Regular users of aspirin may have reduced risk of breast cancer. Few studies have addressed whether risk reduction pertains to specific breast cancer subtypes defined jointly by hormone receptor (estrogen and progesterone receptor) and human epidermal growth factor receptor 2 (HER2) expression. This study assessed the prospective risk of breast cancer  according to use of aspirin and other non-steroidal anti-inflammatory medications (NSAIDs) in a cohort of female public school professionals in California.In 1995 − 1996, participants in the California Teachers Study completed a baseline questionnaire on family history of cancer and other conditions, use of NSAIDs, menstrual and reproductive history, self-reported weight and height, living environment, diet, alcohol use, and physical activity. In 2005–2006, 57,164 participants provided some updated information, including use of NSAIDs and 1457 of these participants developed invasive breast cancer before January 2013. Multivariable Cox proportional hazards regression models provided hazard rate ratios (HRR) for the association between NSAID use and risk of invasive breast cancer as well as hormone receptor- and HER2-defined subtypes.Developing breast cancer was associated inversely with taking three or more tablets of low-dose aspirin per week (23% of participants). Among women reporting this exposure, the HRR was 0.84  0.72–0.98) compared to those not taking NSAIDs and this was particularly evident in women with the hormone receptor-positive/HER2-negative subtype . Use of three or more tablets of “other” NSAIDs was marginally associated with lower risk of breast cancer . Other associations with NSAIDs were generally null.Our observation of reduced risk of breast cancer, among participants who took three or more tablets of low-dose aspirin weekly, is consistent with other reports looking at aspirin without differentiation by dose. This is the first report to suggest that the reduction in risk occurs for low-dose aspirin and not for regular-dose aspirin and only among women with the hormone receptor-positive/HER2-negative subtype. This preliminary study builds on previous knowledge and further supports the need for formal cancer chemoprevention studies of low-dose aspirin. Daily use of low-dose 81 mg) aspirin is formally recommended by the United States Preventive Services Task Force (USPSTF) for broad chemoprevention of cardiovascular disease  mg aspir. RegularTo date, one prospective and two case-control studies have examined detailed use of NSAIDs and risk of breast cancer subtypes defined jointly by HR and HER2 status. The Nurses’ Health Study reported that use of two or more tablets of any dose of aspirin per week was statistically significantly associated with the risk of the luminal A (HR-positive/HER2-negative) subtype but not associated with the luminal B subtype (HR-positive/HER2-positive), indicating the importance of categorizing HER2 in detail . In the n = 1457) including crucial detail on tumor HER2 status since submission of the 2005–2006 questionnaire, we evaluated whether risk of breast cancer varied by recent use of NSAIDs, and explored whether any associations between NSAIDs and risk of breast cancer were modified by HER2-defined breast cancer subtypes or overweight status.To add to the evidence on low-dose aspirin, other NSAIDs including regular dose aspirin (defined as 325 mg), and the risk of HR and HER2-defined breast cancer subtypes, we looked to our long-term prospective cohort of California public school professionals who were asked in 2005–2006 about current use of pain-relieving medications, including low-dose aspirin, regular-dose aspirin, ibuprofen, and other NSAIDs. A prior analysis of NSAIDS and breast cancer in this cohort  was baseThe California Teachers Study cohort (CTS) was established in 1995–1996 when 133,479 active and retired female teachers, administrators and other public school professionals were recruited through the California State Teachers Retirement System . Particihttps://www.calteachersstudy.com/past-questionnaires. The CTS is overseen by the Institutional Review Boards of the Cancer Prevention Institute of California, the California Health and Human Services Agency, the University of California, Irvine, the University of Southern California, and the City of Hope.In 2005–2006, a 10-year follow-up questionnaire collected updated information on frequency of current use of aspirin, low-dose aspirin and other pain-relieving medications (see below), weight, alcohol use, menopausal status, use of hormone therapy (HT), and physical activity. Copies of questionnaires are available at CTS participants are followed annually for changes of address, cancer diagnoses, hospitalizations, outpatient surgeries, emergency room visits, and death. Annual linkage with the California Cancer Registry (CCR) is used to identify incident cancer among cohort members. The CCR is a population-based cancer registry, which is anchored in state legislation that mandates reporting and is estimated to be over 99% complete . Annual Information on all incident breast cancers was obtained from the CCR, including pathologic and clinical features, which are abstracted directly from the medical record. HR status was based on estrogen receptor (ER) and progesterone receptor (PR) status as routinely reported on diagnostic pathology records. HER2 status was also based on pathology report review. Subtypes were defined as follows: HR-positive/HER2-negative was defined as ER-positive or PR-positive and HER2-negative; HR-positive/HER2-positive was defined as ER-positive or PR-positive and HER2-positive; HR-negative/HER2-positive was defined as ER-negative and PR-negative and HER2-positive; and triple-negative was defined as ER-negative, PR-negative, and HER2-negative.On the 10-year follow-up questionnaire, women were asked whether they were currently taking any pain-relieving medications at least once a week, and if yes, the total number of tablets taken per week . The medication choices included low-dose aspirin; aspirin or aspirin-containing product ; ibuprofen ; naproxen, ketoprofen or other non-steroidal ; Cox-2 inhibitors ; and acetaminophen . Women were then asked if they had stopped regular use of any of these medications during the past 3 years, and if yes, why . The baseline questionnaire asked if aspirin  and ibuprofen  were taken regularly (at least once a week), total years taken and how many days per week taken .Each medication type from the 10-year questionnaire was initially categorized as “Never in the past 3 years", “Former", “Current" ,or “Unknown” for that type of medication. Women were classified into the category “Never in the past 3 years” if they reported: (1) current use of 0 or <1 medication per week or left this question blank; (2) never took the medication regularly or did not stop regular use or left this question blank; and (3) did not give a reason for stopping. “Current” users were those who reported: (1) current use of ≥1 tablet(s) per week; (2) “Never took regularly or did not stop use” or left this question blank; and (3) did not give a reason for stopping. “Former” users were those who reported: (1) “Yes, I stopped regular use” or gave a reason for stopping; and (2) reported current use as 0 or <1 medication per week or left this question blank. All other women, including those whose answers were inconsistent or who left both questions blank for all medications, were classified as “Unknown”.For analysis, we: (1) focused on the five NSAIDs from the 10-year questionnaire, excluding acetaminophen; 2) grouped the women who were in the category of “Never in the past 3 years” for the medication of interest into women who reported (a) “No NSAIDs in the past 3 years,” which was used as the reference group, (b) no use of that particular type of medication but had used one or more of the other four NSAIDs in the past 3 years, and (c) no use of that particular type of medication and unknown use of one or more of the other four NSAIDS, which was combined with the “Unknown” category; and (3) combined former and current users of 1–2 tablets per week into one category. For low-dose aspirin, we also examined “Daily” use, which was defined as those with current use of 7+ tablets per week (Table  grouped n = 8867), had a prior history of breast cancer (n = 6216), or had unknown cancer history (n = 135). We also excluded women who prior to the 10-year follow-up questionnaire had died (n = 8654), had requested no further contact from the CTS (n = 926), had moved out of California for more than 4 months (n = 8296), had developed breast cancer (n = 4188), or had a bilateral mastectomy without a diagnosis of breast cancer  (n = 18). Among the remaining 96,179 participants, 57,164 (59%) completed the 10-year follow-up questionnaire. During follow up (from the date a woman completed the 2005–2006 questionnaire and continuing through 31 December 2012), 1457 women were diagnosed with invasive breast cancer after completing the 10-year follow-up questionnaire.For the present analyses, we excluded women sequentially who at baseline were not residing in California , death (n = 3538), a move (for >4 months) out of California (n = 2082), bilateral mastectomy (n = 5), or 31 December 2012 .Follow-up time was calculated as the number of days between the date the 10-year follow-up questionnaire was completed and the first of the following events: a first diagnosis of breast cancer  site code C50)  and 95% CI were estimated using multivariable Cox proportional hazards regression models, with age (in days) as the time metric and stratification by age (in years) at the time of the 10-year follow-up questionnaire. Covariates were included based on their independent association with risk for a given outcome with a Competing risk analysis was used to estimate risk of invasive breast cancer overall and by different receptor subtypes. The 157 women diagnosed with breast cancer during follow up who had missing information on HR or HER2 status were excluded from all models with breast cancer subtype as the outcome. We tested the proportional hazards assumption for each covariate in the model and for the main effect for the different outcomes using a likelihood ratio test of interaction with the time metric (continuous age) based on cross-product terms. We found only one violation of the proportional hazards assumption: alcohol consumption had a statistically significant interaction with time-dependent age for HR-negative/HER2-negative tumors; thus, this interaction was included in the model for that outcome.2) and tested the interaction using a likelihood ratio test and cross-product terms, excluding women with unknown NSAID use.We conducted multivariable analyses in which we assessed the impact of adjusting for history of hospitalization for myocardial infarction  and history of diabetes mellitus . These adjustments did not meaningfully change the HRR when evaluating the association of current use of low-dose aspirin with risk of breast cancer overall or with risk of any of the receptor subtypes. Hence, history of myocardial infarction and history of diabetes mellitus were not included in the final models presented here. We also examined models of low-dose aspirin stratified by body mass index (BMI)  in conjunction with use of regular-dose and low-dose aspirin from the 10-year questionnaire, with no NSAID use reported at both baseline (including aspirin and ibuprofen) and the 10-year follow-up  as the reference group. This analysis was limited to outcomes of breast cancer and the HR-positive/HER2-negative subtype, as we had an insufficient number of diagnoses to examine these associations in the other subtypes.The 1457 cases of invasive breast cancer diagnosed during follow up included 998 (68%) HR-positive/HER2-negative, 120 (8%) HR-positive/HER2-positive, 44 (3%) HR-negative/HER2-positive, 138 (9%) HR-negative/HER2-negative breast cancers, and 157 (11%) with missing data on expression status for at least one receptor. The characteristics of cohort participants are shown in Table The most common NSAID reported as currently used by participants at the 10-year follow-up was low-dose aspirin (Table n = 13). Significant associations did not appear to differ by overweight status Current use of at least three tablets per week of any NSAID was not statistically significantly associated with any particular subtype of breast cancer or breast cancer overall Table . HoweverTo assess associations with risk of breast cancer overall and with risk of one subtype among probable long-term users of NSAIDs, we carried out secondary analyses combining information reported on the baseline and 10-year follow-up questionnaires. Among women currently using 3+ low-dose aspirin tablets per week at the 10-year follow up, risk of breast cancer was comparable between those who reported no NSAID use at baseline  and those who reported using aspirin regularly for 4+ days per week at baseline  compared to those who reported no NSAID use on both the baseline questionnaire and the 10-year follow-up questionnaire (409 cases). Results were similar for those currently using 3+ tablets per week of regular-dose aspirin at the 10-year follow-up  for no NSAID use at baseline; HRR = 0.94, 95% CI 0.67–1.31 (39 cases) for aspirin 4+ days per week at baseline). Similar patterns were observed for the HR-positive/HER2-negative subtype (data not shown).To assess possible confounding by indication, we also assessed associations between breast cancer and acetaminophen, a pain reliever that is not an NSAID. Current use of at least 3 tablets per week of acetaminophen was not associated with breast cancer or any particular subtype of breast cancer in models adjusted for the five NSAIDS  compared to no use of acetaminophen in the last 3 years (1109 cases); for the HR-positive/HER2-negative subtype, HRR = 0.98, 95% CI 0.83–1.16 for current use of 3+ tablets per week (180 cases) compared to no use of acetaminophen in the last 3 years (757 cases); other data not shown).Among CTS participants who reported their detailed, current use of NSAIDs and then were followed prospectively for a median of 7 years, the association between use of specific NSAIDs and the development of invasive breast cancer or its receptor-defined subtypes differed depending on the NSAID used. In the 23% of women who reported using low-dose aspirin at least three times per week, we observed a modest 20% reduction in risk of developing HR-positive/HER2-negative breast cancer, which is likely responsible for the similar association observed between NSAID use and risk of breast cancer overall. This association persisted after consideration of other breast cancer risk factors including use of HT and prior history of myocardial infarction. This association is intriguing because no such association was observed with the use of regular-dose aspirin (325 mg). We suspect that this could relate to the more regular use of low-dose aspirin for cardioprotection, as opposed to a more sporadic pattern of use of regular-dose aspirin to relieve pain. We did not observe any apparent modification of the low-dose aspirin effect by overweight status, nor did we observe stronger associations in women who were likely to be longer-term users, having reported using aspirin 10 years earlier, at baseline. This association should be re-examined in cohorts with larger numbers of incident breast cancers in which HR and HER2 status are recorded.The three studies published previously that assessed HR-defined and HER-2-defined subtypes differed in the definitions of medication dose and duration of use, limiting our ability to compare the results of those studies to ours. The Nurses’ Health Study  conducte2 [In the Nashville Breast Health Study , a case-2 . Our res2 , anotherOur key finding is related to low-dose aspirin and not to regular-dose aspirin. Women who reported using low-dose aspirin were more likely to take it more than three times per week or daily, possibly for cardiovascular disease prevention. In our prior analysis of NSAID use reported at baseline by CTS participants and development of subsequent breast cancer , we coulOur finding of an inverse association between use of 3+ low-dose aspirin tablets/week and risk of breast cancer overall is consistent with the findings of several other observational studies that did not separately examine HR-defined and HER2-defined subtypes. The largest and most detailed prospective study, the VITAL cohort , found tp = 0.68) [In contrast to these studies, in the Women’s Health Initiative observational study  risk of  = 0.68)  among th = 0.68) . AltogetThe biological mechanism by which low-dose aspirin could function as a chemopreventive agent against HR-positive/HER2-negative breast cancer, but not other breast cancer subtypes, is not yet clear. A consistent lowering of COX-2 and prostaglandin activity could prevent or slow carcinogenesis in a number of ways, at the tumor level, by interfering with DNA adduct formation , inhibitStrengths of this study include the complete and accurate prospective ascertainment of HER2-defined breast cancer development based on routine linkage of the cohort to the statewide cancer registry, linkage to hospital discharge summary data to confirm any previous myocardial infarction, and a median of 7 years of follow up. Our study also had limitations. The total number of breast cancer cases was greater than was available in previously published analyses, but the limited numbers available for subtype-specific analyses meant that these were exploratory. It is possible that women who regularly take low-dose aspirin differed from women who did not, based on important health parameters , resulting in residual and unmeasured confounding. For instance, women who regularly take low-dose aspirin could engage in more health-conscious behavior than non-users or infrequent-users. Like most observational studies, we were only able to measure NSAID exposure as “snapshots” of exposure at the time women completed their surveys. We were limited in evaluating possible confounding by indication for cardiovascular disease that did not result in hospitalization for myocardial infarction. Finally, this population is not representative of the general population of California women or women across the USA, particularly with respect to educational status; thus, it is uncertain how generalizable our findings are to the broader population, particularly non-white women and women born outside the USA. At cohort inception in 1996, CTS participants had incidence rates of breast cancer that were over 50% higher than those for age-matched and race-matched women in California , which pIn summary, our study strongly supports the need for further, perhaps experimental, study of low-dose aspirin as a widely available, inexpensive chemopreventive option for the most common subtype of breast cancer, the HR-positive/HER2-negative subtype. Our study adds to the existing evidence on this topic, showing that previously reported associations between low-dose aspirin use and risk of breast cancer overall may be driven by a more specific association with this hormone-sensitive and HER2-negative breast cancer subtype. Furthermore, it suggests that previously reported associations using measures that combined low-dose aspirin use (more likely to be daily or more frequent) with regular aspirin use should reassess these associations. Future studies of aspirin and breast cancer must be able to distinguish low-dose from other formulations and to assess risks separately by molecularly defined subtype. Such studies should not only detail this chemopreventive potential but should also quantify any side effects associated with regular low-dose aspirin use.For 23% of women who reported using low-dose aspirin at least three times per week, we observed a modest 20% reduction in risk of developing HR-positive/HER2-negative breast cancer, which is likely responsible for the similar association observed for breast cancer overall. No such association was observed for use of regular-dose aspirin (325 mg) or other NSAIDs. We suspect that our observations could relate to the pattern of daily use of low-dose aspirin for prevention, as opposed to more sporadic patterns of use to relieve pain. Our data are intriguing as regards the role of low-dose aspirin in breast cancer prevention but this question should be revisited in cohorts with larger numbers of incident breast cancers, in which HR and HER2 status are also recorded.


Full-field digital mammography, which is gradually being introduced in most clinical and screening settings, produces two types of images: raw and processed. However, the extent to which mammographic density measurements, and their ability to predict breast cancer risk, vary according to type of image is not fully known.We compared the performance of the semi-automated Cumulus method on digital raw, “analogue-like” raw and processed images, and the performance of a recently developed method - Laboratory for Breast Radiodensity Assessment (LIBRA) - on digital raw and processed images, in a case-control study (414 patients (cases) and 684 controls) by evaluating the extent to which their measurements were associated with breast cancer risk factors, and by comparing their ability to predict breast cancer risk.Valid Cumulus and LIBRA measurements were obtained from all available images, but the resulting distributions differed according to the method and type of image used. Both Cumulus and LIBRA percent density were inversely associated with age, body mass index (BMI), parity and postmenopausal status, regardless of type of image used. Cumulus percent density was strongly associated with breast cancer risk, but with the magnitude of the association slightly stronger for processed (risk increase per one SD increase in percent density (95 % CI): 1.55 ) and “analogue-like” raw ) than for raw ) images. LIBRA percent density produced weaker associations with risk, albeit stronger for processed ) than raw images ). The percent density values yielded by the various density assessment/type of image combinations had similar ability to discriminate between patients and controls .The findings showed that Cumulus can be used to measure density on all types of digital images. They also indicate that LIBRA may provide a valid fully automated alternative to the more labour-intensive Cumulus. However, the same digital image type and assessment method should be used when examining mammographic density across populations, or longitudinal changes in density within a single population.The online version of this article (doi:10.1186/s13058-016-0756-7) contains supplementary material, which is available to authorized users. Mammographic density (MD) is one of the strongest risk factors for breast cancer , 2, and Screen-film mammography is gradually being replaced by full-field digital mammography (FFDM). In contrast to the former, FFDM produces two types of image. Raw images (“for processing”) are initially captured but subsequently processed (“for presentation”) using manufacturer-specific algorithms  - has been recently developed to quantify MD on both digital raw and processed images . HoweverIn this study, we compared the performance of Cumulus and LIBRA measurements from different types of digital images in a case-control study, by evaluating the extent to which they are associated with breast cancer risk factors, and by comparing their ability to predict breast cancer risk.Details of the study population are described elsewhere . BrieflyData on breast cancer risk factors were collected using a self-administered questionnaire at the time of screening for controls and after diagnostic confirmation for cases, and complemented with data from clinical records. Two-view  and mediolateral oblique (MLO)) FFDM was performed on each breast using Senographe DS units. Both raw and processed digital images were stored  was used to convert the raw digital images into analogue-like images  was also applied to both raw and processed images [2), and of percent density (PD).Cumulus (version 3) readings were performed on raw, processed and analogue-like CC images by a single reader (MCB) in batches of 250–300 images of the same type, with each batch comprising a similar proportion of cases and controls. To assess within-observer reliability each batch contained images of the same type from a 7 % random sample of all participants as duplicates. To compare between-observer reliability across different types of images, all  images from a random sample of 200 women were also read independently by another observer (IdSS). The two readers were kept blind to the characteristics of the women, including their case-control status. The fully automated LIBRA method  was used to examine within-observer and between-observer reliability in the Cumulus readings. Correlation between different approaches was assessed by estimating the Spearman correlation coefficient. Level of agreement between the measurements obtained by the different MD assessment method/image type combinations among controls was investigated by producing Bland-Altman plots. Quintile agreement was assessed as the proportion of women classified in the same quintile, or in the same ±1 adjacent quintile.A square root transformation was used to normalise the area-based MD measurements. The association between each breast cancer risk factor and each density measure  was assessed among controls by linear regression models while adjusting for ethnicity (white versus other), age and body mass index (BMI) at mammography, ages at menarche and first birth, parity (nulliparous versus parous), menopausal status , and ever-use of oral contraceptives and hormonal therapy (HT). Regression coefficients represent the change in each density measure (expressed in number of standard deviations (SD) on the transformed scale) associated with a unit change in the explanatory variable.Logistic regression models were fitted to examine the association between density estimates and breast cancer risk, adjusting for age, BMI and the other variables mentioned previously. Density measurements were included in the models as continuous variables  or as quintiles or tertiles (defined among controls). To assess the robustness of the findings, sensitivity analyses were conducted by restricting the analysis to participants for whom density readings were available for all methods and to those aged <80 years. Multiple imputation methods were also used to impute values for women with missing confounder data. The ability of the various methods to discriminate between cases and controls was compared by estimating the area under the receiving operating curve (AUC). All analysis was performed in Stata 14.1.2, respectively) or reproductive factors . Both Cumulus and LIBRA produced readings for all available images  and 1425 controls were invited to participate. The response rate was 85 % for patients and 51 % for controls but only 414 patients and 684 controls were eligible . Inter-observer reliability was also high among the random sample of 200 women whose images were independently read by a second observer .r) ≥0.80, P < 0.0001 for all; Table The PD measurements yielded by Cumulus on the three types of images were highly correlated  (Table LIBRA PD measurements on raw and processed images among control women were strongly correlated (1) Table , despite1) Table , with th1) Table .r = 0.74 for raw and processed images, respectively; P < 0.0001 for both; Table Cumulus and LIBRA PD measurements taken on the same type of image were moderately to strongly correlated  or hormonal therapy Fig. , or agesP for linear trend ≤0.004 for all). The positive associations between Cumulus PD and risk reflected positive associations between absolute density and risk, and negative associations between absolute non-density and risk  and analogue-like images  than for raw images   assessment method/type of image combinations had a similar ability to discriminate between cases and controls of screening age, i.e. aged 50–69 years. AUC values for PD, age, BMI, parity and menopausal status ranged from 0.61 and 0.64; similar findings were observed for absolute density , reported stronger association between LIBRA PD on raw images and risk  adjusted for the Gail risk factors: 1.64; 95 % CI 1.25, 2.14)  than theIt is noteworthy that the area-based Cumulus and LIBRA approaches examined here produced weaker associations between PD and breast cancer risk than the fully automated volumetric VOLPARA algorithm. The latter was examined in a previous analysis of data from this case-control study   but any potential bias is likely to have affected all MD assessment method/type of image combinations examined similarly. Data on breast cancer risk factors were self-reported but as density is not routinely assessed in the UK, and hence women are not informed about it, any misclassification is likely to have been non-differential. Processed images were missing for 15 % of the control participants due to a logistical error; however, no differences were observed between women with missing images and those for whom processed images were available, in terms of the distribution of breast cancer risk factors.This study demonstrated that Cumulus can be used to produce valid MD estimates from raw, analogue-like and processed digital images. Although the Cumulus measurements yielded by the three types of images were strongly correlated, their distributions were not equivalent. Nevertheless, Cumulus PD estimates were all strongly associated with breast cancer risk regardless of the type of image used, but with the magnitude of this association being slightly stronger for analogue-like and processed images than for raw images. The findings also provide further evidence that LIBRA on processed images may be a valid fully automated alternative to the more labour-intensive Cumulus approach. The associations with breast cancer risk for LIBRA measurements on raw images were weaker than those produced by Cumulus. Nevertheless, LIBRA may be the only feasible option in large-scale studies based on raw images for which it will be prohibitively expensive and time-consuming to use Cumulus, with the weaker association between PD and breast cancer risk being offset by a much larger sample size. The findings also highlighted the need to use the same type of image when comparing MD measurements across populations, or when evaluating longitudinal changes in MD within a single population.


IGF1R gene variant, rs2016347, to result in lower breast density, as well as decreased breast cancer risk. Our objective was to explore these findings in a larger sample of women from the California Teachers Study (CTS).Hypertension in pregnancy has been associated with decreased future risk of breast cancer in many but not all studies. In the Marin Women’s Study, pregnancy-induced hypertension was shown to interact with the T allele of a functional The CTS cohort consists of over 130,000 female educators. DNA was available from a nested case–control study, which included 2,030 non-Hispanic white women who developed breast cancer and 1,552 controls. The current study included all participants from the case–control group with a self-reported history of preeclampsia (80 cases/57 controls).p values of 0.09, 0.03, 0.005, and 0.004 respectively, suggesting a biological effect for each T allele.Comparing TT to GG genotypes revealed adjusted odds ratios of 0.38  for all invasive breast cancers, 0.26  for hormone receptor-positive (HR+) breast cancers, 0.15  for those with age at first birth (AFB) < 30, and 0.10  for those with AFB < 30 and HR+ breast cancers. Trend analysis yielded IGF1R variant rs2016347 is associated with a significant reduction in breast cancer risk in women with a history of preeclampsia, most marked for HR+ breast cancer and in women with AFB < 30.Study findings indicate that the T allele of  Pregnancy is known to have a major impact on the developing breast and results in a transient increase, but a long-term decrease in the risk of developing breast cancer. Hypertensive disorders of pregnancy are characterized by the development of elevated blood pressure after the 20th week of pregnancy and affect 6–8% of all pregnancies. Many but not all epidemiologic studies have demonstrated a lower future risk of breast cancer in women reporting such a history, whether it be hypertension alone , or hypertension with proteinuria (preeclampsia). A pooled meta-analysis of 19 publications in 2013 reported a hazard ratio of 0.86 for preeclampsia and 0.83 for gestational hypertension . AlthougBoth gestational hypertension and preeclampsia are associated with inadequate invasion of the uterine vasculature by placental cytotrophoblasts, resulting in placental ischemia and the subsequent release of numerous biologically active factors such as cytokines, angiogenic factors, and growth factors/inhibitors that could impact the breast during this critical developmental period . Many stIGF-1 is an important mediator of mammary terminal ductal formation during development, and increased activity of the gland’s IGF-1/IGF1R system has been shown to play a major promoting role in the development of breast cancer , 13. A pIGF1R [Prior work in the Marin Women’s Study (MWS) demonstrated that a history of hypertension in pregnancy is associated with lower later-life breast density and, furthermore, that this lower breast density is dependent on the inheritance of at least one T allele of rs2016347, a common and functional SNP located within the 3′UTR of IGF1R . The curIGF1R .The California Teachers Study (CTS) is an ongoing prospective cohort study of breast cancer composed of 133,479 active and retired female public school teachers and administrators recruited in 1995 from the California State Teachers Retirement System. The baseline questionnaire (Q1) captured detailed information on height/weight, physical activity, menstrual/reproductive history, oral contraceptive use, menopausal hormone therapy use, and family history of cancer. A question about preeclampsia was asked on the second CTS questionnaire (Q2) in 1997. Cancer outcomes in the CTS are identified through annual linkage with the California Cancer Registry, a legally mandated statewide population-based cancer reporting system.Blood samples were available from a case–control study established in 2012, which included 2,030 non-Hispanic white women who developed breast cancer after entry into the study and 1,552 controls without invasive or in situ breast cancer. The current study nests within this case–control study, and all participants with a self-reported history of preeclampsia were selected (80 cases/57 controls). Hazard ratios for breast cancer in women with preeclampsia were calculated using Cox proportional hazards models in SAS. Adjusted models included age at baseline, age at first birth, total number of births, body mass index (BMI) at baseline, age at menarche, and family history of breast cancer. Invasive breast cancer cases were annotated as hormone receptor positive (HR+) if they were either estrogen receptor positive (ER+) or progesterone receptor positive (PR+).Genotyping was performed at the Beckman Research Institute of City of Hope using MGB TaqMan Probe Assays from Life Technologies. For these assays, the reaction mix in a final volume of 5 µl included 5–20 ng genomic DNA, 4.5 pmol of each primer, 1.25 pmol of each probe, and 1× TaqMan Genotyping Master Mix from Life Technology. PCR cycling included 40 cycles of a two-step PCR (95 °C for 15 s and 60 °C for 1 min) after an initial 10 min at 95 °C. PCR amplification and allelic discrimination were carried out on an ABI PRISM 7900 HT instrument. For genotyping the samples, 160× master PCR reaction mix for each SNP was prepared; after loading the Master Mix to the DNA samples, 9× of remaining Master Mix was loaded to non-template DNA wells for negative control. The call rate for rs2016347 was 97.1%, and the T allele frequency was 0.51 in all women tested in the CTS cohort.p value < 0.05) in covariates or covariate subgroups. The mean age at baseline was 55.4 in cases and 56.5 in controls.Our study nested within an existing CTS case–control study and the distribution of participant covariates for the cases and controls are presented in Table p = 0.14, and thus did not reach statistical significance , p = 0.01, when looking at all types of invasive breast cancer. When looking at just HR+ breast cancer in women with AFB under 30, the adjusted odds ratio was 0.10 , p = 0.008. Stratification by pre- and postmenopausal breast cancer case status failed to demonstrate any statistically significant findings (data not shown).Models were stratified by age at first birth (AFB) under or over age 30 and by premenopausal or postmenopausal case status to assess possible variations in the associations observed. Among women with an AFB under 30, those with the TT genotype when compared to the GG genotype demonstrated an adjusted odds ratio of 0.15 , p value of 0.09. Trend analysis was significant in the HR+ only group, p = 0.03, the AFB under 30 group, p = 0.005, and the group containing both HR+ cases only and AFB under 30, p = 0.004. This suggests that one T allele likely exerts a biologic effect.In an effort to determine the biologic importance of just one T allele, the GT as well as the TT genotype was compared to the GG genotype, and the results of this analysis are provided in Table We also examined the risk for breast cancer in women with preeclampsia in the full CTS cohort without regard to rs2016347 genotype, providing a 7-year update to the earlier CTS findings and utilizing preeclampsia in any pregnancy as the exposure of interest . PresentIGF1R rs2016347 TT genotype, specifically in those with age at first birth under 30 and for subsequent development of HR+ breast cancer. These results are consistent with prior MWS findings, and both studies demonstrate that a lower risk of breast cancer in women with a hypertensive disorder of pregnancy is dependent on carrying the same functional rs2016347 variant. The protective TT genotype of rs2016347 is presumed to be functional both by its clinical impact (discussed below) and by its association with a reduction in IGF1R mRNA expression in multiple normal human tissues [The CTS results suggest significant breast cancer protection in women with preeclampsia who possess the  tissues .Our findings suggest a SNP-exposure interaction, as the rs2016347 SNP alone has not been shown in multiple genome-wide studies to be associated with changes in the risk of either breast cancer or preeclampsia. We speculate that this functional SNP genotype may interact with one or more of the numerous alterations in hormones and growth factors that occur as a result of the placental insufficiency seen in women with hypertensive disorders of pregnancy. Documented changes in these women include decreased estrogen levels and lower IGF-1 levels with higher levels of IGF-1 binding proteins [IGF1R and, furthermore, that this hypermethylation was associated with a reduction in mammary gland IGF1R mRNA expression [IGF1R 3′UTR, providing a putative mechanism for the predicted functionality of rs2016347 and the T allele dosage effect observed in both our CTS analysis and in the GTEx dataset [Early full-term pregnancy has long been known to have a protective effect on future breast cancer risk. Animal models have demonstrated that presumed epigenetic changes occur in rat mammary glands that persist long after pregnancy and strongly protect against mammary tumorigenesis . Humans pression . Carryin dataset .Animal models have also demonstrated that IGF-1 can obliterate the pregnancy-associated protection against breast cancer by increasing ERα activation . With reA potential early application of these findings could lie in risk prediction. Although efforts at adding SNPs to risk assessment models have resulted in only an incremental improvement in risk prediction across the general population, there may be subgroups of women such as those identified here who may benefit significantly from the addition of a specific SNP to their individualized risk assessment . AccordiThis study possesses a number of significant strengths. First and foremost, it presents data which are consistent with a previous study, thus the findings have now been demonstrated in two analyses performed at different times by separate research teams utilizing distinct cohorts, both finding statistically significant breast cancer protection in women with a history of hypertension in pregnancy who carry the rs2016347 TT genotype. Both analyses have excellent data on reproductive history and other breast cancer risk factors. Although the genotyping process was completed at different labs, the same assay approach and reagents were utilized in both studies, with resultant high call rates.One potential limitation of our comparison between this study and the MWS study is that the “definition” of hypertension in pregnancy differed in the two studies. In the MWS, participants were asked if they had hypertension in pregnancy, while in the CTS participants were asked if they had preeclampsia in pregnancy. Thus, the CTS would not include women with gestational hypertension. However, these disorders are both associated with similar decreases in future breast cancer risk as shown in the referenced meta-analysis . MoreoveIn addition, the current study included only non-Hispanic white women. This was designed to make our CTS analysis more comparable to that of the MWS, but clearly limits generalizability. The small numbers resulting from the relatively low incidence rates of both preeclampsia and breast cancer may have precluded demonstrating statistical significance of relatively low effect size, as evidenced by the lack of statistical significance when looking at all cases of invasive breast cancer by genotype despite an adjusted OR of 0.38. Thus, our CTS findings warrant replication and further study in other large cohorts with similar access to both pregnancy hypertension history and later-life breast cancer risk.IGF1R SNP rs2016347. Stratification of participants demonstrated that this protection is increased in women with age at first birth under 30, and for the later-life development of HR+ breast cancer. The rs2016347 T allele is common in many ethnicities and is likely functional, as recent studies have associated this variant with lower normal tissue expression of IGF1R mRNA and better treatment responses and patient survival from HR+ breast cancer.The results provided from this CTS analysis suggest significant breast cancer protection in women with preeclampsia who inherit the protective TT genotype for the IGF1R 3′UTR, offering a potential mechanistic hypothesis for the functionality of rs2016347 and its ability to interact with alterations of hormones and/or growth factors characteristic of hypertensive disorders of pregnancy and, thereby, to imprint the immature gland with a lasting protective effect from later-life tumorigenesis. Future proof of the mechanistic process may not only help explain why certain pregnancy events can protect some but not all women from breast cancer, but could also foster the design of much needed new breast cancer prevention strategies.The protective T allele appears to encode a new microRNA (miR-432) binding site within the


Breast cancer (breast Ca) is recognised as a major public health problem in the world. Data on reproductive factors associated with breast Ca in the Central African Republic (CAR) is very limited. This study aimed to identify reproductive variables as risk factors for breast Ca in CAR women.A case–control study was conducted among 174 cases of breast Ca confirmed at the Pathology Unit of the National Laboratory in Bangui between 2003 and 2015 and 348 age-matched controls. Data collection tools included a questionnaire, interviews and a review of medical records of patients. Data were analysed using SPSS software version 20. Odd ratios and 95% confidence intervals (CI) for the likelihood of developing breast Ca were obtained using unconditional logistic regression.In total, 522 women with a mean age of 45.8 (SD = 13.4) years were enrolled. Women with breast Ca were more likely to have attained little or no education , to be married , to have had an abortion , and to be nulliparous . Decreased odds of breast Ca were associated with being employed , living in urban areas , late menarche , regular menstrual cycles , term pregnancy  and hormonal contraceptive use .Breast Ca risk factors in CAR did not appear to be significantly different from that observed in other populations. This study highlighted the risk factors of breast Ca in women living in Bangui to inform appropriate control measures. Breast cancer (breast Ca) is the most common cancer and the leading cause of cancer deaths among women worldwide . GloballA risk factor is defined as anything that increases your probability of developing breast Ca. However, on one hand, many of these risk factors are beyond individual’s control, such as sex, age, race, chest X-ray exposure, family history of breast Ca, personal history of breast Ca, pregnancy and breastfeeding. On the other hand, weight, diet, physical activity, smoking, alcohol, exposure to estrogen, use of oral contraceptives, stress and anxiety are called modifiable factors .These lifestyles  as well as reproductive characteristics of women can also increase their risk of developing breast Ca . It has Nulliparity, late age at first live birth and lack of breastfeeding are risk factors for breast Ca in developed countries. Reproductive factors play an important role in the development of breast Ca among women who lack access to good family planning in rich and poor countries .What causes breast Ca? Why a double and even triple increase is seen in recent decades?Indeed, women are now more likely to develop breast Ca than they were a decade ago. Survival rates have also increased. Nearly two in three women with breast Ca now survive the disease beyond 20 years, compared with less than half in the 1990s. More than three-quarters of women diagnosed with breast Ca survive for at least 10 years or more. All these increases were observed as a result of advances made in research. In Africa, this increasing incidence probably reflects the fact that nowadays, women live longer and adopt a lifestyle that favours high incidence rates . A large proportion of breast Ca in Africa has been observed in pre-menopausal women compared with those in Western countries, possibly reflecting the role of some specific risk factors . The burIn recent decades, while the Central African Republic (CAR) began recording a significant reduction of infectious diseases through various national programs implemented, new diseases, including cancer and other non-communicable chronic diseases began emerging as new public health priorities . UnfortuAs part of a larger effort to inform the Ministry of Health on possible interventions to prevent breast Ca, this case–control study was conducted to determine the relationship between breast Ca and reproductive factors in women living in Bangui, CAR. The results of this study will help the Ministry of Health to develop new strategies for prevention, early diagnosis and treatment.We conducted a case–control study at the pathology unit of the National Laboratory, and at the general surgery and gynecology services of two tertiary care institutions in Bangui (CAR).Cases were identified among women with histologically confirmed breast Ca between September 2003 and September 2015. Controls were randomly recruited among women who came for other conditions unrelated to cancer at the National Laboratory of Bangui. For each case, two controls were selected. All controls were free of any cancer. They were matched for age, because breast Ca is an age-related disease and increasing age is the single most important risk factor after female gender . In addiAll consenting women aged ≥ 15 years, living in Bangui, and who presented with histologically confirmed breast Ca between 2003 and 2015.Data was collected from a cancer register of the pathology unit of the National Laboratory and from medical records of patients seen at the general surgery and gynecology services in Bangui. The risks and benefits of the study were explained to all eligible participants. Those who agreed signed an informed consent form before the interview. This interview was conducted in Sango . For participants who did not understand Sango, adult relatives interpreted the content of the questionnaire and consent form for better understanding. For minors or children, a written consent was obtained from close relatives or caretakers before being enrolled in the study. Each potential participant had the choice to accept or refuse to participate in the study. Questions were also granted from volunteers who wish clarification. For cases who had died, their relatives were selected as next of kin to provide data relating to their lifestyle.The following explanatory variables were considered as reproductive factors: age, occupation, economic status, education level, areas of residence , ethnic group and marital status. In addition, age at first menarche, menstrual cycle frequency, dysmenorrhoea, full-term pregnancy, age at first live birth, abortion, parity, breastfeeding, menopausal status and use of hormones .Age was recoded as age groups. Their occupation was classified as a homemaker or paid employment outside of the home. Economic status was defined in terms of family income according to international poverty threshold. Low income if below 2 dollars a day, moderate between 2 and 4 dollars, good between 5 and 10 dollars and excellent above 10 dollars . Place oχ2) test or Fisher’s exact test were used to compare the frequency distribution of categorical variables while the student t-test were used to compare the mean values for continuous variables between cases and controls. Unconditional logistic regression models were used to estimate odd ratios (OR) and their 95% confidence intervals (CI) for the association between reproductive factors and breast Ca. Variables associated with breast Ca at significance level below 0.2 in the univariate analysis were included in the multivariate model. Variables associated with breast Ca at the significant level below 0.05 were kept in the multivariate model following backward elimination. Results were presented as adjusted odds ratio (AOR), 95% CI and P values. All analyses were performed using Statistical Package for Social Sciences  version 20.Pearson chi-square . The age at diagnosis for the cases ranged from 16 to 90 years with a mean of 45.83 (SD = 13.5) years. The mean age for the control was 45.79 (SD = 13.3) years.p = 0.001), economic status (p = 0.01), education level (p < 0.001), area of residence (p <0.001), marital status (p <0.001) and parity (p = 0.008). Over 69% (121/174) of the cases as compared to 82% (287/348) of controls were housewives with a moderate economic status (56.9 and 66.4%). Nearly 13% (23/174) and 14% (51/348) of the cases and controls, respectively, had attained higher level of academic study and lived in cities (85.6 and 96.9%). Unmarried women made up 75.9% (132/174) of cases against 89.9% (313/348) of controls. A small proportion of cases (17.9%) and controls (9.8%) were nulliparous.Table p <0.001 and 95% CI: 1.15–4.99, p = 0.01) among women with little or no education compared with those with university education. The odds of breast Ca were 2.09 times higher among married women compared with singles . Women in employment and those living in cities showed decreased odds of 0.32  and 0.16 , compared with housewives and those living in rural areas, respectively.The odd ratios for the association between socio-demographic factors and breast Ca were summarised in Table p <0.001). Nulliparous women showed a 1.98 times the odds of breast Ca , compared with women with one or more children. Women with late menarche (≥12 years old) and those who had regular menstrual cycles were found to have decreased odds of 0.18  and 0.44  respectively, compared with those with early menarche (< 12 years old) and irregular menstrual cycles (Table p <0.001), 0.62  and 0.20  respectively, compared to those who did not (Table p = 0.43).The odds of breast Ca were 5.41 times higher among women with a history of abortion compared with those with none  and India (2013), which reported a higher risk for married women , 28, butDuring the last decades in the CAR, marriage has been closely linked to the socio-economic status of the future couple and /or their respective families. Unfortunately, only a minority group (20%) of women in this study belongs to the high socio-economic class, with improved access to medical care. This situation makes us believe that marriage is an indication of good socio-economic status. It is important to note that, following the results of this study, demonstrating marriage as a risk factor for breast Ca, we think that these results could have been influenced by selection bias. Moreover, in a context were the woman lacks the partner’s moral support, marriage can harm her well-being and health outcomes; support from others (family or friends) can have a stronger influence on the survival of the patient than the support of a spouse.The results of our study showed that the odds of breast Ca were lower among women who had their menarche after the age of 12 years. Our results contrast with previous studies conducted in Northeast Brazil that have revealed a positive association between early menarche and breast Ca risk . HoweverAccording to the literature, an ovulatory menstrual cycles may have a protective effect on breast Ca . HoweverSome studies consider a high number of pregnancies as a protective factor against breast Ca. A study conducted in Denmark reported that more pregnancies reduce the risk of the disease . Our resAccording to the literature, parity is one of the best established and modifiable factors involved in breast Ca among women . Women aSeveral studies have highlighted the effect of modifiable lifestyle factors such as breastfeeding on the risk of breast Ca. The majority of these reported a protective effect of breastfeeding on breast Ca in pre-menopausal women , 50–52. With regards to the use of hormonal contraceptive pills and their association with breast Ca, our study showed some protective effect with OR of 0.62. This is comparable with some previous studies conducted in Iran (2008) and Pakistan (2015) which also showed OR of 0.41 and 0.92 respectively , 56. HowSome limitations must be considered to explain the findings of this study. Firstly, the study was carried out on a small of population in CAR; therefore known risk factors may be different in the general population of Central Africa. Secondly, information  bias from self-reporting and from relatives. Using women who came for other conditions as controls introduced some selection bias in the study, given that cancer shares some risk factors with other non-communicable diseases. However, the results and limitations of the study are very useful due to the fact they contribute to the ongoing research in the field of breast Ca in CAR. In addition, this study was conducted in a developing country where changes in lifestyle can provide other important information about breast Ca risk factors.Breast Ca risk factors in CAR do not appear to be significantly different from those observed in other populations. This study highlighted the risk factors of breast Ca women living in Bangui to inform appropriate control measures. Other more extensive studies are needed to investigate other unknown determinants of breast Ca.


To explore cross-sectional adherence to cancer prevention recommendations by adults enrolled in a prospective cohort in Alberta, Canada.Questionnaire data were used to construct a composite cancer prevention adherence score for each participant, based on selected personal recommendations published by the World Cancer Research Fund/American Institute for Cancer Research (2007). Data were self-reported on health and lifestyle, past-year physical activity and past-year FFQ. The scores accounted for physical activity, dietary supplement use, body size, and intakes of alcohol, fruit, vegetables and red meat. Tobacco exposure was also included. Scores ranged from 0 (least adherent) to 7 (most adherent).Alberta’s Tomorrow Project; a research platform based on a prospective cohort.n 24 988) aged 35–69 years recruited by random digit dialling and enrolled in Alberta’s Tomorrow Project between 2001 and 2009.Adult men and women (sd): 3·4 (1·1)) than in men (3·0 (1·2)). The extent of overall adherence was also associated with level of education, employment status, annual household income, personal history of chronic disease, family history of chronic disease and age.Of the cohort, 14 % achieved adherence scores ≥5 and 60 % had scores ≤3. Overall adherence scores were higher in women (mean (Reported adherence to selected personal recommendations for cancer prevention was low in this cohort of adults. In the short to medium term, these results suggest that more work is required to identify behaviours to target with cancer prevention strategies at a population level. Future work will explore the associations between adherence scores and cancer risk in this cohort. Annual numbers of new cancer cases worldwide are expected to rise by 70 % over the next two decades1.(–), there is a growing realization that primary prevention through lifestyle and environmental interventions may offer a more sustainable solution for reducing cancer burden.While greater uptake of screening and increasingly effective treatments have reduced mortality rates for some cancers–4, t. However, regardless of the variation in different population-attributable fractions for each risk factor, there is a general consensus that use of tobacco, physical inactivity, low fruit and vegetable intake, high intake of red and processed meats, overweight and obesity, and use of alcohol are responsible for up to 30 % of cancer incidence overall(–).Estimates for the impact of modifiable risk factors on cancer incidence vary according to the assumptions used to create the statistical models and on the source and quality of the underlying data,7. H. The rationale was to provide a robust evidence base to inform the development of policies and interventions to help reduce cancer risk in the general adult population.In 2007, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) produced a series of population goals and personal recommendations for cancer prevention based on these modifiable behaviours and health-related variables14. ThHowever, before moving towards policy development, it is important to understand more about the concurrence between existing health-related variables and behaviours and current recommendations. Such information may be useful in identifying priority areas for further investigation and intervention., based on behaviours and health-related variables reported by adults enrolled in Alberta’s Tomorrow Project (ATP), Alberta, Canada. A comprehensive overview of adherence to cancer prevention guidelines and the associated influential factors can inform cancer prevention strategies and assist in designing consistent targeted strategies to increase population adherence to evidence-based cancer prevention guidelines.The aim of the current study was to explore the extent of adherence to WCRF/AICR cancer prevention recommendations for individuals14, ban 382, 1 %) if possible; but this practice was discontinued in subsequent recruitment waves.Between 2001 and 2009, ATP enrolled 31 212 Albertans aged 35–69 years, with no personal history of cancer other than non-melanoma skin cancer, into a cohort. Participants were recruited by random digit dialling using Regional Health Authority boundaries as the sampling frame. In the first recruitment wave, a second eligible adult within each household was recruited  and signed consent form. Three months after enrolment, participants received two additional questionnaires assessing past-year dietary habits and physical activity. Response rate to the random digit dialling call has been estimated at 32 %15 andThe HLQ queried self-reported sociodemographic, behavioural and health-related variables including age, marital status, education, employment status, annual household income, tobacco use and exposure to second-hand smoke, family health history and body measurements . In addition, participants indicated whether or not a doctor had ever told them that they had any of the following health conditions: high blood pressure, angina, high blood cholesterol, heart attack, stroke, emphysema, chronic bronchitis, diabetes, ulcerative colitis, Crohn’s disease, hepatitis or liver cirrhosis. Participants who answered ‘yes’ to having received a diagnosis of any of these conditions were deemed to have a personal history of chronic disease.. Recent evidence supports that the food list in CDHQ-I is representative of the foods commonly consumed by Canadian adults. CDHQ-I data were analysed using Diet*Calc version 1.4.3  to estimate mean daily intakes of nutrients and food group servings, as well as supplement use.Past-year diet, including supplement use, was assessed by the US National Cancer Institute’s 124-item Canadian Diet History Questionnaire I (CDHQ-I), an FFQ adapted for use in Canada,17. . Total minutes per week performing leisure activities at moderate  and vigorous (>6 MET) intensities were calculated based on reported activities.Past-year recreational activities were assessed using a validated Past Year Total Physical Activity Questionnaire (PYTPAQ)19. To in addition to the other recommendations, second-hand smoke exposure and cigarette smoking were also included in the composite score. Participants scored 1 point for each recommendation met and 0 if it was not met. Recommendations included in the current analyses were: BMI within normal range (18·5–24·9 kg/m2), no daily exposure to tobacco during the past year, no more than two alcoholic drinks daily for men or no more than one daily for women, consumption of five or more servings of fruit and vegetables daily, consumption of less than 500 g of red meat weekly, not taking any dietary supplements and performing at least 210 min of moderate- or vigorous-intensity recreational physical activity weekly. The composite score ranged from 0 (least adherent) to 7 (most adherent).A composite score reflecting adherence of reported behaviours and health-related variables to seven selected WCRF/AICR personal recommendations for cancer prevention was constructed for each participant using data collected upon enrolment to ATP. Recommendations included were those that addressed the general adult population and were identified as quantifiable using baseline ATP data. Recommendations addressing special groups  or that were not quantifiable with ATP data were excluded. It was not possible to quantify adherence to some recommendations , while the data required to quantify some other recommendations were not available for ATP participants . Considering the WCRF/AICR panel emphasized the importance of tobacco exposure for cancer risk14 in Descriptive statistics were presented as group means and standard deviations for continuous variables and as counts and percentages for categorical variables. Multiple linear regression models were used to explore associations between participants’ composite scores and potential influential characteristics. Multiple logistic regression models were used to explore the association between participants’ adherence to each of the seven components of the composite score and potential influential factors. All estimation models were adjusted for age , marital status , education level , employment status , annual household income , first-degree family history of cancer , first-degree family history of chronic disease  and personal history of chronic disease . Analyses of the associations were reported as adjusted regression coefficients for continuous outcomes and adjusted odds ratios for binary outcomes, and corresponding 95 % confidence intervals.α≤0·05 (two-tailed). All analyses were performed using the statistical software package SAS version 9.2.All analyses were stratified by sex and the criterion for statistical significance was set as n 382), outside age range of 35–69 years at enrolment (n 46), pregnant women (n 65), BMI<18·5 kg/m2 , personal history of cancer other than non-melanoma skin cancer prior to enrolment (n 38), not living in Alberta at enrolment (n 61) and biologically implausible energy intake of <3347 or >17 572 kJ/d  for men and <2510 or >14 644 kJ/d  for women (n 1014). Participants were also excluded if their log-transformed total energy expenditure derived from the PYTPAQ fell outside two interquartile ranges from the first and third quartile cut-offs (n 92). Participants who did not return the CDHQ-I or PYTPAQ (n 4212), participants with incomplete data for BMI (n 22), smoking status (n 17), and past-year second-hand smoke exposure (n 55) were also excluded, resulting in a final sample of 24 988.Of 31 212 participants enrolled in ATP, the following were excluded from the current analyses: second in household recruit ( (n 1014)20. Pasd 9·1) years) and 63 % were women (mean age 50·9 (sd 9·2) years). All other baseline sociodemographic characteristics are presented in Among all participants, 37 % were men (mean age 51·1 (v. 23 %), consumption of fruits and vegetables (44 % v. 35 %) and red meat (89 % v. 65 %).Approaches for operationalizing the selected WCRF/AICR personal recommendations, and numbers and proportions of participants whose reported behaviours or health-related variables complied with those recommendations, are presented in sd 1·2)). The proportion of participants (60 %) with an adherence score ≤3 was four times greater than the proportion with a composite score ≥5 (14 %). The mean score in women was 3·4 (sd 1·1) and in men was 3·0 (sd 1·2), P<0·0001. The frequency distribution of women’s reported adherence to cancer prevention recommendations was more favourable than that observed for men . In men, being retired  points higher v. not employed) and in women, a higher annual household income  points higher v. lower annual household income), also showed a strong association with higher overall adherence to recommendations. However, the composite score was 0·10  points lower in women who were employed full-time compared with women who were not employed. Among all the estimated influential factors, a personal history of chronic disease was associated with the lowest overall adherence to cancer prevention recommendations in men  points lower) and women  points lower v. no personal history). A family history of chronic disease in women, but not in men, had a significant negative effect on the adherence to these cancer-specific recommendations.Higher educational attainment was associated with greater odds of adhering to recommendations for body size. A personal history of chronic disease and a family history of chronic disease were associated with lower odds of adherence to the BMI recommendation. Older women (≥50 years) and men living with a partner were less likely to adhere to the BMI recommendation. In women, an annual household income of ≥$CAN 70 000 was associated with higher odds of meeting the body size recommendation, while in men the association was in the opposite direction.A personal history of chronic disease was associated with lower odds of adhering to the physical activity recommendation, but only in women. In men, the odds of adhering to the physical activity recommendation were higher in those who were retired or working part-time relative to men who reported not being employed. In women, adherence was higher only in those who were retired. In men and women, adherence to the physical activity recommendation was lower in participants aged ≥50 years and those who were married or living with a partner. Adherence to the physical activity recommendation was higher in people with a post-secondary education and an annual household income ≥$CAN 70 000.Examination of reported adherence to the fruits and vegetables recommendation demonstrated higher odds of adherence in those who were in older age groups, those who lived with a partner and those who had a post-secondary education. In women, adherence to the fruits and vegetables consumption recommendation was also higher in people with a higher annual household income.Adherence to the recommendation for red meat intake was influenced by age, marital status and educational attainment. Older age and post-secondary education were associated with greater odds of adhering to the recommendation for red meat intake. Conversely, those who lived with a partner had lower odds of adhering to the red meat recommendation.Higher household income in men and women was associated with lower odds of adhering to recommendations for alcohol consumption. Relative to women who reported no current employment, women who were retired or worked full-time had lower odds of adhering to the alcohol recommendation. Men living with a partner or who had a university education and women with a personal history of chronic disease had higher odds of adhering to the alcohol consumption recommendation.Adherence to the recommendation for dietary supplement use was lower in participants with a post-secondary education. In women, adherence was lower in those aged ≥50 years and with a family history of cancer.Adherence to the tobacco exposure recommendation was likely to be higher in participants aged ≥50 years, with a post-secondary education and an annual household income ≥$CAN 70 000. Participants with a personal history of chronic disease were less likely to adhere to the tobacco exposure recommendation, as were women working full-time..Over the past two decades, several organizations have published a series of recommendations that aim to provide guidance on strategies for cancer risk reduction based on modifiable behavioural risk factors. Most focus on the themes of achieving and maintaining a body size within the normal range for BMI, eating lower amounts of red meat, being physically active, not consuming alcohol (or consuming low amounts), and consuming diets that are predominantly plant-based and/or relatively high in fruits and vegetables,–28. However, in common with previous studies(–), we encountered several challenges in determining and applying cut-offs that could be used to determine adherence to recommendations. For example, ambiguity in the language used by the WCRF/AICR 2007 recommendations resulted in an inability to operationalize the recommendation (e.g. ‘limit refined starchy foods’) because it was not possible to quantify the term ‘limit’. In other cases, we made assumptions or used a proxy indicator. Furthermore, the recommendation to ‘maintain body weight within the normal range from age 21’ was operationalized as BMI within the normal range at the time of completing the enrolment HLQ. Although the body fatness recommendation in the WCRF/AICR report contains three personal recommendations, the other two  could not be included due to a lack of data pertaining to lifetime body weight and waist circumference of the cohort participants. Others may have chosen different approaches to quantification and, as such, it is difficult to compare our findings directly with other studies. The WCRF/AICR panel did acknowledge the challenges of quantification assessing adherence to recommendations when they included phrases such as ‘limit’ or ‘consume sparingly’, but noted that it is not always possible to establish clear cut-off points. Others have suggested that there is a clear need for agencies that set guidelines or recommendations to work more closely with researchers and organizations responsible for population health surveillance to ensure that behaviours are well defined and that adherence can be assessed in ways that are practical, feasible, meaningful and also comparable across different populations.In the current study, we aimed to examine the extent to which participants enrolled in a longitudinal cohort reported behaviours that adhered to selected personal recommendations described in the 2007 WCRF/AICR report14. Ho. Other studies that have calculated adherence scores have reported that adherence to cancer prevention guidelines may reduce overall cancer risk, reduce postmenopausal breast cancer risk and reduce overall risks of cancer, as well as breast and colon cancers. Conversely, a recent study from the Framingham Offspring Cohort reported no significant associations between overall adherence scores and risk of obesity-related cancers. However, in the latter study, the sample size was relatively small (n 2983) and therefore may have had insufficient power to detect the effects of composite long-term exposure on cancer risk.Despite these challenges, we did identify seven reported behaviours and health-related variables that could be operationalized and used to create a composite score for each individual to indicate adherence. Overall adherence was higher in women than men. These observations are similar to those reported by the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which also examined concordance with WCRF/AICR 2007 recommendations in 386 355 men and women across nine European countries33. Ot, even though some may not be associated with risk of cancer at specific sites. More robust estimates of the associations between composite scores and cancer risk may be obtained if different weights were applied to different elements included in such scores. However, the complexities associated with such a task are not to be underestimated. Future work should attempt to include the determination of appropriate weighting for scoring individual items in the assessment of individualized risk.One challenge with the composite score approach is that it gives equal weight to all recommendations included in the score38, ev, so the proportion of ATP participants exposed to second-hand smoke may decrease in future follow-up questionnaires.When each element of the composite score was examined separately, it was clear that some recommendations were more easily adhered to than others. In the ATP cohort, the lowest level of reported adherence was with the tobacco exposure recommendation. Although 15 % of participants were current smokers, 85 % were exposed to tobacco. It should be noted that the majority of participants completed the baseline HLQ prior to the Alberta provincial legislation banning smoking in workplaces coming into effect in 2008. Previous research has indicated that legislative changes in tobacco regulation have decreased exposure39, so. Some dietary supplements have beneficial effects for health or long-term health conditions, such as neural tube defects, iron-deficiency anaemia and osteoporosis; however, some supplements could increase cancer risk. The CDHQ-I data on supplement use do not provide any information on participant motivation for taking dietary supplements. The WCRF/AICR recommendation is that dietary supplements not be used for cancer prevention, which provides the general public with inconsistent messages when compared with recommendations for the prevention and/or treatment of other conditions.Adherence to the dietary supplement recommendation was also very low (20 %). This is consistent with the extensive use of supplements (70 %) previously reported in ATP participants40. SoAdherence to the recommendation to maintain body weight in the normal range was also low. In the ATP cohort, 77 % of men and 60 % of women reported heights and weights that put them in the overweight and obese categories for BMI. Although the physiological mechanisms linking body size with cancer risk are not clear, the WCRF/AICR graded the evidence linking obesity and risks of cancers of the pancreas, colorectum, breast (postmenopause), endometrium and kidney as convincing, suggesting that continued efforts to prevent or reduce the prevalence of obesity in the population should be explored more vigorously as means of helping reduce overall cancer risk and risk of specific cancers. states that ‘if alcoholic drinks are consumed, limit consumption to no more than two drinks a day for men and one drink a day for women’. This recommendation is based on the assumption that alcohol may have a cardioprotective effect. However, the evidence linking alcohol consumption with increased cancer risk remains convincing, consistent with the fact that ethanol has been classified as a class I carcinogen, and supports a recommendation of zero alcohol consumption for cancer prevention. Only 15 % of participants reported consuming no alcohol in the past year, which is consistent with Canadian data concerning alcohol use. J/U-shaped relationships between alcohol intake and all-cause mortality have been reported, again providing inconsistent messaging between preventive behaviour recommendations for different diseases.The highest adherence reported in the present study was to the recommendation for alcohol consumption. The WCRF/AICR report14 sta. One challenge in understanding the effects of activity on health is that there is little consensus on how to assess activity in free-living people. Previous research on a subgroup of the ATP cohort has demonstrated relatively low levels of leisure-time activity compared with occupational and household activities, and it has also been reported previously that ATP participants take part in insufficient leisure-time activity for cancer risk reduction. Although the personal recommendation does not specify types of activity, the WCRF/AICR Panel did note that all forms of physical activity protect against some cancers. As dose–response to exercise is investigated further, it may be determined that levels of physical activity required for cancer prevention may be different from levels required for CVD and obesity prevention. Since evidence is emerging to suggest that overall activity energy expenditure and sedentary time as independent factors may both be important for cancer and chronic disease risk reduction(–), it will be necessary to work towards identifying and applying consistent approaches to assessing and reporting the exposure.Adherence to the recommendation for physical activity was 48 %. This observation is consistent with other reports that Canadian adults are inactive and do not participate in sufficient activity to benefit health50. OnStrengths of the present study include its large sample size that increased statistical power and provided the potential for subgroup analysis. However, due to the cross-sectional nature of the study, it is not yet possible to draw conclusions about the impact of adherence to cancer prevention guidelines on subsequent cancer incidence. The prospective design of the ATP will allow for the development of a longitudinal data structure to explore the associations in future research.(–). However, reporting of descriptive characteristics of the cohort demonstrates that ATP participants represent a diverse cross-section of baseline demographic and behavioural characteristics, with very few differences in general characteristics from the Canadian Community Health Survey Cycle 3.1, therefore suggesting that the cohort represents a broad range of the population. The relatively low adherence to the selected recommendations is particularly concerning when longitudinal cohort participants are typically expected to be more health conscious than the general population(–). The operationalization of the adherence composite score presented some challenges and resulted in the exclusion of some of the WCRF/AICR recommendations. The use of typical epidemiological assessment tools is challenging in the assessment of adherence to some of the WCRF/AICR recommendations. Future longitudinal work may be able to address the recommendations pertaining to changes over time and incorporate them into cancer risk models.Limitations of the present study include the participant bias of responses in self-reported questionnaires. In addition, it is recognized that this cohort does not represent the entire population of Alberta, and it has been suggested that those who choose to enrol in a prospective cohort may be more health conscious than the general population–59. The overall adherence to current cancer prevention guidelines in the cohort was low. Specific areas with low adherence were identified, such as body size and tobacco exposure, suggesting that these may be targets for intervention. Future work that attempts to weight the importance of individual recommendations may identify additional intervention targets that could have more impact in cancer risk reduction, despite potentially having better adherence to recommendations overall. Population health work should stress the need for specific, targeted messaging provided by health-care resources.


Background. Vietnam has a low age-standardized incidence of breast cancer, but the incidence is rising rapidly with economic development. We report data from a matched case-control study of risk factors for breast cancer in the largest cancer hospital in Vietnam. Methods. 492 incident breast cancer cases unselected for family history or age at diagnosis and 1306 control women age 25–75 were recruited from the National Cancer Hospital (BVK), Hanoi. Structured interviews were conducted and pathology data was centrally reported at the National Cancer Hospital of Vietnam, in Hanoi. Results. Our analysis included 294 matched pairs. Mean age at diagnosis was 46.7 years. Lower mean parity, older age at first parity, increasing weight and BMI at age 18, and increasing BMI at diagnosis were positively correlated with breast cancer cases compared to controls. Age at first menarche and duration of breastfeeding were not statistically different between cases and controls. Conclusions. In this study we demonstrate that breast cancer in Vietnam is associated with some but not all of the published risk factors from Western populations. Our data is consistent with other studies of breast cancer in Asian populations. The incidence of breast cancer in developing countries is increasing, and low and middle income countries now account for most deaths from breast cancer globally . The ageSeveral hormonal and reproductive risk factors have been implicated in the development of breast cancer in women of European ancestry, but it is not clear to what extent these factors contribute to breast cancer in Asia. These include reproductive  and anthropometric risk factors ) –7. The iVietnam has a population of 87 million and reports one of the lowest age-standardized incidence rates of breast cancer in the world, at 15–27 cases per 100,000 per year [In the current study, we sought to identify hormonal, reproductive, and anthropometric risk factors for both pre- and postmenopausal breast cancer in Vietnamese women.This single-center, hospital-based, case-control study was conducted between January 2007 and August 2013 at the National Cancer Hospital of Vietnam in Hanoi, Vietnam. This is the largest tertiary care cancer hospital in Vietnam and is also the site of the National Institute for Cancer Control.We defined a case as a woman aged 25 to 75 years of age, who was diagnosed with invasive breast cancer in the 12 months prior to study enrollment. Cases were recruited from the inpatient and outpatient departments of the National Cancer Hospital of Vietnam, in Hanoi.Women who had a previous history of breast cancer (in-situ or invasive) were not eligible for this study. Women were considered to be premenopausal if they had reported a menstrual period within the 12 months prior to their breast cancer diagnosis. Women who had not experienced a menstrual period for 12 consecutive months or women who had a hysterectomy (with or without) oophorectomy were considered postmenopausal.For the 492 cases of breast cancer, pathology data was systematically recorded at the National Cancer Hospital. Data collected included histopathological type, Nottingham grade, TNM stage, and ER/PR/Her2 status. Immunohistochemistry for ER/PR/Her2 was performed on-site. Her2 testing was performed by immunohistochemistry alone.A potential control was a woman aged 25 years or older who had no prior history of breast cancer and who was unrelated to cases. Controls were recruited from a variety of settings, including outpatient clinics at the National Cancer Hospital of Vietnam and from rural primary care clinics. The National Cancer Hospital is located in Hanoi, the metropolitan area which has approximately 7 million citizens. Controls were also purposefully recruited from rural areas, where epidemiological surveillance for many health conditions is routinely undertaken and from where many women with breast cancer at the National Cancer Hospital would likely come from.As urban residence is a recognized risk factor for breast cancer in other populations studied, we purposefully sampled controls from both rural and urban areas and then matched cases with controls on this basis, as described below.Cases and controls were matched by date of birth within one year, place of birth , and place of current residence .2). We defined four categories of BMI according to the World Health Organization classification [2; normal range 18.50 to 24.99 mg/m2; overweight ≥ 25 mg/m2; and obese ≥ 30 mg/m2. For both cases and controls, we relied on self-reported values of weight in order to calculate the BMI at the age 18 years. Although there have been attempts to tailor BMI categories for Asian populations, the World Health Organization recommends that the current cut-off points should be retained as the international classification.Written informed consent was obtained, and structured interviews were conducted by a single Vietnamese research associate based at the National Cancer Institute and included a questionnaire regarding demographic, hormonal, reproductive, and anthropometric factors. Specifically, the questionnaire asked about date of birth, income, education, age at menarche, age at first childbirth, total number of children, duration of breast feeding (in months), current height (meters), weight at the age 18 years (kg), and weight at the time of breast cancer diagnosis . For each study subject we calculated body mass index (BMI) by the weight in kilograms divided by the square of the height in meters  and the Research Ethics Committee and administration of the National Cancer Hospital, Hanoi.p < 0.05 was considered statistically significant. All p values were two-tailed.Conditional logistic regression analysis was performed to evaluate the association of various risk factors with the risk of breast cancer, displayed as odds ratios, OR with 95% confidence intervals. A The clinical features and pathological data for cases are shown in p = 0.03), a higher BMI at age 18 , and a higher BMI at the date of diagnosis .The distributions of the hormonal, reproductive, and anthropometric characteristics of the 294 breast cancer cases and their matched controls are presented in p < 0.001) and older age at first childbirth . There were no significant differences seen between cases and controls for the other reproductive factors including age at menarche , breastfeeding , height , or menopausal status . Breast cancer cases had a significantly lower mean parity .Body mass index was positively associated with breast cancer risk. Compared to women with a BMI less than 18 kg/mp = 0.004) and the adjusted odds ratio was 0.17 . Age at menarche, age at first parity, total months breastfeeding, oral contraceptive use, and menopause were not associated with increased breast cancer risk in this analysis.The most profound risk factor was parity. Compared to nulliparous women, increasing parity was associated with a significantly decreased risk of breast cancer; that is, for four or more births, the unadjusted odds ratio was 0.16  and BMI at age 18  for cases compared to controls. Age at first birth was not associated with the risk of premenopausal breast cancer .We performed subgroup analysis for premenopausal cases (196 cases and 196 matched controls) Tables  and 5. AWe also performed the same analysis for ER-positive cases only. However, the odds ratios did not vary significantly from those in the whole dataset (data not shown).p = 0.004), compared with 1.72 (p = 0.003).Lastly, although WHO does not recommend a revised international standard for BMI categories, some reports suggest a tailored evaluation for individual Asian populations. We therefore reclassified BMI groups by the frequency of BMI 18 for cases, at 33.33% and 66.66%. The odds ratio results were very close to our original classification; for example, BMI > 20.46 (rather than >20.00) yielded a multivariate OR 1.73 .Greater weight at age 18, BMI at age 18, and BMI at diagnosis were positively correlated with breast cancer in this study. This trend was strengthened by selection for premenopausal cases only. This differs from studies in Western populations, where overweight or obesity at age 18, increased BMI at age 18, and BMI at diagnosis have been associated with a lower risk of premenopausal breast cancer –6. Howev2 increment of BMI in premenopausal Asian women but decreased by 9% per 5 kg/m2 increment of BMI in premenopausal North American women [Our findings agree with a meta-analysis of cohort studies that showed that breast cancer risk was increased by 16% per 5 kg/man women .Nichols and colleagues performed a risk factor analysis of premenopausal breast cancer in Vietnam . They alBreast cancer epidemiological studies in other Asian countries suggest that breast cancer risk factors vary with ethnicity. A cohort study of 4211 Chinese women demonstrated that family history, increased BMI, and later menopause were strongly correlated with breast cancer risk . HoweverTaken together, our study is in keeping with others from Asia, which demonstrates that breast cancer risk factors vary across different ethnic groups , 24–26.Our study has several limitations. Study participants were asked to recall their weight (and thus body mass index) at age 18. Controls were also asked to recall their current weight.However, there is no reason to suspect a systemic bias in recalling weigh between cases and controls. Very few women from either group were able to report a family history of cancer (data not shown). This may be for social and/or cultural reasons, which have been suggested as a cause of underreporting of cancer family histories in other Asian studies including our previous study on family history and BRCA 1 and 2 mutations in Vietnam , 28.n = 93) and triple negative breast cancer (n = 44). This is important because studies in Western populations have demonstrated that breast cancer is highly heterogeneous and risk factors may differ between different breast cancer subtypes [Our study was underpowered to examine risk factors among specific breast cancer subtypes, such as ER negative breast cancer (subtypes , 29, 30.Breast cancer is a heterogeneous disease with variations in the prevalence of risk factors across ethnicities. In this study we demonstrate that breast cancer in Vietnam is associated with some but not all of the published risk factors from Western populations. Our data is consistent with other studies of breast cancer in Asian populations. This has potential implications for education and health promotion about breast cancer, as well as risk assessment tools of relevant women in Vietnam, where the incidence of breast cancer continues to increase annually.