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Abstract: Background: WISDOM is a 100,000 healthy women preference-tolerant, pragmatic study comparing annual to personalized risk-based breast screening. The novelty of WISDOM personalized screening is the integration of previously validated genetic and clinical risk factors (age, family history, breast biopsy results, ethnicity, mammographic density) into a single risk assessment model that directs the starting age, timing, and frequency of screening. The goal of WISDOM is to determine if personalized screening, compared to annual screening, is as safe, less morbid, enables prevention, and is preferred by women. The study is registered on ClinicalTrials.gov, NCT02620852. Methods: Women aged 40-74 years with no history of breast cancer or DCIS, and no previous double mastectomy can join the study online at wisdomstudy.org. Participants can elect randomization or self-select a study arm, and provide electronic consent and Release for Medical Information using DocuSign. For all participants, 5-year risk of developing breast cancer is calculated according to the Breast Cancer Screening Consortium (BCSC) model. Participants in the personalized arm undergo panel-based mutation testing, and their 5-year risk is calculated using the BCSC score combined with a Polygenic Risk Score (BCSC-PRS) that includes 75 single nucleotide polymorphisms (SNPs, increase to 229) known to increase breast cancer risk. SNPs and mutations (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, ATM, PALB2, and CHEK2) are assessed by saliva-based testing through Color Genomics. 5-year risk level thresholds are used to stratify for low-, moderate- and high risk. Risk stratification determines age to start, stop, and frequency of screening. Enrollment: As of July 2018, the WISDOM study is open to all eligible women in California, North Dakota, South Dakota, Minnesota and Iowa. To date, 23,329 eligible women have registered and 14,393 women have consented to participate in the trial. We analyzed 3,255 participants who have completed risk assessment in the personalized arm. The median age was 56 years. 82% were Caucasian, 1% African-American, and 6% Asian. 9% self-reported as Hispanic. We are partnering with health insurers and self-insured companies using coverage with evidence progression. To strengthen generalizability, we are expanding to other states. WISDOM enrollment will continue past 2019. Feasibility: To evaluate the addition of PRS, we used paired statistical tests (McNemar) to compare the distributions of BCSC, and BCSC-PRS risk estimates around low-risk (6%) thresholds, the latter corresponding to 5-year risk of a BRCA mutation carrier. The median 5-year risk was 1.5% (IQR 1.0-2.1%) using the BCSC model, and 1.4% (IQR 0.8-2.5%) using the BCSC-PRS model. The BCSC-PRS model classified more women into the low (

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value

BackgroundObservational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.MethodsWe used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.ResultsOverall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.ConclusionsHigher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Objective Investigate the impact of socioeconomic status and other demographic variables on adherence to the National Comprehensive Cancer Network ovarian cancer treatment guidelines among patients with stage I/II disease. Methods Patients diagnosed with stage I/II epithelial ovarian cancer between 1/1/96-12/31/06 were identified from the California Cancer Registry. Univariate analysis and multivariate logistic regression models were used to evaluate differences in surgical procedures, chemotherapy regimens, and overall adherence to the NCCN guidelines according to increasing SES quintiles (SES-1 to SES-5). Results A total of 5445 stage I and II patients were identified. The median age at diagnosis was 54.0 years (range = 18-99 years); 72.5% of patients had stage I disease, while 27.5% had stage II disease. With a median follow-up time of 5 years, the 5-year ovarian cancer-specific survival for all patients was 82.7% (SE = 0.6%). Overall, 23.7% of patients received care that was adherent to the NCCN guidelines. Compared to patients in the highest SES quintile (SES-5), patients in the lowest SES quintile (SES-1) were significantly less likely to receive proper surgery (27.3% vs 47.9%, p < 0.001) or chemotherapy (42.4% vs 53.6%, p < 0.001). There were statistically significant trends between increasing SES and the likelihood of overall treatment plan adherence to the NCCN guidelines: SES-1 = 16.4%, SES-2 = 19.0%, SES-3 = 22.4%, SES-4 = 24.2% and SES-5 = 31.6% (p < 0.001). Multivariate logistic regression analysis revealed that compared to SES-5, decreasing SES was independently predictive of a higher risk of non-standard overall care. Conclusions For patients with early-stage ovarian cancer, low SES is a significant and independent predictor of deviation from the NCCN guidelines for surgery, chemotherapy, and overall treatment.

Introduction: The increasing number of targeted therapies, together with a deeper understanding of cancer genetics and drug response, have prompted major healthcare centers to implement personalized treatment approaches relying on high-throughput tumor DNA sequencing. However, the optimal way to implement this transformative methodology is not yet clear. Current assays may miss important clinical information such as the mutation allelic fraction, the presence of sub-clones or chromosomal rearrangements, or the distinction between inherited variants and somatic mutations. Here, we present the evaluation of ultra-deep targeted sequencing (UDT-Seq) to generate and interpret the molecular profile of 38 breast cancer patients from two academic medical centers.Methods: We sequenced 47 genes in matched germline and tumor DNA samples from 38 breast cancer patients. The selected genes, or the pathways they belong to, can be targeted by drugs or are important in familial cancer risk or drug metabolism.Results: Relying on the added value of sequencing matched tumor and germline DNA and using a dedicated analysis, UDT-Seq has a high sensitivity to identify mutations in tumors with low malignant cell content. Applying UDT-Seq to matched tumor and germline specimens from the 38 patients resulted in a proposal for at least one targeted therapy for 22 patients, the identification of tumor sub-clones in 3 patients, the suggestion of potential adverse drug effects in 3 patients and a recommendation for genetic counseling for 2 patients.Conclusion: Overall our study highlights the additional benefits of a sequencing strategy, which includes germline DNA and is optimized for heterogeneous tumor tissues. © 2013 Harismendy et al.; licensee BioMed Central Ltd.

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction= 2.4×10-6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction= 3.1×10-4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of

BackgroundSomatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.MethodsA single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC).ResultsRs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).ConclusionCommon germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Introduction: The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy.Methods: We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT).Results: The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT= 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT= 0.002; overall PACT= 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women.Conclusions: We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT. © 2011 Lee et al.; licensee BioMed Central Ltd.

Introduction: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.Methods: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.Results: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.Conclusions: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified. © 2010 Milne et al.; licensee BioMed Central Ltd.

Background: We investigated the association between hypertension, antihypertensive (AH) medication use, and breast cancer in a large prospective study, the California Teachers Study (CTS). Methods: Information on history of hypertension and lifetime regular use of AH medications was collected from 114,549 women in 1995-1996. Among them, 4,151 invasive breast cancers were diagnosed between 1995 and 2006. Additional information on AH use was collected from 73,742 women in 2000-2001, and 1,714 of these women were subsequently diagnosed with breast cancer. Cox proportional hazards regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for breast cancer. Results: Use of AH medication for ≥5 years, when compared with no use, was associated with a modest increased risk of invasive breast cancer (RR = 1.18, 95%CI 1.02-1.36). This increased risk appeared to be confined to estrogen receptor (ER)-positive tumors (RR = 1.21, 95%CI 1.03-1.43) and pre-/peri-menopausal women (RR = 1.58, 95%CI 1.11-2.25). Conclusions: Increased risk of invasive breast cancer was observed for long-term (≥5 years) AH use, and this appeared to be confined to ER + breast cancer and younger women. © 2010 The Author(s).

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Purpose We sought to compare the quality of life (QOL), characteristics, and survival of patients with non-Hodgkin lymphoma (NHL) with and without human immunodeficiency virus (HIV) infection. Methods Using the population-based cancer registry for Orange and San Diego Counties, We recruited 50 patients with HIV and systemic NHL (cases) and 50 age, sex and race-matched NHL patients without HIV (controls) diagnosed with NHL during 2002-2006. Patients completed a medical history survey and QOL instrument, the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) for cases and Functional Assessment of Cancer Therapy-General (FACT G) for controls. Results HIV-infected patients had worse overall QOL and survival than uninfected patients. QOL differences were more marked in the areas of functional, physical and social well-being than in the area of emotional well-being. HIV-infected patients had lower income and were less likely to have private insurance and more likely to have diffuse large B cell histology than uninfected patients. Conclusion HIV-infected NHL patients had worse QOL and survival than uninfected patients, due to a combination of co-morbidity, aggressive histology and lack of social support. However, their emotional well-being was comparable to that of uninfected NHL patients and better than historical norms for the HIV-infected.

OBJECTIVE: In California, leukemia represents ~35, 5, and 2% of all cancers in children (aged 0-14), adolescents (15-29), and young adults (30-39), respectively. Poorer survival has been previously noted in individuals residing in lower socioeconomic status (SES) neighborhoods. We explored the relationship between SES and survival as modified by age and race/ethnicity using data from the California Cancer Registry. METHODS: A total of 7,688 incident cases of first primary leukemia diagnosed during 1996-2005 in individuals aged 0-39 at diagnosis were included in this study. Univariate analyses of overall survival were conducted using the Kaplan-Meier method and multivariate survival analyses were performed using Cox proportional hazard regression to estimate hazard ratios. RESULTS: Multivariate analyses showed that overall survival and lymphoid cancer-specific survival was reduced in those individuals aged 15-39 compared to children aged 0-14. Although shorter survival was observed in non-whites, an association between lower-SES neighborhood and shorter survival was significant only for non-Hispanic whites (NHWs) (p value for trend

Family history of haematopoietic malignancies appears to be a risk factor for non-Hodgkin's lymphoma (NHL), but whether risk varies by family member's gender is unclear. Among 121 216 women participating in the prospective California Teachers Study, NHL risk varied by type of haematopoietic malignancy and gender of the relative.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

7558 Background: Platinum-based adjuvant chemotherapy in randomized trials has failed to provide a survival benefit in stage I non-small-cell lung cancer (NSCLC). Using data from California Cancer Registry (CCR), we explored factors that have detrimental effect on survival in stage I NSCLC to identify a subset of patients at high risk for relapse and subsequent mortality. Methods: 19,702 stage I NSCLC cases in the CCR from 1989 to 2003 were identified and subgrouped into stage IA & IB disease. Patient demographic factors, tumor characteristics and treatment delivered were examined. Kaplan-Meier survival curves were calculated to estimate survival rates. Cox proportional hazards ratios were used to identify independent prognostic factors for survival. Results: Advanced age at diagnosis, male sex, low socioeconomic status (SES), non-surgical treatment & poorly-differentiated histologic grade (stage IA: hazard ratio [HR] = 1.14; 95% confidence interval [CI]: 1.08–1.19 & stage IB: HR = 1.11; 95% CI: 1.07–1.16) were factors identified with increased mortality risk on multivariate analysis. Non-upper lobe tumor location (RML/RLL/LLL) and tumor size ≥ 4 cm (vs < 4 cm; HR = 1.22; 95% CI: 1.15–1.30) were additional factors with increased mortality risk among stage IB patients. Conversely, bronchioloalveolar carcinoma (BAC)(vs adenocarcinoma: stage IA: HR = 0.81; 95% CI: 0.72–0.91 & stage IB: HR = 0.87, 95% CI: 0.77–0.98) & Asian ethnicity (vs Caucasian: stage IA: HR = 0.81, 95% CI: 0.70–0.94 & stage IB: HR = 0.80, 95% CI: 0.72–0.90) were associated with decreased mortality risk in stage I NSCLC. Lobectomy had the lowest HRs for death among all surgical techniques for both stage IA & IB NSCLC in the Cox proportional hazards model. Conclusions: Poorly-differentiated stage IA & IB NSCLC and stage IB NSCLC located in non-upper lobes or tumor size ≥ 4 cm carried an increased mortality risk on adjusted analysis. No significant financial relationships to disclose. [Table: see text]

Objectives. Some risk factors for cervical cancer in situ convey risk for malignancies of the cervix and other sites. We estimate risk of several malignancies following in situ cancer of the cervix for Hispanic Americans and non-Hispanic Whites. Methods. Using California Cancer Registry data (1988-1999) we identify 56,020 women with cervical cancer in situ and observe subsequent malignancies in that cohort, with over three million woman-months of follow-up, We focus on cancers of the reproductive system and cancers related to smoking. Risk estimates are standardized incidence ratios, accounting for age, time at risk, cancer type, and race/ethnicity. Results. There is elevated risk for invasive cervical cancer (SIR=4.1, 95% Cl: 3.5-4.7), which is significantly higher for Hispanics than for non-Hispanic Whites (SlRs = 5.2 and 3.2, respectively, X-2(l)=7.66, P=0.006). Excluding cervix, non-Hispanic Whites show elevated risk for a pool of reproductive cancers (SIR= 1.8, 95% Cl: 1.4-2.4). While both groups show elevated risk for a pool of smoking-related cancers, only non-Hispanic Whites show significant risk specifically for lung cancer (SIR= 1.7, 95% CI: 1.4-2.1). Non-Hispanic Whites show elevated risk for ovarian cancer (SIR = 1.8, 95% CI: 1.3-2.4). Ovarian cancer following in situ cervical cancer is disproportionately of borderline histology (G(2)(l)=7.43, P=0.006). Conclusions. These results have implications for public health planning for women, as well as better understanding of disparities in care or biologic paths to malignancies in women with in situ cancer of the cervix. (c) 2006 Elsevier Inc. All rights reserved.

8023 Background: Survival data for malignant melanoma patients of various ethnic backgrounds are lacking. Furthermore, the modifying effect of socioeconomic status (SES) on survival in melanoma patients is unknown. This study was performed to analyze survival differences for cutaneous melanoma patients of each major ethnicity, including analysis of the effect of SES on outcomes, using a statewide cancer registry. METHODS: A case-only analysis of data from the California Cancer Registry database during 1992-2002 was conducted. The primary outcome measured was overall survival for each ethnic group. Univariate survival analyses were conducted using the Kaplan-Meier method and log-rank test; multivariate survival analyses were performed using Cox proportional hazards ratios. RESULTS: 46,218 incident cases of invasive cutaneous melanoma were identified, including 39,741 Caucasians (93.47%), 2263 (5.32%) Hispanics, 331(0.78%) Asians, 172 (0.40%) African-Americans, and 12 (0.03%) Native Americans (P

Purpose Classification changes for bronchioloalveolar carcinoma (BAC) by the WHO in May 1999 narrowed its definition. This study was undertaken in an attempt to characterize the impact of these changes on the epidemiology of BAC. Patients and Methods This retrospective study involves data analysis from the population-based Cancer Surveillance Programs of three Southern California counties from 1995 to 2003. BAC cases diagnosed after May 1999 are compared with BAC cases before that time by clinicopathologic variables including survival. Results Incident cases (11,969) of non-small-cell lung cancer (NSCLC) were analyzed, including 626 cases of BAC (5.2%). Median overall survival (OS) for BAC patients diagnosed after May 1999 (> 53 months) was significantly improved over median OS for BAC patients before May 1999 (32 months; P = .012). This survival benefit remained after adjustment for sex, smoking status, and stage at presentation (hazard ratio for time of diagnosis before May 1999 compared with a diagnosis after May 1999 = 1.43; P = .015). Median CS for non-BAC NSCLC patients diagnosed before May 1999 (9 months) did not differ from the median OS of such patients afterwards (110 months; P = .09). Conclusion This epidemiologic study is the first to demonstrate a survival advantage for BAC patients diagnosed after May 1999 compared with BAC patients diagnosed before this time-a finding that persists after adjustment for sex, smoking status, and stage at presentation. We believe that this observed survival benefit likely reflects changes in the revised 1999 WHO classification.

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

Recent reports suggest that two ATM gene mutations, 7271T>G and IVS10-6T>G, are associated with a high risk of breast cancer among multiple-case families. To assess the importance of these two mutations in another 'high-risk' group, young women (under age 51) with multiple primaries, we screened a large population-based series of young women with bilateral breast cancer and compared the frequency of these mutations among similar women diagnosed with unilateral breast cancer. The 1149 women included were enrolled in an ongoing population-based case-control study of the genetic factors that contribute to bilateral breast cancer; they were not selected on the basis of family history of cancer. Screening for 7271T>G and IVS10-6T>G ATM gene mutations was conducted using DHPLC followed by direct sequencing. The 7271T>G mutation was detected in one out of 638 (0.2%) women with unilateral breast cancer and in none of the bilateral cases, and the IVS10-6T>G mutation in one out of 511 (0.2%) bilateral and in eight out of 638 (1.3%) unilateral breast cancer cases. Carriers of either mutation were not limited to women with a family history. Given the likelihood that young women with bilateral breast cancer have a genetic predisposition, the observed mutation distribution is contrary to that expected if these two mutations were to play an important role in breast carcinogenesis among individuals at high risk.

ObjectiveThe aim of this study was to describe recruitment strategies for a single-visit cervical cancer prevention study.MethodsFrom January through December 1999, low-income, predominantly Latino women were recruited to participate in a single-visit cervical cancer prevention study. For the first 6 months, all women who had ever visited one of two community-based study clinics were invited to participate (clinic registry recruitment). For the remainder of the year, recruitment was modified to be primarily inclusive of advertisements in English- and Spanish-language community newspapers and fliers left in local businesses and organizations (media campaign recruitment). Eligible volunteers were randomized to one of two study arms, usual-care program or single-visit program. All study subjects completed demographic and medical questionnaires delivered by bilingual staff. Women who declined to participate in this study were asked to provide reasons for this preference. Statistical analyses included the use of chi-square, logistic regression, and Student's t test.ResultsThe proportion of women who agreed to participate was higher in the media recruitment group than in the clinic registry group [51% (535/1041) compared to 26% (405/1542), P < 0.001]. The no-show rate among participants solicited from the media strategy was significantly less than that from the clinic registry. There were no significant differences in the median age, number of months since the last Papanicolaou smear, incidence of abnormal Papanicolaou smear, education, or income of the subjects based on the recruitment strategy.ConclusionA media-based recruitment strategy was effective for this single-visit cervical prevention study. This approach may be effective for recruitment of other low-income groups to clinical trials.

To evaluate the effect of daily beta-carotene (30 mg) versus placebo over a 2-year period on cervical intraepithelial neoplasia (CIN) 2 and 3 lesions. Human papillomavirus (HPV) typing was done to determine whether lesion regression was related to HPV. Micronutrient levels were measured to determine whether levels were predictive of regression. Variables that influence the risk of HPV infection and CIN, such as cigarette smoking and sexual behavior, were evaluated. Women were randomized to beta-carotene or placebo, with cytology and colposcopy every 3 months. Cervical biopsies were performed before treatment and after 6 and 24 months to evaluate response. Persistence of or progression to CIN 3 resulted in removal from the study, whereas treatment continued for 2 years on all others. The presence and type of HPV was determined by PCR. Response was defined as an improvement in CIN by 2 grades. Mantel-Haenszel chi(2) test was used to analyze response to treatment. Fisher's exact test was used to determine the effect of HPV and CIN grade on response Wilcoxon's rank-sum tests were used to compare micronutrient levels between groups. Twenty-one of 124 enrolled women were not randomized because they either moved, became pregnant, voluntarily withdrew, or the pathological review of their initial cervical biopsies did not confirm CIN 2 or 3. Of the remaining 103 women, 33 experienced lesion regression, 45 had persistent or progressive disease, and 25 women did not complete the study and were considered nonresponders in the final analysis. The overall regression rate (32%) was similar between treatment arms and when stratified for CIN grade. Data on 99 women with HPV typing showed that 77% were HPV-positive and 23% HPV-negative at enrollment. HPV-positive lesions were subdivided into indeterminate-, low-, and high-risk categories; the response rate was highest for women with no HPV detected (61%), lower for indeterminate/low-risk (30%), and lowest for high-risk (18%; P =.001). CIN regression was negatively correlated with retinol levels. In conclusion, beta-carotene does not enhance the regression of high-grade CIN, especially in HPV-positive subjects.

The majority of renal cell carcinomas (RCCs) are sporadic, and increasing incidence rates suggest that such environmental risk factors as smoking play a role in the etiology of the disease. Cases with RCC were selected from the population-based cancer registry of Orange County, California, between 1994 and 1997; controls were recruited by telephone using random digit dialing. A total of 115 case and 259 control subjects were genotyped for N-acetyltransferase 2 (NAT2), which codes for a polymorphic enzyme involved in tobacco-carcinogen metabolism. Subjects with slow acetylator genotypes were found to be at twofold increased risk (odds ratio (OR) = 1.8; 95 percent confidence interval (CI): 1.1, 2.9) of RCC. Although cancer risk doubled among smokers (OR = 2.2; 95 percent CI: 1.3, 3.7), stratified analysis revealed gene-environment interaction among slow acetylators that smoked (OR = 3.2; 95 percent CI: 1.7, 6.1) compared with rapid acetylators that smoked (OR = 1.4; 95 percent CI: 0.7, 2.9). A dose response was found for pack-years among slow acetylators (p < 0.01) but not among rapid acetylators (p = 0.06). Although smoking is a well-established risk factor of RCC, our data suggest that the risk is pronounced among slow rather than rapid acetylators.

Background & aimsColorectal cancer screening beginning at age 50 is recommended for all Americans considered at "average" risk for the development of colorectal cancer.MethodsWe used 1988-1995 California Cancer Registry data to compare the cost-effectiveness of two 35-year colorectal cancer screening interventions among Asians, blacks, Latinos, and Whites.ResultsAverage annual age-specific colorectal cancer incidence rates were highest in blacks and lowest in Latinos. Screening beginning at age 50 was most cost-effective in blacks and least cost-effective in Latinos (measured as dollars spent per year of life saved), using annual fecal occult blood testing (FOBT) combined with flexible sigmoidoscopy every 5 years and using colonoscopy every 10 years. A 35-year screening program beginning in blacks at age 42, whites at age 44, or Asians at age 46 was more cost-effective than screening Latinos beginning at age 50.ConclusionsColorectal cancer screening programs beginning at age 50, using either FOBT and flexible sigmoidoscopy or colonoscopy in each racial or ethnic group, are within the $40,000-$60,000 per year of life saved upper cost limit considered acceptable for preventive strategies. Screening is most cost-effective in blacks because of high age-specific colorectal cancer incidence rates.

Breast and ovarian cancers account for approximately 210000 newly diagnosed cases per year. More than half a million American women are estimated to be carriers of a breast cancer susceptibility gene. The purpose of this study was to assess the association of characteristics such as, age at diagnosis, race/ethnicity and family history of cancer with inherited BRCA1 mutations in a population-based sample of breast and ovarian cancer cases. No selection was made by race, age at diagnosis or positive family history of breast or ovarian cancer. The population under study was all breast cancer cases diagnosed in Orange County, CA, during the 1-year period beginning 1 March 1994 and all ovarian cancer cases diagnosed in Orange County during the 2-year period beginning 1 March 1994. This report focuses on the first consecutively ascertained 802 participating probands enrolled in the study, of which 9 were male breast cancer probands, 673 were female breast cancer probands and 120 were ovarian cancer probands. We observed 11 BRCA1 mutations or 1.6% (95% CI: 0.8-2.9) among the 673 female breast cancer probands and 4 BRCA1 mutations or 3.3% (95% CI: 0.8-8. 3) among the 120 ovarian cancer probands. No BRCA1 mutations were identified among the 98 non-white breast and ovarian cancer probands. The prevalence of BRCA1 mutations in non-Hispanic-white breast cancer cases below the age of 50 years was 2%. Positive family history of breast or ovarian cancers was significantly associated with BRCA1 mutation status among breast cancer probands. Similarly, positive family history of breast or ovarian cancer was significantly associated with BRCA1 mutation status among the ovarian cancer probands. In summary, we present results on the prevalence of BRCA1 mutations in a significantly larger sample of population-based breast and ovarian cancer cases than previously reported. The results indicate that, using a conservative approach to targeted genotyping of BRCA1, the frequency of mutations was consistent with those reported using similar methods of population-based case ascertainment.

Breast cancer risk has been hypothesized to increase with exposure to heterocyclic aromatic amines (HAAs) formed from cooking meat at high temperature. HAAs require enzymatic activation to bind to DNA and initiate carcinogenesis. N-acetyltransferase 2 (NAT2) enzyme activity may play a role, its rate determined by a polymorphic gene. We examined the effect of NAT2 genetic polymorphisms on breast cancer risk from exposure to meat by cooking method, doneness and estimated HAA [2-amino-1-methyl-6-phenylimidazole[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)] intake. Women were recruited with suspicious breast masses and questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses. For 114 cases with breast cancer and 280 controls with benign breast disease, NAT2 genotype was determined using allele-specific PCR amplification to detect slow acetylator mutations. HAAs were estimated from interview data on meat type, cooking method and doneness, combined with a quantitative HAA database. Logistic regression models controlled for known risk factors, first including all controls, then 108 with no or low risk (normal breast or no hyperplasia) and finally 149 with high risk (hyperplasia, atypical hyperplasia, complex fibroadenomas). Meat effects were examined within NAT2 strata to assess interactions. We found no association between NAT2 and breast cancer. These Californian women ate more white than red meat (control median 46 versus 8 g/day). There were no significant associations of breast cancer with red meat for any doneness. White meat was significantly protective (>67 versus