We hypothesized that this polymorphism might affect susceptibility to various epithelial malignancies. The -1327C>T polymorphism was examined in 1,551 consecutive autopsy cases , and we focused on its effect on the risks of overall and each primary malignancies. The polymorphism was further studied in 391 clinical prostate cancer patients who were diagnosed via prostate biopsy, using autopsy cases as controls. In the autopsy cases, the risk of epithelial malignancy, after adjusting for age, sex, smoking, and drinking habits, was significantly lower for the TT genotype than the CC (reference) genotype . Among primary malignancies, latent prostate cancer, colorectal cancer, and lung cancer were the most strongly associated with the polymorphism. In the study using clinical prostate cancer patients, susceptibility to clinical prostate cancer was lower for -1327 T carriers than for -1327 T non-carriers, but this finding was not significant. The data suggest that the hTERT promoter polymorphism, -1327C>T, is an independent factor influencing the risk of various epithelial malignancies in elderly Japanese.Telomeres are repetitive nucleotide sequences that cap the end of eukaryotic chromosomes. Attrition of these structures has been associated with carcinogenesis in many tissues, and therefore, they are essential for chromosome stabilization. Telomeres are maintained by telomerase complexes, of which human telomerase reverse transcriptase (hTERT) is an essential component. A functional polymorphism, -1327C>T (rs2735940), located in the promoter of the The online version of this article (doi:10.1186/2193-1801-2-249) contains supplementary material, which is available to authorized users. In 89 of 103 prostate cancer cases, the disease was first diagnosed at autopsy  and found before death  in the remaining 14 cases. All of the malignancies  found in the autopsy cases are listed in Additional file \The genotypic frequencies of -1327C>T were 44% for CC, 45% for CT, and 11% for TT. The minor allelic frequency was 34%, and the allele distribution was consistent with Hardy-Weinberg equilibrium (p = 0.79). The genotypic distribution was similar to a previous finding for the Japanese population  were tested, Bonferroni correction was performed. The association was still significant after the correction, where a significance level of 0.05/2 = 0.025 was used .An association between -1327C>T hTERT genotype and susceptibility to malignancy was particularly strong for colorectal, lung and latent prostate cancers  and after  adjustment. In the recessive model, the T-allele was associated with a lower risk of lung cancer before  and after  adjustment.The risk of colorectal cancer was significantly lower for cases with TT genotype compared with CC, before  and after  adjustment. In the recessive and additive models, the T-allele was associated with a lower risk of colorectal cancer before ) and after  adjustment.The crude risk of latent prostate cancer was significantly lower for cases with the CT and TT genotype compared to CC ; adjustment did not alter this association . In the dominant and additive models, theT-allele was associated with a lower risk of latent cancer before  and after  adjustment.When Bonferroni-corrected significance level  were used, the association for all cancer types were insignificant. However, this correction might be too conservative, because the risks for each type of malignancy are supposed to be not independent.hTERT genotype before Bonferroni correction (data not shown).The occurrence of other malignancies, including leukemia, malignant lymphoma, and gastric, breast, hepatocellular, pancreatic and bile duct carcinomas, did not reveal significant associations with the Because only 14 cases of clinical prostate cancer were included in the 1,551 autopsy cases, the polymorphism was further studied in 391 patients diagnosed by prostate biopsy before death. Residence-matched autopsy cases of 323 males who did not have cancer were used as control subjects. After adjusting for age by logistic regression analysis, the risk of developing clinical prostate cancer was lower in cases with a T-allele than in cases without it, but the differences were not significant , colorectal and lung cancer in the elderly Japanese population. The results warrant further investigation with a larger number of cases of each type of malignancy, and with a wide variation in ages.This study presented evidence that the -1327C>T polymorphism in the The group of autopsy subjects consisted of 1,551 consecutive cases  from Tokyo Metropolitan Geriatric Hospital, a community-based geriatric hospital in Tokyo, that were registered in the Internet-based Database of Japanese SNPs for Geriatric Research (JG-SNP)  in accordance with the manufacturer’s instructions. The sequences of the hTERT-specific primers were 5′-ACAATTCACAAACACAGCCCTTTAAAA-3′ (forward) and 5′-CCCTCCCTGGGCTGTCA-3′ (reverse). The sequence of the TaqMan reporter probe was 5′-CTTAGGATTAC[G/A]GGTCGCT-3′. The PCR reaction was performed in a 20-μl volume using TaqMan Universal PCR Master Mix, No AmpErase UNG (ABI). Each well contained 10 ng of genomic DNA. The cycling protocol was as follows: initial denaturation at 95°C for 10 min, followed by 40 cycles of 92°C for 15 sec and 60°C for 1 min. Genotype could be determined in 99.3% of cases.Genomic DNA was extracted from the renal cortex (of autopsy cases) or from the peripheral blood specimen  by the phenol-chloroform method. Genotyping of the -1327C>T (rs2735940) SNP in the Statistical analysis was performed using JMP version 9.0.0 . Chi-square tests were conducted to examine the Hardy-Weinberg equilibrium, to compare sex ratios, smoking status (smoker or non-smoker) and drinking status (drinker or non-drinker) between the genotypes. The odds ratio (OR) and 95% confidence interval (CI) adjusted for age, sex, smoking status, and drinking status were calculated using an unconditional logistic regression model when estimating the risk of malignancy for each genotype. The risks of overall malignancy and each primary malignancy were evaluated. Co-dominant, dominant, recessive and additive models were applied in the analysis. All tests were 2-tailed, with statistical significance set at p < 0.05. Bonferroni correction was performed by dividing the significance level (0.05) by the number of cancer types tested. In the analysis using clinical prostate cancer patients, the OR was adjusted using only age as covariant, because histories on smoking and alcohol drinking were not available for the patients. However, confounding effects of smoking /drinking would be minor because there is no evidence, to our knowledge, which definitely shows that smoking /drinking is associated with the risk of prostate cancer.Additional file 1: Table S1: Malignancies in autopsy cases. (XLS 9 KB)Additional file 2: Table S2: Characterization of the autopsy cases . (XLS 10 KB)hTERT genotype. (XLS 10 KB)Additional file 3: Table S3: Characterization of the autopsy cases of each -1327C>T Additional file 4: Table S4: Genotype frequencies in autopsy cases with each type of malignancy. (XLS 10 KB)


To investigate whether the relationships between established risk factors and breast cancer risk differ between three ethnic groups in New Zealand, namely Māori, Pacific, and non-Māori/non-Pacific women.The study is a multi-ethnic, age-, and ethnicity-matched population-based case–control study of breast cancer in women. Women with a primary, invasive breast cancer registered on the New Zealand Cancer Registry between 1 April 2005 and 30 April 2006, and Māori or Pacific women diagnosed to 30 April 2007 were eligible. Control women were identified from the New Zealand Electoral Roll, stratified by ethnicity, then frequency matched on age to the cases. Logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CI) between exposures and breast cancer risk in three ethnic groups separately. Likelihood ratio tests were used to test for modification of the effects by ethnicity. Post-stratification weighting of the controls was used to account for differential non-response by deprivation category.The study comprised 1,799 cases  and 2,543 controls , based on self-identified ethnicity. Māori women were more likely to have ER and PR positive breast cancer compared to other ethnicities. There were marked differences in exposure prevalence between ethnicities and some differing patterns of risk factors for breast cancer between the three main ethnic groups. Of interest was the strong relationship between number of children and lower breast cancer risk in Pacific women  and a higher risk of breast cancer associated with smoking  and binge drinking  in Māori women. Some of the documented results were attenuated following post-stratification weighting.The findings of this study need to be interpreted with caution, given the possibility of selection bias due to low response rates among some groups of women. Reducing the burden of breast cancer in New Zealand is likely to require different approaches for different ethnic groups. The burden of breast cancer in both developed and developing countries is high and continues to rise. A large body of evidence of risk factors for breast cancer exists internationally. The most clearly established risk factors are reproductive variables , for exaMāori are the indigenous people of New Zealand, comprising about 15 % of the population. Pacific people, who have migrated from small Pacific islands , comprise a further 7 %. Migration began as early as the late 1800s, but the majority of migration of Pacific people to New Zealand occurred in the 1960s and 1970s. The remainder of the population is composed primarily of people, originating from the United Kingdom and Europe (77 %), with a further 10 % of peoples from Asian countries . These last two groups are hereafter referred to as non-Māori/non-Pacific. The figures quoted here add up to over 100 %, since people who identify with more than one ethnicity are included in each ethnic population with which they identify [Evidence regarding ethnic differences in breast cancer rates in New Zealand is mixed, because of changes in how ethnicity is measured, as well as changes in incidence over time. Older data for Māori suggest that their higher risk is restricted to those who identify as solely Māori, but is not apparent in the total Māori population . More reEpidemiological studies of causal effects are limited by issues of confounding. Since most studies of breast cancer risk factors have been undertaken in countries where confounding structures are similar, it is not possible to know whether repeatedly observed associations are causal, or whether they are due to confounding. Alternative methods to address these issues have been proposed, including comparison of results from populations where confounding structures may differ . New ZeaThe overall aim of the study was to explore the relationship between health behaviors across the lifecourse and breast cancer risk in three ethnic groups . This initial paper describes the methods used, response rates obtained, and demographics of the participants in the study and explores whether the relationships between established risk factors and breast cancer differ between three ethnic groups in New Zealand.The study is a multi-ethnic, age-, and ethnicity-matched population-based case–control study of breast cancer in women, with over-sampling of Māori and Pacific women, to ensure sufficient statistical power for most ethnic-specific analyses.To address issues of likely response rates and acceptability of the questionnaire content, a pilot study of 15 cases and 15 controls was conducted between November 2003 and February 2004. Cases were identified from the New Zealand Cancer Registry (NZCR); controls were selected from women on the New Zealand Electoral Roll, as described in detail under the main study, below. The pilot study identified that this method was inappropriate for Pacific women, most probably due to their higher levels of mobility and English as a second language. We therefore expanded our methods for recruitment of Pacific women controls in the main study. No issues of unacceptability or other methodological problems were identified during the pilot study.All women with a primary, invasive breast cancer (ICD10 C50.0-C50.9), registered on the NZCR between 1 April 2005 and 30 April 2006, were eligible for inclusion. In addition, to ensure sufficient numbers of Māori and Pacific women, cases who were identified on the Registry as being of Māori or Pacific ethnicity, diagnosed between 1 April 2006 and 30 April 2007 were eligible. Using data on the NZCR, the facility where the woman had been diagnosed was identified, and the Clinical Records Department (CRD) of that hospital was contacted, to ask for details of the woman’s GP. GPs were contacted, to ask if they knew of any reason why the woman should not be contacted, and if not, to supply contact details for the woman. Two attempts were made to contact each GP. Following this, each woman was contacted by post, followed by a reminder letter if no reply was received. The cases completed their questionnaires between January 2006 and December 2008.Control women were stratified by ethnicity, then frequency matched on age, based on the expected age distribution in the cases from previously published incidence data, using 5-year age bands. The main method to identify population-based controls was through the electoral roll, registration for which is mandatory in New Zealand. There are two electoral rolls, “General” and “Māori.” Māori people can choose the electoral roll on which they want to be included. All people on the General Electoral Roll are asked to self-identify whether or not they are Māori or the descendent of a Māori.Throughout the control selection process, which took place between November 2005 and October 2009, the most recent of the 2005, 2006, or 2008 Electoral Rolls was used. Māori women were randomly chosen in equal numbers from the General and Māori Electoral Roll, using the “Of Māori descent” indicator on the General Electoral Roll to identify Māori. For Pacific women, it was originally planned to use the General Electoral Roll to identify population-based controls. The first, middle, and last names of all women were searched on the General Electoral Roll, to identify whether these women were likely to be of Pacific ethnicity. Given that the majority of Pacific women in the target age group would be first generation migrants, we expected that the validity of this method would be relatively high. However, the response rate to this method was low (see below). Therefore, this was supplemented through two methods: (1) GPs of Pacific cases were invited to identify one of their patients, matched by age to the case at their practice, who: self-identified as being of Pacific ethnicity; had never had a diagnosis of breast cancer, and were not too ill to participate (2) controls were selected by trained Pacific nurses working at the Pacific Community Health Services from the main District Health Board (DHB) areas, namely Auckland, Wellington, and Canterbury. The nurses identified eligible controls on their current case list using the same criterion listed above for GPs and invited them to participate. For non-Māori/non-Pacific women, controls were identified from the General Electoral Roll among those eligible to act as controls, that is, based on the age distribution of cases, without the “Of Māori descent” indicator, and without a Pacific-sounding name.All women were given the option of completing the questionnaire at home and returning it by post, or by completing it over the telephone. In the latter case, the participant had a copy of the questionnaire in front of her, while she answered the questions which were asked by the trained interviewer. Māori and Pacific women were also given the option of face-to-face interviews. All study materials were translated into Samoan and Tongan  and provided to the participants on request. Face-to-face and telephone interviews were conducted in the language of choice of the interviewee.The questionnaire comprised sections on socio-demographics, childhood exposures, lifecourse exposures to health behaviors, and comprehensive occupational and reproductive histories. For current exposures, both cases and controls were asked to report their lifestyles 1 year previously. Control women were asked about attendance at screening, and cases were asked about their route to diagnosis and experiences associated with that process. Where possible, validated questions were used –14, and n = 118) and women of 49 years and older were considered postmenopausal (n = 490). The cut off of 49 years was used as this is the median age at menopause reported in recent UK and New Zealand data [Age was defined as age at diagnosis for the cases and age at interview for the controls. Due to an error in the questionnaire, age at menopause could not be determined for the majority of women. The following rules were used to determine pre-/postmenopausal status at the time of diagnosis for the cases and at the time of questionnaire completion for the controls. Women were classified as premenopausal if they had a menstrual period in the last 3 months, or if their periods had stopped due to pregnancy/lactation, or use of hormonal birth control. Women were classified as postmenopausal if they reported natural menopause, surgical menopause involving bilateral oophorectomy, or use of hormone replacement therapy (HRT). Women who did not fall into these categories, who reported surgical menopause without bilateral oophorectomy, and other or unknown reasons for menses cessation were classified in an “other amenorrhea” category. This category was then dichotomized for analysis; women less than 49 years were considered premenopausal  hierarchy . During Continuous variables were categorized using pre-defined cut-offs or quantiles; Chi squared tests were used to compare variable distributions across ethnic groups. Logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CI) adjusted for age group (four categories) and menopausal status at diagnosis. Analyses were reported stratified by ethnic group. Where effects were found, exploratory analyses were conducted, stratifying results by menopausal status, and/or adjusting for likely confounders. These results were presented in the text rather than tables. In addition to visual inspection of the ethnic-specific results, likelihood ratio tests were used as formal tests of interaction between explanatory variables and ethnicity. Due to the relatively small levels of missing data, these were excluded from all models, with the exception of nulliparous women in the analyses of age at first live birth and ever having breast-fed, in which case they were entered as a separate category.Because of the low response rates in the control group (see below) and the evidence of differential non-response by deprivation quintile, we performed a sensitivity analysis to investigate non-response bias, using post-stratification weights. A weight was calculated for each stratum of ethnicity * deprivation, by dividing the expected deprivation distribution of each ethnic group by the observed deprivation distribution in the controls from our study. The expected distributions were estimated from the 2002/2003 New Zealand Health Survey (unpublished data) and were 2, 3, 10, 20, and 65 % for Māori and Pacific women in quintiles 1–5 of the NZDep2006 categories and 23, 20, 20, 20, and 17 % for non-Māori/non-Pacific women. Logistic regression models were then weighted using the “svy: logistic” command in Stata.The pilot study was approved by the Wellington Ethics Committee, and the full study granted approval by the Multi-Region Ethics Committee (WGT/03/12/126).n = 1,612, 89 %); the remainder were completed over the telephone with an interviewer  or at a face-to-face interview . Based on the ethnicity from the NZCR, the response rates in cases were 81 % in Māori, 46 % in Pacific, and 78 % in non-Māori/non-Pacific women.A total of 2,984 women with breast cancer were identified from the NZCR. Four women had a date of death on the same day as the date of diagnosis, and 70 women had incomplete files, so were not followed up. The remainder of CRDs, then GPs, was contacted. A total of 2,356 women were invited to take part, of whom 2,074 (88 %) responded, 1,869 (76 %) agreed to take part, and 1,799 women completed a questionnaire. Further details are shown in Fig. Details of recruitment of controls are shown in Fig. In summary, the study comprised 1,799 cases  and 2,543 controls , based on self-identified ethnicity. There was good agreement between the self-reported ethnicity and the data on ethnicity from the NZCR (cases), kappa = 88 %, and Electoral Roll (controls), kappa = 85 %. Among cases, the median time (inter quartile range) from diagnosis to interview was 8.4 months in non-Māori/non-Pacific women (7.3–11.4), 12.1 months in Māori women (8.6–19.1), and 15.1 months in Pacific women (11.7–19.2). The cases on the NZCR who took part were compared to those who did not take part. Non-Māori/non-Pacific and Pacific participants tended to be slightly younger than non-participants , but no difference in median age between Māori participants and non-participants was evident (53.9 vs. 53.7 years).Table Reproductive variables differed by ethnic group. Mean age at menarche was lower in Māori (12.6 years) and non-Māori/non-Pacific (12.9 years) than Pacific (13.4 years) women. Greatest use of oral contraceptives and hormone replacement therapy (HRT) was reported in non-Māori/non-Pacific women, with lowest use in Pacific women. Over 45 % of Pacific controls reported having had four or more children, although it is noticeable that this pattern was not seen in the cases, see below for further discussion. Numbers of children were lower in Māori and non-Māori/non-Pacific women; Māori women reported the greatest proportion of births under age 20. Non-Māori/non-Pacific women were more likely than other ethnic groups to have ever breast-fed, but the total duration of breast feeding was highest in Pacific women.Māori women reported a very high prevalence of ever having smoked. Over half of Pacific women reported never drinking alcohol; the majority of Māori and non-Māori/non-Pacific women were light drinkers. However, Māori women who did drink alcohol reported that they drank a higher number of drinks per occasion than other ethnic groups. Māori women appeared to be less active and Pacific women more active than non-Māori/non-Pacific women.p = 0.002.Over 98 % of cases were histologically confirmed, and this proportion did not differ by ethnicity. Further details of the cancers in the cases are given in Table Associations between “known” risk factors and breast cancer are shown in Table Although for some risk factors, the association with breast cancer was similar between ethnic groups, for others, there were interesting patterns of difference. For anthropometric variables, Māori and non-Māori/non-Pacific women had similar patterns of associations, with women reporting a higher BMI, a higher WHR, or diabetes having a higher risk of breast cancer than women without those risk factors. The effect of weighting the controls for differential non-response attenuated many of these relationships. Restricting the results to women who were interviewed within 1 year of diagnosis did not change the effect of BMI on postmenopausal non-Māori/non-Pacific women, but attenuated the effect in postmenopausal Māori women.2 1.19, 95 % CI 0.92–1.52), which was not apparent for premenopausal breast cancer . When stratifying the Pacific women by menopausal status, the effect of WHR tertile and diagnosis of diabetes were both stronger in postmenopausal women, but none of the effects approached statistical significance. Analyzing the WHtR as a dichotomous variable, split at 0.5, gave similar patterns of associations as were seen for other measures of obesity; the OR were 1.37 (95 % CI 1.17–1.61) in non-Māori/non-Pacific women, 1.64 (95 % CI 1.12–2.42) in Māori women, and 1.47 (95 % CI 0.29–7.30) in Pacific women.The overall patterns were less clear for Pacific women. However, when Pacific women were restricted to those who were postmenopausal at diagnosis/interview, there was a suggestion of a positive association between BMI and breast cancer . On stratification, the effect was apparent for postmenopausal not premenopausal non-Māori/non-Pacific women (adjusted OR 0.60 95 % CI 0.48–0.75). The effect was weaker in the weighted analysis. No clear relationship between ever use of HRT and breast cancer was detected, although in non-Māori/non-Pacific women, the expected increased risk was apparent, having weighted for differential non-response in the controls.Evidence for an expected protective effect of later age at menarche was weak in all ethnic groups. The protective effect of having more children and ever having breast-fed was particularly strong in Pacific women; age at first birth was not strongly related to breast cancer risk in this study, although there was a suggestion of a lower risk of breast cancer among women who had had their first child over the age of 30 years. Longer duration of breast feeding was associated with a lower risk of breast cancer in all ethnic groups.Although smoking is not traditionally thought of as a “known” breast cancer risk factor, it was included in our analysis because of its importance for Māori public health. There was clear evidence for an interaction with ethnicity, with Māori women who had ever smoked having a 76 % higher risk of breast cancer than those who had never smoked. This was only partly explained by levels of deprivation and education; further adjustment for these factors only reduced the OR to 1.62 (95 % CI 1.14–2.30). The effect in Māori women was attenuated when weighted for differential non-response by deprivation level; in Pacific women, the effect, although unstable, showed a suggestion of a strengthening of effect. An estimation of the population attributable fraction for smoking and breast cancer in Māori based on this adjusted OR suggests that approximately 31 % of the burden of breast cancer in Māori women is attributable to smoking; however, this is likely to be an overestimate due to residual confounding and misclassification of deprivation and education.Because of the relative rarity of frequent drinking, the two upper categories of frequency of alcohol consumption (“2–4 drinks” and “4 or more drinks” per week) were combined for analysis. There was weak evidence of an inverse association between frequency of alcohol consumption and breast cancer risk, although as shown in Table The findings presented here report the first nationwide, population-based, multi-ethnic study of breast cancer in New Zealand. The results show differences in exposure prevalence between ethnicities and differing patterns of risk factors for breast cancer between the three main ethnic groups.Many of the findings in this study are in agreement with those previously reported, but we have also highlighted some important differences. Some of the lack of associations in Pacific women in particular may be due to insufficient statistical power, since this was the smallest ethnic group studied. More generally, our study is affected by the limitations of case–control studies, particularly those involving interviews, principally the potential for selection and recall bias. Non-differential misclassification is also likely to have affected the results. To minimize selection bias, we attempted to maximize the response rate. Although this was good among cases (over 75 %), the response rates were poor among controls, ranging from 15 % in Pacific women to 59 % in non-Māori/non-Pacific women. The Pacific controls are therefore unlikely to be representative of the population of Pacific women in New Zealand. However, the paucity of research in this population group means that our work is the first documentation of breast cancer risk factors, measured on an individual level, in Pacific women.If non-response is non-differential across determinants of breast cancer risk, the effect of the low response rates will simply be to reduce the numbers of women available for analysis, that is, the “non-responders” will be “missing” completely at random. However, this is unlikely to be the case. Although we did not have much information on the non-responders, we used the national distribution of the deprivation measure to investigate this further. Importantly, we found that our response rates were lower in women living in the most deprived areas, which may have biased the results based on markers of socio-economic position, as well as those which are socially patterned. The post-stratification weighting that we used was intended to address this. The greatest effect that the weighting had was on the effect of deprivation itself. For other factors, the weighting tended to dilute the observed effects. We therefore remain cautious in our interpretation of the results presented, given the potential for selection bias in our study.Unlike any other ethnic group, the greatest burden of breast cancer in the Pacific women in the study is in the under 50s. This is consistent with data from Hawaii, where the “Asian/Pacific Islander” group is reported to have a lower age at diagnosis than white women , 20. A rBreast cancer has repeatedly been demonstrated to be a disease more common in affluent people –23. AlthThe very strong association that we demonstrated between number of children and breast cancer risk in Pacific women is of interest. It is possible that this is a true effect, detectable more readily in Pacific women because of the higher number of children borne by women in the most extreme category (four or more children). The mean number of children in this highest group was 5.1 in Pacific women, 4.9 in Māori, and 4.5 in non-Māori/non-Pacific women. It is also possible that this effect is stronger in Pacific women than in other women, because of differences in confounding structures between ethnic groups. For example, there was an apparent inverse association between number of children and BMI in Pacific women, as opposed to a strong positive relationship between number of children and BMI in Māori, which was weaker but still evident in non-Māori/non-Pacific women.A recent analysis of the Women’s Health Initiative observational study found a positive association between smoking and postmenopausal breast cancer risk . Among MWe did not find an association between height and breast cancer, despite clear evidence for an association from systematic reviews . It is iThe suggestion of differential effects of BMI across ethnic groups could be due to chance, as we have performed multiple significance tests in this initial report, although we have restricted these analyses to “established” risk factors. In non-Māori/non-Pacific women, the detrimental effect is clear in overweight women, but is not stronger in obese women. In Māori women, on the other hand, the excess risk appears to be restricted to obese women. Small numbers hamper the ability to look at this clearly in Pacific women. The stronger effect of WHtR than BMI is similar to that detected in cardiovascular disease , but thiThe expected association between alcohol and breast cancer risk was not seen in this study; further investigation of this is ongoing. We found some evidence of a detrimental effect of binge drinking, particularly in Māori women. This is consistent with recently reported data from the Nurses’ Health Study . The ratThe lack of an association between HRT and breast cancer is contrary to that reported in prospective studies and clinical trials. A likely explanation is the crude measure of “ever use of HRT” that was used in this study; the risk is higher for combined estrogen/progesterone HRT compared to estrogen-only HRT  and alsoIn summary, we have documented some expected, and other unexpected, associations between environmental factors and breast cancer risk in New Zealand; we have also found ethnic differences in exposure to risk factors and the associations of these factors with breast cancer. Despite methodological and statistical attempts to reduce the impact of selection bias on the results, we urge that these are interpreted with caution. This is the first such nationwide study to be conducted in New Zealand, with adequate numbers of women in different ethnic groups. Future studies need to ensure the use of appropriate methodologies to allow recruitment of participants from all ethnic groups. Most promising avenues for future research are likely to be investigations into the detrimental effects of smoking and binge drinking in relation to breast cancer risk. Reducing the burden of breast cancer in New Zealand is likely to require different approaches for different ethnic groups.


Little is known about the experience of young women who become aware of their parent’s BRCA1 or BRCA2 (BRCA) mutation status as adolescents or young adults. There is also currently a gap in the literature pertaining to those who are found to be negative for their familial mutation. We aimed to investigate the experience of these mutation-negative young women from hereditary breast and ovarian cancer (HBOC) families.Using a semi-structured questionnaire we interviewed 8 women. All of the women were non-carriers of their familial mutation and had learned of the mutation in their family as adolescents or young adults at least 6 months prior to undergoing genetic testing. All interviews were audio recorded, transcribed, and independently analyzed by the investigators. This was followed by an in-depth cross-case analysis, enabling the formulation of emergent themes.The women’s age ranged from 22 to 37 years old and all were of Ashkenazi Jewish descent. Prominent emergent themes from the interviews included the impact of how and when the familial mutation status was disclosed, the factors influencing when a young woman chooses to undergo predictive genetic testing, the predictors of post-test adjustment and risk perception, as well as the impact of familial cancer experience versus the familial mutation.By eliciting detailed patient narratives we have begun to show that this generation of BRCA mutation-negative young women is likely still affected by the degree of cancer history in their family, even with their understanding of the genetic contribution to disease. Larger studies with tightened participant characteristics, as well as studies involving women from different cultural backgrounds, are needed to further define the experience and needs of true negative young women from HBOC families. Since the discovery of the BRCA genes in the mid 1990’s much information has been gained regarding the cancer risks to both men and women who carry a germline mutation in one of these two genes. The greatest risk is for women where mutation carriers have about a 50-85% risk before the age of 70 years of developing breast cancer and about a 10-45% risk of developing ovarian cancer  either [you] have [the] time to deal with it. Like, process it yourself. And then just, like, take it in, then be told what it is. Or it's like: you read it, and you freak out, not know what it is, and then, it's, you're up here, and then you're like, 'Ah, okay. Oooh.’ I don't know, maybe somewhere in the middle maybe if you're having a family discussion then they bring it up. (This 26-year-old participant learned of the mutation in her family at 20 years old by discovering documents related to the presence of the mutation in her father. She subsequently underwent predictive genetic testing less than one year later).I really appreciate the way my family handled it, being open about it even if I didn't necessarily grasp it at the age I was told. I think it's better to know and to kind of have those years to kind of ease yourself into the idea…than to be told when there's already, like, some kind of you know, sickness in the family, or newly diagnosed individual, because then it's just too much shock. (This 30-year-old woman learned that her mother is a mutation carrier in her mid-teens through an open family discussion. She underwent predictive genetic more than 10 years later).Even when my mother did explain it to me, and, I guess, at the time, she sort of pitched it like, maybe to soften the blow, in a sense, but just that, if it did affect us, it was so many years away. Like, we were only in our twenties. .Age was most often discussed with respect to the women’s decision regarding undergoing predictive genetic testing. An important age-dependent determinant for the timing of testing was the age at which the individual perceived being diagnosed with cancer to be an actual threat, that which was based on their familial or societal stereotypes of cancer. Other age-dependent factors were dating, marriage, and both career and family planning. Undergoing testing at an age that allows one time before screening and the consideration of surgical interventions was also important to those advocating testing at a younger age.The participants were split on the issue of undergoing predictive genetic testing prior to versus after having children. The three women with children at the time of their interview all agreed that testing should wait until the completion of one’s family. Proponents of postponing testing argued that because ovaries and breasts are needed to have and to nurse children, undergoing prophylactic surgery prior to having children would not be an option, therefore genetic testing was not necessary until after. Those advocating testing before childbearing argued that the results of such testing might dictate when and even if having children would be considered.I wouldn't wanna do [genetic testing] too late. Because what if you wanna start a family? I would say you have to do it before you start a family. Because that could play in your idea of having a family. (This 24-year-old participant learned of the mutation in her family in her late-teens and underwent predictive genetic testing at the age of 21. She did not have children at the time of testing).Cancer is something that, you know, can affect anybody. And if you can control a little bit of it by getting tested younger, I think that people should do that. Just so that they have more options as they get older of how to minimize their risks, or to control some parts of it. (This 22-year-old woman learned of the mutation in her family in her early-teens and underwent predictive genetic testing at the age of 21. She did not have children at the time of testing).[In] my early thirties, it wasn't as much about critical timing as if I would have been already in my forties or later forties. I finished having my kids, and after my little one was already in daycare. Because, I knew that if I did the testing, I would have made the decision to have a mastectomy pretty quickly. (This 37-year-old participant learned of the mutation in her family in her mid-twenties and underwent predictive genetic testing at the age of 34. She had two children at the time of testing).Many of the women believed they were a mutation carrier before undergoing predictive genetic testing and felt a great sense of relief after learning that they were not a carrier. However, because of the dichotomy created between their mutation-negative status and their positive familial status, conflicting emotions of relief, happiness, guilt, fear, and anger were also present. One participant even expressed a desire to have been mutation-positive.They all understood their posttest population risk of developing breast and ovarian cancer, but some desired to have additional screening as a result of their familial cancer experience and residual cancer worry. Despite this, none were actively seeking further treatment or screening beyond what is recommended to the general population for their age category. One participant expressed a more intense ongoing residual cancer preoccupation and worry.I have trouble believing that I'm going to escape this lifetime without getting breast cancer. And I should be thrilled that I'm negative and I am, and as every year goes on that I don't get breast cancer I know treatments are getting better and research is getting better and there is more help out there, but somehow it doesn't make me feel completely confident. .I don't feel like I need to be hyper-vigilant, or anxious about [cancer]. I don't know, I think that. I know that anxiety is not necessarily something that you can consciously control, but I did get a sense of relief from being negative and the fact I can, you know, not worry about this on a daily basis anymore. .But I still have some chance. But at least, you know, I'm more cautious. Just cause I don't have [the mutation] doesn't mean anything. A lot of people say, 'Oh, I don't have [the mutation]. Okay, I'm okay.’ Which is not true. You know, it's just, now your chances are lower.” .It's one of those things that you've been stressing about for so long and then afterwards it's one of those things; it's like a break-up, like you just slowly forget about it overtime. .The general feeling among most of the women was that, even though they are non-carriers, their experience of the burden of hereditary breast and ovarian cancer is not over. They explained that their lives continued to be burdened by new cancer diagnoses in the family and the identification of other mutation-positive family members. Although this is true, many pointed to the fact that with each subsequent generation there is a gain in knowledge. This knowledge of the presence of the gene mutation in the family also shaped their lives in terms of relationships, dating, marriage, family planning, and having to contemplate one’s own mortality at a young age. Growing up with the knowledge of a genetic mutation in the family has also motivated at least several of the women to become advocates for genetic testing and for other families burdened by cancer.I'm lucky enough not to have [the mutation], but it's a part of my family. It's still a big deal of who we are. (This 24-year-old participant underwent predictive testing at age 21 after learning of the mutation in her family in her late-teens. Her younger sister has yet to pursue predictive genetic testing).I always thought that you know maybe if, God forbid, I have the gene I can get married a little younger, have kids, you know that way I don't need to be pressured or rushed to have kids like towards my thirties. Because if, God forbid, cancer comes around, you know, I didn't want it to be like a lingering factor always, though, like in my mind. (This 22-year-old young woman underwent predictive genetic testing at the age of 21 after learning about the mutation in her family in her early-teens. She was recently married at 22 years old).I think it makes you think about things that you wouldn't normally think about in your twenties. I mean, I think not just dealing with the potential mortality of a parent, which is kind of normal even if it's at young age, you kind of, you know, think about that. But I don't think, at twenty, most people think about their own mortality. So, I think even in University, when everyone's just thinking about, you know, 'Where am I gonna get a job?’I was thinking about, you know, 'What will my future be?’ .If it's something that you suspect is in your family, and it's available to get the genetic testing, I think people should know. You're in your fifties and then you have breast cancer, there might have been things you could have done in your forties and your thirties. I think it's always better to know, if you can, and then know what you're dealing with. So, I think that's the most important thing I try to tell people. (This 37-year-old participant learned of the mutation in her family in her mid-twenties and underwent genetic testing more than 5 years later).Although each participant’s journey has been unique, there are several salient themes that can be drawn from their collective experience of being a non-carrier from a HBOC family. The more salient of which are discussed here and, if corroborated, have the potential to influence cancer genetic practice and counseling.Many factors are known to influence the communication of genetic risk within families including the perceived relevance of the information, closeness of family members, family patterns and rules, as well as the type, amount and timing of the information being disclosed . After rLearning that their parent carried a deleterious BRCA mutation as an adolescent or young adult did not seem to have any obvious negative consequences among the participants in our study. Bradbury and colleagues also report that offspring learning their parent’s carrier status before the age of 25 have a good understanding and do not express any negative consequences pertaining to the disclosure .In contrast, we identified two participants who were not told of their parent’s carrier status by way of direct parental communication. Rather, both discovered documents pertaining to the presence of the mutation in their parent. This lack of disclosure is not necessarily surprising given the complexities and dilemmas faced by parents and the fact that disclosure does not occur 100% of the time . The expAccording to our participants, it can be said that there is no “perfect” time to undergo genetic testing, there exists only a time that is “better” than others. There are many factors that dictate when might be the most appropriate time in a woman’s life for testing.Since the clinical availability of BRCA testing there has been much controversy with regard to testing adolescents and young adults, as is the case with many other adult-onset hereditary conditions. Although age is certainly a key factor, the ideal age to have genetic testing is personal and is perceived differently by each individual. We found that a precise age might be less important than other factors in one’s life when considering genetic testing. In fact, in her review, Pasacreta found that age was not associated with one’s interest in pursuing BRCA genetic testing and its significance in the actual utilization of genetic testing remained unclear .Among our participants, timing to be tested also appeared to be influenced by the women’s general state at that moment in time. To emphasize, five of the eight women were going through a period of stress and instability in their lives, according to the Holmes and Rahe Social Readjustment Rating Scale, when they made the decision to undergo predictive genetic testing . These sTaken all together, age is important when considering the key psychosocial factors predicting the most appropriate time for a woman to undergo BRCA genetic testing, however it should not be considered the sole determinant for testing. It is also important to remember that the decision to know one’s mutation status is much different than the decision to act on it.One of our main objectives was to describe the adjustment and risk perception of mutation-negative women after having undergone genetic testing. Although not formally assessed with standardized items, the participants described the ways in which cancer and their mutation status has affected them in ample detail.feel at this population risk.Posttest risk was accurately expressed by the women in our study as being similar to the population risk level, yet most had a self-professed moderate degree of cancer worry. This is not surprising given the results of various studies, such as that by Quillin and colleagues . The autAlthough many had a continued sense of cancer worry, none of the women were actively seeking cancer screening beyond what was recommended for the general population. However, it will be interesting to know whether these women do go on to pursue additional breast or ovarian cancer screening in the future. In fact, it has been previously shown that the cancer screening practices of mutation-negative woman from HBOC families far exceeds what is recommended. It is not clear, however, if this excess screening is patient-driven or physician-driven .Furthermore, when compared to the older women studied by Bakos and colleagues , adjustmIt is important to note that we are observing these women as a cross-sectional snapshot of their experience and their cancer risk perception and preoccupation might not necessarily be stable over time. At the time, only one participant expressed ongoing cancer preoccupation and worry despite the fact that her absolute risk of developing breast and ovarian cancer was clearly understood. Further evaluation her experience is necessary to build a better sense of what the underlying factors causing this persistent preoccupation might be.Using previously reported findings, it possible to begin to formulate hypotheses with respect to this anomalous patient in our study group. For one, it is known that both general and cancer-specific distress at baseline is highly predictive of later psychological responses in members of BRCA mutation-positive families . HilgartAnother approach to understanding this participant is by way of heuristics, which are inferential cognitive shortcuts. Heuristics are often employed in the study cancer genetics, particularly with respect to its influence on risk perception among members of hereditary cancer families. To emphasize, Kenen and colleagues reported that women utilize three main heuristics when interpreting their breast and ovarian cancer risk, that of the representative, availability, and illusion of control . Women uWith respect to this unique participant with excess cancer worry, the “simulation heuristic” might have more relevance in explaining her current state. The simulation heuristic was first described by Kahneman and Tversky in 1982 as a mental operation that brings things to mind by way of mentally constructing scenarios that allows one to answer complex questions by using this simulation model . NormallWithout doubt, understanding how the knowledge of the presence of a BRCA mutation in a parent has impacted or shaped the lives of young women is a difficult task. It is often challenging to distinguish what has been the impact of a potential genetic predisposition to cancer versus the familial experience of cancer itself. From the narratives of our participants it is clear that the effects have been widespread and significant as a result of learning about a gene mutation that is responsible for their familial cancer experience. It can be argued, however, that some of the effects on marriage, family planning, and prophylactic surgery, for example, were caused not only by the presence of the gene, but also their unique experience with how the gene mutation has manifested itself in their family.In some cases, the presence of the gene mutation has also enabled the young women to redefine their family history of cancer. The sense of endless suffering felt by the women can be attributed to the presence of the familial gene mutation. However, because they are non-carriers, there is a sense of freedom that has allowed them to focus on others in the family, as well as their community at large. For some, especially where prophylactic surgery was a planned and accepted reality, the fact of being a non-carrier has certainly altered the course of their life.Ultimately, this “second generation” of women to undergo predictive BRCA genetic testing are growing up with a strong family history of cancer in addition to the genetic knowledge and their lives and identities have been shaped by both of these realities. As Margaret Lock and colleagues emphasized, it is unlikely that this genetic information will supplant one’s other identity claims. Rather, it is more likely that this genetic identity will combine and interact with other identities . This isTo our knowledge this is the first study to report on this particular group of women in such detail. Employing a qualitative approach with our highly selected group of women provided the opportunity to explore a complex topic without the restrictions of specific hypotheses. While a sample of 8 is deemed sufficient for in-depth exploration , some miAnother potential limitation is that the participants were all English-speaking and Ashkenazi Jewish. This population does represent a subset of women presenting for genetic testing at our center, but given that cultural background plays a central role in shaping one’s life, important differences might exist among other HBOC families. Another important element of homogeneity was that the women all had at least one first degree relative affected with breast or ovarian cancer. This proximity to disease and familial experience of cancer has likely significantly contributed to their overall experience as a mutation-negative woman in a mutation-positive family. We also acknowledge that the women’s age range, as well as the time since disclosure of the mutation in their family, was rather broad. As outlined earlier, because of the restrictions with regard to age and timing of genetic testing, only a limited number of women were eligible to be contacted.Testing for mutations in the BRCA genes has now been available for more than a decade and a half. During this time, research has uncovered many of the psychosocial elements surrounding BRCA genetic testing, as well as the dynamics of HBOC families. At this time we have the beginning of a new cohort of young women who have been aware of their parent’s mutation status since their adolescence and have subsequently chosen to undergo genetic testing as young adults. Prior to this study, little was known about this group of young women, particularly those who are found to be non-carriers of their familial mutation. By eliciting direct patient narratives we have found that this group of women is likely to be affected in different ways by the degree of cancer history in the family, even with their understanding of the genetic contribution to the disease.Just as with older non-carrier women from HBOC families, this younger generation still appears to carry a heavy burden related to being a member of a HBOC family. Will this still be true of subsequent generations of HBOC families where we hope to see less cancer burden through early screening and intervention? In the meantime, the detailed narratives of these women have provided insight that has the potential, through additional research, to influence current cancer genetic practice and counseling. Larger studies with tightened participant characteristics, as well as studies involving women from different cultural backgrounds, are needed to further define the experience and needs of true negative young women from HBOC families. Of particular interest are whether residual cancer worry in these young women will translate into an unnecessary increase in cancer screening in the future and whether a better social prototype for non-carrier women will be available so that they may have the support needed to help understand their risks as well as their place within their family.BRCA: BRCA1 and BRCA2; HBOC: Hereditary breast and ovarian cancer; MINI: McGill illness narrative interview.The authors declare no competing interests.LM participated in the design of the study, conducted all interviews, provided thematic analysis of the data, and drafted the manuscript. ADN provided intellectual expertise and insight throughout the study. CGL provided critical analysis and final approval of the manuscript. NW conceived of the study, participated in the design and coordination of the study, provided thematic analysis of the data, and helped to draft the manuscript. All authors read and approved the final manuscript.LM holds a MSc. and is a faculty lecturer in the Departments of Medicine and Human Genetics at McGill University, as well as a genetic counselor at the Jewish General Hospital, Montreal, Quebec, Canada. ANS holds a MD and PhD. and is an associate professor in the Psychiatry Department, Faculty of Medicine at Federal University of Rio de Janeiro. Rio de Janeiro, RJ, Brazil, as well as a postdoctoral fellow at the Division of Social and Transcultural Psychiatry, McGill University. Montreal, Quebec, Canada. CGL holds a RN and PhD. and is an associate professor in the School of Nursing at McGill University, holds Christine and Herschel Victor/Hope and Cope Chair in Psychosocial Oncology, and is program leader of the Psychosocial Oncology Research Training program, as well as senior Fonds de la Recherche en Santé du Québec researcher at the Jewish General Hospital. Montreal, Quebec, Canada. NW holds a MS and is a faculty lecturer in the Departments of Medicine and Human Genetics at McGill University and a genetic counselor at the Jewish General Hospital. Montreal, Quebec, Canada.


Published results suggests that high adiponectin level may decrease the risk of breast cancer. However, available evidence on breast cancer is conflicting. Therefore a meta-analysis was performed to assess the association between blood adiponectin and breast cancer risk. PubMed database, Web of Science, Elsevier Science, Springer Link and bibliographies of retrieved articles were searched for epidemiological studies published up to March 2013. Meta-analysis was performed on the combined effect values (OR) as well as standardized mean difference (SMD) including 17 studies. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. The publication bias was assessed by the Egger’s regression asymmetry test and Begg’s rank correlation test with Begg’s funnel plot. Subgroup analyses and sensitivity analysis were also performed. A total of 13 studies involving 3578 breast cancer cases and 4363 controls contributed to the OR analysis. The high adiponectin level did not significantly affect breast cancer risk . After excluding articles that were the key contributors to between-study heterogeneity, the OR of high adiponectin level was associated with decreased breast cancer risk . There was a significantly association between high adiponectin level and postmenopausal breast cancer women ; and it was not associated with premenopausal breast cancer women . The result of pooled measure on SMD was that the high adiponectin level was associated with decreased breast cancer risk  after excluding articles which were the key contributors to between-study heterogeneity. Our findings indicate that high adiponectin level might decrease the risk of postmenopausal breast cancer. More randomized clinical trials and observational studies are needed to confirm this association with underlying biological mechanisms in the future. Breast cancer is the most common cancer and the leading cancer-related cause of death among women worldwide, with 1.38 million new cases diagnosed in 2008 and causing 458,000 deaths .A recent hypothesis suggests a major role for adipose tissue in carcinogenesis. During many years, the adipose tissue was only considered as a fat storage of energy. This tissue is now described as an endocrine organ secreting a large range of molecules called adipokines. Among these adipokines, adiponectin may play a major role in cancers. Adiponectin is considered as a protective hormone, as it plays a major role in the regulation of glucose with potent insulin-sensitizing activity affecting the uptake of glucose in the muscle, in lipid homeostasis, and is involved in the pathophysiology of atherosclerosis with anti-inflammatory activity . NumerouEnglish language papers on research in female and human were considered in this study. A comprehensive search was conducted for relevant articals published up to March 16th, 2013 from the following databases : (1) PubMed; (2) Web of Science; (3) Elsevier Science; (4) Springer Link. Search term (adiponectin or Adipo or APN) and (breast cancer or breast carcinoma or mammary cancer) were used in combination to retrieve the relevant literatures in all these databases. Reference lists of articles were scrutinized to identify additional articles. This systematic review was planned, conducted, and reported in adherence to standards of quality for reporting meta-analysis .Studies were included in the meta-analysis if they met the following criteria: (1) the study must be an original epidemiologic study of cohort or case-control; (2) the exposure of interest must be the (serum or plasma) adiponectin detecting in blood samples; (3) the outcome of interest must be breast cancer; (4) the article must report odds ratio (OR) or relative risk (RR), corresponding 95% confidence intervals(CI) or data to calculate these(5); mean and standard deviation (SD) or data provided from which mean and SD could be calculated. Two investigators (Li-yuan Liu and Meng Wang) reviewed all studies independently to identify and determine whether an individual study was eligible for inclusion in this meta-analysis. If there was disagreement between the two investigators about eligibility of the article, it was resolved by consensus with a third reviewer.LL and UL), confounders adjusted for in multivariate analysis. Meanwhile, the study quality was evaluated using the 9-star Newcastle-Ottawa Scale [The following data were extracted from each study: the first author’s last name, publication year, country where the study conducted, study design, number of subjects, mean and SD, ORs and 95%CI  [P values) were two-sided ,with P<0.05 considered statistically significant except where otherwise specified.We investigated the association between the blood adiponectin and the risk of breast cancer. Heterogeneity of effect size among studies was assessed by the Cochran’s r chance . If subsI2>50%) , the ranI2>50%) ; OtherwiI2>50%)  and BeggI2>50%) , which dThe detailed steps of our literature selection are shown in Q=40.67, P<0.001, I2=73.0%) and a random-effects model was therefore used. The ORs from studies on blood adiponectin level and breast cancer risk were inconsistent, with both inverse and positive associations reported. The pooled OR of adiponectin in blood was 0.902  for breast cancer , 3 studies were conducted in America (USA), 3 studies in Europe , and 1 study in Australia. Besides, there are 8 researches collected the serum sample ,26–31, 5t cancer .Australasia, respectively.When we stratified the analysis by the geographic region of studies and the menopausal status, only 5 studies offered relevant available data. The total effect value was 0.75(95%CI=0.60-0.94)  for postQ=12.22, P=0.201, I2=26.3%). The pooled OR of adiponectin in blood was 0.838  for breast cancer.To explore the heterogeneity among studies of adiponectin in breast cancer, we performed the sensitive analysis. A sensitivity analysis omitting 1 study at a time and calculating the pooled ORs for the remainder of the studies showed that 2 studies by Al Awadhi SA et al  and HancIt indicated that no individual study had excessive influence the stability of pooled effect except for the study of Al Awadhi SA . A positP=0.459) nor Begg’s rank correlation test (P=1.000) gave a statistically significant result.The Begg’s funnel plot showed no striking evidence of publication bias . NeitherQ=720.35 P<0.001, I2=98.3%), the high adiponectin level was associated with decreased breast cancer risk  . We didn’t stratify the analysis by the menopausal status because only 2 studies offered relevant available data.Thirteen studies were available to evaluate the SMD of adiponectin with breast cancer risk. A formal test for heterogeneity gave a significant result (--0.217) . After eAs we know the result of a single research may be affected by many factors, in order to reduce the bias and increase the efficiency of the small sample study of statistics, our study in view of the 17 studies to further explore the relationship between blood adiponectin and breast cancer in our meta-analysis. Overall, our results suggest that the blood adiponectin level are no associated with breast cancer risk. However, the subgroup analysis indicated that there is an evident inverse association of adiponectin with breast cancer risk in postmenopausal women. To our knowledge, it was probably the first to attempt to synthesize the existing world literature to evaluate the effect of blood adiponectin on breast cancer.Adiponectin, a 244-amino acid protein secreted predominantly by white adipose , represeThe well-established association of obesity and some adipokines with breast cancer risk logically leads to the speculation that adiponectin possibly plays a role in breast cancer development. Although there are a number of studies have shown that adiponectin is closely related to breast cancer, but the inconsistent results from relatively small studies are underpowered to detect the true effect. Our meta-analysis is the appropriate approach to obtain a more definitive conclusion regarding the role of adiponectin on risk of breast cancer. Our meta-analysis, 3578 cases and 4363 controls (OR), 1407 cases and 1438 controls (SMD), allows a much greater possibility of reaching reasonably strong conclusions. The results of our meta-analysis suggest that there is not a significantly positive association of adiponectin with breast cancer. Furthermore, there are no association remains statistically significant in almost all stratified analyses exploring study characteristics and quality factors. Although many studies had shown the high adiponectin level could decrease the risk of breast cancer. Miyoshi et al was the first to report that high adiponectin levels are significantly associated with decreased risk of breast cancer . This poOur present result linked high adiponectin level to a decreased risk only for postmenopausal breast cancer, which were confirmed by a few reviews findings ,46. Sinc2 =73.0%, SMD: I 2 = 98.3%). Thus we used sensitivity analysis [I2 >50% as the criterion and stratified analysis with study location, our results showed that higher blood adiponectin level could decrease the breast cancer risk, there is a statistical significance with confidence interval not including 1, which is distinct from the overall result before sensitivity analysis. The omitted article [I2 =54.6%). Meantime, this suggests we need more large samplings studies to verify our results. Nevertheless, the result of menopausal status group further confirmed previously findings, because there are no data of menopausal status in the omitted study.The heterogeneity of between-study is common in meta-analyses, our meta-analysis also showed the significant between-study heterogeneity Click here for additional data file.Flow Diagram S1(DOC)Click here for additional data file.


A diagnosis of a second primary breast cancer  occurs in between 2-11% of women affected by breast cancer in the general population, but is increased in frequency in women with a family history of breast cancer. We investigated whether the common genomic variants described in breast cancer GWAS studies were determinants of the risk of bilateral breast cancer and compared the effect to that of family history.The Victorian FCC Translational Breast Cancer Cohort consists of the index cases of 1374 families with a high risk family history of breast or ovarian cancer. The cohort has been extensively characterised, including detailed personal and family history and has undergone genetic testing for both high penetrance genes and low penetrance variants associated with breast cancer. 1143 women in the cohort have had at least one breast cancer and 208 women have had multiple primary breast cancers. For this study genotypic data from 22 common genomic variants (SNPs) previously identified in breast cancer GWAS were analysed for each index case and compared to the same set of genotypes from an Australian population based control group . A Polygenic Risk Score (PRS) was calculated using a multiplicative model as the sum of the log odds ratios associated with each allele. Unilateral and bilateral cases were compared on the basis of both the measured polygenic risk and family history parameters.768 women affected by breast cancer were identified in whom BRCA1 or 2 mutation was excluded by sequencing and MLPA. The cohort was followed up an average of 8.8 years since their diagnosis of breast cancer with 135 (18%) women having a diagnosis of a second primary breast cancer. The average Polygenic Risk Score in the group was 1.30 (Log OR) but was significantly increased in the women with a history of bilateral versus unilateral breast cancer (1.40 vs 1.28 p=0.018), with no difference between the groups in follow up (or time to cancer diagnosis)  or age of first diagnosis . Measures of the family history including the number of breast cancers in first degree or any relatives, family history of bilateral breast cancer, male breast cancer or ovarian cancer were also examined but showed no significant differences between women with unilateral or bilateral breast cancer.To examine the clinical significance of the difference in PRS the cohort was divided into high, intermediate and low polygenic risk groups. The OR for bilateral breast cancer between the high and low risk groups was 1.9  and survival analysis showed a significantly increased rate of second primary breast cancer in the high versus low polygenic risk group (cumulative hazard to 20 years of 0.39 vs 0.24).Analysis of polygenic risk, determined by common genomic variants, has the potential to stratify women affected by familial breast cancer in relation to their risk of second primary breast cancer, independent of measures of family history.


In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium . In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L.In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I In recent years, the scientific evidence linking vitamin D (vit D) to breast cancer has grown notably. Garland and Garland first hypothesized a role of exposure to solar radiation in explaining geographic variation in breast cancer incidence. Accordingly, lower levels of vit D resulting from weaker UV-B radiation were suggested to explain higher breast cancer rates at higher latitudes. However, this ecological observation was only partially substantiated by subsequent epidemiological studies Several observational studies have focused on the association between breast cancer risk and circulating levels of 25 (OH) hydroxyvitamin D (25-OH vit D), which is the precursor of the active hormone 1,25 (OH)2 vit D and the most commonly used biomarker of vit D status. Results from case-control studies have consistently revealed an inverse association between 25-OH vit D and breast cancer Several systematic reviews including randomized controlled trials (RCTs) have recently focused on vit D and health outcomes. Autier investigated the impact of vit D supplementation on death from any cause including cancer. Vit D was associated with a slight reduction in death from any cause . Eighteen RCTs were included, but only two of them reported on cancer incidence and mortality, overall and for colorectal cancer So far, no systematic review has specifically addressed the role of vit D supplementation in breast cancer prevention. We aimed to investigate risk of breast cancer development in a systematic review of women participating in RCTs of vit D supplementation compared with placebo/no treatment.This systematic review was performed in full agreement with an ad-hoc study protocol which was submitted to the Italian Agency of Drugs (AIFA) in 2008 (study protocol code: FARM8L2B5L).In April 2012, a qualified librarian used OVID to electronically search MEDLINE (R) (January 1950 onward), EMBASE (January 1980 onward), and the Cochrane Central Register of Controlled Trials (CENTRAL) . We designed and applied the search strategy using sensitivity criteria potentially capturing RCTs of vit D use in both breast cancer prevention and treatment. To this aim, we combined terms for vit D and cancer (Appendix 1) with search filters for RCTs No language restrictions were applied.Included studies were RCTs of vit D in breast cancer. Studies suitable for inclusion were RCTs of vit D in breast cancer. We considered RCTs if vit D was administered as a single agent compared with placebo/no treatment or as part of combined regimens including supplements and lifestyle modifications as long as the administration of the co-intervention was planned to be the same in all groups. For multi-arm RCTs, we included all pairwise comparisons with arms differing by vit D use only. Breast cancer incidence and mortality were the outcomes of interest in RCTs focused on breast cancer prevention. We planned to consider survival, time to recurrence, risk of ipsilateral and/or contralateral disease, health related quality of life and toxicity as outcomes of interest in RCTs of vit D in breast cancer treatment. However, only trials of vit D in breast cancer prevention were included. RCTs involving pregnant or lactating women were excluded.Two reviewers independently completed title and abstract screening and full text review. Disagreements were solved through discussion or consultation of a third reviewer. A pilot-tested form was used for data extraction. Collected data related to methodological quality, participants, intervention, comparison and outcomes. In regards to outcome data, Risk Ratios (RRs) were calculated by treatment arm for breast cancer incidence. For mortality, we planned to abstract the log hazard ratio [log(HR)] and its variance Risk of bias was assessed using the Cochrane risk of bias tool. Two reviewers independently assessed methodological quality and resolved disagreements by discussion. Their evaluation focused on randomization, blinding, percentage of lost to follow-up, early stop for benefit or harm, intention-to-treat (ITT) principle, incomplete outcome data, selective reporting. In order to assess reporting bias, we compared the list of outcomes from the protocol to the outcomes reported in the published paper We calculated the agreement between the two reviewers for the assessment of eligibility using kappa statistic.The RRs for breast cancer development were pooled using the Der Simonian-Laird random-effects model 2 test and judged considerable if ≥75% Heterogeneity was assessed using the IThe flow diagram of the trial selection process appears in The April 2012 search identified 5690 unique citations. Based on the title and abstract screening, we rejected 5597 citations. Among the remaining 93 unique citations, 91 were excluded for the following reasons: 1. Eight did not report on cancer outcomes The first study was a randomized factorial-design trial of cholecalciferol and calcium supplementation for the secondary prevention of fragility fractures in 5292 people aged 70 years and older. Women represented about 85% of the overall sample. Participants were randomized to daily cholecalciferol (800 IU), calcium (1000 mg), both, or placebo for 24–62 months, with a minimum follow up for long term outcomes of three years. Cancer incidence and mortality were listed among the secondary outcomes along with overall mortality and mortality from vascular diseases. Overall, the study did not rule out a significant role of vit D or calcium on cancer incidence and mortality  Lappe and co-authors carried out a 4-year, placebo-controlled, randomized trial to assess the impact of calcium and cholecalciferol supplementation on the skeletal status and calcium homeostasis in healthy postmenopausal women aged 55 years and older. The 1180 participants were randomized to placebo, consisting of both a vit D placebo and calcium placebo, calcium  and a vit D placebo, calcium and 1000 IU cholecalciferol/day. Cancer incidence was a secondary outcomes. The study results showed a decreased risk of cancer development in women randomized to calcium and cholecalciferol as well as in participants taking calcium compared with placebo  Overall results of risk of bias assessment appear in In both RCTs, randomization was centralized, computer-generated. Participating women were blind to treatment assignment due the use of placebo. No specific details are reported on whether blinding was extended to caregivers, data collectors, outcome assessors and analysts.In the study from Lappe and co-authors, about 13.2% of the study participants (156 out of 1180) were lost to follow up. Reasons for drop out and droppers’ distribution across the study arms are not reported. Incomplete outcome data are not addressed by Avenell et al.We found no evidence of selective reporting for the two studies included. In both the RCTs, the outcomes listed in the methods section of the cited manuscripts fully matched with those reported by the original protocols None of the two RCTs was stopped earlier. Authors from both RCTs reported conducting ITT analyses. However, in Lappe and co-authors the number of participants randomized to treatment assignment does not exactly match with the number of participants followed up due to the exclusion of one woman after randomization. Reasons for exclusion are described in details. We could not identify further potential sources of bias for the studies included.Both the included trials contributed patients to this outcome.st), while women in the vit D arm were compared to participants randomized to placebo (Avenell A 2012-2nd). Conversely, the study from Lappe et al contributed only partly to the quantitative synthesis on breast cancer incidence. Indeed, we included participants randomized to cholecalciferol and calcium (446/1180) and compared them to women allocated to calcium only (445/1180). Study participants assigned to placebo were not considered (288/1180). Women participating in this trial tended to be significantly younger and with higher serum concentration of 25-OH vit D at baseline (i.e. 71±20.3 nmol/liter) compared to those participating in the trial from Avenell and colleagues  (2: 0%)  . Meta-re (2: 0%) .The number of breast cancer-related fatal events was available for one single study at three years of follow up. Deaths from breast cancer out of the total events due to cancer by study arm were as it follows: 7/78, 7/73, 9/95 and 4/83 in women allocated to vit D and calcium, vit D and  placebo, (vit D) placebo and calcium or placebo, respectively. The lack of point-in-time data refrained us from extracting the log HR and its variance for breast cancer mortality. However, since mortality data were provided exclusively by one trial We conducted a systematic review of RCTs focused on vit D supplemenation in breast cancer prevention. Based on pre-stated selection criteria, only two trials were included. Results from the pooled analysis do not support a role of vit D in reducing breast cancer risk in postmenopausal women. When compared to controls allocated to calcium and/or placebo, healthy women taking vitamin D either as a single agent or part of a combined treatment did not show a reduced risk of breast cancer development. In sensitivity analysis, vit D dosage and mode of administration did not affect the outcome of interest at a significant extent, although treatment efficacy appeared somewhat greater when vit D was administered at the highest dosage and in combination with calcium.This systematic review has the following strengths. We followed the Cochrane Collaboration methods for the conduct of systematic reviews of intervention trials. A qualified librarian designed an extensive search strategy, which was applied with sensitivity criteria to the first phase of the reference screening. The search of three major databases, use of the related tools and other reference sources, along with the lack of language restrictions, increase our confidence in the identification of all relevant trials.There are some limitations to this review. Our efforts to identify published trials were not paralleled by the systematic attempt to locate unpublished studies. Moreover, we could not assess publication bias by funnel plots due to the restricted number of RCTs included. On this basis, publication bias cannot be excluded. Among unpublished trials, those with non-significant results represent the vast majority In addition, all women participating in the included studies were postmenopausal. This limits our ability to make inference regarding vit D use for breast cancer prevention in healthy premenopausal women. The number of studies judged eligible was particularly low. This result, along with the relatively low number of women included (i.e. 5372) and the paucity of breast cancer events , might have conferred to our meta-analysis an insufficient power to detect the effects of interest. Moreover, when singularly considered, none of the included studies was primarily tailored to detect incident cancers, either overall or by primitive cancer site. Our results were largely driven by the RCT from Avenell and co-authors. Women participating in this trial were older and had poorer vit D status at recruitment than those participating in the other trial. However, baseline, circulating levels of 25-OH vit D were assessed in only a very small subgroup of 60 participants and might not be representative of the wider trial population. In this same group, supplementation was associated with an increase in circulating 25-OH vit D from 38 to 62 nmol/liter, which could still be suboptimal Dose adequacy represents a further, critical issue. Adults aged 50–70 and 70 years and older require at least 600 and 800 IU of vit D daily, respectively. However, to raise the blood level of 25-OH vit D above 75 nmol/liter requires at least 1500–2000 IU daily 2 0%). This could suggest that the reduced risk of cancer development is due to the effect of calcium rather than vit D. However, the inclusion of RCTs with co-interventions balanced across the compared groups should have minimized the differential contribution of calcium to the overall treatment effects.When combined with calcium, vit D showed a slight, not significant protective role towards breast cancer development compared with calcium alone Click here for additional data file.


Previous studies have suggested an inverse relationship between bone mineral density (BMD) and breast cancer incidence. The primary objective of this study was to assess whether BMD is associated with risk of subsequent breast cancer occurrence in the female population of southern Israel.The electronic medical charts of women who underwent BMD at the Soroka Medical Center (SMC) between February 2003 and March 2011 were screened for subsequent breast cancer diagnoses. Women were divided by tertiles of BMD at 3 skeletal sites: lumbar spine , total hip (TH) and femoral neck (FN). The incidence of breast cancer was calculated.Of 15268 women who underwent BMD testing, 86 were subsequently diagnosed with breast cancer. Most women in the study were older than 50 years . Women who subsequently developed breast cancer had a higher mean body-mass index (BMI) (30.9±5.5 vs. 29.1±5.7 p = 0.004) and the mean BMD Z-score was significantly higher than in those without breast cancer for all 3 skeletal sites . Women in the highest Z-score tertiles at the FN and TH had a higher chance of developing breast cancer compared to the lowest tertile; odds ratio of 2.15, 2.02, respectively (P = 0.004 and 0.01 respectively). No association was found between the BMD Z-score and the stage, histology, grade or survival from breast cancer.This study provides additional support for an inverse association between BMD and the risk of breast cancer. The incidence of both osteoporosis and breast cancer increases following menopause Several observational studies have suggested that a higher bone mass is associated with increased breast cancer risk and less favorable prognosis of an existing breast cancer In view of these conflicting data, we conducted this retrospective study with the primary objective to assess whether BMD is associated with risk of subsequent diagnosis of breast cancer in an unselected population of women of southern Israel.The study protocol was approved by the institutional review board (IRB) at Soroka Ben-Gurion University medical center. This study was based on a retrospective database analysis, therefore the need for an informed consent form was waived by the IRB.We retrospectively identified all the women who underwent a BMD measurement at Soroka Medical Center, Beer-Sheva, Israel, a 1000 bed tertiary-care hospital, between February 2003 and March 2011. We excluded those under age 18 and women with a known history of breast cancer at the time of BMD testing. Only the initial test was included in the analysis for women who underwent more than one BMD measurement. The electronic medical charts of the patients were screened for breast cancer diagnosed after BMD testing; using ICD-9 codes (174.0–175.9). Any diagnosis of breast cancer was included, irrespective of grade or stage. The following data were collected: demographic data, mortality data, BMI, laboratory results, and breast cancer characteristics .Bone mineral density was measured by dual energy X-ray absorptiometry (DEXA) using a Prodigy densitometer .2), T-score (standard deviation from the mean for young women) or Z-score (standard deviation from the mean for age-matched women adjusted for body mass).Z-score and T-score were calculated according to the Lunar-Prodigy manufacturer’s internal database and, based on NHANES III data.Bone mineral density was assessed at the lumbar spine (LS), femoral neck (FN) andtotal hip (TH) and was expressed as either bone density (in g/cmVitamin D status was reported when available. Vitamin D levels were determined by measuring patients’ serum 25-hydroxyvitamin D (25(OH)D) levels by the IDS Octavia 25-OH-D kit . Results were expressed as ng/ml, normal range: 20–58 ng/ml.PTH status was reported when available. Serum PTH levels were determined by using the Immulite 2000 intact PTH kit . This determination is based on a solid phase, two-site chemiluminescent enzyme – labeled immunometric assay. Results were expressed as pg/ml; normal range: 14–72 pg/ml.To assess the association between BMD and breast cancer, we defined the primary endpoint as the incidence of new breast cancer diagnosis (consistent with the ICD-9 codes) recorded after the BMD testing date.P-value of ≤0.05 was considered significant. The statistical analysis was done using SPSS version 18.The results are presented as the mean ± SD for continuous variables and as the total patients  for categorical data. T-test and one-way ANOVA were used for comparison of the continuous variables and chi-square or Fisher’s exact tests for categorical data. We used Mann-Whitney test for the comparison of variables with non-normal distribution. Correlations between BMD and breast cancer stage and grade were assessed by Spearman’s rank correlation coefficient. Time to diagnosis of breast cancer and survival analyses among breast cancer patients, were calculated by Kaplan-Meier survival analysis and the log-rank test. Multivariate analyses were performed using Cox regression, where BMD divided into tertiles was adjusted for age and BMI.A two-tailed Between February 2003 and March 2011 a total of 16,179 BMD tests were performed at the Soroka University Medical Center. During a median follow up of 47 months (inter-quartile range of 26–66 months) following BMD measurement, 86 women were diagnosed with breast cancer. For the present study, we compared the 86 women who developed breast cancer following BMD measurement with 14,461 who remained cancer free.Mean BMD was somewhat higher, at all skeletal sites, in women who developed breast cancer compared to those who remained cancer-free . Mean BMBMD results were divided into 3 cohorts based on tertiles of Z-score. Among the 86 women diagnosed with breast cancer following BMD testing, we did not find any association between BMD at any of the skeletal sites and breast cancer stage, histology or grade . ER receThis is the first study reporting on the association between bone mineral density and the risk of breast cancer in an Israeli population. Our results show that women who subsequently developed breast cancer had a higher baseline BMD at all three skeletal sites  compared with those who remained free of breast cancer during the follow-up period. Furthermore, higher BMD Z-scores at the femoral neck and total hip maintained the association with an increased risk of incident breast cancer, even after adjustment for age and BMI.Our results are in line with several previously reported prospective and retrospective studies which revealed higher incidence of breast cancer in postmenopausal woman with higher BMD The largest cohort, reported by Grenier et al. and originating from Manitoba, Canada, consisted of 37,860 woman 50 years and older who were followed for a median of 5.4 years after BMD measurement. The study revealed an increased breast cancer risk for the third and fourth quartiles of lumbar spine BMD and for the third quartile for femoral neck BMD after adjusting for age and HRT use Hadji et al reported the results of MABOT I and II prospective trials that found higher bone mineral density both by quantitative ultrasound and DEXA measurements in new breast cancer patients compared to controls A number of studies have challenged the existence of association between higher BMD and increased breast cancer risk both in peri-menopausal and early menopausal women These studies showing no association between BMD and future breast cancer raise the possibility that BMD may reflect lifetime estrogen exposure rather than being an independent risk factor for future breast cancer risk. Estrogen exposure, as reflected by age at menarche and menopause, gravidity, parity and use of postmenopausal HRT is an established risk factor for breast cancer Vitamin D may be an additional common confounder for the association of breast cancer with higher BMD, as higher levels of 25(OH)D are associated with higher BMD Our retrospective study is the first to show a positive association of higher BMD with higher incidence of breast cancer in an Israeli population, which is a mix of both Ashkenazi and Sephardi Jews and Arabs. Although several studies have suggested a relationship of the type we observed, others have not. The conclusions that have been reached in this unique population are important for Israel and also support the studies that showed higher rates of incident breast cancer in women with higher BMD.One limitation of our study is the lack of data regarding parameters of estrogen exposure . According to the NCI website, the 5 year risk for breast cancer of a woman with an age similar to the mean age of our group (67 years), is between 1.1–2.1%, while the rate of breast cancer in our cohort was lower 0.6%, which is also low compared to that reported in other studies The study strength is based on the unique structure of Israeli national health-insurance system which includes the entire population and a fully computerized medical record system which maximizes availability of baseline and follow-up data from cradle to grave.In conclusion, our retrospective study demonstrates a positive correlation between BMD and breast cancer incidence in the population of southern Israel. In view of the contradictory data on the association of BMD and breast cancer risk, a large prospective trial is required, which may allow a further characterization of this association and shed light on possible confounders.


Previous meta-analysis indicated conflicting results in case–control versus cohort studies on the association of green tea with breast cancer risk, and conflicting results were also found in case–control versus cohort studies in another meta-analysis on the association of black tea with breast cancer risk. Many studies were published after the previous meta-analysis. Besides, the dose-response relationship of tea consumption with breast cancer risk is unclear. Thus the association of tea consumption with breast cancer risk was assessed incorporating new publications. Summary relative risk (RR) for highest versus lowest level of tea consumption was calculated based on fixed or random effect models. Dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. The combined results from 9 studies suggested no significant association between green tea consumption and breast cancer risk . No significant association was found among cohort studies and case-control studies after sensitivity analysis, respectively. A linear but not significant dose-response association was found between green tea consumption and breast cancer risk. The combined results from 25 studies demonstrated no significant association between black tea consumption and breast cancer risk , and no significant association was found in subgroup analysis. A linear but not significant dose-response association was found between black tea consumption and breast cancer risk. Based on the current evidence, black tea and green tea might not contribute significantly to breast cancer risk, respectively.The online version of this article (doi:10.1186/2193-1801-2-240) contains supplementary material, which is available to authorized users. The median or mean level of tea consumption for each category was assigned to corresponding RR for every study. If the upper boundary of the highest category was not provided, we assumed that the boundary had the same amplitude as the adjacent category. We extracted the RR that reflected the greatest degree of control for potential confounders.I2 of Higgins and Thompson was used to assess heterogeneity  was found, otherwise, the random effect model was adopted (I2 ≥ 50%). Besides, combining studies regardless of the between-study heterogeneity had been widely criticized  . No significant association was found among cohort studies . A marginally significant association was found among case-control studies , however, the association was not significant after sensitivity analysis . Data from 7 studies  but not significant dose-response association was found between green tea consumption and breast cancer risk  for every 2 cups/day increment in green tea consumption. The RR (95% CI) of breast cancer was 0.97 (0.91-1.03), 0.94 (0.86-1.04), 0.93 (0.84-1.04), 0.93 (0.83-1.03), 0.92 (0.81-1.04) and 0.91 (0.79-1.04) for 1, 2, 3, 4, 5 and 6 cups/day of green tea consumption. No publication bias was detected (P = 0.68).For green tea, data from 9 studies   and case-control studies , menopausal status categorized as premenopausal status  and postmenopausal status , estrogen receptor (ER) and progesterone receptor (PR) status  categorized as ER+/PR +  and ER-/PR- , as well as body mass index (BMI) categorized as BMI < 25 kg/m2  and BMI > 25 kg/m2 . After sensitivity analysis with I2 > 50% as the criteria, the association was still not significant for ER+/PR + breast cancer , and no significant association was found among subjects with BMI < 25 kg/m2 . Data from 19 studies  but not significant dose-response association was found between black tea consumption and breast cancer risk  for every 2 cups/day increment in black tea consumption. The RR (95% CI) of breast cancer was 1.02 (0.99-1.05), 1.01 (0.98-1.05), 0.99 (0.95-1.03), 0.97 (0.92-1.02), 0.95 (0.89-1.01) and 0.93 (0.85-1.01) for 1, 2, 3, 4, 5 and 6 cups/day of black tea consumption. No publication bias was detected (P = 0.79).For black tea, data from 25 studies  Figure . The assOverall, this analysis suggested that black tea and green tea might not contribute significantly to breast cancer risk based on the current evidence, respectively. However, further researches deserve to address the possible interaction effects between tea and other dietary/genetic cofactors.