke exposure was not independently associated with asthma. Grandmaternal smoking during the mothers fetal period was associated with increased asthma risk in her grandchildren (OR, 2.1; 95% CI, 1.4 to 3.2). CONCLUSIONS Maternal and grandmaternal smoking during pregnancy may increase the risk of childhood asthma.

Variation of Breast Cancer Risk Among BRCA1/2 Carriers

CONTEXT The risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers. OBJECTIVES To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics. DESIGN, SETTING, AND PARTICIPANTS Probands were identified from a population-based, case-control study (Womens Environmental Cancer and Radiation Epidemiology [WECARE]) of asynchronous contralateral breast cancer conducted during the period of January 2000 to July 2004. Participants previously diagnosed with contralateral breast cancer or unilateral breast cancer were genotyped for mutations in BRCA1 and BRCA2. All participants had their initial breast cancer diagnosed during the period of January 1985 to December 2000, before the age of 55 years. MAIN OUTCOME MEASURE Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families. RESULTS Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P = .04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P = .28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics. CONCLUSION There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

Exposure Stratified Case-Cohort Designs

A variant of the case-cohort design is proposed for the situation in which a correlate of the exposure (or prognostic factor) of interest is available for all cohort members, and exposure information is to be collected for a case-cohort sample. The cohort is stratified according to the correlate, and the subcohort is selected by stratified random sampling. A number of possible methods for the analysis of such exposure stratified case-cohort samples are presented, some of their statistical properties developed, and approximate relative efficiency and optimal allocation to the strata discussed. The methods are compared to each other, and to randomly sampled case-cohort studies, in a limited computer simulation study. We found that all of the proposed analysis methods performed well and were more efficient than a randomly sampled case-cohort study.

Dose to the Contralateral Breast From Radiotherapy and Risk of Second Primary Breast Cancer in the WECARE Study

PURPOSE To quantify the risk of second primary breast cancer in the contralateral breast (CB) after radiotherapy (RT) for first breast cancer. METHODS AND MATERIALS The study population included participants in the Womens Environmental, Cancer, and Radiation Epidemiology study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were <55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted conditional logistic regression models. RESULTS Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR = 2.5, 95% CI 1.4-4.5). No excess risk was observed in women >40 years of age. Women <40 years of age with follow-up periods >5 years had a RR of 3.0 (95% CI 1.1-8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI 0.1-3.0). CONCLUSIONS Women <40 years of age who received a radiation dose >1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.

Treatment of uterine sarcomas.

During a 21‐year period, 66 patients with uterine sarcomas were treated at California Medical Center. Histological diagnoses were mixed mesodermal sarcoma in 32 patients (48%), leiomyosarcoma in 24 (36%), and endometrial stromal sarcoma in 10 (15%) patients. The majority of patients (73%) had Stage I tumors. The treatment consisted of surgery alone in 27 (41%), surgery in combination with radiation therapy in 36 (55%), and radiation therapy alone in three (4%) patients. The overall 1‐, 2‐, and 5‐year actuarial survival was 74%, 57%, and 38%, respectively. The 1‐, 2‐, and 5‐year actuarial survival for the 27 surgery alone patients was 73%, 50%, and 25%, which compared with 75%, 61%, and 44% for the 36 surgery plus radiation therapy patients (P = 0.12). The disease‐free survival was better for the surgery plus radiation therapy patients, as compared with the surgery alone group (38% vs. 18% at 5 years, P = 0.081). The 5‐year survival by histology was 70% for the 10 endometrial stromal sarcoma patients, 40% for the 24 leiomyosarcoma patients, and 23% for the 32 mesodermal sarcoma patients (P = 0.064). As expected, survival depended on the stage of disease (P < 0.0001). Treatment failure was observed in 35 (53%) patients, which included 9 (14%) with failure in the pelvis. There was no difference in the incidence of failure among patients in the three treatment groups and also in the three histologic groups. There was, however, a significant difference in the incidence of pelvic failure between surgery alone and surgery plus radiation therapy patients. in the 27 surgery alone patients, nine (33%) relapsed in the pelvis, whereas none of the 36 surgery plus radiation therapy patients had locoregional failure, P < 0.0001. Adjuvant radiation therapy is an important treatment in the management of patients with sarcoma of the uterus.

Early Introduction of Dairy Products Associated with Increased Risk of IDDM in Finnish Children

Associations between infant-feeding patterns and risk of IDDM were investigated in a nationwide Finnish case-control study of 690 IDDM children <15 yr of age. Each child was matched by date of birth and sex to a randomly selected population-based control child. Univariate analysis revealed that the risk of IDDM was increased by ∼1.5 in children for whom breast-feeding was terminated at <2 mo of age, doubled in those who were exclusively breast-fed for <2 mo, and doubled in those who were introduced to dairy products at <2 mo of age. In further multivariate analyses of these factors, it was found that introduction of dairy products at an early age was the most important risk factor, and the observed univariate effects of duration of breast-feeding variables were explained by their correlation with this factor. This is the first observational study to show that early introduction of dairy products is independently associated with an increased risk of IDDM. Adjustment for mothers education and age, childs birth order, or birth weight did not affect the results.

Maternal Fish Consumption During Pregnancy and Risk of Early Childhood Asthma

Maternal fish consumption during pregnancy may affect childrens asthma risk by modulating early-life immune development. Type of fish intake may be important because of differences in fatty acid content. To test this hypothesis, we conducted a nested case-control study, selecting subjects from the Childrens Health Study, a population-based study of school-aged children in southern California. Cases had physician-diagnosed asthma and controls were asthma-free by age 5 years. Mothers or guardians provided information on fish consumption during pregnancy in telephone interviews. We computed odds ratio (OR) and 95% confidence interval (CI) by using conditional logistic regression models that accounted for the sampling. In children born to mothers with a history of asthma, the OR of asthma was 0.20 (95% CI = 0.06–0.65) when mothers ate oily fish at least monthly during pregnancy compared with no consumption (ptrend = 0.006). Maternal oily fish consumption during pregnancy did not benefit children of non-asthmatic mothers. In contrast, fish stick (a source of trans-fats) consumption during pregnancy increased asthma risk in children (OR = 2.04; 95% CI = 1.18–3.51). Our results suggest that maternal oily fish intake during pregnancy may protect offspring from asthma; however, eating fish sticks during pregnancy may increase asthma risk in children.

Study design: Evaluating gene–environment interactions in the etiology of breast cancer – the WECARE study

IntroductionDeficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.DesignTo examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.ConclusionsOur study design improves the potential for detecting gene–environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case–control sets and enhanced our ability to detect radiation–genotype interactions.

TRAFFIC DENSITY AND THE RISK OF CHILDHOOD LEUKEMIA IN A LOS ANGELES CASE-CONTROL STUDY

PURPOSE To investigate the relationship between traffic density and the risk of childhood leukemia. METHODS The study group consisted of 212 cases and 202 controls from the London et al. (1991) study of childhood leukemia conducted in the Los Angeles area during 1978 to 1984. Using GIS methods, traffic counts on all streets within 1500 feet of each subjects residence of longest duration were determined. From these counts, an integrated distance-weighted traffic density measure was calculated for each subject for use as the analytic variable. Additional information, including magnetic fields and wire-code, was obtained from the original case-control study. Association between traffic density and leukemia, and confounding and effect modification by other variables, were assessed using standard matched case-control analyses. RESULTS Although the unadjusted traffic density-childhood leukemia rate ratios were slightly elevated, this weak association was explained by confounding by wire code. Wire code remained associated with leukemia after controlling for traffic density. There was little evidence of effect modification between traffic density and magnetic fields, wire code or other variables. CONCLUSIONS There is no evidence of an association of traffic density with childhood leukemia in the Los Angeles case-control study.