FGF) receptor pathway is activated in many tumors. FGFR2 has been identified as a breast cancer susceptibility gene. Common variation in other FGF receptors might also affect breast cancer risk. We carried out a case-control study to investigate associations of variants in FGFR3 and FGFR4 with breast cancer in women from Heilongjiang Province.The fibroblast growth factor  and 1.364 (95%CI = 1.177-1.580), respectively. However, no significant associations were detected between other SNPs and breast cancer. Analyses of the disease characteristics showed that SNP rs351855 was associated with lymph-node-positive breast cancer with a dose-dependent effect of the minor allele (P = 0.008).The minor alleles of rs1966265 and rs351855 in FGFR4 were associated with breast cancer in a northern Chinese population.SNPs rs1966265 and rs351855 in  FGFs) and their signaling pathways appear to play significant roles, not only in normal development and wound healing but also in tumor development and progression [FGFR2 gene as a breast cancer susceptibility locus [FGFR2 is a breast cancer susceptibility gene [FGFR2 belongs to the human fibroblast growth factor (FGF) and receptor family, which consists of genes that play critical roles in cancer development due to their angiogenic potential and direct enhancement of tumor growth [FGFR2 is highly conserved across all FGF receptors [FGF receptor genes may also be implicated in the development of breast cancer. We hypothesized that common variants in other genes in the FGF pathway might also raise breast cancer risk, and we carried out this case-control study to identify associations between breast cancer risk and common variants in the FGF receptor genes FGFR3 and FGFR4 by genotyping selected tag-SNPs in women from Heilongjiang Province, northeast of China.Breast cancer is a complex disease and one of the most common malignancies in women worldwide. The incidence of female breast cancer in both developing and developed countries continues to rise . Many stgression . Genome-ty locus , 4. Furtity gene -8. FGFR2r growth . The amieceptors . The othThe 747 cases and 716 controls were similar with regard to age at interview, age at first birth and family history .Four SNPs were selected in this case-control study: rs2234909 and rs3135848 in the FGFR4 gene were strongly associated with breast cancer in Chinese women of Heilongjiang Province, with ORs of 1.335 (95%CI = 1.154-1.545) and 1.364 (95%CI = 1.177-1.580), respectively. We further analyzed the effect of the genotypes of these SNPs under three different genetic models (Table P = 3 × 10−5). For rs351855, the GA and AA genotype also significantly increased breast cancer risk compared to the GG genotype in the dominant model . These results still showed statistical significance after Bonferroni correction.The results showed that the minor allele of rs1966265 and rs351855 in the P = 0.594). Compared with the rs3135848 TT genotype, the TC and CC genotype possibly conferred increased risk for breast cancer in the dominant model .Compared with the rs2234909 TT genotype, the TC and CC genotype showed a possible decreased risk for breast cancer in the dominant model . For the patients whose age was greater than 50, in the dominant model, combined genotypes (AG+GG) of rs1966265 had a 1.597-fold increase breast cancer risk compared with the genotype AA . For rs351855, the carriers with GA and AA genotypes had a similar breast cancer risk . Both rs1966265 and rs351855 were still associated with breast cancer risk under co-dominant and dominant models when stratified by BMI, age at menarche and menopausal status (corrected P < 0.05).The results of stratified analyses are shown in We then analyzed the effects of these SNPs on a series of disease characteristics in the patient cohort, including lymph node metastasis, tumor size, tumor grade, clinic stage, and the status of estrogen receptor (ER) or progesterone receptor (PR), HER2, P53, Ki67, and intrinsic subtypes  .FGFR4 gene, it was found that the patients with genotypes GA and AA were more likely to have lymph-node-positive tumors compared to the patients with genotype GG (P = 0.008). Furthermore, we observed a dose-dependent effect of the A risk allele; each additional copy increased the probability of lymph node metastasis. For SNP rs1966265, the patients with AG and GG genotypes had a trend toward having lymph-node-positive tumors compared to the patients with genotype AA (P = 0.066). We did not find associations for the two SNPs with other disease characters, including tumor size, tumor grade, clinic stage, and the status of ER or PR, HER2, P53, Ki67, and intrinsic subtypes. Additionally, in this study, there were no significant associations between rs2234909 and rs3135848 in the FGFR3 gene and all disease characters.For SNP rs351855 in the FGFR4 gene, rs1966265 and rs351855, and two polymorphisms in the FGFR3 gene, rs2234909 and rs3135848, and evaluated their association with breast cancer risk in women from Heilongjiang Province, northeast of China. We found that SNPs rs1966265 and rs351855 in the FGFR4 gene could increase breast cancer risk in northern Chinese women, especially for lymph-node-positive breast cancer.In this study, we genotyped two polymorphisms in the FGFR4 gene is located at chromosome 5q35–qter. Several studies have shown that FGFR4 polymorphisms are associated with the progression of various tumor types, such as breast, colon, prostate, and sarcoma tumors [FGFR4 gene is a missense variant. A consistent result from the Breast Cancer Association Consortium (BCAC) showed that rs1966265 increased breast cancer risk for Europeans and Asians [P = 0.006) for European women and 1.08  for Asian women. The authors in BCAC thought that the power was much lower for Asian and African–American women, and certainly required independent replication. Our study showed that the G allele of rs1966265 increased a 1.360-fold risk for breast cancer in northern Chinese women, which was higher than the BCAC results. Our results were consistent with the previous study. We also found that the G allele of rs1966265 had a possible trend of a correlation with lymph node metastasis in the breast cancer patients.The a tumors -16. SNP d Asians . The estFGFR4 gene. It corresponds to the SNP rs351855 in the dbSNP database (www.ncbi.nlm.nih.gov/SNP) [FGFR4 and poorer prognosis in lymph-node-positive breast cancer was also demonstrated. Thussbaset et al. found that this mutation played a role in the resistance to adjuvant systemic therapy because knockdown of FGFR4 increased sensitivity to chemotherapeutic agents and attenuated growth [MMP1, suggesting that loss of the wild-type receptor would adversely affect disease progression [The Arg388Gly polymorphism, in which glycine is substituted for arginine (G388R) at codon 388, is an important polymorphism of the gov/SNP) , 18. We gov/SNP) . Seitzergov/SNP) . A relatd growth . The homgression .FGFR3 gene, which is located on chromosome 4p16.3, comprises 19 exons and 18 introns, spanning 16.5 kb [FGFR3 gene mutations were associated with many epithelial malignancies, including cervical carcinoma, nasopharyngeal carcinoma, colorectal cancer and bladder cancer [FGFR3 mutant tumors were associated with a good prognosis [FGFR3 mutations were associated with an increased risk of recurrence [FGFR3 gene were associated with breast cancer risk. We also did not find associations of these two SNPs with clinical pathological characteristics.The  16.5 kb , 22. Prer cancer -26. Theyrognosis . Multivacurrence . In our FGFR3 and FGFR4 genes with breast cancer in Chinese women from northeastern China and confirmed the associations of SNPs rs1966265 and rs351855 with breast cancer. The two SNPs were also associated with lymph-node-positive breast cancer. Although this study might provide new insights to understand the association of FGFs family with breast tumorigenesis and contribute to the early detection of breast cancer, these results await further confirmation by an ethnicity-matched larger study. Further studies are also needed to characterize the functional sequences that cause breast cancer.In conclusion, we evaluated the associations of four SNPs in the A total of 1,463 individuals-747 breast cancer patients and 716 healthy controls-were included in this study. Patients with sporadic breast cancer were recruited from the Department of Breast Surgery at the Third Affiliated Hospital of Harbin Medical University. Breast cancer in these patients was diagnosed based on their surgical and pathological evaluation, and their disease information was obtained from their medical files Tables . The conFGFR3 and FGFR4 gene from the dbSNP and HapMap databases. The minor allele frequencies (MAF) of these SNPs were greater than 5%, and the pair-wise r2 values were greater than 0.8. Genomic DNA was isolated from EDTA anti-coagulated whole blood using the AxyPrep Blood Genomic DNA Miniprep Kit . The SNaPshot SNP assay was carried out to detect the polymorphisms at the four SNP loci. The resulting data were analyzed with GeneMapperTM 4.0 software . For quality control purposes, genotyping was performed without knowledge of the case/control status of the subjects, and a 5% random sample of cases and controls was genotyped twice by different persons; the reproducibility was 100%.We performed a combined analysis of functional significance and Tag SNP strategies to select four potentially functional SNPs in the t-test (for continuous variables). Disease characteristics were compared with patient genotypes using the chi-square test  or one-way ANOVA (for continuous variables). Associations between genotypes and breast cancer risk were estimated by computing odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression with adjustment for age, body mass index (BMI), age at menarche and menopausal status. Homozygotes for major allele were the reference group, and then heterozygotes and homozygotes for the minor allele were compared with the reference group, respectively. The dominant model was run with the homozygote for the minor allele and the heterozygote versus the reference group. All statistical tests were two-sided; a P value equal to or less than 0.05 was considered statistically significant, and a P value less than 0.1 was considered a possible trend that could be explored further in larger study groups. Statistical analyses were performed using SPSS for Windows . The P value was adjusted for the four analyzed SNPs using Bonferroni correction, and a corrected P value < 0.013 (corrected α = 0.05/4) was considered statistically significant.The genotype frequencies were tested for Hardy–Weinberg equilibrium using the chi-square test among the controls. Differences between cases and controls in demographic characteristics and risk factors were evaluated by the chi-square test  or Student's


The uptake of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) for the primary prevention of breast cancer is low, despite their proven efficacy in several randomized clinical trials. This review summarizes the latest data on physicians’ and women’s barriers to breast cancer preventive therapy. Physicians’ challenges include: identifying suitable candidates for preventive therapy, inadequate training and confidence in risk assessment and counselling, insufficient knowledge of risk-reducing medications, and lack of time. High-risk women fear medication side effects, and they often weigh experiences of others more heavily than statistical probabilities to guide their decision-making. Despite decision aid interventions to help women make an informed decision, acceptance of preventive therapy will remain low until: risk/benefit profiles are more favorable, physicians are better educated and skilled in having these discussions, and suitable biomarkers to monitor drug efficacy and better clinical risk prediction models to assess true individual risk are available. Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are FDA-approved for the primary prevention of breast cancer—tamoxifen for both pre- and post-menopausal women, and raloxifene for post-menopausal women only •, 2. TwoSERMs and AIs have been evaluated for the primary prevention of breast cancer in women aged ≥35 years in several randomized clinical trials •. Women The NSABP Breast Cancer Prevention Trial BCPT P-1) randomized healthy pre- and post-menopausal women aged 35 years and older with a 5-year Gail model risk score of ≥1.66 % or a history of LCIS to receive tamoxifen 20 mg daily for 5 years versus placebo. Results demonstrated that treatment with tamoxifen significantly reduced the risk of invasive and noninvasive breast cancer by 49 and 50 %, respectively . The red randomizAdditional European studies have evaluated the effect of tamoxifen in women at average and increased risk of breast cancer. These studies demonstrated that tamoxifen reduced ER-positive breast cancers by about one third when compared to placebo –10.Raloxifene is a second-generation SERM that was initially shown to be as effective as tamoxifen in reducing the risk of ER-positive breast cancers . The StuTwo AIs, exemestane and anastrozole, have been evaluated for the primary prevention of breast cancer in post-menopausal women. In a randomized, placebo-controlled trial, exemestane significantly reduced invasive breast cancers  without the toxicities  associated with SERM therapy . ArthralSimilar to the MAP.3 trial, the IBIS-II trial compared the AI anastrozole to placebo, demonstrating a significant decrease in risk of invasive breast cancer and a reduction in ER-positive tumors by 50 and 58 %, respectively . OverallDespite the large number of women who qualify for breast cancer preventive therapy and the US Preventive Services Task Force’s recommendation  to counsA major barrier to discussing or prescribing preventive therapy is lack of confidence in identifying suitable high-risk patients. Primary care physicians (PCPs) are often the first contact person for a woman who wants to discuss her family history and concerns about preventing breast cancer, and PCPs consider it their responsibility to assess breast cancer risk , 18. TheOther factors that prevent physicians from discussing preventive therapy with high-risk women include: lack of knowledge and insufficient training in risk counselling  , 21, lacPhysicians are more comfortable advising about lifestyle modifications , which according to observational studies may reduce breast cancer risk by up to 30 % •. It is Other factors that steer physicians away from recommending preventive therapy include the lack of evidence of a decrease in breast cancer-specific and all-cause mortality •, concerp < 0.0001) [The acceptance of breast cancer risk-reduction therapy is low, with significantly higher uptake rates in clinical trials (25.2 %) than in non-trial settings  , 27. FacThe most important barrier to accepting breast cancer preventive therapy by high-risk women is fear and concern about medication side effects. The most feared side effects are endometrial cancer, risk of blood clots and strokes (SERMS), and decrease in bone mineral density (AIs) –28. WomeAwareness of the availability of breast cancer preventive therapy is limited , even amChemoprevention is often confused with chemotherapy , 28, 30,A general aversion to medications is another important barrier to preventive therapy. Many women view medications as “unnatural”  and declSocio-demographic factors such as age, race, education, income or employment status, insurance status, and costs have not been associated with lower uptake rates , 26. In Some women report doubting risk calculation scores, because they worry that not all risk factors (such as breast density) are taken into account in these calculations . AnotherWomen with a history of breast lesions imparting an increased breast cancer risk   and withAn estimated 10 million American women are eligible for breast cancer chemoprevention , yet <5 Women are motivated to consider preventive therapy when they feel highly vulnerable, such as when they have physical signs and symptoms or abnormal mammographic findings . High-riPCPs’ difficulty in identifying suitable high-risk candidates has been cited as one barrier to discussing or prescribing breast cancer preventive therapy . To addrDespite decision aid interventions using currently available risk calculators and discussions with PCPs about the risk/benefits of preventive therapy to help women make an informed decision, its acceptance will remain low, until medications have fewer side effects, biomarkers can be identified to monitor drug efficacy, and newer clinical risk prediction models can provide true individual risk versus population risk.Future directions and strategies to improve preventive therapy uptake requires attention to the ABC (Agents-Biomarkers-Cohorts) paradigm: the availability of effective non-toxic Agents, effective intermediary Biomarkers to assess response to medication, and better identification of high-risk Cohorts •.New research on genome-wide association studies has led to more recent understanding of combined association of single nucleotide polymorphisms (SNPs) with increased risk for developing breast cancer. Incorporating SNP information into clinical risk prediction models has the ability to better inform individual risk, which in turn could improve uptake of preventive therapy going forward .Overcoming a major obstacle to breast cancer pharmacotherapy necessitates improving its side effect profile. One strategy might be to either offer low- or intermittent doses of existing preventive agents, which would cause fewer adverse side effects •. Clinicp < 0.001) in mammographic density after 18 months on tamoxifen, as compared to placebo [The lack of surrogate biomarkers is another obstacle to the uptake of preventive therapy by high-risk women. Mammographic density has been identified as a risk factor for breast cancer, and it is now being investigated as a biomarker of response to breast cancer chemoprevention •, 41. En placebo , with a  placebo .To realistically decrease breast cancer incidence rates, non-pharmacologic interventions such as lifestyle modifications, which may reduce breast cancer risk by 30 %, should be offered alongside chemoprevention •, 51, 52The uptake of SERMs and AIs for the primary prevention of breast cancer is low, despite its proven efficacy in randomized clinical trials over the past decade. PCPs have difficulty identifying suitable candidates, lack knowledge about therapeutic options and confidence to counsel about preventive therapy. High-risk women’s decision to accept chemoprevention is complex, and their choice often reflects lived experiences, rather than statistical probabilities. Despite decision aid interventions to help women make an informed choice about preventive therapy, acceptance will remain low until physicians are better educated and more skilled in having these discussions, medications are safer and better tolerated, suitable biomarkers to monitor drug efficacy are identified, and clinical risk prediction models using genomic information can provide true individual risk. Risk/benefit counselling about preventive therapy, alongside lifestyle modifications to high-risk women, will simultaneously address breast cancer risk-reduction, and the prevention of co-morbidities, such as diabetes and cardiovascular disease.


P = 0.049); however, longer duration of breast feeding was related to moderately reduced risk of thyroid cancer, suggested by pooled analysis in all cohort studies . The pooled RR in hospital-based case-control studies implicated that parous women were more susceptible to thyroid cancer than nulliparous women . The present meta-analysis suggests that older age at menopause and parity are risk factors for thyroid cancer, while longer duration of breast feeding plays a protective role against this cancer. Nevertheless, more relevant epidemiological studies are warranted to investigate roles of hormonal and reproductive factors in thyroid carcinogenesis.Many studies have investigated the association between hormonal and reproductive factors and thyroid cancer risk but provided contradictory and inconclusive findings. This review was aimed at precisely estimating this association by pooling all available epidemiological studies. 25 independent studies were retrieved after a comprehensive literature search in databases of PubMed and Embase. Overall, common hormonal factors including oral contraceptive and hormone replacement therapy did not alter the risk of thyroid cancer. Older age at menopause was associated with weakly increased risk of thyroid cancer in overall analysis (RR = 1.24, 95% CI 1.00–1.53,  Thyroid cancer is the most common type of endocrine malignancy, which accounts for nearly 3% of all malignancies . DespiteGender discrepancy is well known in thyroid malignancies. Thyroid cancer occurs three times more frequently in women than in men, and the incidence decreases among postmenopausal women. It has been well established that female sex hormones, particularly estrogens, can influence the proliferation and invasion of thyroid cancer cells by recognizing corresponding hormonal receptors expressed in those cells, such as estrogen receptor alpha and beta –5. It haWe searched studies on the association between hormonal and reproductive factors and thyroid cancer risk in PubMed and Embase databases from their inception up to September 10, 2014, using the following items: thyroid cancer, or thyroid carcinoma; and oral contraceptive, hormone replacement therapy, reproductive factors, menstrual factors, age at menarche, age at first birth, menopausal status, age at menopause, parity, pregnancy, reproductive history, or breast feeding; and incidence, or risk factor. References of relevant studies were also screened for additional papers. If studies were duplicated, only the most complete study was included.The included studies must conform to the following inclusion criteria: (1) studies on the association of hormonal and reproductive factors with thyroid cancer risk; (2) cohort or case-control studies; (3) publications presenting odds ratios (ORs), relative risks (RRs), or hazard ratios (HRs) with 95% confidence intervals (95% CIs). Studies not associated with hormonal and reproductive factors and thyroid cancer risk, case-only, animal research, case reports, and duplicated studies were all excluded.Two investigators independently extracted data from each study by use of the following terms: name of first author, year of publication, study design, country of origins, sample size, study period, matching or adjusted factors, and RRs or HRs or ORs with 95% CIs for the estimation of thyroid cancer risk related to hormonal and reproductive factors. Disagreements were solved by discussion.P < 0.05 was suggested to be statistically significant. The between-study heterogeneity was estimated by Cochran's Q and I2 tests, and P < 0.05 and I2 > 50% implicated obvious between-study heterogeneity [Roles of hormonal and reproductive factors in thyroid cancer risk were assessed by calculating pooled RRs with 95% CIs by use of STATA 12.0 software . ogeneity , 34. Theogeneity ; otherwiogeneity . Stratifogeneity , 38.112 studies were retrieved after a comprehensive literature in databases of PubMed and Embase. However, 87 studies were excluded due to irrelevance, reviews, animal research, and case reports. 25 independent studies on the association between hormonal and reproductive factors and thyroid cancer risk were finally included into our study . Among tP = 0.215; for hormone replacement therapy: RR = 1.04, 95% CI 0.91–1.19, P = 0.527)  . SensitiStratified analysis by study design showed that no significant relationship was observed between hormonal factors and thyroid cancer risk in cohort studies and studies in population-based case-control design . We failP = 0.049) (P = 0.021) (P = 0.004)  , whereas= 0.021) . Stratif= 0.004) . No sign= 0.004) . SensitiI2 = 61.2%, P < 0.001). Stratified analysis by study design suggested that the main source of between-study heterogeneity resulted from studies in cohort design .No significant between-study heterogeneity was found in most comparisons of overall and stratified analyses, except for the estimation of parity's effect on thyroid cancer risk .P = 0.049). Besides, longer duration of breast feeding was associated with moderately decreased risk of thyroid cancer, which had been suggested by the pooled analysis in cohort studies . Moreover, the pooled result in hospital-based case-control studies revealed that parous women were more susceptible to thyroid cancer than nulliparous women . Additionally, other reproductive factors including age at menarche, age at first birth, menopausal status, age at menopause, and breast feeding status did not modify the risk of thyroid cancer.Hormonal and reproductive factors have been implicated in the development of thyroid cancer, but the precise association and underlying molecular mechanisms have not yet been fully understood. A previous pooled analysis has investigated the association between female reproductive factors and thyroid cancer risk . UnfortuThe risk of thyroid cancer in women increases at the time of puberty and declines after menopause , 40, supIt has been well established that estrogen receptors are found in thyroid cancer tissue and confer effects on different molecular signaling pathways involved in the growth and function of thyroid , 41, 42.The effect of breastfeeding on thyroid cancer risk is still not clear. Kabat and colleagues demonstrated that duration of breastfeeding did not alter the susceptibility to thyroid cancer . HoweverThe status of parity conferred diverse effects on thyroid cancer risk in different populations. A recent study by Braganza et al. showed that parous women were at an elevated risk of thyroid cancer, as suggested by a recent epidemiological study . InteresAge is a main confounding factor for the association between hormonal and reproductive factors and thyroid cancer risk . We failThe current meta-analysis suggests that older age at menopause and parity are associated with increased risk of thyroid cancer, while longer duration of breast feeding plays a protective role against this cancer. In addition, the precise association needs further investigation by more epidemiological studies with sufficient statistical power in the future.


BRCA1/2 mutation prevalence in this population. Amidst calls for population-based screening for hereditary breast cancer risk, much can be learned from the experiences of Jewish women about their needs. The present study is a secondary analysis of psychoeducational program satisfaction and evaluation data previously collected by a community organization dedicated to serving women of all Jewish backgrounds facing, or at risk for, breast cancer. Among respondents (n = 347), over one-third were referred to the organization by family or friends, most often after a cancer crisis. Of the information and support resources offered, the greatest level of engagement occurred with the one-on-one peer support and health care symposia resources. Respondents endorsed high levels of satisfaction with the programs and services, and a strong desire to give back to the community. These data suggest that culturally-relevant information and support services for Jewish women could be scaled-up for larger dissemination to meet the anticipated needs in this special population.Approximately 12% of women living in the United States will be diagnosed with breast cancer during their lifetimes. While all women face formidable challenges posed by the threat of living with or at increased risk for breast cancer, those of Ashkenazi Jewish descent face additional challenges owing to higher  BRCA1 and BRCA2; BRCA1/2), and Central or Eastern European Jewish heritage (primarily Ashkenazi Jewish descent), radiation therapy to the breast or chest at a young age, as well as other breast health conditions or dense breasts [BRCA1/2 mutation [BRCA1/2 mutation face significantly increased lifetime risks of developing breast cancer [Approximately 12% of women in the United States (USA) will be diagnosed with breast cancer during their lifetimes [mutation , and womt cancer ,5. Breast cancer .BRCA1/2 mutation prevalence is higher in this population than it is in the general population of women from non-Ashkenazi Jewish backgrounds (1:40 vs. 1:400). Regarding psychological outcomes, a study by Metcalfe and colleagues found that among Jewish BRCA mutation carriers, self-reported cancer-related distress increased significantly in the year following genetic testing but did not change among women without a mutation [Although overall breast cancer survival rates are improving, there remain significant health and quality of life impacts among those at increased risk, those who are newly diagnosed and at young ages, and those surviving with the disease . Importamutation . Among Jmutation , and themutation .BRCA1/2 mutations, and other factors. Clinical and public health approaches to screening and testing for BRCA1/2 mutations have evolved over the past two decades. Recommendations focus on incorporating family history-taking and conducting a cancer risk assessment for patients, and subsequently deciding on whether to proceed with genetic testing [In order to potentially act on available risk-reducing and breast cancer management options, it is necessary to first identify women who may be at increased risk for breast cancer owing to family history,  testing . Yet, ge testing . The can testing ,14,15. C testing ,17. Howe testing . Other r testing . Populat testing ,21. WithBRCA1/2 mutations and those already diagnosed with breast cancer, such resources can be offered outside of the health care setting to augment professional services. As described in widely-accepted conceptual models [As such, it is critical that women facing a risk of hereditary breast cancer be adequately educated and counseled along their journey, both medically and psychosocially, before and after learning about their cancer risk and disease status ,23,24. Gl models ,27,28,29l models . Furtherl models . Work adl models ,33. HoweAs noted by the Centers for Disease Control and Prevention, evaluation is the systematic application of scientific methods to assess programs, services, and resources organized by community agencies and the like . Given tIn this work, we report on the results of an outcome evaluation conducted by Sharsheret, a not-for-profit community-based organization whose mission is to connect Jewish women of all backgrounds with no-cost, culturally-targeted resources at all points along their cancer journey: from risk prevention, to diagnosis and during treatment, to survivorship care. The name Sharsheret is Hebrew for chain. The chain symbolizes connections made among Jewish women, families, and communities facing breast cancer together. Through Sharsheret’s outreach activities, each connection made is a link that strengthens the chain of information and support for constituents nationwide. The evaluation included measures and metrics of community referral practices to Sharsheret, service and program engagement and satisfaction, and additional resource needs among the target group of Jewish women at risk for or living with breast cancer.i.e., resources) that are culturally-targeted and based on constituent needs noted during telephone or E-Mail interactions. The present analysis focuses on an evaluation of six of Sharsheret’s signature resources, each of which is described below. These resources are: (1) Peer Support Network; (2) Embrace; (3) Busy Box®; (4) Best Face Forward®; (5) Genetics for Life®; and (6) Health Care Symposia.This is a secondary analysis of anonymous annual self-report surveys collected by Sharsheret. The purpose of the annual survey is to ascertain satisfaction and other outcome data about Sharsheret’s psychoeducational programs and services. The survey included a combination of both open- and closed-ended items, with Likert-type responses. Surveys were program-specific and developed by the organization. The study protocol was reviewed and exempted by the Institutional Review Board at Georgetown University Medical Center. This exemption is in accordance with Title 45 of the Code of Federal Regulations Part 46.102 (d), as well as Part 46.102 (f). Briefly, upon contacting Sharsheret, support staff members direct constituents to one or more information and support programs and services . Jewish parents of young children face unique concerns, such as communicating with their children about their cancer diagnosis and possible hereditary implications for the family. The program is tailored to the constituent’s expressed needs and concerns, as well as the age and gender of child(ren) and potential religious observances. The program includes pamphlets related to coping with a breast cancer diagnosis and family communication. Age-appropriate toys and games are also provided to children for constituents undergoing treatment.Best Face Forward provides resources and materials addressing the cosmetic side effects of radiation and chemotherapy treatment for Jewish women. Informational materials and a kit are provided, which includes brochures about body image and related topics.BRCA1/2 genes, which are known to impact women of Ashkenazi Jewish descent. This information is delivered through various channels: (1) inquiring to the organization’s “Genetic Hotline”; (2) matching with another woman for a one-to-one telephone call; and (3) reviewing an educational booklet, Your Jewish Genes, exploring hereditary breast cancer and ovarian cancer risk in the Ashkenazi Jewish community.Genetics for Life addresses the concerns of Jewish women at higher risk of developing hereditary breast and/or ovarian cancer. This program provides constituents with information related to deleterious mutations in the Sharsheret’s Health Care Symposia educate Jewish women nationwide on a spectrum of issues within breast cancer prevention and treatment. Through national teleconferences, seminars, and webinars, issues are presented through a culturally-relevant lens. Symposia topics include discussions on physical activity and nutrition, fertility and treatment side effects, spirituality and Jewish holidays/cultural and life-cycle events, as well as interpersonal relationship issues. Symposia topics are generated from within the constituent group through symposia evaluations, focus groups, and staff recommendations based on communications with constituents.The target population for this analysis included constituents served by Sharsheret who were at risk for and/or living with breast and/or ovarian cancer, and with contact information maintained in an administrative database. At the end of each calendar year of service , constituents who had provided an E-Mail address to Sharsheret were sent an invitation and follow-up invitation reminder through an E-Mail marketing service to complete a program evaluation by clicking on a URL that was not unique to the intended recipient.  This E-Mail marketing service does not have the capacity to monitor individual invitation deliveries, but is able to track responses. Based upon information made available to the study team, 36% of E-Mailed invitations distributed to constituents were opened, 28% of opened invitations clicked-through to the survey, and 89% of opened surveys were completed. This resulted in an overall E-Mailed survey response rate of 9%, which is not uncommon among Internet surveys. Sharsheret does not proactively update constituents’ contact information: contact information is updated upon the request of constituents, or at the time of subsequent contact with the organization. Thus, it is difficult to determine the survey’s exact response rate as undeliverable surveys could not be traced or eliminated from the denominator.The survey itself was administered online through the provided URL that linked to a separate secure survey research platform. Inspection of the survey platform data indicated that 97% of surveys were completed from unique Internet Provider (IP) addresses. Multiple responses from the same IP address might have indicated that a single constituent responded to the survey twice, or that multiple constituents accessed the survey from within the same computer network , which could not be further determined. In only one instance did we identify that the same IP address was used to complete an annual survey for two consecutive years. This suggested that the vast majority of surveys likely reflected the experiences of unique survey respondents. For those constituents who did not provide an E-Mail address but who provided a physical mailing address, a paper survey was sent by regular mail. (No data were available for 2011 as Sharsheret was engaged in a nationwide needs assessment survey for young breast cancer survivors.)Survey domains included methods of referral to Sharsheret, engagement and satisfaction with Sharsheret resources, and inquiries about information and support needs among Jewish women. Demographic characteristics of survey respondents , as well as clinical characteristics  and family composition  were assessed for the 2013 annual survey only. These data are provided on this subset of respondents as they are likely representative of survey respondents overall.vs. Agree, Somewhat agree, Somewhat disagree, Disagree) some variables were dichotomized to reflect constituents’ survey responses for data harmonization purposes. Only those survey items that were consistently administered across all three years of survey data collection were included in the analysis. Overall satisfaction with services provided is represented by the mean of all individual program satisfaction scores for each participant, excluding programs that the participant did not engage in. These scores are stratified by each resource and provided overall . As shown in BRCA1/2 mutation carriers, and about one-quarter of respondents were also trained as a Sharsheret peer supporter.The study sample included 347 survey respondents. Again, only those who completed the 2013 survey were asked to report on sociodemographic and individual-level information , and most commonly after a new breast cancer diagnosis (44%). Otherwise, constituents located the organization through a health care provider, online, or through another organization or outreach event.Sharsheret offers multiple resources to Jewish women of all backgrounds. Annual survey data indicate that constituents engaged with an average of two resources assessed, as shown in Composite satisfaction scores were derived from each evaluated resource on the corresponding annual survey. The data revealed that the majority of survey respondents reported very high levels of satisfaction with the resources from Sharsheret that they engaged with , over one-half (53%) of respondents expressed interest in doing, which is further testament to the success of the resource and the interests of Jewish women to give back to their communities.The purpose of this paper was to describe how Jewish women facing the risk of or surviving with breast cancer seek-out, utilize, and evaluate information and support provided by a not-for-profit community-based organization (Sharsheret) dedicated to culturally-targeted, no-cost resources. Annual self-reported survey results indicate that constituents initially connected with Sharsheret after referral from a friend or family member while they were in a time of medical crisis or transition, such as a new breast cancer diagnosis. Typically engaging with two or more resources, constituents were overwhelmingly satisfied with the information and support programs and services they encountered. The two resources with the highest levels of engagement were Sharsheret’s one-on-one peer support network and its health care symposium format designed to educate Jewish women about breast cancer prevention and treatment. Thus, as an organization, Sharsheret is meeting this special population’s needs for resources that deeply understand and attend to cultural and religious beliefs and values held by Jewish women of all backgrounds. Each of the resources was evaluated as highly satisfying among survey respondents. These resources share a common focus on meeting the information and support needs of Jewish women about breast cancer, but differ in their communication modality and format. By offering a range of programs and services, Sharsheret is better able to target and tailor their programs to constituents across the cancer prevention-control spectrum.Support, including social support, was provided through the Peer Support and Embrace programs, and is commonly demonstrated in individual and group-based programming . InformaThe findings from this evaluation should be considered in light of several important limitations. First, evaluation data were generated from a relatively small, non-representative convenience sample, with the potential influence of multiple selection biases towards those who were more satisfied/engaged with Sharsheret’s resources. Importantly, just over one-quarter of the surveyed sample self-identified as being peer supporters of the organization—meaning they had received Sharsheret’s services themselves, and then went on to help other constituents. Second, the total number of surveys distributed electronically and to valid recipient addresses could not be accurately determined due to tracking restrictions, which adversely impacted our ability to derive the survey’s response rate. Regarding completed surveys, 97% were linked to unique IP addresses, suggesting they were completed by independent respondents, but this cannot be entirely verified. Third, with some minor differences in Likert response structure by year, only those items consistently present in the annual outcome surveys were included. Consequently, while the review contains data merged from all three years, demographic data were only available for one evaluation year. Also, survey items were agency-specific and did not include well-validated scales and measures. Finally, we could not stratify our analysis based on self-reported clinical characteristics, such as cancer status at the time of the survey, because such data were unavailable for the entire sample. Further examination of this population and additional validation of results over time is necessary.The high level of satisfaction paired with requests for additional information and support among this population present an opportunity to deepen and expand such resources to fill gap areas in the care of Jewish women affected by or at high risk of developing breast cancer. These needs can be met by organizations dedicated to increased breast cancer awareness, empowerment, and service. Community health workers and patient navigators are increasingly becoming integrated into cancer care and preventive medicine. Community engagements that focus on genetic and environmental determinants of cancer can favorably impact upon utilization of screening and genetic testing for familial breast cancer risk. These services should be evidence-based, and grounded in interpersonal and ecological theories to consider constituents’ self-efficacy and structural facilitators and barriers of health promotion and health behavior. Early adopters within communities may facilitate increased adoption among others later on. Embracing cultural targeting allows for support services to be highly salient to the intended community of interest, such as Jewish women facing the prospect of or living with breast cancer. This is particularly timely if and when population-based screening for breast cancer genes becomes commonplace and more Jewish women are seeking information about hereditary breast cancer or otherwise affected by breast cancer in their lives.


Several dietary indices have been developed to measure overall diet quality, including the Healthy Eating Index-2005 (HEI-2005), which measures adherence to the 2005 Dietary Guidelines from the USDA; the Alternative Healthy Eating Index-2010 (AHEI-2010), which is based on foods and nutrients predictive of chronic disease risk; and the Alternate Mediterranean Diet Score (aMDS), which is an index that characterizes traditional food patterns of Mediterranean countries. Few studies have evaluated diet quality and ovarian cancer risk.We assessed the associations of the HEI-2005, AHEI-2010, and aMDS with risk of epithelial ovarian cancer prospectively among women in the Nurses’ Health Study. We used Cox proportional hazards models, adjusting for known ovarian cancer risk factors.Ptrend) of epithelial ovarian cancer comparing the highest with the lowest quintile were 1.03  for the AHEI-2010, 0.85  for the HEI-2005, and 0.91  for the aMDS.During 24 years of follow-up, we documented 696 incident epithelial ovarian cancer cases among 82,948 women with diet information. The multivariate adjusted hazard ratios  contains supplementary material, which is available to authorized users. Ovarian cancer is the fifth leading cause of cancer death for women in the U.S. . There aa priori defined dietary patterns and are designed to evaluate an individual’s overall diet, usually derived from adherence to dietary guidelines. This measurement considers dietary intake as an overall pattern, rather than evaluating individual nutrients or food groups, which could lead to important information that may represent new pathways for prevention. While most diet quality scores were developed to predict cardiovascular outcomes [Prior studies of diet and ovarian cancer generally have evaluated only one food or nutrient at a time e.g. -10). Die. Die10])outcomes ,12, theroutcomes -15. Onlyoutcomes .Using Food Frequency Questionnaire (FFQ) data collected from women in the Nurses’ Health Study (NHS), we prospectively examined the associations between three diet quality scores and risk of ovarian cancer. The diet-quality scores examined were the Alternative Healthy Eating Index 2010 (AHEI-2010), HEI-2005, and the Alternate Mediterranean Diet Score (aMDS).The NHS is a prospective cohort initiated in 1976, when 121,700 female registered nurses, 30 to 55 years of age and residing in 11 U.S. states, completed an initial questionnaire. In 1984, we used a comprehensive FFQ to collect dietary data from participants. The cohort has been followed by biennially mailed questionnaires to update covariate information and ascertain non-fatal incident diseases. Deaths in the cohort are usually reported by family or postal authorities. We also search for names of non-responders in the National Death Index ,18. The Dietary information was measured by a self-administered semi-quantitative, 131-item FFQ, which was completed every 2 to 4 years in the cohort. For each food, a portion size was given and women were asked to choose from 9 intake frequencies, from never to ≥6 servings per day averaging over the prior year’s intake. Consumption of cold breakfast cereals, cooking oils, margarines, and multiple vitamins was specified by brand. The validity of our FFQ was evaluated by comparison with diet records in 192 NHS women; the average correlation for all foods was 0.63 .The HEI-2005 measures adherence to the USDA Dietary Guidelines established in 2005, and is based on dietary recommendations to ensure adequate nutrient intake ; the comThe AHEI-2010 was created as an alternative to the HEI; this index was designed to incorporate foods and nutrients that have been consistently associated with chronic disease risk . It inclThe aMDS is an index that characterizes traditional food patterns of Mediterranean countries. We used a modified version of the original MDS constructed by Trichopoulou and colleagues . The aMDWe collected extensive information on potential covariates, including demographic characteristics, body mass index (BMI), parity, oral contraceptive use, menopausal status, HT use, tubal ligation, caffeine intake, family history of ovarian cancer (in first degree family members), and other lifestyle factors. In general, most covariates were updated every 2–4 years.Ovarian cancer cases were identified either by self-report of the disease on a biennial questionnaire or through family members, the postal service, or the National Death Index. Women or their next of kin were asked for permission to obtain and review pathology reports to confirm the diagnosis and classify cancers by behavior (invasive vs. borderline), histologic type , and stage. For cases without medical records we attempted to confirm the diagnosis through the appropriate state cancer registry. We compared the pathology report histology with a review of slides by a gynecologic pathologist for 215 cases. The concordance was 98% for morphology and 83% for histology .At baseline we excluded women diagnosed with any cancer other than non-melanoma skin cancer , women who reported a prior bilateral oophorectomy , or menopause due to pelvic irradiation (n = 90). In addition, 1,448 NHS participants died before start of follow-up in 1986. Lastly, participants who did not complete the 1984 FFQ, had an implausible caloric intake in 1984 , or left more than 70 items blank on the 1984 FFQ as well as participants who did not have dietary score data available in 1984  did not enter the analysis until they had valid dietary data. Participants accrued person-time from the return date of the 1986 questionnaire  until the earliest of the following events: ovarian cancer diagnosis, any other cancer diagnosis (excluding non-melanoma skin cancer), bilateral oophorectomy, pelvic irradiation, death, or the end of follow-up .Our primary exposure variables were cumulatively averaged diet scores (in quintiles) assessed at least 2 years before diagnosis  to account for potential influences of subclinical disease on dietary patterns. With this method, we used the diet score values from 1984 as the exposure for the follow-up period from 1986 to 1988, the average of the 1984 and 1986 values as the exposure for 1988 to 1992, the average of the 1984, 1986, and 1990 values as the exposure for 1992 to 1996, and so on. This approach allows the evaluation of long-term dietary intake with reduced measurement error, but maintaining true variations in diet . We testWe used Cox proportional hazards models, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) associated with quintiles of diet-quality scores. We handled time-varying covariates using the Andersen-Gill data structure , with co2), parity , number of additional pregnancies (continuous), oral contraceptive use duration , smoking (pack-years), menopausal status , type and duration of PMH use , age at menarche (years), hysterectomy , unilateral oophorectomy , lactose intake (g/d), caffeine intake (mg/d), and physical activity .For multivariate models, we adjusted for known and putative risk factors for ovarian cancer, including age (months), total energy intake , family history of ovarian cancer , tubal ligation , BMI  between HEI-2005 and AHEI-2010 scores, 0.43 (P < .0001) between HEI-2005 and aMDS, and 0.56 (P < .0001) between AHEI-2010 and aMDS.We documented 696 incident epithelial ovarian cancer cases over 24 years of follow-up among 82,948 women. At the midpoint of follow-up 1998), women with a high AHEI-2010 score had lower BMI, higher physical activity, lower caffeine intake, higher lactose intake, and smoked less than those with lower scores . Compared to women with AHEI-2010 ≤ 42, the multivariate adjusted HRs (95% CI) were 1.02 (0.78-1.32) for AHEI-2010 >42-48, 1.23 (0.96-1.59) for AHEI-2010 >48-53, 1.11 (0.86-1.43) for AHEI-2010 > 53-59, and 1.03 (0.80-1.34) for AHEI-2010 > 59  and when we restricted to women without a family history of ovarian cancer.Overall, the AHEI-2010 was not statistically significantly associated with epithelial ovarian cancer risk (P trend = 0.57) and women with aMDS > 5.5 versus ≤2.6, the HR was 0.91 . No heterogeneity was observed comparing different ovarian cancer subtypes for the HEI-2005 (P heterogeneity ≥ 0.32) or aMDS (P heterogeneity ≥ 0.41) and the results were similar when restricting to women without a family history of ovarian cancer.No clear associations were observed for the HEI-2005 Table  or the aIn this large prospective study, we did not observe any clear associations between three diet quality scores and the risk of epithelial ovarian cancer. Further, no association between the diet scores and risk were observed for specific ovarian cancer subtypes defined by invasiveness, histology, or tumor aggressiveness.Our results are consistent with one small study of the HEI-2005 and ovarian cancer risk, which observed no association  and a prThe major strengths of our study are the large number of ovarian cancer cases; this enabled us to examine risk by tumor characteristics. We also had comprehensive information on diet and important covariates. All this information was collected prospectively, which reduces the potential for recall bias. In addition, dietary and covariate data were assessed multiple times throughout follow-up, which allows us to use long-term, cumulative average exposures and thus reduce within person variation. To reduce potential reverse causation by sub-clinical ovarian cancer influencing diet, we used a 2-year lagged analysis. Finally, the dietary scores calculated in our study have a wide distribution except for aMDS, suggesting that we have a good representation of different dietary habits in the US.Several methodological issues should be considered in interpreting our findings. First, the diet scores are calculated using arbitrary weights that are assigned to each component, in part based on research on cardiovascular disease risk. Second, we cannot distinguish brands or processing methods for the food items on the FFQ, which may cause misclassification in nutrient content. Finally, self-reported diet assessed by FFQ has measurement error, even though we validated it with dietary records ,38,39. WOverall, in this large prospective cohort study among US women, we did not observe any clear associations with three scores of diet quality, AHEI-2010, HEI-2005, or aMDS, with the risk of epithelial ovarian cancer, suggesting that current dietary recommendations in the US may not influence ovarian cancer incidence. Given the limited number of ovarian cancer cases in individual cohorts, a pooled analysis of prospective cohorts should be considered to evaluate potential differential associations for more rare tumor subtypes and consideration of other dietary scores that better reflect factors associated with cancer is warranted.


Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores . Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy . These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment. All participants provided informed consent to take part in PGSNPS.The data used in this study is held by the Trial Management Group for PGSNPS, where the original concept for this analysis was designed. Any access requires appropriate ethical approvals and would be assessed by the Trial Management Group which includes the respective Chief Investigators of the clinical trials and PGSNPS. Transfer of data would require a specific Data Transfer Agreement.This study investigated two common and clinically important chemotherapy-induced toxicities: neutropenia and taxane-related sensory neuropathy . For all patients, toxicity information was collected prospectively and graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 2 or 3, depending on the clinical trial from which the patient was recruited into PGSNPS. Rates and grades of neutropenia were recorded in 1676 patients who received any of the trial chemotherapy regimens in NEAT, tAnGo and Neo-tAnGo (data for neutropenia was not available from BR9601) or were not in a trial and received E-CMF. Rates and grades of neuropathy were recorded in 1279 patients who received a paclitaxel-containing regimen (tAnGo and Neo-tAnGo).−5). Samples were removed that had >10% of all variants missing. Principle components analysis (PCA) was used to identify and exclude individuals with non-European ancestry and control for population substructure. Genome coverage was increased by imputation using SHAPEIT [Samples were genotyped using the Affymetrix 6.0 SNP array. Quality control procedures were applied to remove variants that were missing in >5% of samples; had minor allele frequency (MAF) < 1%; or had MAF<5% and were missing in >1% samples. Variants were also removed if their genotype frequencies deviated from those expected under Hardy-Weinberg equilibrium  and controls  see . LogistiInteresting associations between polygenic risk and toxicity were followed up with exploratory pathway analysis to investigate whether a subset of the breast cancer variants, lying in a common pathway, were responsible for the observed association. The breast cancer variants were mapped to the genes in which they lay or to the nearest gene if they were intergenic. These variant-gene pairs were ranked using the p-value for association between each variant and toxicity, from most strongly to least strongly associated, regardless of the direction of effect on toxicity. Where more than one variant mapped to the same gene, the most significant toxicity-associated variant was used for ranking. The top 50% of the ranked genes were entered into the Database for Annotation, Visualization and Integrated Discovery (DAVID) version 6.7 functional annotation tool ,20. DAVIThis study was well powered to detect significant associations between breast cancer polygenic risk score and the toxicity endpoints examined. Assuming a 30% prevalence of moderate-severe toxicity  in breast cancer patients, the power to detect a small difference of 0.1 in mean risk score between patients with moderate-severe toxicity and patients with no or mild toxicity, at p-value<0.05, would be 96% in the neuropathy sample and 99% in the neutropenia sample. This difference in mean risk score is equivalent to a relative risk of moderate-severe toxicity of 1.1 for patients with a higher polygenic risk score.The total number of patients included in this study was 1677. Patient characteristics are summarised in −4 level.The non-weighted risk score was significantly associated with a decreased risk of neutropenia (grade ≥3) on univariable analysis ; p = 0.04) . This fiCCND1, CHEK2, MDM4) in the p53 signalling pathway appeared in the top 38 genes. However, this observed enrichment did not remain significant following Bonferroni correction for the multiple pathways tested by the DAVID tool .Pathway analysis was performed to investigate whether a specific molecular pathway was driving the trend between increased breast cancer risk and reduced risk of neutropenia. The individual breast cancer risk variants were ranked according to their p-value for association with neutropenia and the ranked variant-gene pairs were compiled to create a list of 76 genes. et al 2015) plotted against their effects on neutropenia in the PGSNPS sample; there is no visible relationship between the effects. Pathway analysis did not identify any significant pathway enrichment in the genes representing the top-ranked breast cancer risk variants.The hypothesis behind this study was that common genetic variants known to increase the risk of breast cancer may also increase the likelihood of developing treatment-related toxicity following chemotherapy for breast cancer. In this well powered study, no evidence was found for an association between common variants known to increase breast cancer risk and taxane-related sensory neuropathy in the PGSNPS cohort. Interestingly, and contrary to our hypothesis, there was some evidence of a relationship between carrying an increased number of breast cancer risk alleles and decreased risk of experiencing chemotherapy-induced neutropenia grade ≥3 ). Weighting the alleles by the estimate of their effect on breast cancer risk reduced the strength of this association. This suggests that the magnitude of effect that these variants have on risk of neutropenia is not equal to their magnitude of effect on risk of breast cancer. This is demonstrated in None of the individual variants were significantly associated with chemotherapy-induced toxicity. The original work that confirmed the association of the 94 genetic variants with breast cancer risk was performed by BCAC and based on samples of over 100,000 patients. In contrast, the PGSNPS breast cohort studied in the current analysis has fewer than 2,000 patients. Therefore, the power to detect a true association at genome-wide significance is much lower than that of the breast cancer susceptibility studies. With an increased sample size, there would be greater power to detect strong associations between individual variants and chemotherapy toxicity.et al have shown that in a cohort of over 6000 early breast cancer patients from randomised clinical trials, those who achieved neutropenia grade ≥3 during their treatment had statistically significant improved relapse-free survival ; p = 0·02) [The observed association between polygenic breast cancer risk and decreased neutropenia suggests that breast cancer patients who present with a high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy and may experience less neutropenia compared to patients with low genetic risk of breast cancer. There is strong evidence to support the relationship between neutropenia or leukopenia and improved survival –23. Abra = 0·02) .Given the potential relationship between neutropenia and clinical outcome, the finding that patients with high polygenic risk of breast cancer experience less neutropenia may, firstly, reflect the fact that for some patients standard chemotherapy regimens are sub-optimal and, secondly, suggests that genetic risk of cancer may potentially distinguish these patients, who may tolerate more intense chemotherapy that could improve survival. If this is the case, common breast cancer risk variants may be a useful tool for predicting which patients are likely to have poorer prognosis. We evaluated the relationship between the breast cancer risk polygenic score and relapse-free survival in the same cohort of patients. The polygenic risk score was predictive of relapse-free survival such that patients who have an increased risk of breast cancer (and therefore lower risk of neutropenia) tended to have shorter relapse-free survival ; p = 0.06). This equates to a 23% increase in risk of relapse or death for every 10 extra risk alleles that a patient carries ; p = 0.06). This difference in hazards is illustrated in a Kaplan-Meier plot in In conclusion, for breast cancer patients who are carrying common genetic variants known to increase the risk of breast cancer, standard chemotherapy for breast cancer, although safe, may not be adequately effective. It is likely that there are less common variants and rare mutations that have large effects on toxicity response to chemotherapy and these may prove more useful for predicting patient drug response in the clinic. Thus, targeted sequencing of candidate genes or whole-exome/genome sequencing in large patient samples should be a next step in the search for pharmacogenetic determinants of chemotherapy toxicity.S1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


MicroRNAs (miRNAs) are short regulatory RNAs that can modulate gene expression and function as negative regulators. Common genetic variants like single nucleotide polymorphisms (SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences in carcinogenesis. Therefore, we evaluated the genetic variants in pre-miRNAs: hsa-miR-146a G/C (rs2910164), hsa-miR-196a2 C/T (rs11614913), and hsa-miR-499 T>C (rs3746444) for their role in breast cancer susceptibility.In silico analysis was done using various bioinformatics tools .The study comprised 121 breast cancer patients, 115 with benign breast disease, and 164 controls. The genotypic frequency of miRNA polymorphisms was determined by PCR-RFLP assay. Logistic regression was used for statistical analysis using SPSS Software version 15.0. p < 0.05, OR = 0.5) as compared to controls. On the contrary, no significant difference was observed in the distribution of miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) polymorphisms in any groups both at genotype and allele levels. On the other hand, in multivariate analysis, we found that the miR-196a2 (rs11614913) C>T was associated with an increased risk of breast cancer risk in postmenopausal females . We also attempted to find out the risk of malignant breast disease in relation to each of the above SNPs on dividing our data on the basis of benign and malignant status, but no significant difference was observed. In silico analysis using F-SNP showed change in transcriptional regulation by miR-146a G/C (rs2910164), miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) variations; the functional score was 0.100, 0.065 and 0.277, respectively.The heterozygous variant of miR-146a G/C (rs2910164) is associated with the reduced risk of breast cancer at the genotype level as well as at the allele level (The results of the present study demonstrate that miR-146a G/C (rs2910164) polymorphism is associated with reduced genetic susceptibility to breast cancer. However, multivariate analysis showed as miR-196a2 (rs11614913) C>T to be associated with increased risk of breast cancer risk in postmenopausal females. Further multicentric studies involving a large number of cases need to be carried out to strengthen the present results. Breast cancer is the most frequently diagnosed cancer among women. It is the leading cause of cancer death in the less-developed countries . AccordiMany environmental and genetic factors are known to play an important role in the breast cancer genesis and prognosis. The BRCA1 and BRCA2 mutations together account for about 20–25% of hereditary breast cancers  and abouMicroRNAs (miRNAs) are small, non-coding, approximately 22-nucleotide miRNAs that regulate gene expression . They fuSo, this present case control association study was designed to evaluate the role of pre-miRNA genetic variations miR-196a2 C/T (rs11614913), miR-146a G/C (rs2910164) and miR-499 T>C (rs3746444) polymorphisms in susceptibility to breast cancer.In the present case control study, we recruited 121 breast cancer (CaB) patients, 115 with benign breast disease, and 164 healthy controls. The cases and the controls included in the present study were unrelated and were of similar ethnicity, i.e., North Indian. The subjects were recruited from the department of surgical oncology, King George Medical University, Lucknow, India. The healthy controls were recruited from unrelated individuals within the general population. The inclusion criteria for the controls were: absence of prior history of cancer or precancerous lesions and absence of any chronic disease/malignancy and were frequency-matched to cancer cases for age, gender, and ethnicity. Written informed consent was obtained from all the individuals. The study protocols and the work were approved by the institutional ethical committee, and the authors followed the norms of the World’s Association Declaration of Helsinki.et al  = 0.5; p = 0.01; [OR] = 0.6). On the contrary, no significant difference was observed in the distribution of miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) polymorphisms in any groups both at the genotype and allele levels.The study did not find any significant association of all the selected variants miR-146a G/C (rs2910164), miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) on the basis of segregation of CaB patients according to tumour stage and lymph node involvement (data not shown).p = 0.02, [OR] = 3.2] (Data not shown), whereas no association of other variants (p > 0.05) was found. We did not find any association in any of the above parameters on comparing the benign and malignant groups.The present study did not find any significant association of all selected variants miR-146a G/C (rs2910164), miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) on the basis of ER, PR, and HER2 presence or absence in case only analyses. In multivariate analysis, miR-196a2 (rs11614913) C>T was associated with increased risk of breast cancer in postmenopausal group , miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) variations  in pre-miRNAs with 115 benign breast disease and 121 breast cancer patients, and 164 controls in a North Indian population. It was found that the heterozygous variant of miR-146a G/C is associated with a statistically significant reduced risk of breast cancer. On the contrary, no significant difference was observed in the distribution of miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) polymorphisms in any groups both at genotype and allele levels.http://www.microrna.org/) are deregulated in many cancers [Mir-146a regulates many genes like IRAK1, ST7L, BCORL1, CARD10, and MMP16 [et al showed the association between miR-146a genetic variants and colorectal cancer [Several previous studies have been reported in the literature showing the influence of miRNA 146a in various cancers. However, there are very few studies in the literature showing the role of miRNA 146a C>G polymorphism in breast cancer. A recent study reported that the rs2910164 C>G in pre-miR-146a may contribute to genetic susceptibility to lung cancer . A studyl cancer . Thus, met al has shown that miR-499 influences the expression levels of miR-499a-5p during the tumourogenesis of oral squamous cell carcinoma. The authors have concluded that miR-499a may contribute to an increased risk of BQ-related oral sub mucous fibrosis, but a decreased risk of oral squamous cell carcinoma [et al has clarified that three polymorphisms in microRNAs have different effects on cancer risk in the Asian population [A polymorphism study by Hou arcinoma . A meta-pulation . Evidencpulation .We also tried to find out the risk of malignant breast disease in relation to each of the above SNPs on dividing our data on the basis of benign and malignant status but no significant difference was observed. The correlation of pre-micro RNA polymorphisms mir-146a, mir-196a2 and mir-499 with clinicopathological parameters (lymph node and tumour stage) did not find any significant difference. In the multivariate analysis, the miR-196a2 C/T (rs11614913) was associated with increased risk of breast cancer risk in postmenopausal group, but no association was found when comparing the benign and malignant group.In silico analysis using FSNP showed a change in transcriptional regulation by miR-146a G/C (rs2910164), miR-196a2 C/T (rs11614913) and miR-499 T>C (rs3746444) variations .An However, the limitations and strengths of our study need to be mentioned. The disease was histopathologically confirmed in all the cases, and the controls were matched for age, gender, and ethnicity. However, the sample size in the present study is sufficient to yield 80% power, but is limited in subgroup analysis.p = 0.02). However, the mechanisms underlying this association need to be further explored. Further studies investigating the role of pre-miRNA genetic variants in breast cancer and replication of the present study in diverse ethnic groups are needed to better understand the pathobiology of breast cancer.Our study shows that miR-146a G/C (rs2910164) may confer a reduced risk of breast cancer. We have found in a multivariate analysis that miR-196a2 (rs11614913) C>T is associated with increased risk of breast cancer in the postmenopausal group (The authors have no conflicts of interest to declare.


No study has been conducted to investigate the spatial pattern and association of socioeconomic status (such as income) with breast and colorectal cancer incidence in Texas, United States. This study aimed to determine whether median household income was associated with the risk of developing breast and colorectal cancer in Texas and to identify higher cancer risks by race/ethnicity and geographic areas.This was a retrospective cohort study with an ecological component in using aggregated measures at the county level. We identified 243,677 women with breast cancer and 155,534 men and women with colorectal cancer residing in 254 counties in Texas in 1995–2011 from the public-use dataset of Texas Cancer Registry. The denominator population and median household income at the county level was obtained from the U.S. Bureau of the Census. Cancer incidence rates were calculated as number of cases per 100,000 persons and age-adjusted using the 2000 US population data. We used the ArcGIS v10.1 (geographic information system software) to identify multiple clustered counties with high and low cancer incidences in Texas.Age-adjusted breast cancer incidence rate in the highest median income quintile group was 151.51 cases per 100,000 in 2008–2011 as compared to 98.95 cases per 100,000 in the lowest median income quintile group. The risk of colorectal cancer appeared to decrease with increasing median income in racial/ethnic population. Spatial analysis revealed the significant low breast cancer incidence cluster regions located in southwest US-Mexico border counties in Texas.This study demonstrated that higher income was associated with an increased risk of breast cancer and a decreased risk of colorectal cancer in Texas. There were geographic variations with cancer incidence clustered in high risk areas in Texas. Future studies may need to explore more factors that might explain income and cancer risk associations and their geographic variations.The online version of this article (doi:10.1186/s12885-016-2324-z) contains supplementary material, which is available to authorized users. Breast cancer has the highest incidence rate in women and colorectal cancer is the third most common cancer in both men and women in the United States –4. PreviHere, we classified counties into five median household income categories by calendar year to examine whether median household income was correlated with the risk of breast and colorectal cancer in Texas , 27, 28.This was a retrospective cohort study with an ecological component in using aggregated measures at the county level. The Texas Cancer Registry (TCR) granted the permission to access the public-use dataset which was used to identify incident breast and colorectal cancer cases. The TCR is a statewide and population-based cancer registry with gold certification by the North American Association of Central Cancer Registries . The TCRBecause individual income information was not available at the TCR dataset, the aggregated median household income at county level was analyzed as SES. County median household income was chosen in this study because the median household income was more homogeneous with respect to SES and more accessible with wide representative of individual income factor . Previouth quintile) to the lowest (1th quintile) in Texas.Median household income at the county level was obtained from the U.S. Census Bureau . It was n = 35). Using TCR dataset, we obtained age, sex, and race/ethnicity for breast and colorectal cancer cases at an individual level [Incident breast and colorectal cancer cases were identified from TCR data using the following criteria: breast cancer among women and colorectal cancer among both men and women, diagnosed between 1995 and 2011, and no missing records on county at diagnosis. Breast cancer cases were identified using the “Primary Site” variable in TCR, coded as C500-C509 according to “International Classification of Diseases for Oncology, Third Edition (ICD-O-3), and Topography Section” . Colorecal level . Cases wal level .Spatial analyses have become an important tool used in public health research to identify potential cluster disease regions –20. In tThe denominator of population data used to calculate incidence rates were acquired from the U.S. Census Bureau’s Population Estimates Program . BecauseFurthermore, cancer incidence rates were stratified by tumor stage for each median household income categories. Tumor stage at diagnosis includes in-situ, localized, regional, distant, and unstaged, which were defined according to the staging manual of National Cancer Institute . The in-Table P < 0.001). In other areas of Texas, only a few isolated counties were identified as low cold spot regions. Cold spot maps were provided in supplemental materials  and screening patterns for breast and colorectal cancer were not measured in our study, this report cannot address how these factors might explain the observed associations between income and cancer risk, but only demonstrated that higher income was associated with an increased risk of breast cancer and a lower risk of colorectal cancer in Texas. In particular, the mechanism of the finding that the trend of an increased risk of breast cancer in association with higher median income was statistically significant only in non-Hispanic white women after adjusting for age may need further research. There were some other limitations to be noted in this study. First, the income variable was the median household income at county level but not at individual level. Hence, there was a potential ecological fallacy in which the income at group level may not necessarily represent the income at individual level. Second, median household income alone may not be a good proxy for socioeconomic status. Ideally, education, occupation, and health knowledge, which are strongly associated with higher cancer screening rates and healthy lifestyles, should all be taken into consideration in the analyses. Third, the denominator populations by county in the non-census years were estimated by the U.S. Bureau of Census. We were unable to verify specific populations by year and age, particularly when Texas has one of the largest population growth and change in demographics in the U.S. The lack of accuracy in population estimates might have led to biased calculations for cancer incidence rates.In conclusion, this statewide and population-based study demonstrated that higher income was associated with an increased risk of breast cancer and a decreased risk of colorectal cancer in Texas. There were also geographic variations with cancer cases clustered in high and low risk areas in Texas. Future studies may need to explore more factors that might explain these income and cancer risk associations and geographic variations.The Institutional Review Board of the Texas Department of State Health Services and the Committee for the Protection of Human Subjects at the University of Texas Health Science Center granted ethics approval to our study. The informed consent was waived because the study was retrospective in design and from public datasets.Not applicable because this manuscript does not contain any individual persons data.http://www.cprit.state.tx.us/texas-cancer-registry [http://www.census.gov/did/www/saipe/index.html [The de-identified datasets on incident breast and colorectal cancer cases in this study cannot be shared due to the release policy requirement by the Texas Cancer Registry (TCR). However, these public-use datasets can be obtained from TCR by following a few appropriate procedures at registry . Informadex.html , 29.


Polycystic ovary syndrome (PCOS) is a common condition affecting ∼8% of women. The objective of the present study was to quantify separately the risk of endometrial cancer, ovarian cancer and breast cancer in women with PCOS compared with non-PCOS controls, and quantify separately the risk to women of all ages as well as the risk to premenopausal women.We conducted a systematic review and meta-analysis of observational studies. Studies were eligible for inclusion if they compared women with PCOS to non-PCOS groups for fatal or non-fatal gynaecological cancers. Studies listed in MEDLINE and EMBASE published up to 7 October 2013 in any language were identified, and relevant papers were also searched by hand. Relevant data  were extracted and tabulated.P < 0.008), but the risk of ovarian and breast cancers was not significantly increased . However when studies which included women aged over 54 years were excluded from the analysis, the risk for women with PCOS increased further for endometrial cancer , became significantly increased for ovarian cancer , but remained non-significant for breast cancer .From 698 references, 11 studies  met the inclusion criteria for the meta-analysis (919 women with PCOS and 72054 non-PCOS controls). Using the Mantel–Haenszel method, with fixed or random effects model as appropriate, women with PCOS were at a significantly increased risk of endometrial cancer (odds ratio (OR), 2.79; 95% confidence interval (CI), 1.31–5.95, This is the first meta-analysis to examine gynaecological cancers in women with PCOS younger than 54 years of age compared with controls of similar age. Current data suggest that women of all ages with PCOS are at an increased risk of endometrial cancer but the risk of ovarian and breast cancer was not significantly increased overall. These results highlight the potential risk of gynaecological cancer morbidities associated with PCOS. However, the available evidence is far from robust and variation in diagnostic criteria for PCOS, associated risk factors (particularly obesity), and selection bias in the studies may have resulted in an exaggeration of the increased risk. Furthermore, women who have PCOS should also be made aware that any increased risk for endometrial cancer must be judged in the context of its relatively low incidence in the general population. A large well-controlled prospective study is required in order to gain a more accurate estimate of the risk of gynaecological cancers in women with PCOS.CRD42012003500. Polycystic ovary syndrome (PCOS) is a very common hormonal disorder affecting ∼5–8% of women of reproductive age . The disConcerns that women with PCOS might be at increased risk of cancer date back to the 1940s  but thisThe first reports of an association between PCOS and cancer related to endometrial disease  at age 70 years. One in eight women develop breast cancer, and this occurs post-menopausally in 80% of cases. Similarly, most cases of ovarian cancer occur post-menopausally . The lasThe guidelines issued by The study reported the actual number of women from each group who experienced the event and the number who did not experience the event;The studies reported other relevant data, e.g. the number of women in each group;Papers with titles or abstracts that indicated that they were not relevant, for example, animal studies, reviews, or single case studies, were excluded. Papers not published in English were reviewed.Studies that compared cancer events in women with PCOS to non-PCOS controls were eligible for inclusion provided that:The search replicated that by Data were collected and coded based on clinical relevance, for example BMI data were collected because of the clinical relevance of BMI to the development of cancer (Information was extracted from each study regarding: (i) characteristics of the participants ; (ii) the comparison (PCOS compared with controls); (iii) the outcome(s) measured ; and (iv) the study design (case–control or cohort). Additional data were extracted in order to assess the methodological quality of each study. The quality assessment criteria were: (i) whether the PCOS diagnosis was sound; (ii) whether selection bias could be ruled out; (iii) whether the control group was selected from hospital or the community; (iv) whether the control group was assessed for PCOS status; (v) whether the PCOS and control group were comparable in terms of age and BMI; (vi) ascertainment of diagnosis; (vii) whether the ascertainment of diagnosis was similar for PCOS and control group; (viii) whether the response rate was similar in the PCOS and control group.P < 0.00002). Discrepancies were examined and discussed before a final score was agreed upon and assigned.Each article was assessed by authors J.A.B. and P.J.H., and articles that fitted the main criteria  were accessed. Methodological quality was assessed by J.A.B. and M.M.A. based on the criteria of the NOS for case–control studies ; The NOSThe raw numbers of events in each study in each of the PCOS and non-PCOS samples from each study were identified and calculated as a common unit, the OR. The OR is the ratio of the odds of the outcomes in each group. The Mantel–Haenszel method was used, with a random effects model in most cases, to generate an OR for all included studies combined. Results were considered statistically significant where the probability value was below the 0.05 threshold. Review Manager statistical software, version 5.2, was used to analyse data.The outcome measure was a diagnosis of cancer. With the exception of some of the women in one study  are listed in Table Regarding the quality of the studies, in general the NOS scores were moderate. Table I2 and χ2 statistics. I2 values of 30% or above were considered likely to indicate moderate heterogeneity and I2 value >50% indicative of substantial heterogeneity. χ2P-values <0.10 were considered to represent significant heterogeneity. Therefore studies showing tolerable levels of heterogeneity  were analysed using a fixed effects model, and studies showing any greater degree of heterogeneity were analysed using a random effects model.Heterogeneity was assessed using Figures P < 0.008), but not for ovarian cancer (P < 0.11), nor breast cancer (<0.78). When women aged over 54 years old were excluded from the analysis, the risk for women with PCOS increased further for endometrial cancer (P < 0.00001), became significantly increased for ovarian cancer (P < 0.03)  and remained relatively unchanged for breast cancer (P < 0.35).Table To assess publication bias, funnel plots were created Figs –7.FigurN = 3) is small, it is difficult to draw firm conclusions regarding publication bias.The funnel plot of the findings for endometrial cancer Fig.  is asymmThis is the first systematic review of gynaecological and breast malignancies in women with PCOS to be published since 2009 and the first ever to separately analyse the risk in premenopausal and post-menopausal women  with this syndrome. Our analysis identified two studies published during the 2 years since the last meta-analysis  confirmed previous suggestions that the risk of endometrial cancer may be even higher in this subgroup of women with PCOS. It is of interest that in the three studies which reported ovarian cancer, the increased risk in women with PCOS was not significant, but the OR was higher and significant in the single study of women aged <54 years. The risk for breast cancer was not significantly different in PCOS compared to the control women overall, or in the subgroup analysis of the two studies of younger women with breast cancer. This finding for endometrial disease is consistent with the observation that post-menopausal women tend to have type II endometrial cancer, which has not been shown to be associated with PCOS, unlike type I , and selection bias may have resulted in an exaggeration of the increased risk. Women who have PCOS should be made aware that the increased risk we report for endometrial cancer must be judged in the context of the relatively low incidence in the general population .The current uncertainty regarding cancer risk in PCOS is not likely to be resolved by additional case–control studies, the design of which allows limited scope for controlling for the effect of different confounding factors and interactions between them. It is imperative that any association between PCOS and cancer is examined further in the context of an appropriately powered prospective longitudinal cohort study. The results of such a study will not only define the risk more clearly, but could facilitate the development of screening of subgroups at greatest risk. This is important because there may be primary interventions, such as lifestyle changes  and declare that (i) J.A.B. and P.J.H. have support from UCL for the submitted work; (ii) J.A.B., M.M.A. and P.J.H. have no relationships with companies that might have an interest in the submitted work in the previous 3 years; (iii) their spouses, partners or children have no financial relationships that may be relevant to the submitted work; and (iv) J.A.B., M.M.A. and P.J.H. have no non-financial interests that may be relevant to the submitted work.All authors have completed the Unified Competing Interest form at


During the period 1985-2000 the breast cancer incidence rates increased 50% in the age group invited to mammography screening in Norway and Sweden. Simultaneously, use of hormone replacement treatment therapy (HT) increased 5 times. Several influential observational studies showed that HT was associated with 50% to 100% increased risk of breast cancer and most for those using combined (estrogen plus progestin) hormone replacement therapy (CHT). In contrast, the randomized WHI trial reported that CHT increased the risk by 10% for those not having previously used hormones and 24% when including previous users in the analyses. In another randomized trial, estrogen use only was not associated with any increased risk at all. After the WHI trial was published in 2003, use of HT dropped 70% within 5 years in Norway and Sweden while breast cancer rates were essentially unchanged. After 2008, HT use has dropped further and breast cancer incidence rates have started increasing again. The study objective is to calculate and to explain potential bias in the observational study design.Here we use data from the randomized WHI trial and analyze these data as done in the observational studies to calculate the magnitude of the potential biases in the observational study design. Time varying effect of hormones and categorization of the follow-up time may increase the hazard ratio for long-term users from 1.10 to 1.48. Selective retrospective reporting of hormone use may further increase the hazard ratio to 1.68.We suggest that the mechanism causing higher hazard ratio of breast cancer  is the time-varying effect of CHT on the breast cancer risk and selective retrospective reporting of hormone use. Other risk factors for the increase in breast cancer risk in the age group 50-69 years should be considered, for example, overdiagnosis. In the period 1985–2000 breast cancer incidence increased about 50% in the age groups invited to screening . Use of In contrast to the observational studies, the Women’s Health Initiative (WHI) trial reported only 24% increased risk of invasive breast cancer after on average 5.6 years follow-up among women randomized to CHT . Among wAnother important observation in the WHI trial was that CHT had a biphasic effect on the breast cancer incidence. Compared to the control group, the incidence was temporarily reduced by 41% in the first 2 years of the follow-up  for womAnother problem in observational studies is that some people reporting no CHT use at study start will start using hormones during the follow-up. Usually, unreported CHT use among women assumed not to be using CHT , leads to an underestimation of the drug effect. However, in this case and very contra-intuitively, it causes overestimation because an influx of women who use CHT for less than three years and who have lower breast cancer risks than no-users.Retrospectively reporting the length of drug use may be associated with information bias . FinallyThe objective is to quantify the sizes of bias in observational studies of CHT and breast cancer using 3 different realistic scenarios all with 3 years follow-up. We use data from the more reliable randomized WHI trial  to calcuIn the WHI trial 8506 women were randomized to CHT and 8102 to placebo treatment . After eBased on the incidence rates in the WHI trial, we constructed 3 data sets (or scenarios) which we later used in observational studies with similar follow-up and categorization of CHT users as reported in the observational studies –4. FirstWhen constructing the data set for our observational study, we assumed that the duration of CHT use at study start was uniformly distributed over 0–12 months for the short-time users /day per 1000 women in the period 1991–2000 ,7; i.e. In We used 6277 as the number of individuals at risk in groups A and B, and 6020 for the control groups in Tables We used Poisson regression to calculate HR in the observational study with 3 year follow of women who had no prior CHT-exposure  first usIn the observational studies, many women in the non-user group started using CHT during the follow-up period –4. In thIn the constructed observational study, the HRs of breast cancer for women who had used CHT for less than 1 year and for 1–5 years at entry were 0.96 and 1.27, respectively , model 1We also calculated HR when only 5% of the non-users started using CHT in each year of the follow-up period . The HRsA simple calculation demonstrates that the numbers in We show that the discrepancy between the randomized WHI trial and the observational studies can be explained by bias in observational studies with short follow-up. First, when analyzing the data in the WHI trial using an observational study design, HR increases from 1.10 to 1.27 in the long-term users (model 1). The difference in HRs is caused by differences in the start of follow-up and in the length of the follow-up: all women have used CHT for 6 years in the randomized study design and follow-up starts from time of randomization, while in the observational design (model 1) long-term users have used CHT on average for 6 years (varying from 4 to 8 years) but the follow-up starts 1–5 years after randomization and the follow-up is 3 years. A combination of time-varying incidence rates and the influx of new CHT users in the non-user group after study start decreases the incidence in non-users leading to a further increase of the HR from 1.27 to 1.48 (model 2). Usually, drug use in the control group leads to an underestimation of the difference; however, in this case the effect is the opposite of what is intuitively expected: the difference is overestimated. Furthermore, retrospectively recording the length (leading to information bias) of the CHT use causes a further increase from 1.48 to 1.68 (model 3). The WHI study also reported higher HR when adjusting for low adherence, which may explain further differences; however, we are not able to quantify these.An alternative interpretation of model 3 is that the sum of a time-varying affect of CHT on the incidence rate (no effect in the first 2 years and then a strong effect in the next 4 years with a 24% incidence increase after 6 years follow-up) and with an influx of new CHT users in the non-user group after study start causes the HR to increase from 1.24 to 1.68.Our assumption that long term users have higher risk than short term users is crucial for our analysis and it is actually supported by the observational studies too –4. HowevFrom year 2002 to 2007 use of HT (including CHT) dropped 70% to the level of 1990 in Norway, while the breast cancer incidence rate was essentially unchanged ,7. In thOne may argue that there are major differences in the age composition in the studies. Women in the WHI trial were older than women in the observational studies; however, there were no significant age difference in the WHI trial . It has In our regression analyses we have adjusted for a 2.5 years difference in age between the control group and the CHT users groups. Without age adjustment the HR would have been about 0.1 higher for women that had used CHT for 1 to 5 years at baseline, but the HR would have been lower for women who had used CHT for 0 to 1 years.If for example 20% of women aged 50 to 69 years were using CHT and the breast cancer incidence increases is as in the WHI trial  and the The average length on HT varies between studies. In the WHI observational study women had used CHT for on average 6.9 years at entry and were followed-up in 7 years . This isIn contrast to Europe, a much larger decline was reported in the US after the release of the WHI study . But it Ioannidis ,21 notedNo approval from an ethical committee or informed consent was needed.