Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study

Study population The WECARE Study is an international multicenter population-based case-control study of cases with asynchronous contralateral breast cancer (CBC) and individually matched controls with unilateral breast cancer (UBC). Recruitment and data collection for the WECARE Study were conducted in two phases, herein referred to as WECARE I (2001–2004) and WECARE II (2009–2012). The study design of the first phase (WECARE I) has been described in detail elsewhere [Bernstein JL, et al 2004, PMID: 15084244]; the second phase (WECARE II) employed a nearly identical approach [Langballe R, et al 2016, PMID: 27400983]. Participants in each phase were identified through eight population-based cancer registries, including six in the United States that contribute to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program: Los Angeles County Cancer Surveillance Program; Cancer Surveillance System of the Fred Hutchinson Cancer Center (Seattle region, WA); State Health Registry of Iowa; Cancer Surveillance Program of Orange County/San Diego-Imperial Organization for Cancer Control (Orange County/San Diego, CA); the Greater Bay Area Cancer Registry (San Francisco Bay Area region and Santa Clara region, CA); and the Sacramento and Sierra Center Registry (Sacramento region, CA). Participants were additionally identified using the Ontario Cancer Registry (Canada) and the Danish Breast Cancer Cooperative Group Registry, supplemented by data from the Danish Cancer Registry. The study protocol was approved by the institutional review or regulatory ethics boards at each study site. Data collection Study participants were interviewed by telephone using a structured questionnaire aimed at evaluating known or suspected breast cancer risk factors, including personal demographics, medical history, menstrual and reproductive history, family history of cancer, use of hormones, smoking, and alcohol intake. Risk factor status was assessed during the period prior to first diagnosis, as well as between first diagnosis and reference date (i.e., the at-risk period for CBC). Detailed data on treatment and tumor characteristics were obtained directly from cancer registry records or by abstracting medical records, including pathology and surgical reports, radiation oncology clinic notes, and systemic adjuvant treatment data. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Biospecimens were collected from study participants for genotyping: blood collected from WECARE I women; and saliva collected from WECARE II women. ]]>
In the WECARE Study, all participants were diagnosed with a first primary unilateral invasive local/regional breast cancer at age <55 years between 1985 and 2008. Cases were subsequently diagnosed with an in situ or invasive CBC = 1 year after the first diagnosis. Controls were women with unilateral breast cancer (UBC) who were individually matched to cases on year of birth (±5 year), year of first diagnosis (±4 year), cancer registry region, self-reported race and ethnicity, and no subsequent diagnoses of cancer during the interval between the matched case's first and second breast cancer diagnoses. DNA was extracted from either blood or saliva samples using standard methods and genotyping was performed using Illumina HumanOmni1-Quad v1.0 or Axiom Precision Medicine Diversity Array (PMRA). Pre-imputation quality control (QC) filtering by SNP/sample call rate < 95% and Hardy-Weinberg Equilibrium (HWE) P < 10-7 was performed with the exclusion of multi-allelic, duplicated non-SNP, and monomorphic sites. The imputation was performed using the Trans-Omics for Precision Medicine (TOPMed) genotype imputation server. SNPs with imputation R2 < 0.3 or minor allele frequency (MAF) < 0.05 were excluded before downstream analyses. The identification of descent was examined using PLINK v2.0. The principal components for genome-wide association analysis were calculated by EIGENSTRAT. The reference genome is GRCh37/hg19.The sample size included in the analysis is 2887 (1195 CBCs and 1692 UBCs) and covariates are age, offset, and the first 5 principal components.Eligible cases were women with contralateral breast cancer diagnosis who: (1) were diagnosed between 1985 and 2009 with a first invasive breast cancer that did not spread beyond regional lymph nodes at diagnosis and a second contralateral primary breast cancer at least 1 year after the first breast cancer diagnosis (reference date), Invasive and in-situ CBCs were eligible for WECARE I, whereas only invasive CBCs were included in WECARE II; (2) were younger than 55 years at first diagnosis; (3) had no previous or intervening cancer diagnosis except non-melanoma skin cancer or cervical carcinoma in situ; (4) were alive at the time of contact and able to provide informed consent to complete the interview and provide a biospecimen; and (5) resided in the same cancer registry reporting region for both diagnoses. Eligible controls were women with a unilateral breast cancer diagnosis with an intact contralateral breast were identified using the same eligibility criteria, and individually matched to cases (1:2 in WECARE I; 1:1 in WECARE II) on the following criteria: year of birth (5-year strata), year of diagnosis (4-year strata), cancer registry region, and race/ethnicity. For each control, reference date was created by adding the at-risk period of her matched case to the date of her breast cancer diagnosis. WECARE I cases and controls were counter-matched on radiation exposure, such that two members of the case-control triad had received radiation therapy for their first breast cancer. ]]>