Patient reluctance toward tamoxifen use for breast cancer primary prevention

Background: The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamoxifen reduces the incidence of new breast cancers by 49% in women at increased risk for breast cancer development. Tamoxifen does have side effects, however, including marginally increased risks of endometrial cancer and thromboembolic events. In this study, women at increased risk for breast cancer development were offered tamoxifen. Their knowledge of tamoxifen as a chemopreventive agent was assessed, and factors influencing their acceptance of tamoxifen and willingness to take it were determined.Methods: Forty-three patients were identified who qualified to take tamoxifen for primary prevention. Patients qualified by having at least a 1.7% 5-year risk of developing breast cancer, the criteria for entry into the NSABP P-1 trial. Patients initially completed questionnaires designed to assess their knowledge of tamoxifen and its associated risks and benefits. Patients were then provided neutral educational sessions and literature delineating the actual risks and benefits of tamoxifen. Subsequently, patients decisions regarding taking tamoxifen were reassessed.Results: Mean patient age was 52.8 years, with a range of 39 to 74 years. Ten patients (23.2%) qualified based on the presence of lobular carcinoma in situ (LCIS), seven patients (16.3%) qualified based on increased risk secondary to age >60 years, and 26 patients (60.5%) age range 35 to 59 qualified based on risk profiles demonstrating significantly increased risk. Of the total 43 patients, two (4.7%) elected to start taking tamoxifen. Fifteen patients (34.8%) declined immediately, and 26 patients (60.5%) were undecided initially but ultimately declined. Educational sessions did not influence patients decisions. Fear of side effects, including endometrial cancer, thromboembolic events, and menopausal symptoms, was the most commonly cited reason for declining to take tamoxifen.Conclusions: In this study, the vast majority of patients at increased risk for breast cancer perceived that the risks of taking tamoxifen outweighed the benefits and declined to take it.Presented at 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16–19, 2010434_2001_Article_580.     

Adjuvant endocrine therapies for postmenopausal women with early breast cancer: standards and not

Hormonal manipulations have been used for more than 100 years for the treatment of metastatic breast cancer and after definition of the concept of micro-metastases also in the adjuvant setting. In the postmenopausal population, tamoxifen has played the most important role for almost four decades. Progestins or the first generation of aromatase inhibitors (AIs) were only marginally used in the adjuvant setting due to their prohibitive toxicity. The new generation of anti-estrogen compounds, the selective estrogen receptor down-regulators (SERDs) like fulvestrant have a higher affinity for the estrogen receptor than tamoxifen, but none of its agonist activities, and have shown promising clinical activity in the treatment of advanced breast cancer. The third generation of AIs investigated in six large trials has been reported to be superior to tamoxifen in terms of disease-free survival, but not in terms of survival. These trials will be discussed in terms of results in different subpopulations and of toxicity.     

The impact of tamoxifen brand switch on side effects and patient compliance in hormone receptor positive breast cancer patients

BackgroundIn 2006 Nolvadex was discontinued and replaced by a variety of alternative generic tamoxifen brands for the adjuvant treatment of breast cancer. Anecdotally, patients are switching brands and taking alternative medications to reduce treatment related symptoms. Nevertheless, more severe side effects may equate to better relapse prevention. This study evaluates generic tamoxifen adherence and its correlation with side effects and brand switch.MethodsConsecutive disease free ER positive patients (stage I–III) were invited to respond to a questionnaire. 165 of 327 questionnaires were returned (50% response). Pearson's Chi Square test was used for data analysis.Results63 patients (38%) reported a switch between generic tamoxifen. 59% of all patients experienced side effects associated with tamoxifen treatment of which 53% were severe. Patients experiencing differential symptoms dependent on tamoxifen brand reported more severe side effects (p = 0.02). Non-prescribed supplements were taken by 42% of all patients with no significant improvement in climacteric symptoms (p = 0.05). The concomitant use of SSRIs appeared to have no effect on symptoms. A significant number of patients considered discontinuing tamoxifen because of the side effects (p = 0.001), yet this did not translate into discontinuation or non-adherence (p = 0.8 and 0.08 respectively).ConclusionSevere tamoxifen side effects are commonly experienced by breast cancer patients and can be significantly altered by change in tamoxifen brand.Most patients will continue to take tamoxifen, despite side effects to avoid cancer relapse. Supplementation and antidepressants did not improve tamoxifen related side effects in our cohort.     

The effect of high dehydroepiandrosterone sulfate levels on tamoxifen blockade and breast cancer progression

BACKGROUND: We investigated the stimulatory potential of dehydroepiandrosterone sulfate (DHEA-S) on tamoxifen-treated cells and assessed its effect on cancer progression in the adjuvant setting. METHODS: Mean serial serum levels of sex hormones from 44 patients receiving tamoxifen were correlated with follow-up status. T-47D (ER+/PR+) and HCC1937 (ER-/PR-) breast cancer cells were pretreated with 100 microM anastrozole, with or without tamoxifen, and stimulated with 22.8 microM DHEA-S. Rapid colorimetric assays allowed calculation of growth percent change. RESULTS: Clinically, development of metastatic disease correlated only with > or =90 microg/dL DHEA-S (P = 0.005). In vitro, T-47D cells stimulated with DHEA-S after anastrozole showed 35% increased growth. Addition of 0.01 nM tamoxifen demonstrated -7% inhibition. Increasing the DHEA-S/tamoxifen ratio reversed suppression to +25%. CONCLUSIONS: DHEA-S > or =90 microg/dL is a risk factor for recurrence in the adjuvant setting. In vitro, although tamoxifen inhibits cell growth at high doses it can be circumvented by DHEA-S. These results indicate that DHEA-S contributes to tamoxifen resistance and disease progression.     

Pterostilbene and tamoxifen show an additive effect against breast cancer in vitro

Background

Tamoxifen is widely used for the treatment of breast cancer. Pterostilbene, a bioavailable stilbenoid found in blueberries, has been found to inhibit breast cancer growth in vitro. It was hypothesized that combining pterostilbene with tamoxifen would produce additive effects on estrogen receptor-positive breast cancer cells.

Methods

Two estrogen receptor-positive breast cancer cell lines, MCF7 and ZR-751, were pretreated with graduated doses of pterostilbene for 24 hours, followed by 5 μmol/L tamoxifen. MTT proliferation assays and Cell Death Detection ELISA^PLUS tests evaluated cell viability and apoptosis.

Results

MCF7 cells showed inhibition (10 and 20 μmol/L, P < .001; 30 μmol/L, P < .05) at all time points when combined with tamoxifen. ZR-751 cells showed additive reductions in cell viability (P < .001). Cell Death Detection ELISA^PLUS indicated increased apoptosis (P < .01).

Conclusions

Pterostilbene shows an additive inhibitory effect on breast cancer cells when combined with tamoxifen, most likely from augmented cancer cell apoptosis.     

Evaluation of endometrial thickness in hormone receptor positive early stage breast cancer postmenopausal women switching from adjuvant tamoxifen treatment to anastrozole

Evaluation of endometrial thickness by transvaginal ultrasonography (TVUS) in postmenopausal estrogen receptor positive breast cancer patients treated with anastrozole after tamoxifen therapy. This study included 70 postmenopausal estrogen receptor positive breast cancer patients who switched to anastrozole after tamoxifen; patients had endometrial thickness >4 mm and no endometrial malignancy. Endometrial thickness was measured after anastrozole treatment. Endometrial thickness during anastrozole therapy was lower than after tamoxifen therapy (p < 0.001); the mean reduction in endometrial thickness was 4.5 mm (±3.0). Cystic endometrial appearance was more frequent in patients under tamoxifen than in those under anastrozole (p < 0.001). Duration of tamoxifen therapy was not correlated to the endometrial thickness at the time of its suspension. Duration of tamoxifen therapy and endometrial thickness at the time of tamoxifen suspension was correlated to the relative reduction of endometrial thickness during anastrozole therapy. Anastrozole reverses tamoxifen-induced increased endometrial thickness and sonographic endometrial cystic appearance.     

The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival

Background

The goal of this study was to compare the characteristics of breast cancers and survival rates in HRT users versus nonusers.

Methods

Data were analyzed for 1055 patients ≥50 years of age who had definitive therapy for breast cancer from 1994 through 2002.

Results

There were 471 (45%) HRT users. The median age at diagnosis was 61.0 years for HRT users and 68.0 years for HRT nonusers (P < .001). HRT users more often had tumors that were <1 cm (P = .007), node negative (P = .033), and grade I (P = .016). HRT users had a decreased risk of death versus nonusers (hazard ratio = .438, 95% confidence limit = .263 to .729, P = .002).

Conclusions

HRT users developed breast cancer at a younger age than nonusers; HRT use was associated with the development of biologically more favorable cancers than those that developed in nonusers; and overall and disease-free survival rates were higher in HRT users than nonusers.     

Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype

BackgroundCYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM).Patients and methodsComprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg).ResultsEleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively).ConclusionIn CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype.     

Personalized prevention in high risk individuals: Managing hormones and beyond

Increasing numbers of women are being identified at ‘high-risk’ of breast cancer, defined by The National Institute of Health and Care Excellence (NICE) as a 10-year risk of ≥8%. Classically women have been so identified through family history based risk algorithms or genetic testing of high-risk genes. Recent research has shown that assessment of mammographic density and single nucleotide polymorphisms (SNPs), when combined with established risk factors, trebles the number of women reaching the high risk threshold. The options for risk reduction in such women include endocrine chemoprevention with the selective estrogen receptor modulators tamoxifen and raloxifene or the aromatase inhibitors anastrozole or exemestane. NICE recommends offering anastrozole to postmenopausal women at high-risk of breast cancer as cost effectiveness analysis showed this to be cost saving to the National Health Service. Overall uptake to chemoprevention has been disappointingly low but this may improve with the improved efficacy of aromatase inhibitors, particularly the lack of toxicity to the endometrium and thrombogenic risks. Novel approaches to chemoprevention under investigation include lower dose and topical tamoxifen, denosumab, anti-progestins and metformin.Although oophorectomy is usually only recommended to women at increased risk of ovarian cancer it has been shown in numerous studies to reduce breast cancer risks in the general population and in those with mutations in BRCA1/2. However, recent evidence from studies that have confined analysis to true prospective follow up have cast doubt on the efficacy of oophorectomy to reduce breast cancer risk in BRCA1 mutation carriers, at least in the short-term.     

Axial BMD, change in BMD and bone turnover do not predict breast cancer incidence in early postmenopausal women

Previous studies have indicated a relationship between bone mineral density and the incidence of breast cancer in middle-aged and elderly women, with women with higher BMD being at significant increased risk. We investigated whether there was such a relationship in younger women who were perimenopausal or in their early postmenopausal years. As part of a population-screening program for osteoporosis, 5,119 women aged between 45 and 54 years were scanned between 1990–1994 at the Osteoporosis Research Unit. In 1997–2001, 3,884 returned for follow-up scans and questionnaires, and 3,144 returned a postal questionnaire in 2002. All cases of incident breast cancer were noted. One hundred sixty-six women indicated that they had suffered from breast cancer, of which 87 were incident cases (59 had prevalent breast cancer at baseline and 20 had benign or unconfirmed diagnosis and were excluded because of the use of agents that may interfere with BMD, e.g., tamoxifen). We compared therefore the incident breast cancer group (BC group; n =87) with a control group (C group; n =3,013). There were no significant differences using a t -test between the BC group and C group for baseline DXA of the spine or femoral neck. Further changes in BMD over a mean period of 6.9 years demonstrated no significant hazard ratio for the lumbar spine or femoral neck. No relationship was seen between the bone turnover markers pyridinoline/creatinine or deoxypyridinoline/creatinine assessed at their second study visit and incidence of breast cancer. In conclusion, in perimenopausal or early postmenopausal women there is no relationship between the incidence of breast cancer and BMD, change in BMD or bone turnover.     

microRNAs在乳腺癌及乳腺癌干细胞中的研究进展

microRNAs在乳腺癌形成和发展中发挥着重要的作用,其可能扮演着原癌基因、抑癌基因、肿瘤转移侵袭、凋亡、耐药调节者等角色。此外,越来越多的证据表明,miRNAs参与乳腺癌干细胞的增生、自我更新、分化及肿瘤形成。本文分别综述了microRNAs和乳腺癌、乳腺癌干细胞之间的关系及其用于肿瘤治疗的研究进展。     

Goserelin plus tamoxifen compared to chemotherapy followed by tamoxifen in premenopausal patients with early stage-, lymph node-negative breast cancer of luminal A subtype

ObjectivesTo study the outcomes of adjuvant goserelin combined with tamoxifen (GosTam) compared to chemotherapy followed by tamoxifen (ChemTam) in premenopausal patients with early stage, luminal A breast cancer.MethodsFrom 2008 until 2013, data were retrospectively collected for premenopausal patients who underwent surgery for invasive tumors that were ≤2.0 cm, node-negative, strongly positive for estrogen and progesterone receptors, HER-2-negative, and Ki-67 < 25%. The patients were divided into two groups according to adjuvant regimen, either GosTam or ChemTam. All patients who underwent different adjuvant regimens were excluded.ResultsIn total, 235 patients underwent GosTam and 171 patients underwent ChemTam. There were significantly more patients younger than 40 years in the GosTam group (32% GosTam vs. 22% ChemTam, p = 0.031). Mean tumor size was significantly smaller (1.19 cm vs. 1.48 cm, p < 0.001), Ki-67 significantly lower (p = 0.049), and nuclear grade was low in a significant number of patients in the GosTam group (2% vs. 13%, p < 0.001). After a median follow-up of 51.3 months, there was no mortality in either group. There was no significant difference in 5-year disease-free survival (DFS) between the two groups even after univariate analysis considering age, tumor size, nuclear grade, and P53% (GosTam = 98.9% vs. ChemTam = 95.7%, HR = 0.404, 95% CI = [0.073, 2.222], p = 0.248).ConclusionThere was no difference between treatment groups, and neither chemotherapy nor ovarian suppression seemed to improve the outcome. Thus, tamoxifen alone might be a sufficient option for this low-risk patient population.     

Hormone replacement therapy and breast cancer risk in California

Numerous studies have documented increased breast cancer risks with hormone replacement therapy (HRT), but these do not give a woman her specific absolute risk for the remainder of her life. This article estimates the magnitude of the effect of HRT on breast cancer incidence in California and calculates a woman's cumulative risk of breast cancer with different formulations and durations of HRT use. The effects of HRT on the underlying breast cancer incidence were estimated using the attributable fraction method, applying HRT prevalence data from the 2001 California Health Interview Survey and published rates of higher relative risk (RR) from HRT use from the Women's Health Initiative (WHI) study and Million Women's Survey (MWS). The annual number of breast cancers potentially attributable to HRT in California was estimated, along with individual cumulative risk of breast cancer for various ages to 79 years according to HRT use, duration, and formulation. Using the WHI data, 829 of 19,000 breast cancers (4.3%) in California may be attributable to HRT. This figure increases to 3401 (17.4%) when the MWS RRs are applied. Use of estrogen-only HRT or short-term (approximately 5 years) use of combined HRT has a minimal effect on the cumulative risk calculated to the age of 79 years; application of the MWS data to a Californian woman commencing HRT at the age of 50 years (no HRT, 8.5%; estrogen only, 8.6%; combined, 9.1%). Prolonged (approximately 10 years) use of combined HRT increases the cumulative risk to 10.3%. This article demonstrates that HRT will generate a small additional risk of breast cancer in an individual. The reduction in perimenopausal symptoms may be considered sufficient to warrant this extra risk. However, this view needs to be balanced because the small increases in individual risk will be magnified, producing a noticeable change in population cancer caseload where HRT use is high.     

The impact of medication side effects on adherence and persistence to hormone therapy in breast cancer survivors: A quantitative systematic review

BackgroundHormone Therapy (HT) is recommended for most women with HR-positive primary breast cancer. When taken as intended, HT reduces breast cancer recurrence by 40% and mortality by one-third. The recommended duration of treatment ranges from 5 to 10 years depending on risk of recurrence and the specific HT regimen. However, recent data indicates that rates of HT non-adherence are high and research suggests this may be due to the impact of HT side effects. The contribution of side effects to non-adherence and non-persistence behaviours has rarely been systematically explored, thereby hindering the implementation of targeted intervention strategies. Our aim is to identify, evaluate and summarise the relationship between HT side effects and patterns of adherence and persistence.MethodsElectronic searches were conducted from inception and were completed by September 2021, utilising Cochrane CENTRAL, Medline, Embase, Web of Science and PsycINFO databases. Searches included a combination of terms related to breast cancer, adherence, hormone therapy and side effects.ResultsSixty-two eligible papers were identified and study quality varied by study type. Most observational and cross-sectional studies were rated good quality, whereas most controlled intervention studies were rated fair quality. Three studies were rated poor quality. The most frequently measured side effects were pain, low mood, hot flashes, insomnia, anxiety, fatigue, weight gain, concentration/memory problems.ConclusionsThis review identified a lack of consistency in the measurement of adherence and the definition of persistence across studies. The instruments used to measure side effects also varied significantly. This variation and lack of consistency makes it difficult to evaluate and summarise the role of HT side effects in HT adherence and persistence behaviour.     

Prognostic and predictive value of TFF1 for adjuvant endocrine therapy in Chinese women with early ER positive breast cancer: Comparing aromatase inhibitors with tamoxifen

Factors that predict in favor of an aromatase inhibitors (AIs) over tamoxifen (TAM) in estrogen receptor (ER) breast cancer remains to be identified. We compared progesterone receptor (PR) and trefoil factor 1 (TTF1) status (+ve versus −ve) as predictive of superior effect of AI’s over tamoxifen among a total of 1973 Chinese women with early ER+ breast cancer. The expression of TFF1 was independently associated with ER and PR. However, there was no correlation with TFF1 and HER-2 expression. Treatment effect was more pronounced in the ER+/TFF1+ postmenopausal patients with a hazard ratio favoring AIs (HR = 0.397, 95%CI 0.183-0.860), but not in the PR positive cohorts (HR = 0.466, 95%CI 0.186-1.164). We suggested that AIs was better than TAM especially in the postmenopausal patients with ER+/TFF1+ breast cancer; however the clinical application of this observation still requires further prospective studies.     

Effects of tamoxifen and aromatase inhibitors on the risk of acute coronary syndrome in elderly breast cancer patients: An analysis of nationwide data

BackgroundAromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen.MethodsWe analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE.ResultsWe included 47,569 women for the final analysis. Patients were classified into ‘No hormonal treatment (n = 18,807), ‘Switch (n = 2097)’, ‘Tamoxifen (n = 7081)’ and ‘AI (n = 19,584)’. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74–0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84–1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47–0.84).ConclusionsOur results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE.     

Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer

Breast cancer growth is regulated by steroid hormones and by polypeptide hormones and growth factors. Endocrine therapies for breast cancer have been designed to interrupt estrogen signaling by either blocking its receptor (ER) or by lowering the amount of estrogen available in the cell for binding. These therapies are very effective in many patients but de novo and acquired resistance are common. Growing evidence suggests that cross-talk between ER and growth factor receptor pathways contributes to the development of this resistance. Signaling via the EGF receptor and HER-2/neu can activate both ER and the important ER coactivator AIB1. In turn, ER located in the cell membrane can activate the growth factor receptor pathways. Breast tumors with high levels of AIB1 and HER-2 may be resistant to tamoxifen because of an increase in its estrogen agonist activity.     

Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up

BACKGROUND: We previously reported that breast cancer patients who used hormone replacement therapy (HRT) had significantly lower stage tumors and higher survival than never-users. We present an update with longer follow-up, HRT use data, and in vitro research. METHODS: Our database of 292 postmenopausal breast cancer patients was updated to include HRT type, duration, and disease status. In vitro effects of estrogen (E) and/or medroxyprogesterone (MPA) on breast cancer cell growth were measured. RESULTS: Tumor prognostic factors were better and survival rates higher for both E and combination HRT users of any duration. Use greater than 10 years correlated with node-negative disease, mammographically detected tumors, and 100% survival. E supported minimal proliferation; MPA induced cell death; E+MPA results were similar to E alone. CONCLUSIONS: HRT users, regardless of type or duration of HRT use, continued to have higher survival rates. In vitro results supported the clinical finding that outcomes for users of E and E+MPA were similar.     

Family history of breast cancer,mammographic breast density and breast cancer risk: Findings from a cohort study of Korean women

BackgroundThis study investigated whether the association between family history of breast cancer in first-degree relatives and breast cancer risk varies by breast density.MethodsWomen aged 40 years and older who underwent screening between 2009 and 2010 were followed up until 2020. Family history was assessed using a self-reported questionnaire. Using Breast Imaging Reporting and Data System (BI-RADS), breast density was categorized into dense breast (heterogeneously or extremely dense) and non-dense breast (almost entirely fatty or scattered areas of fibro-glandular). Cox regression model was used to assess the association between family history and breast cancer risk.ResultsOf the 4,835,507 women, 79,153 (1.6%) reported having a family history of breast cancer and 77,238 women developed breast cancer. Family history led to an increase in the 5-year cumulative incidence in women with dense- and non-dense breasts. Results from the regression model with and without adjustment for breast density yielded similar HRs in all age groups, suggesting that breast density did not modify the association between family history and breast cancer. After adjusting for breast density and other factors, family history of breast cancer was associated with an increased risk of breast cancer in all three age groups (age 40–49 years: aHR 1.96, 95% confidence interval [CI] 1.85–2.08; age 50–64 years: aHR 1.70, 95% CI 1.58–1.82, and age ≥65 years: aHR 1.95, 95% CI 1.78–2.14).ConclusionFamily history of breast cancer and breast density are independently associated with breast cancer. Both factors should be carefully considered in future risk prediction models of breast cancer.