Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls.n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1–5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time.Eligible cases (3) than the normal breast (− 0.39% and − 2.74 cm3) for a difference of 0.13%  and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (− 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54  for VPD and 0.56  for DV.Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (− 0.26% and − 2.10 cmThere is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer. Mammographic breast density (MBD) has been shown to be a major risk factor for breast cancer –3 and inAutomated volumetric density measures for full-field digital mammography (FFDM) have the potential to replace or at least complement the radiologist’s BI-RADS density assessment as they provide objective, reproducible density estimates , 13. AutBreast cancer usually develops in one breast and has the same radiographic X-ray attenuation as normal dense fibroglandular tissue , 16–20. The participating studies included two retrospective case-control studies nested within large breast screening facilities at Mayo Clinic Rochester (MCR) and in the Bay Area that participate in the San Francisco Mammography Registry (SFMR) . Passiven = 1322) and did not have breast implants or a prior breast cancer diagnosis (DCIS or invasive).Since 2006, women were included in the underlying mammography cohort if they had a FFDM at one of four facilities . Women wn = 648) and did not have breast implants or a prior breast cancer diagnosis (DCIS or invasive).Women from the tri-state region of Minnesota, Iowa, and Wisconsin who had FFDM at MCR between April 2008 and December 2015 serve as the underlying mammography cohort [Because our goal was to assess the density change between breasts over time, we required a bilateral screening or diagnostic FFDM within 2 months prior to the cancer diagnosis and at least one additional FFDM 1–5 years prior to diagnosis to be included as cases. Patient age, clinical risk factors, and tumor characteristics were obtained from clinical questionnaires or abstracted from medical records and tumor registries. Due to missing data on menopause, we defined menopausal status as age 55 or older .Women without prior breast cancer, and with bilateral FFDM over the same time period, were matched to each case on age (within 5 years), race (as close as feasible), date of mammogram (within 1 year), FFDM machine (exact), and facility (exact).Volpara™  is a fulBaseline characteristics were summarized using number and percentage for categorical variables and median and quartiles for continuous variables. Using the Volpara™ calculations for each breast, the change in DV and VPD between mammograms was calculated for each breast separately. To assess the difference between breasts among cases, we subtracted the change in DV and VPD in the normal contralateral breast from the change in the breast with cancer . The difference  was examined by tumor size, clinical BI-RADS density (grouped into dense (heterogeneously or extremely dense) vs. non-dense (fatty or scattered density)), and menopausal status (defined as age ≥ 55 years) at the time of the earliest mammogram. The above analysis was done in a similar fashion in the controls by defining the “ipsilateral” and “contralateral” sides based on the sides of the matched case. By analyzing the difference in the change between the two breasts within each woman, we control for systemic variables that should affect both breasts equally, such as aging, hormone therapy, and weight change. Statistical significance of the change was evaluated using the Wilcoxon signed-rank test.p ≤ 0.05.A secondary analysis was performed to simulate clinical practice, where the cancerous breast is not known at the time of the mammogram review. In this analysis, the change in VPD and DV between mammograms was again defined for left and right breasts separately. However, the absolute difference in the change between breasts was calculated for cases and controls without knowledge of the cancerous breast; change was defined as the absolute value of the maximum difference between the two breasts. The correlation of change between the two breasts was examined using Lin’s concordance correlation coefficients, which summarizes the agreement along the line of identity. The cumulative distribution of the absolute difference in VPD and DV was examined in cases and controls. Logistic regression was used to evaluate the ability of the absolute difference to discriminate breast cancer case status from controls, with and without adjustment for age, BMI, change in BMI, and time between mammograms. The difference in the area under the ROC curve (AUC) between the baseline model  and the model including the absolute difference was calculated and summarized with corresponding 95% confidence interval. The analysis was done using SAS version 9.4 , and statistical significance was set at A total 1160 of the 1970 potential cancer cases met eligibility criteria. Reasons for exclusion included 795 without an available bilateral mammogram within 2 months of diagnosis and 15 without a prior bilateral mammogram within 5 years of diagnosis. Distributions were not markedly different when analyzed by study cohort . For DV, the ipsilateral breast decreased 2.10 cm3 and the contralateral breast decreased 2.74 cm3 for a difference of 0.63 cm3 (p = 0.002).The median (IQR) time between the oldest prior mammogram within 5 years and the mammogram closest to the diagnosis was 3.0 years IQR 1.9, 3.9). Over this period, both VPD and DV decreased on average among both cases and controls Table . Among c.9, 3.9. n = 540) had a difference of 0.11% (p < 0.001) and 0.63 cm3 (p = 0.002) between the breast with cancer and the normal breast for VPD and DV, respectively. Women with dense breasts (n = 480) had a difference of 0.21% (p = 0.11) for VPD and 0.61 cm3 (p = 0.38) for DV (Table p = 0.23) and DV difference of 0.02 cm3 (p = 0.76) between the cancerous and non-cancerous breasts. For women with cancers 2.1–5 cm, the difference increased to 0.40% (p < 0.001) for VPD and 4.15 cm3 (p < 0.001) for DV. For women with cancers > 5 cm, the difference was even greater with 1.18% for VPD (p < 0.001) and 12.97 cm3 (p < 0.001) for DV. Similar results were found for post-menopausal women (age ≥ 55) when analyzed as a sub-group  assessed at the earliest mammogram, tumor size and menopausal status, the VPD and DV of the cancerous ipsilateral breast decreased to a lesser degree than the contralateral breast without cancer in all subsets; but not all results reached statistical significance. Women with non-dense breasts ( p = 0.00 between N = 2360), selecting the sides corresponding to the matched case. Similar to breast cancer cases, mammograms spanned a median of 3.1 years (IQR 2.0. 4.1), and density decreased on average over this time period (Table p = 0.92) for VPD and 0.05 cm3 (p = 0.77) for DV (Table p = 0.93) and 0.09 cm3 (p = 0.89), respectively) and for those with dense breasts (difference − 0.00% (p = 0.97) and − 0.02 cm3 (p = 0.77), respectively). Similar findings were seen among the subset of post-menopausal women (age ≥ 55)  in VPD and DV were 0.54  and 0.56 , respectively. Importantly, the asymmetry measures only slightly improved discrimination over the baseline model  for VPD and 0.03  for DV.In order to simulate clinical practice, where the laterality of malignancy is not known at the time of mammogram interpretation, we compared the absolute difference in density change between breasts among cases and controls. The cumulative distribution of this difference for cases and controls is shown in Fig. Commercially available automated density assessment methods provide volumetric density calculations for each breast separately in addition to assigning a single overall density category per woman, similar to clinical BI-RADS. We evaluated the potential of Volpara™-automated density measures (VPD and DV) calculated for each breast separately to identify clinically relevant differential change between breasts in women with breast cancer. Comparing the automated measures at the time of diagnosis to those from prior mammograms within 5 years, we found that VPD and DV decreased on average in both breasts, but to a lesser degree in the breast with cancer. Density measures also decreased over time in the controls, but this decrease was symmetric with no significant difference between breasts.Prior studies report that mammographic feature asymmetry between breasts, using complex computerized feature analysis, predicts individual near-term breast cancer risk –23, 28 oThe attenuated decrease in density in the breast with cancer, compared to the normal breast, found in this study is consistent with our hypothesis that the presence of breast cancer can result in an asymmetric density increase in that breast. However, this finding alone does not appear to be a good discriminator between cases and controls using the automated density method in this study. Using the absolute difference in DV and VPD between the two breasts, irrespective of knowing which breast has cancer, the improvement in the discrimination of cases from controls was minimal . This automated density measure may incrementally improve discrimination, but our results suggest that it cannot be used in a stand-alone fashion in clinical practice to determine whether further examination is indicated.Our findings in controls provide important information for future studies. Many published studies evaluating breast density and cancer risk use the non-cancerous breast to avoid possible bias in the density measurement , 31, 32.The strengths of this study include the large number of cases and controls from two breast imaging practices using FFDM. In addition, by comparing right and left breasts, we controlled for variation in density due to systemic factors that affect both breasts such as weight change, hormones, and aging. However, by restricting our study to participants with a bilateral mammogram near diagnosis, we eliminated multiple women and potentially reduced the generalizability of our findings. The relatively small number of cases with tumors greater than 2 cm at diagnosis limited our ability to perform subset analyses. We also evaluated FFDM raw images rather than tomosynthesis, which is rapidly replacing FFDM in clinical practice. Although studies have shown a high correlation between FFDM and tomosynthesis density measures assessed using Volpara™ , 34, it The results of this study showed a relative increase of DV and VPD over time in the breast with cancer compared to the contralateral normal breast, as well as compared to a set of healthy controls. This automated asymmetry density measure may incrementally improve discrimination of cancer risk, but our results suggest that it cannot be used in a stand-alone fashion in clinical practice to determine whether further examination is indicated.Additional file 1. Supplementary tables.


There was no relationship between WBC count and ER+/PR+ breast cancer among premenopausal obese women. Furthermore, premenopausal non-obese women and postmenopausal obese women with ER+/PR+ breast cancer had higher WBC counts than those with ER−/PR− breast cancer. Further larger-scale prospective cohort studies are warranted to determine these associations in the future.Breast cancer is a heterogeneous disease that among Korean women has a peak incidence in the perimenopausal period. The full epidemiological characteristics of breast cancer in Korean women are not yet properly understood. We investigated whether white blood cell (WBC) is related to breast cancer burden according to estrogen receptor (ER) and progesterone receptor (PR) status in the context of body mass index and menopausal status. We conducted a large case-control study and compared WBC counts between patients with breast cancer  and propensity score-matched controls  selected from the Korean National Health and Nutrition Examination Survey (KNHANES). We stratified the study sample by ER/PR status, menopausal status, and body mass index and assessed the association between WBC count and breast cancer burden using multinomial logistic regression. Compared with controls, non-obese patients with ER Contrary to the recent drop in the breast cancer incidence in Western countries, the incidence in Korea has been gradually rising for more than a decade4. The peak incidence of breast cancer in Korea is among women 45–49 years of age, whereas that in the USA and Canada is among women 75–79 years of age6. Although estrogen exposure, unfavorable lifestyles, and genetic factors are known to be major risk factors for breast cancer, the unique epidemiological features of breast cancer among Korean women are not properly understood. Recently, insulin resistance and metabolic syndrome were shown to be associated with an increased risk of breast cancer9. However, among Korea women, those relationships are limited to only one subtype of breast cancer in postmenopausal women10.Breast cancer has by far the highest incidence of all cancer types among women around the world13. White blood cell (WBC) count, an inflammatory biomarker, has become a useful predictor of certain diseases as well as a marker of infection17. An elevated WBC count, even within the normal range, has been associated with cancer incidence and mortality and with atherosclerotic cardiovascular diseases20. The role of WBC count as a surrogate for inflammation has not been examined in the context of well-known effect modifiers for breast cancer development.An increasing body of evidence suggests that chronic low-grade inflammation could be linked to the pathogenesis of some cancers23. Several studies have attempted to identify the association between WBC counts and breast cancer risk, but no consistent evidence has been found, and those studies were not conducted without stratification by menopausal status and BMI25. Furthermore, hormone receptor positive- and negative- breast tumors are heterogeneous with respect to risk factors and etiology27. In this regard, we would like to shed light on the interaction between inflammation, as indicated by WBC count, and breast cancer burden according to estrogen receptor (ER) and progesterone receptor (PR) status in the context of body mass index and menopausal status. We conducted a case-control study to investigate whether WBC count is related to breast cancer burden according to ER/PR status in the context of body mass index and menopausal status.Previous epidemiological studies have demonstrated that obesity, as indicated by body mass index (BMI), can influence the breast cancer risk, which can be altered differently according to menopausal statusin situ or invasive carcinoma of the breast between November 2005 and December 2012 and subsequently underwent surgery for breast cancer. Throughout this period, baseline characteristics of breast cancer patients were similar and sequentially registered enough to secure proper stratification by BMI, menopausal status, and hormone receptor status. We excluded patients for whom there was no available information about menopause or BMI, those with Stage IV breast cancer, and those less than 20 years of age at the time of diagnosis , which was, as a fifth period survey, sampled without duplication of participants and performed on well-refined setting, while the earlier KNHANES were sampled again at every period due to the possibility of collective and relative duplication of missing data. We used households as the sampling units and selected individuals using a stratified, multistage, probability-sampling design according to geographic area, sex, and age. We excluded males, individuals with unknown menopause status or BMI, and individuals with a history of cancer. We assigned each eligible individual a sampling weight indicating the probability of being sampled. Therefore, we consider our results to appropriately represent the entire Korean population.2). After a 12 h overnight fast, blood samples were obtained through an antecubital vein from the controls. WBC counts were quantified using XE-2100D . Fasting plasma glucose, total cholesterol, triglyceride, HDL-cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using an automated chemistry analyzer . Also, an overnight-fasting venous blood specimen was collected from all patients within one week after breast cancer diagnosis. WBC counts were quantified by an automated blood cell counter . Fasting plasma glucose, total cholesterol, triglyceride, HDL-cholesterol, AST, and ALT were measured using Hitachi 7600–110 Chemistry System Autoanalyzer . Previous study comparing automated blood cell counters has shown that there is no difference in reference intervals for WBC counts between two analyzers used in controls and cases, respectively28. After definitive surgery for breast cancer, tumor specimens were stained for ER and PR. Specimens with more than 1% nuclear-stained cells were defined as positive for ER and/or PR according to the guidelines of the American Society of Clinical Oncology-College of American Pathologists29. Menopause status, menarchial age, menopausal age, and history of breastfeeding were documented among the patients and the controls by a self-administered questionnaire. Menopause was defined as the cessation of menstruation for more than 12 months or surgical menopausal status in cases and controls.We adopted the same variables for analysis from the Severance Hospital registry and the KNHANES. Body weight and height were measured to the nearest 0.1 kg and 0.1 cm, respectively, with the participants wearing light indoor clothing without shoes. BMI was calculated as the ratio of weight (kg) to squared height  according to menopausal status. This stratification was based on previous meta-analysis showing the different association between body weight and breast cancer risk among ER−/PR−, ER+/PR− or ER−/PR+, or ER+/PR+ by menopausal status27. We performed an analysis of covariance (ANCOVA) adjusted for WBC counts of controls to compare differences in WBC counts between matched patients and controls among groups in which the patients were ER−/PR−, ER+/PR− or ER−/PR+, or ER+/PR+. Using multinomial logistic regression, we measured the strength of correlation between WBC count (×103 cells/μL) and breast cancer burden according to ER/PR status stratified by BMI and menopause after adjusting for continuous variables  and categorical variables , including significant variables (p < 0.05) in univariate analysis with clinically important variables, while further considering multicollinearity. To test the combined effect of menopause status, BMI, and WBC, we tested their interactions with the interaction term for menopause status*BMI*WBC by multinomial logistic regression models for outcome. The interaction among menopause status, BMI, and WBC was tested at a significance level of 0.2. We conducted all analyses using the SAS statistical software, version 9.2 . All statistical tests were two-sided, with statistical significance determined by p < 0.05.We compared the characteristics of the patients and propensity score-matched controls using paired t-tests for continuous variables and McNemar’s test for categorical variables. Propensity score was created using age, the most well-known confounding variable. We examined potential effects on WBC counts of obesity (BMI ≥ 25 kg/m²) and ER/PR status (ER2) was higher than that of the patients . There was no significant difference in mean BMI between the postmenopausal controls (24.2 ± 3.3 kg/m2) and patients (24.2 ± 3.2 kg/m2). Regardless of menopausal status, the patients in each group had higher WBC counts, systolic blood pressure, diastolic blood pressure, and fasting plasma glucose than the controls (p < 0.001 for each comparison). HDL cholesterol was lower in the premenopausal patients than in the matched controls, while there was no difference in HDL cholesterol between the postmenopausal patients and controls. Regardless of menopausal status, history of breastfeeding was more prevalent among the controls, whereas history of medication for hypertension was more prevalent among the patients. History of medication for diabetes was more prevalent among the postmenopausal patients than among the matched controls, however there was no difference in history of diabetes medication between the premenopausal patients and controls.Table −/PR− or ER+/PR+ breast cancer had higher WBC counts than their matched controls . Postmenopausal women with ER+/PR− or ER−/PR+ breast cancer exhibited similar trends, but the difference between the patients and controls was not significant. In contrast to the patterns in premenopausal non-obese women, premenopausal obese women with ER−/PR− breast cancer or ER+/PR− or ER−/PR+ breast cancer did not have higher WBC counts than their age-matched controls, and the trend for higher WBC counts relative to those in the controls was weakened in those with ER+/PR+ breast cancer . Among postmenopausal women, the difference in WBC counts between patients and controls was greater for patients with ER+/PR+ breast cancer than for those with ER−/PR− breast cancer or ER+/PR− or ER−/PR+ breast cancer, regardless of whether the women were obese  or non-obese .Figure +/PR+ breast cancer had higher WBC counts than their age-matched controls . Likewise, postmenopausal non-obese patients with ER+/PR+ breast cancer had higher WBC counts compared to their age-matched controls . Furthermore, premenopausal non-obese patients with ER+/PR+ breast cancer had higher WBC counts than premenopausal non-obese patients with ER−/PR− breast cancer . Similarly, postmenopausal obese patients with ER+/PR+ breast cancer had higher WBC counts than postmenopausal obese patients with ER−/PR− breast cancer . Menopause*WBC, BMI*WBC, and menopause*BMI*WBC were all shown to have significant interactions by multinomial logistic regression models for outcome .Finally, we assessed the association between WBC count and breast cancer burden according to ER/PR status, BMI, and menopausal status. For the analysis, we used multinomial logistic regression analysis after adjustment for age, systolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, HDL cholesterol, alanine aminotransferase, the use of hypertension and diabetes medications, history of breastfeeding, menarchial age, and menopausal age Table , Fig. 3.+/PR+ breast cancer had elevated WBC counts compared with both controls and premenopausal non-obese women with ER−/PR− breast cancer. Those trends were weaker in premenopausal obese women. Postmenopausal non-obese women with ER+/PR+ breast cancer had elevated WBC counts compared with controls, while postmenopausal obese women with ER+/PR+ breast cancer had elevated WBC counts compared with postmenopausal obese women with ER−/PR− breast cancer.In this case-control study, we found that WBC count was associated differently with breast cancer burden depending on menopausal status, BMI, and ER/PR status. Premenopausal non-obese women with ER30, but their interaction may differ according to menopausal status32. Positive associations between obesity and breast cancer risk have been consistently observed in postmenopausal women36. However, there is substantial evidence that there is an inverse association between obesity and breast cancer risk in premenopausal women39. Our results showed that WBC count was not associated with breast cancer burden in premenopausal obese women.Emerging evidence suggests that chronic low-grade inflammation plays an important role in cancer development. Both menopause and obesity can also play a crucial role in the development of breast cancer40. Unless ROS and NOS are properly neutralized by the antioxidant defense system, they can cause damage to cellular proteins, lipids, and DNA that may lead to the accumulation of genetic instability, affecting single nucleotide polymorphisms (SNPs) or upregulating the PI3K-Akt pathway for carcinogenesis41. Large-sample studies that attempted to evaluate the association between WBC counts and breast cancer risk without stratification by menopausal status and obesity have produced inconsistent results25. A prospective study demonstrated that leukocyte counts may be a predictor of breast cancer, but the study included only postmenopausal women20. Akinbami et al.42 reported that WBC counts were higher in patients with breast cancer than in controls, but their study did not include information about menopausal status. Okuturlar et al. showed that neutrophil levels were associated with the risk of breast cancer, including Stage IV breast cancer43. None of the previous studies included ER/PR status in their analysis. A recent meta-analysis assessed the association between the neutrophil-to-lymphocyte ratio as a biomarker using WBC subtypes and breast cancer prognosis44. In that study, which was performed in patients with breast cancer without control, patients with a higher neutrophil-to-lymphocyte ratio had a higher relapse and a shorter overall survival. Subgroup analysis showed that studies performed in Eastern countries had perfectly homogeneous results, whereas Western countries did not. A distinguishing feature of our study is that it attempts to elucidate a role of the interaction between WBC count and ER/PR status in the context of menopause and BMI.WBCs, including neutrophils, monocytes, and eosinophils, produce reactive oxygen species (ROS) and nitric oxide species (NOS), which are chemically reactive molecules45, but the incidence of breast cancer has increased over the last decade4. The age-frequency distribution of breast cancer among Korean women is unimodal, with peak incidence at 45–49 years of age5. Dense breast on mammography, a potent risk factor for breast cancer, is more prevalent among Korean women, especially before menopause, than among women from Western countries46. Those distinctive epidemiological features warrant more investigation of the interplay between well-known risk factors such as obesity and menopause and the emerging role of inflammation in cancer development.The prevalence of obesity among Korean women has gradually decreased since 20019, there are controversies, regarding discrepancies according to menopause23, as well as some limitations in Korean women. One Korean cohort study in which 23,830 Korean women 50–64 years of age were examined reported that metabolic syndrome was related to the risk of breast cancer after adjustment for age and BMI47. That study did not account for menopausal status, although most of the participants were likely postmenopausal, nor did it consider different breast cancer subtypes. A recent epidemiological study of postmenopausal Korean women showed that insulin resistance was independently associated only with luminal B subtype breast cancer10, which is included in the ER+/PR+ phenotype48.While metabolic syndrome and insulin resistance, as inflammatory conditions, have been noticed to be associated with breast cancer development and subsequent progression+/PR+ breast cancer than for ER−/PR− breast cancer27. Approximately 40% of ER+ breast cancers fail to respond to hormone therapy49. ER and PR status can be a precipitating factor in breast cancer development through its interplay with inflammation, which may also influence endocrine resistance. Pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), increase the transcriptional activity of the NF-κB and JNK pathways and may subsequently induce tumorigenesis or resistance to hormone therapy50. In a case-case analysis of epidemiological risk factors for breast cancer, women less than 50 years of age with ER−/PR− tumors were more likely to be obese than those with ER+/PR+ tumors51. Obesity per se has been mainly associated with postmenopausal ER+/PR+ breast cancer27. Our study reported that menopausal status, BMI, and WBC showed a significant interaction by multinomial logistic regression models. Considering how previous studies have shown that obesity can be associated differently with breast cancer status, our findings suggest that among non-obese women, WBC may be related to breast cancer burden. Among Korean women, breast cancer has peak incidence in the perimenopausal period, with the number of obese women being lower than that of non-obese women52.ER and PR are found in about two-thirds of breast cancers, representing favorable therapeutic and prognostic factors. In terms of breast cancer pathogenesis, the risk of breast cancer development associated with weight gain, a surrogate for increasing subclinical inflammation, has been shown to be higher for ER54, which may have led to differential misclassification of laboratory errors. Prospective longitudinal studies are needed to verify the effects of those interactions on the development of breast cancer, especially in Asian women. Second, some inflammatory markers such as C-reactive protein, interleukin-6, serum amyloid-A, and prostaglandin E2 were not measured at the beginning of the study. Those markers can be indicators of chronic low-grade inflammation but have not been taken into consideration when relating breast cancer to the presence of obesity. Third, cases were selected from hospital registry between 2005 and 2012, but controls were selected between 2010 and 2012 from KNHANES, albeit for proper stratification in cases and for excluding duplication of participants and minimizing missing data in controls.Our study has a few limitations. First, because our study was a case-control study, the exact cause-effect relationship between WBC count and ER/PR status according to obesity status and menopausal status remains unclear. Although it is plausible that WBC may reflect underlying inflammation and, in turn, affect breast cancer risk, higher WBC counts may result from the stress that comes after receiving a cancer diagnosis. Also, WBC counts in controls and cases were measured separately in different laboratories, with very high concordance of general blood cell counts among various automated hematology analyzers+/PR+ breast cancer, irrespective of menopause. Further larger-scale prospective cohort studies are warranted to determine these associations in the future.In conclusion, compared with those in controls, WBC counts were significantly elevated in non-obese patients with ER


Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49–0.90) and of HER2‐enriched tumours , but there was no association with overall  or postmenopausal  breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2‐enriched tumours , but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2‐enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2‐enriched tumours.Preeclampsia and hyperemesis gravidarum are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox regression adjusting for known breast cancer risk factors. During 7.5 years average follow‐up of 82,053 parous women, 1,969 were diagnosed with invasive or  What's new?Although the link of preeclampsia and hyperemesis gravidarum with altered sex hormone levels is well established, relatively little is known about the association of these pregnancy complications with breast cancer risk. Here, the authors found that a history of preeclampsia decreased the risk of premenopausal breast cancer and tumors enriched for the receptor tyrosine‐protein kinase HER2. In contrast, hyperemesis gravidarum increased the risk to develop HER2‐enriched tumors, pointing to nuanced differences of sex hormone alterations during pregnancy with respect to breast cancer subtypes and menopausal status. BMIbody mass indexCIconfidence intervalERoestrogen receptorHER2human epidermal growth factor receptor 2HRhazard ratioUKUnited KingdomBreast cancer is the most common type of cancer among females worldwide and has a hormonal aetiology. During pregnancy, breast tissue is exposed to hormonal surges including of oestrogen and progesterone, which may be related to the transient increased risk of breast cancer after pregnancy, followed by a decreased risk long‐term.Preeclampsia is a disorder characterised by the onset of hypertension and proteinuria in the second half of pregnancy, affecting around 2–8% of pregnancies,Hyperemesis gravidarum (hereafter referred to as ‘hyperemesis’) is characterised by severe nausea, vomiting and faintness in the first half of pregnancy. It has been hypothesised that it could be associated with a raised risk of maternal breast cancer via elevated estradiol levels in pregnancy.We therefore examined the association between history of preeclampsia and hyperemesis and maternal risk of breast cancer in women within the Generations Study, a large prospective cohort study in the UK, in which detailed information on pregnancies, breast cancer risk factors and breast cancer characteristics was available.The Generations Study is a cohort study of over 113,700 women from the United Kingdom (UK), aged 16 years or older, designed to investigate the aetiology of breast cancer. Questionnaire information and informed consent were gained at recruitment since 2003. The first follow‐up questionnaire (2½ years after recruitment) was completed by 99% of non‐deceased participants, the second (6 years after recruitment) by 96%, and the third (9½ years after recruitment) by 94% of those recruited long enough ago to have entered this round of follow‐up. The study was approved by the South East Multi‐Centre Research Ethics Committee and has been described in detail previously.Breast cancers occurring in the cohort were identified from recruitment and follow‐up questionnaires and spontaneous reports to the study centre, and where necessary from ‘flagging’ at the National Health Service Central Registers . Confirmation of diagnosis was obtained from UK cancer registries, pathology reports and correspondence with patients' general practitioners.Information on pregnancies was collected in the recruitment and second follow‐up questionnaires. Participants were asked if they had experienced preeclampsia or hyperemesis gravidarum , and about birth outcome, gestational length, offspring sex and birth weight at each of their pregnancies. Age at first and last pregnancy and time since last pregnancy with preeclampsia and hyperemesis were calculated using information from individual pregnancies.Information on menopausal status and age at menopause was obtained from the recruitment and second follow‐up questionnaires, in which women were asked how old they were when their periods stopped completely . For women who did not provide an age at menopause but who reported that they became postmenopausal during follow‐up, we defined menopausal age to be the youngest of either the woman's age at the questionnaire at which she first reported that she was postmenopausal or age 50.in situ breast cancer, and were either parous (defined as pregnancies of ≥26 weeks resulting in a live birth) at recruitment or became parous during follow‐up. The recruitment cut‐off at December 2013 was selected because at the time of analysis the second follow‐up was virtually complete, two‐thirds had reached the third follow‐up, and we had ‘flagging’ information to June 2017 for these recruits. Participants entered risk at the date of return of their recruitment questionnaire, or if they were nulliparous at recruitment and became parous during follow‐up, the date of first delivery, and were censored at the earliest of: first invasive or in situ breast cancer; death; most recent follow‐up questionnaire (depending on date of recruitment), if completed, or the date the most recent follow‐up questionnaire was due if cancer and vital status was known from ‘flagging’; or the date of the last completed questionnaire, if lost to study follow‐up. We additionally censored at the first age of having a twin or higher‐order birth, since such births are associated with higher hormone exposures.The analytic cohort in our study is based on all women who were recruited to the Generations Study before 31 December 2013, did not have a previous diagnosis of invasive or in situ breast cancer, or prophylactic mastectomy. Women who remained nulliparous throughout follow‐up  and women who had a twin or higher‐order birth before entry to the study  were excluded from the analysis. The analytical cohort included 82,053 women who were either parous at baseline questionnaire  or became parous during follow‐up  and therefore entered follow‐up at their first parous birth. Three hundred and twenty nine women were censored at their first twin or higher‐order birth during follow‐up. During follow‐up, 1.2% of women died. Of the remainder, cancer and vital status was known for 97.4% from completion of the relevant follow‐up questionnaire, and a further 2.4% from ‘flagging’ at the National Health Service Central Registers. The remaining 0.2% were lost to follow‐up at an earlier date. The follow‐up completeness  was 99.7%. There were 1,969 incident breast cancers during follow‐up , of which 99.6% were confirmed through national cancer registration or medical records and the remaining eight cases were self‐reported with treatments that implied breast cancer. ER information was available for 91.2% of breast cancers , and of these 83% were ER positive.During 2003–2013 the recruitment questionnaire was completed by 106,628 study participants who had no previous invasive or The median age at recruitment was 49.0 years (inter‐quartile range: 39–58) and participants contributed an average of 7.5 years of follow‐up. Characteristics of the participants overall and by preeclampsia and hyperemesis history are given in Table ptrend = 0.29) across the number of pregnancies with preeclampsia. Risk reductions for premenopausal women were significant for women whose first preeclamptic pregnancy was at ages 25 or over , or whose last preeclamptic pregnancy was at ages under 30 years , or during the 20 years after the last preeclamptic pregnancy . The risk of premenopausal breast cancer was also significantly reduced for preeclampsia experienced at a first  or a last pregnancy . The relative risk of premenopausal breast cancer in relation to a history of preeclampsia remained significantly decreased when the analyses were restricted to invasive breast tumours only (Supporting Information Table S1). For postmenopausal breast cancer, there was no significant association of risk with any of the above preeclampsia variables.Women who reported a history of preeclampsia during a pregnancy had a similar risk of breast cancer overall compared to parous women who had never experienced preeclampsia  , nor with subdivisions of this, except for a positive association in women aged under 25 years at their first preeclamptic pregnancy . Ever having had preeclampsia was associated with a significantly decreased risk of human epidermal growth factor receptor 2 (HER2)‐enriched breast cancer , but there was no association with other intrinsic subtypes (Table Relative risks with respect to preeclampsia were similar for ER positive and ER negative tumours Table . Risk ofpint = 0.23 and pint = 0.67). Relative risks with respect to preeclampsia did not vary significantly according to whether the subject also had a history of hyperemesis, or vice versa (pint = 0.21) (Supporting Information Tables S2 and S3).Relative risks with respect to preeclampsia did not vary appreciably according to whether the subject's mother had experienced preeclampsia at the subject's birth Table . The relptrend = 0.44) or time since last hyperemetic pregnancy (ptrend = 0.83), and no association with the age at hyperemetic pregnancy or with hyperemesis at first or last pregnancy. Relative risks did not vary by menopausal status at follow‐up, or ER status or invasiveness of breast cancer (Supporting Information Table S4). Risk of HER2‐enriched breast cancer was significantly raised in women who had experienced hyperemesis , but there was no association with other intrinsic subtypes of breast cancer  Table . There wIn this large prospective investigation, women who experienced preeclampsia during a pregnancy were at significantly reduced risk of breast cancer at premenopausal ages and of HER2‐enriched breast cancer. Risk reductions amongst overall, ER positive and invasive breast cancers were observed during the 20 years since the last pregnancy with preeclampsia, with strongest reductions observed amongst premenopausal women, but not in those who last experienced preeclampsia >20 years after the pregnancy with preeclampsia. We observed no significant associations of breast cancer risk with a history of hyperemesis except for a significant positive association with HER2‐enriched breast cancer.in situ breast cancer, in accord with the only previous study that analysed this.The literature on breast cancer risk in women with a history of preeclampsia is inconsistent. Some studies have reported an inverse association,6 and IGF1RPotential mechanisms for risk reductions in breast cancer for women with a history of preeclampsia could be due to lower levels of oestrogenset al.et al.et al.Although there is no evidence to suggest an association between sex of the offspring and long‐term risk of breast cancer in pregnancies without complications,Since a maternal history of preeclampsia in the pregnancy leading to the subject's birth is a risk factor for experiencing preeclampsia in the subject's own pregnancy,An adverse effect of hyperemesis on breast cancer risk has been proposed because of reported higher estradiol levels in pregnancies with hyperemesis.To our knowledge there have been no previous investigations of risk by tumour intrinsic subtypes of breast cancer in relation to history of preeclampsia or hyperemesis. We found that the strongest associations for both pregnancy complications were for HER2‐enriched tumours. Risk of this type of breast cancer was reduced in women with a history of preeclampsia, which is associated with lower levels of estriol,While there are several strengths to our study, including its large size, prospective design, high completeness of follow‐up and quality of covariate data, we are dependent on self‐reported history of preeclampsia and hyperemesis, although collected prior to breast cancer diagnosis and therefore unbiased by outcome. Registry‐based cohort studies have been based on records of women hospitalised for pregnancy‐complications, therefore reflecting confirmed diagnoses, but did not have complete data on other important breast cancer risk and lifestyle factors. In the Generations Study extensive pregnancy and other breast cancer risk factor data were collected and our analyses were adjusted for a wide range of potential confounders.In conclusion, our results suggest that preeclampsia is associated with a decreased risk of breast cancer at premenopausal ages and of HER2‐enriched breast cancer. We did not find evidence that a history of hyperemesis was associated with breast cancer risk overall, but there was a positive association with the HER2‐enriched subtype.Supporting Information TableClick here for additional data file.


Despite strong evidence of benefit, breast cancer risk assessment and chemoprevention are underutilized by primary care physicians. This study evaluates the impact of an educational program on knowledge and utilization of the NCI Breast Cancer Risk Assessment Tool (BCRAT) by internal medicine residents.Internal medicine residents at the primary care clinic at William Beaumont Hospital participated in an educational program on breast cancer risk assessment and chemoprevention. A questionnaire was used to assess knowledge and practice before and after participation. Electronic health records of women between the ages of 35 and 65 who were seen by participating residents for annual health exams between Dec 15, 2015 and Dec 14, 2016 were reviewed. Utilization of BCRAT by the residents was compared pre- and post-educational program.n = 10, 83.3%) had not used it in the last six months. For each question on the pre-educational knowledge assessment, fewer than 10% of the residents responded correctly. After implementation of the educational program, there was a significant increase in the proportion of residents who answered correctly .A total of 43 residents participated in the study. 31 (72.1%) residents reported no prior knowledge about BCRAT. The remaining 12 (27.9%) reported limited knowledge of BCRAT, but the majority of these (p < 0.05). However, a majority  of eligible patients from both groups did not undergo breast cancer risk assessment.Electronic health records of 301 clinic patients were reviewed, 118 (39.2%) in the pre-educational program group and 183 (60.8%) in the post-educational program group. There was a higher use of BCRAT in the post-educational program group compared to the pre-intervention group  contains supplementary material, which is available to authorized users. One in eight women in the United States will develop invasive breast cancer in her lifetime . In 2017https://bcrisktool.cancer.gov/). The National Comprehensive Cancer Network guidelines endorse the BCRAT to identify women who may be candidates for chemoprevention with one of the currently approved agents for risk reduction. [The Gail model was originally designed in 1989  and thenduction.  also advduction. .Several important medical decisions may be impacted by knowing a woman’s underlying risk of developing breast cancer . For womDespite the availability of these breast cancer risk assessment tools and their clinical validation, they have received very little attention outside of the oncology clinic . The useOur study focuses on one specific group of PCPs – internal medicine residents – since a prior study has demonstrated that resident PCPs are even less likely to use breast cancer risk assessment tools compared to their attending physicians . Hence, The primary objective of this study was to evaluate the impact of a comprehensive educational program on the knowledge and utilization of BCRAT by internal medicine residents. The secondary objective was to evaluate the feasibility of such an educational program.The study was conducted over an eight-month period, from April 2016 to November 2016. Each month internal medicine residents (PGY-1 through PGY-3) assigned to an outpatient clinic rotation were offered participation. The residents took part in a thirty-minute interactive educational program at the beginning of their clinic month. The program consisted of a didactic lecture focused on breast cancer risk assessment, chemoprevention and importance of high-risk screening. In addition, the residents were provided with current literature including professional societies’ guidelines, on the topic of breast cancer risk assessment and pharmacologic prevention. A smart-phrase was created in the electronic health system (EPIC) to assist in performing BCRAT. Pre- and post-educational program questionnaire  of women between the ages of 35 and 65 who were seen by the participating residents in the clinic for annual health exams between December 15, 2015 and December 14, 2016 were reviewed. Women with a prior history of breast cancer or a known genetic mutation were excluded. Utilization of BCRAT by the residents was assessed pre- and post-program implementation.p < 0.05.Data was collected in Microsoft Excel (Ver. 2007) and statistical analysis was performed using SPSS 21. Fischer’s exact test was used for categorical variables and Mann-Whitney U-Test was used for continuous variables. All tests were two sided. Statistical significance was considered at A total of 43 (54.4%) out of the eligible 79 residents participated in the study. A majority of these residents were graduates of a United States/Canadian medical school and were in the first year of their residency training Table .Table 1Bn = 43) completed the pre-educational program questionnaire. When asked about their comfort level in assessing a woman’s risk for developing breast cancer, using an incremental linear scale from 0 to 10, more than half (58.1%) of the residents responded with a score of 5 or less . 31 (72.1%) residents stated that they had never heard of the Gail model or the NCI BCRAT before. The remaining 12 residents (27.9%) had heard of the Gail model but 10 (83.3%) out of the 12 stated they had never used it in the last six months.All participating residents (p < 0.001) in the proportion of correct answers in the post-program questionnaire, with more than two-thirds answering each of the questions correctly  patients had been seen by the residents prior to their participation in the educational program , while 183 (60.8%) were seen after the residents’ participation in the program . Both groups of patients were similar in terms of their baseline demographic characteristics (Table p < 0.05). Although the sample of the residents in each sub-group was small, there was no difference in the likelihood of performing BCRAT by place of training (US/Canada vs. Other) or level of training (Post-graduate year) for the residents.In total, 7 (3.8%) patients in the post-educational group underwent breast cancer risk assessment. There was a modestly higher use of BCRAT in the post-educational group of patients compared to the pre-educational group  patients, 118 from the pre-educational program group and 176 from the post-educational program group, did not have a breast cancer risk assessment performed. Out of these 294 patients, 40 (13.3%) had sufficient information in the chart to calculate their Gail risk retrospectively, and 5 (12.5%) out of these 40 women had a 5-year risk of breast cancer ≥1.67%. For the remaining 254 patients, Gail risk could not be calculated from the existing information in EHR. Of these 254, 102 patients were from the pre-educational group while 152 patients were from the post-educational group, constituting 86.4 and 83.0% of their corresponding groups respectively. In more than two-thirds of the patients, information on age at menarche and age at first live birth was not available in the EHR, thus making the BCRAT calculation not possible. However, among these patients, 28 (11%) had at least one first degree relative with breast cancer.Our study demonstrates that a comprehensive lecture-based educational program improved the knowledge of BCRAT in internal medicine resident PCPs. A prior study that evaluated the role of a multimodal curriculum to teach internal medicine residents evidence-based breast health demonstrated improvement in knowledge after implementation of the program, but did not evaluate the impact on clinical practice . To the In our study, more than two-third of the residents expressed that they had no knowledge of the Gail model/BCRAT prior to implementation of our program, and among those who knew about it, the self-reported utilization was minimal. Evaluation of EHR of 118 eligible patients who were seen by these residents prior to their participation in the program revealed that none of the patients had breast cancer risk documented. Although the utilization rate of BCRAT by PCPs has been shown to be low in prior studies , 17, 19,The low rate of utilization of breast cancer risk assessment by resident PCPs is concerning. Whether this observation holds true in other residency programs is not known, but warrants further investigation. Our study serves as a cautionary reminder for other training programs to evaluate their curriculum and to emphasize on utilization of BCRAT in the context of teaching early detection and prevention of breast cancer. Considering the fact that residency training impacts future practice behavior , 21, it Chemoprevention agents such as tamoxifen and raloxifene have demonstrated clear benefit in reducing risk of breast cancer in high-risk women , 24–26. On a more positive note, our study demonstrates that internal medicine residents are willing and able to absorb knowledge on breast cancer risk assessment and prevention. However, despite this improvement in knowledge and understanding, the uptake of BCRAT increased only to a modest 3.8%. Our study did not assess for reasons behind why the residents did not assess breast cancer risk despite having adequate knowledge to do so. There are several potential reasons for the low uptake including time constraint in a busy clinic, not attributing enough clinical significance to breast cancer risk assessment over other preventative measures and not being required to perform BCRAT by attending physicians. Future studies should aim to explore some of these potential reasons. Our study also suggests that knowledge of BCRAT may not be the only barrier to implementing a successful program on breast cancer risk assessment.Our study primarily focused on didactic lecture as the means of conveying information, but future studies should evaluate more innovative methods such as team-based or problem-based learning techniques, which may be more effective than the traditional lecture forum –32. AlsoThere are several limitations of our study including the small number of residents from a single institution and limited scope of our intervention. We did not evaluate the long-term impact of our educational program nor did we specifically look at reasons for low uptake. We did not evaluate or educate the residents on how to effectively communicate the results of BCRAT to patients, which is another limitation. Future studies should build upon our findings and include ongoing education to reinforce the important concepts of breast cancer risk assessment and prevention.Our study demonstrates that an educational program geared towards resident PCPs improves knowledge and utilization of BCRAT. Despite this improvement, there is a need to expand the scope and duration of this intervention in order to optimize the use of BCRAT in a busy clinic. Combining educational programs with other teaching modalities and innovative use of technology may further improve the utilization of BCRAT and therefore, should be investigated in future studies.Additional file 1:Pre- and Post-educational Questionnaire. Description: List of questions used in pre- and post-educational questionnaire for the resident physicians. (DOCX 20 kb)


Women with early-stage breast cancer may still have a future child wish, while chemotherapy may impair fertility. To pursue on fertility preservation shortly after breast cancer diagnosis is complex. This review holds a critical reflection on all topics that need to be counseled to give them the opportunity to make a well-informed decision before starting any oncological treatment.A comprehensive literature review was performed on papers published in English language on breast cancer in young women, risk of chemotherapy-induced infertility, fertility preservation techniques, impact of possible mutation carriership, and future pregnancy outcome.BRCA gene mutation should also be informed about the possibility of pre-implantation genetic diagnosis.Below 40 years of age, the risk of permanent chemotherapy-induced ovarian function failure is approximately 20%, where taxanes do not significantly add to this risk. Overall, 23% of reported women who performed fertility preservation by cryopreserving oocytes or embryos returned for embryo transfer. Of these, 40% gave live birth. Both fertility preservation in women diagnosed with breast cancer and pregnancy after treatment seem safe with respect to breast cancer survival. Women who have a genetic predisposition for breast cancer like Women with an early stage of breast cancer and a possible future child wish should be referred to an expertise center in breast cancer, fertility preservation, and genetics in this complex decision-making process, shortly after diagnosis. Breast cancer is the most commonly diagnosed malignancy in women . AnnuallCurrently, young breast cancer patients are given the opportunity to consider fertility preservation. Among the diverse possibilities for fertility preservation, freezing embryos or oocytes during an in vitro fertilization (IVF) procedure for later use is most frequently used . CryopreWomen with early-stage breast cancer have to decide shortly after breast cancer diagnosis if they want to pursue a fertility preservation procedure . TherefoA comprehensive literature review was performed on papers published in English language on breast cancer in young women regarding risk of chemotherapy-induced ovarian function failure and role of adjuvant endocrine therapy, safety, and effectiveness of fertility preservation techniques, and impact on future pregnancy and breast cancer outcome. These papers were found by multiple searches through the PubMed database and by following cited references. Additionally, updates from the main conferences in the field of oncology, assisted reproduction, and fertility preservation were used.It is reported that independent of age and tumor characteristics, third-generation chemotherapy regimens reduce breast cancer mortality by one-third . A low aBreast cancer in young women has less favorable biological features, including higher histological grade, higher Ki67, and lymphovascular invasion and therefore a higher risk of recurrence. Online nomograms are available for estimating survival rates based on patient and tumor characteristics, but these nomograms do not perform well in the very young , 10.Chemotherapy can cause significant side effects, which may especially be troubling in these young women. They are in the middle of their working, social, and family life , 12. ForIn conclusion, many young women with early breast cancer diagnosis may substantially benefit from chemotherapy in terms of survival gain, but this has to be balanced against the risk of undesired long-term side effects. Counseling on the possible benefits and harms of chemotherapy, including impact on fertility, is important to optimize decision-making on the indication of chemotherapy.Regarding the risk of chemotherapy-induced menopause and risk of infertility, both the type of chemotherapy and the patients’ age are important factors to consider.Although the mechanisms of chemotherapy-induced ovarian function failure are not entirely understood, Adriamycin and cyclophosphamide are known to cause double-stranded DNA breaks, and thereby apoptosis of primordial follicles and depletion of the follicular pool . AdriamyPreviously, it was reported that in patients aged 40 years or less, four cycles of Adriamycin-cyclophosphamide (AC) chemotherapy was associated with a low risk (< 20%), cyclophosphamide, methotrexate, 5-fluorouracil (CMF) with a low to an intermediate risk (< 60%), and AC followed by taxane with an intermediate risk (40–60%) of premature menopause , 18. HowNoteworthy, the moment of developing amenorrhea differs per type of chemotherapy. During CMF chemotherapy, amenorrhea occurs in over half of the patients, with no recovery after the end of chemotherapy and a continuous further rise in amenorrhea to approximately 80% of women after 3 years . ConversRecently, more studies reported the impact of taxanes Table  20–28].–28.20–28In conclusion, with the currently used chemotherapy regimens, the risk of permanent chemotherapy-induced ovarian function failure is on average 20% in patients below 40 years of age. This risk is not increased when taxanes are added to the AC chemotherapy regimen.In patients with low-risk hormone receptor-positive breast cancer, 5 years of tamoxifen is considered a standard therapy. For high(er) risk hormone receptor-positive breast cancer patients, prolonged endocrine treatment for 10 years in combination with ovarian function suppression may be considered, in addition to chemotherapy , 33.Tamoxifen does not increase the risk of permanent ovarian function failure, but due to its action, the menstrual cycle may be absent while using tamoxifen , 29–31. In conclusion, hormonal therapies  do not have irreversible effects on ovarian function but should be timely interrupted when trying to become pregnant, considering the risk of teratogenicity.During chemotherapy in patients with breast cancer, antimullerian hormone (AMH) levels drop. Low pretreatment AMH levels predict low recovery rates of AMH levels after chemotherapy –38. TherWomen with a definitive chemotherapy-induced menopause have significant lower pre-chemotherapy AMH values than in those with recovery of ovarian function within 6 months to 2 years –42. HoweP = 0.13) [On the other hand, AMH is a well-established ovarian reserve test as it is a proven predictive marker for ovarian response during in vitro fertilization (IVF) stimulations . However = 0.13) . But dueWe conclude that there is no added value of measuring pre- or post-chemotherapy AMH values in predicting infertility. AMH assessment to optimize dosage of gonadotropins does not seem to increase live birth rates. However, in the fertility preservation setting, cycle cancellation due to poor response should be avoided. Gonadotropin dosage should be sufficient and individualized on AMH or other ovarian response markers.Cryopreservation of embryos or oocytes is a well-established technique of fertility preservation , 48. DatIn Table The first live birth after cryopreserved oocytes for an oncologic indication was reported in 2007 . The numData were generally published 1–4 years after freezing of oocytes or embryos. Return rates are also influenced by the general advice to wait at least 2 years after diagnosis before trying to become pregnant , 66. MorThe twin birth rate as mentioned above seems relatively high. This is a result of multiple embryo transfer in most studies. Twin pregnancies have higher obstetric and neonatal risks . Single When women are single at the time of fertility preservation, oocyte cryopreservation is usually used. Moreover, oocyte cryopreservation may even be preferred in all situations, since both partners have ownership over the cryopreserved embryos introducing difficulties if the relationship ends , 69.Unfortunately, older patients who have a higher risk of permanent chemotherapy-induced ovarian function failure are those with the poorer results with cryopreservation techniques. The ovarian response to stimulation is often lower with fewer oocytes available and oocyte quality is diminished often due to more chromosomal abnormalities. Even though there is no consensus on a definite age limit to propose cryopreservation techniques, both physicians and patients should be informed that the probability of conceiving using oocytes vitrified after 35 are rapidly declining , 71.Ovarian cryopreservation is another technique for fertility preservation, still considered experimental but advancing quickly, and may evolve to become a standard approach in the future , 72–74. In conclusion, cryopreservation of embryos or oocytes is a well-established technique of fertility preservation. It should be considered to prefer oocyte cryopreservation over embryo cryopreservation, due to the ethical difficulties that can rise once a relationship is broken or once one of both partners deceases. About half of the collected oocytes will develop into an embryo, irrespective of the moment of fertilization (before or after cryopreservation). The reported return rates for embryo transfer are low (23%), probably as a result of a short follow-up period. Further analysis of non-returning patients is needed. Although the data on live birth rate after cryopreservation are limited, the results are encouraging. Of women returned, on average 40% had at least one live birth. The data suggest that for breast cancer patients, the live birth rates are even higher . HoweverOvarian cryopreservation is an alternative option that may be considered if it is not possible to perform an ovarian stimulation for oocyte or embryo cryopreservation, which in daily practice is seldom the case.Prevention of ovarian depletion could be a better approach to prevent infertility than preserving fertility by freezing oocytes, embryos, or even ovarian tissue. The use of gonadotropin-releasing hormone analogues (GnRHa) has been hypothesized as an agent used for gonadal protection . UnfortuIn a recent update of the ASCO guideline on fertility preservation by Oktay and colleagues, seven randomized controlled trials evaluating GnRHa use during chemotherapy were discussed . In the P = 0.04) [P = 0.018) [P = 0.043). These findings should be interpreted with great care considering the missing data and non-adjustment for pregnancy desire.The POEMS trial is the only trial reporting on number of pregnancies as a preplanned secondary end point . They fo = 0.04) . Lambert= 0.018) . The addThe ASCO guideline states: “There is conflicting evidence to recommend gonadotrophin-releasing hormone agonists (GnRHa) and other means of ovarian suppression for fertility preservation. The Panel recognizes that, when proven fertility preservation methods are not feasible, and in the setting of young women with breast cancer, GnRHa may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. GnRHa should not be used in place of proven fertility preservation methods.” In line with this statement, we conclude that patients interested in reducing the risk of post-treatment amenorrhea and menopausal symptoms may choose this approach. However, it is important to inform patients on the controversy and uncertainty regarding the efficacy of GnRHa as a “fertility preservation” approach.Breast cancer could theoretically be stimulated by the temporally hyperestrogenic state during an in vitro fertilization (IVF) procedure in the context of fertility preservation, and an early state of hormone-sensitive breast cancer might disseminate. After a regular IVF procedure, there is no increased risk to develop breast cancer compared with women who did not undergo IVF , althougSo far, there are no signs of a higher recurrence rate of breast cancer in woman who opt for a fertility preservation procedure after breast cancer diagnosis, although the follow-up period of most studies is short –89. In tThe urgency to continue oncological treatment and perform fertility preservation in a short period of time is inconvenient when deciding on which stimulation protocol is needed. Recent literature shows that fertility preservation can start randomly in a menstruation cycle, without a negative effect on the number of oocytes retrieved .In conclusion, fertility preservation in women diagnosed with breast cancer seems safe with the use of tamoxifen or letrozole. Fertility preservation before neoadjuvant chemotherapy is probably safe in patients with hormone receptor negative tumors, although follow-up data are very sparse. In patients with hormone receptor-positive disease, we recommend to first perform breast surgery. With current procedures, fertility preservation can start randomly in a menstruation cycle, hence not causing a significant delay in oncological treatment.P = 0.03), with no interaction according to hormone receptor status.Several studies have shown that pregnancy does not negatively impact breast cancer prognosis , 90–92. Three population-based studies have been performed on birth outcome in women treated for breast cancer –95. TheiIn conclusion, pregnancy after breast cancer does not seem to impact the risk of breast cancer recurrence. Pregnancy may result more often in a preterm birth and lower birth weight (relative increase of 50%) as compared with the general population.BRCA1 or BRCA2 mutation detection rate in female breast cancer patients depends on factors such as age at diagnosis and breast cancer subtype. Of women diagnosed before the age of 45 years with a positive family history, 12.0% carried BRCA1 or BRCA2 germline mutations [The utations . Mutatioutations .BRCA1 and BRCA2 mutation carriers, the knowledge that risk-reducing salpingoopherectomy is recommended between 35–40 and 40–45 years of age respectively, may add to the decision to choose for fertility preservation [Hereditary predisposition for breast cancer might influence the decision to choose for a fertility preservation procedure. For ervation . The poservation , 100.BRCA mutation carriers can perceive a pressure to fulfill their child wish at an earlier age, for example due to a shortened reproductive life span [BRCA mutation carriers [ife span . Therefocarriers .BRCA mutation carries after an IVF stimulation versus no IVF stimulation. Breast cancer incidence was comparable in both groups, therefore, performing an IVF stimulation in these women can be considered safe [Women with an increased risk of hereditary breast cancer may have extra concerns about the safety regarding a fertility preservation procedure. One study compared red safe .BRCA1 gene might contribute to ovarian ageing as it is involved in DNA double-strand break repair [BRCA mutation compared with controls [Regarding the reproductive decisions a woman has to make, the concerns regarding ovarian reserve in these women should also be taken into account. Specifically, the k repair –106. Howcontrols . This diBRCA) gene mutations should be informed about the possibility of PGD. The advice to perform risk-reducing salpingoopherectomy should be counseled as well, since this could also be a reason to perform fertility preservation. There are no concerns regarding safety and oocyte outcome in an IVF procedure in these women.In conclusion, besides the counseling on fertility preservation options young women with (The conclusions of this critical reflection are summarized in Table


Recently, breast cancer prevalence has increased in South Korea. In this study, we investigated the correlation between breast cancer prevalence and socioeconomic status. This study enrolled 27,331 people who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) IV–VI (2007–2015). In addition, we obtained data from the Korean Statistical Information Service (KSIS) on the breast cancer age-standardized incidence rate (AIR), the age-standardized mortality rate (AMR), the number of women screened, and the number of newly diagnosed patients. The KHANES data showed that breast cancer prevalence was significantly associated with educational level . However, there was no significant association of breast cancer prevalence with monthly household income. In a separate analysis of the AIR, AMR, and number of women screened for breast cancer, the AIR increased with the number of women screened, whereas the AMR did not. Furthermore, the number of newly diagnosed patients in all age groups increased over time. The present results demonstrate that the recently increased breast cancer prevalence documented in South Korea may be attributable to earlier detection rather than to a real increase in prevalence, and that breast cancer may be overdiagnosed. Cancer is one of the leading causes of death worldwide; 8.8 million patients died from cancer in 2015 . A low SIn South Korea, the thyroid cancer incidence rate has increased rapidly over the past two decades . It has Thus, we examined the correlation between breast cancer prevalence and SES using two data sources: 1) the Korean National Health and Nutrition Examination Survey (KNHANES) IV–VI (2007–2015) for data on SES, health related behaviors, and healthcare utilization; and 2) the Korean Statistical Information Service (KSIS) for data on the breast cancer age-standardized incidence rate (AIR), the age-standardized mortality rate (AMR), the number of women screened, and the number of newly diagnosed patients.We conducted this study using KNHANES IV–VI (2007–2015) data. The Korea Centers for Disease Control and Prevention (KCDCP) conducted the KNHANES, which uses a nationally representative, cross-sectional design . KNHANESAs described in detail previously , all subThe smoking status was assessed by self-report; subjects who had smoked more than 100 cigarettes in their lifetime were classified as past or current smokers based on their current smoking habits. Alcohol intake in the past month was assessed by exploring drinking behavior during the month prior to interview. Physical activity was coded “yes” when a subject walked for > 30 min more than five times per week. Cancer examination in the prior 2 years was coded “yes” when a subject had undergone cancer screening within the prior 2 years for any type of cancer, including breast, lung, colon, skin, and ovarian cancer, etc. Previous pregnancy was coded “yes” for subjects had ever been pregnant, including normal pregnancy, ectopic pregnancy, still birth, spontaneous abortion, and induced abortion. The prevalence of breast cancer was measured by asking: “Before study enrollment, were you ever diagnosed by a doctor with breast cancer?” We classified those who answered “yes” as having breast cancer.Subjects were divided into monthly household income quartiles: low , medium-low , medium-high , and high . Subjects were also classified by educational level: ≤ 6 years, 7–9 years, 10–12 years, and ≥ 13 years.We obtained the breast cancer AIR and AMR, the numbers of women screened, and the numbers of newly diagnosed patients, from the KSIS .2 test. The odds ratios (ORs) with 95% confidence intervals (CIs) for the association of breast cancer prevalence with potential risk factors were compared using a multiple logistic regression model. Age and survey year were included as confounders in Model 1. Waist circumference, marital status, residential area, current smoking, alcohol use in the past month, physical activity, cancer examination in the prior 2 years, previous pregnancy, current or past use of oral contraceptives, post-menopausal, and age at menarche were adjusted for in Model 2, in addition to the variables included in Model 1. Educational level or monthly household income and the variables included in Model 2 were adjusted for in Model 3. A p-value < 0.05 was deemed to reflect statistical significance.We used SAS software version 9.3  for the statistical analyses. The survey responses were weighted by reference to the multistage, complex, probability sampling design. Data were expressed as estimated percentages (with standard errors [SEs]) and the distributions of monthly household income and educational level were assessed by the χA total of 236 had breast cancer. In terms of marital status, 15.6% were single and 84.4% married. With respect to residential area, 81.4% and 18.6% lived in urban and rural areas, respectively. Of all the subjects, 7.2% currently smoked and 66.1% consumed alcohol in the past month; 83.2% had ever been pregnant and 15.5% were currently using, or had used oral contraceptives in the past .Higher monthly household income tended to be associated with younger age, lower WC, a higher educational level, being single, residing in urban areas, a lower likelihood of being a current smoker, higher alcohol intake in the past month, completion of a higher number of cancer examinations in the prior 2 years, less experience of pregnancy, less use of oral contraceptives, pre-menopausal status, and a younger age at menarche .Higher educational level tended to be associated with younger age, lower WC, higher monthly household income, being single, residing in urban areas, higher alcohol intake in the past month, less previous pregnancy, less use of oral contraceptives, pre-menopausal status, and a younger age at menarche .When adjusted for age and survey year (Model 1), the breast cancer prevalence was significantly associated with monthly household income . However, after additionally adjusting for WC, marital status, residential area, current smoking, alcohol intake in the past month, physical activity, cancer examination in the past 2 years, previous pregnancy, current or past use of oral contraceptives, post-menopausal status, age at menarche (Model 2) and educational level (Model 3), the associations between breast cancer prevalence and monthly household income were attenuated and no longer statistically significant. .When adjusted for age and the survey year (Model 1), breast cancer prevalence was significantly associated with educational level . When also adjusted for WC, marital status, residential area, current smoking status, alcohol intake in the past month, physical activity, cancer examination during the past 2 years, previous pregnancy, current or past use of oral contraceptives, post-menopausal status, and age at menarche (Model 2), the associations between breast cancer prevalence and educational level remained significant . When additionally adjusted for monthly household income (Model 3), the associations remained significant  .We examined the relationship between breast cancer prevalence and SES using KNHANES IV–VI (2007–2015) and KSIS data. Our results demonstrated that higher educational level was significantly associated with breast cancer prevalence after adjusting for other covariates.In Western countries, it is well established that higher SES is associated with an elevated incidence of breast cancer –14. HoweOur results demonstrated that breast cancer prevalence was not associated with monthly household income, whereas it was associated with educational level. This difference may be due to the Korean national cancer screening program; the government introduced the program for the entire Korean population in 1999 to cover five cancers: stomach, breast, colorectal, cervical, and liver. Furthermore, cancer screening is also provided free of charge for the poorest in society, and is of very low cost for the rest of the population . In a prIn our present study, we found that a higher SES was associated with a greater prevalence of breast cancer. Several plausible explanations may be advanced. First, the well-known risks for breast cancer including nulliparity, late maternal age at first birth, and use of hormone replacement therapies and oral contraceptives, are all associated with a higher SES –26. HoweThe relationship between a higher SES and a greater prevalence of breast cancer deserves discussion. Socioeconomic disparities in breast cancer status  are apparent , 30. HowSeveral years ago, both public health experts and major Korean newspapers spoke out about thyroid cancer overdiagnosis , 40. As Our study had several limitations. First, the fact that the work was cross-sectional in nature renders it impossible to draw cause-and-effect conclusions. Second, there may have been a survival bias: if women with a lower SES are more likely to die after being diagnosed with breast cancer, analyses of cancer prevalence would tend to overestimate the correlation between SES and breast cancer. A previous study of Korean breast cancer patients demonstrated that the breast cancer survival rate of those in the highest SES category was 94.1%, while that of those in the lowest SES category was 85.7% . When weThe present results demonstrated that the recently increased breast cancer prevalence observed in Korea may be attributable to more effective early detection, rather than to a real increase in breast cancer prevalence, and that breast cancer is, in fact, overdiagnosed. Further prospective studies are needed to explore the correlations between SES, breast cancer incidence, and histopathological data, including tumor size and cancer stage.S1 Dataset(SAS7BDAT)Click here for additional data file.


NF1). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing breast cancer compared with the general population. Impaired emotional functioning is reported as a comorbidity that may influence the participation of NF1 patients in regular clinical surveillance despite their increased risk of breast and other cancers. Despite emphasis on breast cancer surveillance in women with NF1, the uptake and feasibility of high-risk screening programs in this population remains unclear. A retrospective chart review between 2014–2018 of female NF1 patients seen at the Elizabeth Raab Neurofibromatosis Clinic (ERNC) in Ontario was conducted to examine the uptake of high-risk breast cancer screening, radiologic findings, and breast cancer characteristics. 61 women with pathogenic variants in NF1 enrolled in the high-risk Ontario breast screening program (HR-OBSP); 95% completed at least one high-risk breast screening modality, and four were diagnosed with invasive breast cancer. Our findings support the integration of a formal breast screening programs in clinical management of NF1 patients.Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin ( Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system genetic disorder affecting 1 in 3000 individuals worldwide. Causative germline variants in the NF1 tumor suppressor gene are 100% penetrant; however, the wide variable expressivity, rate of progression, and disease severity that exists among NF1 patients makes disease management challenging . The disNF1-associated breast cancers typically arise at a younger age and have the highest incidence in women under 40 years of age; women with NF1 less than 50 years of age have been recently identified to have an up to five-fold increased risk of breast cancer . After aAmong NF1 patients, breast cancer may be difficult to detect by examination or conventional mammography due to the presence of cutaneous neurofibromas, which have been reported to appear as oval/round nodules with well-defined borders on mammogram and may therefore hide the presence of other benign or malignant neoplastic lesions. This can lead to false-positive screening mammography recalls  interferThe increased risk of breast cancer in NF1 has now been reported by numerous groups, including a recent review of the literature which examined 32 published epidemiological studies focused on the potential association of NF1 and increased breast cancer risk ,10,11,12NF1 gene variant followed at the Elisabeth Raab Neurofibromatosis Clinic (ERNC) in the University Health Network (UHN) are offered an HR-OBSP referral. Enrolment into the HR-OBSP is limited to confirmed carriers of pathogenic variants. Consequently, patients with solely a clinical diagnosis and/or no pathogenic NF1 gene variant are not screened through the HR-OBSP. Herein, we report on the uptake and effectiveness of breast screening through the HR-OBSP among women with NF1 to determine the feasibility of routinized high-risk screening in this population.In the province of Ontario, breast cancer screening with annual mammography and breast MRI is facilitated through an organized provincial high-risk screening program called the High-Risk Ontario Breast Screening Program (HR-OBSP). Through the HR-OBSP, high-risk women are assessed through the use of digital mammography and breast MRI  on the same day or within a week of time between tests, providing early detection of breast cancer in high-risk Ontario women . KnowledNF1, six women were excluded from the study because they declined genetic testing and 59 women were excluded because they tested negative for pathogenic variants in NF1. Methods for NF1 germline genetic analysis included Sanger sequencing, multiplex ligation probe amplification, next generation sequencing, and/or RNA sequencing for deep intronic variants.461 unrelated NF1 cases were seen at the ERNC between 2014 and 2018. Among these cases, 245 (53%) were female, 105 (43%) of whom qualified for referral to the HR-OBSP. Of the 140 (57%) women not referred to HR-OBSP, 75 were <30 years of age. As enrolment into the HR-OBSP is limited to patients with a confirmed pathogenic variant in Genetic testing was administered based on the availability of genetic testing technology at the time of diagnosis. Of the 105 women who qualified for HR-OBSP referral, 28 were transferred to an outside same program facility, seven were unable to be reached by the nurse navigator, two declined HR-OBSP enrolment at the time of referral, and one woman was diagnosed with breast cancer prior to HR-OBSP referral. Of the 67 (64%) remaining women, 6/67 (9%) had screens pending at the time of referral, leaving 61/67 (91%) enrolled in HR-OBSP at UHN .A total of 61 women with NF1 ranging from 30 to 67 years of age (median 40) were enrolled in high-risk breast screening through the HR-OBSP from January 2014 to December 2018. A total of 112 screening full-field digital mammography, three supplementary screening with breast ultrasound and 108 supplementary screening with breast magnetic resonance imaging tests were performed during the screening period. Dense breast tissue (American College of Radiology mammographic density C and D) was reported in 71% of patients during baseline screen and moderate or marked background parenchymal enhancement in 59% of patients at the time of the initial breast MRI.A total of 95 imaging findings classified as “typically benign” or “incomplete screening for diagnostic assessment”, were reported during the screening period amongst our cohort of 61 NF1 patients enrolled in the HR-OBSP. 37/95 (39%) of these imaging findings were considered to be actionable. Actionable is defined as an imaging finding that requires further imaging investigations and/or percutaneous breast biopsies. Of the total 95 imaging findings, the majority 70/95 (74%) were described by MRI, 2/95 (2%) by ultrasound and 7/95 (7%) by mammography. The most common imaging finding reported was well-circumscribed cutaneous masses in all imaging modalities. The presence of masses in the fibroglandular breast tissue, with either a solid or cystic nature, were the second more frequent imaging finding reported.Of the 37 actionable imaging findings, 15/37 (41%) findings were further evaluated by percutaneous imaging-guided breast biopsy. There were 10 actionable imaging findings recalled by mammography: one distortion, one mass lesion, four calcifications, three asymmetries and one other. Breast MRI showed 27 actionable imaging findings: eight mass lesions, eight non-mass enhancements, two focus and nine other. The mammography recall rate was 9% (10/112) and the MRI recall rate was 25% (27/108) .Patient screening uptake was evaluated for all female NF1 patients who were referred to the HR-OBSP at UHN and seen by the nurse navigator. Women who completed at least one breast screening test  through the HR-OBSP during the study period were considered primary screen compliant; women who completed more than one breast screening test  through the HR-OBSP during the study period were considered secondary screen compliant . At the NF1 variants: one intragenic deletion, splice site, in-frame deletion and frameshift, respectively  of the 61 women enrolled in screening through the HR-OBSP had at least one first and/or second degree relative with breast cancer. Moreover, 37/61 (61%) women were presumed or confirmed de novo cases of NF1: 22/61 (36%) as familial NF1 and 2/61 (3%) as indeterminate. There was no reported genetic and/or clinical diagnosis of NF1 in any of the first or second-degree relatives diagnosed with breast cancer .Of 60 women who were scheduled at least one breast screen  with the HR-OBSP, 26/60 (43%) rescheduled at least once. Breast MRIs were the most likely to be rescheduled, with a total of 26 rescheduling events across all 60 women who were scheduled for high-risk breast screening, compared to five events for mammograms and seven for breast ultrasounds. Although 19/60 (32%) women rescheduled their MRIs, only 4/19 (21%) rescheduled ≥2 times. 14/19 (74%) women eventually completed their high-risk MRI screen, leaving only 5/19 (26%) who did not complete their rescheduled MRIs at all.NF1 variants are investigated, our understanding of genotype-phenotype correlations in NF1 will improve, and ultimately enhance the clinical management of this patient population. Our study highlights the utility of annual high-risk breast screening in this population of women and underscores a complex need for cross-specialty coordination and benefits of precautionary screening practices in the NF1 patient population. To our knowledge, this the first study of high-risk breast screening uptake in female NF1 patients, and the first to report cases of breast cancer in an Ontario NF1 cohort. Overall, high-risk screen uptake was high, with 95% and 97% of patients completing primary and secondary screens, respectively. Importantly, 100% of women completed recall assessments following abnormal breast imaging and 7% were ultimately diagnosed with breast cancer.This 4-year retrospective chart review investigated the uptake of high-risk breast screening, nature of radiological findings and breast cancer incidence in a cohort of female NF1 patients referred to the High-Risk Ontario Breast Screening Program (HR-OBSP) at a tertiary cancer centre in Ontario (UHN). In the province of Ontario, high risk screening is available through the HR-OBSP and entails yearly mammograms and breast MRIs  which whA total of four invasive breast cancers were detected by breast MRI in our cohort, with none being detected by mammography. This finding is in accordance with a recent study in a Canadian high-risk population  demonstrThe majority (74%) of all radiological findings in our NF1 cohort were detected by breast MRI, which is not surprising considering that the detection sensitivity of MRI is >4-fold higher than mammography , 31]. M. M31]. MBRCA1/2 [Despite the emphasis of previous reports on the importance of breast cancer surveillance and follow-up in women with NF1 ,13,14,34BRCA1/2 ,36,37,38A cross-specialty screening methodology that combines breast MRI, mammogram and ultrasound may represent a feasible strategy to screen women at high risk of breast cancer, specifically NF1 patients. Indeed, when combined with clinical breast examinations (CBE), these three screening modalities were found to yield a sensitivity of 95% compared to 45% for mammography and CBE combined in women at >25% risk of breast cancer . For womNF1. Enrolment of NF1 patients into the HR-OBSP is limited to patients with a confirmed pathogenic variant in NF1. Based on the nature of this study, patients with only a clinical diagnosis of NF1 and/or who tested negative for pathogenic NF1 were excluded. Methods for NF1 germline genetic analysis included Sanger sequencing, multiplex ligation probe amplification, next generation sequencing, and/or RNA sequencing for deep intronic variants. Genetic testing was administered based on the availability of genetic testing technology at the time of diagnosis.Adults with NF1 seen between January 2014 and December 2018 were identified and taken from the ERNC at UHN using the ERNC clinical database. Eligible participants met the following inclusion criteria: (1) female, (2) age 30–69 years, (3) identified pathogenic variant in NF1. Participants were excluded if they (1) have previously undergone bilateral mastectomies, (2) elected to have HR-OBSP screening outside of UHN, (3) had a diagnosis of breast cancer prior to HR-OBSP referral or (4) tested negative for pathogenic variants in A retrospective chart review was undertaken to identify cases of breast cancer in women diagnosed with NF1 seen at the ERNC between January 2014 and December 2018 and evaluate the uptake and utility of high-risk breast cancer screening in this patient population. The following steps were taken: (1) Identify participants: A search of the ERNC database was conducted to identify women who met eligibility criteria. (2) Determine if screening has been completed: A review of the patient’s electronic medical record was conducted, including imaging reports and consultation notes from the UHN HR-OBSP Nurse Navigator (3) Identify cases of breast cancer and examine the utility of high-risk screening: A review of the patient’s electronic record was conducted, including pathology reports, breast imaging reports. A review of individual patient electronic medical records was conducted to collect information regarding patient date of birth, NF1 variant, date of referral for high risk screening, date of consultation with the Nurse Navigator, date of mammogram, and date of breast MRI. The imaging data was assessed using capture BI-RADS Breast Imaging Reporting and Data System  assessmeAlthough our study focused on NF1 patient screening uptake exclusively within the context of a pre-existent government-funded high-risk breast screening program (HR-OBSP), our findings illustrate the potential of a multidisciplinary and regular breast screening program to act as a feasible clinical strategy for cancer surveillance in this underserved patient population. The implications of our findings however, are limited due to our small sample size, exclusion of gene negative NF1 patients, and retrospective design. To shed insight into the long-term sustainability and cost-effectiveness of an integrated screening approach for this unique patient population, we recommend a long-term multi-centre prospective study be conducted to examine high-risk breast screening uptake in a larger cohort of all women diagnosed with NF1.