Association of the Interaction Between Mammographic Breast Density, Body Mass Index, and Menopausal Status With Breast Cancer Risk Among Korean Women

Key Points Question Is the interaction between mammographic breast density and overweight or obesity associated with breast cancer risk, and if so, does any association vary according to menopausal status? Findings In a cohort study of 3 248 941 premenopausal and 4 373 473 postmenopausal women aged 40 years or older screened for breast cancer, a positive additive interaction between high breast density and high body mass index was associated with an increased risk of breast cancer, especially among women in the postmenopausal period. Meaning This study suggests that women with overweight or obesity and dense breast tissue might benefit from tailored breast cancer screening strategies; these 2 factors should be incorporated into risk stratification in population-based breast cancer screening.


Introduction
Female breast cancer is the most commonly diagnosed cancer, accounting for 11.7% of all new cases of cancer in 2020. 1 Of the various risk factors for breast cancer, dense breast tissue has become an important issue, with a strong association between dense breast tissue and increased breast cancer risk regardless of menopausal status. 2,3 Meanwhile, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) appears to have the opposite association with breast cancer risk according to menopausal status. A high BMI had no association or was associated with a reduced breast cancer risk, 4 whereas increased adiposity was positively associated with increased postmenopausal breast cancer. 5 Although dense breast tissue and obesity were individually proven to be strong risk factors for breast cancer, controversy exists regarding the magnitude of the combined associations of these 2 factors with breast cancer risk, in addition to heterogeneity of the associations according to menopausal status. [6][7][8][9] In particular, whether the combined association of breast density and BMI with breast cancer risk varies according to menopausal status has yet to be comprehensively examined, to our knowledge. Some findings suggest that women with overweight or obesity and dense breast tissue may have a high risk of breast cancer regardless of menopausal status. [10][11][12] However, 1 pooled analysis from 4 case-control studies reported minimal modification by BMI of the associations of breast density with breast cancer risk. 13 Mammographic breast density and BMI could be measured during health examinations, and evaluating their joint associations could provide information on future breast cancer risk during screening and consequently help identify women at an elevated risk of breast cancer. Thus, this study aimed to explore the interaction of breast density and BMI and risk of breast cancer according to menopausal status.

Study Design and Population
carcinoma in situ (D05.0-D05.9), in combination with the catastrophic illness code. 15 Screening results and questionnaire data were transferred to the NHIS database after obtaining written informed consent from the women. Our study was approved by the institutional review board of the Hanyang University College of Medicine. In addition, permission to use the NHIS database was approved by the National Health Insurance Sharing Service system, and deidentified data were available to the researchers. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We used data of women who underwent mammography screening between January 1, 2009, and December 31, 2013. Information on breast cancer incidence was followed up until December 31, 2018. When a woman underwent mammographic screening more than once, information on the first screening was used. Among 8 116 653 women who underwent screening for breast cancer between 2009 and 2013, those who underwent screening at younger than 40 years of age, those with any cancer history before the date of mammographic screening, or those with missing information on menopausal status, BMI, or breast density were excluded. In addition, participants who received a diagnosis of any type of cancer or died within 180 days after breast cancer screening were excluded to prevent possible inclusion of prevalent cancer cases; the remaining 7 622 414 women were

Measurement of Mammographic Breast Density
Mammographic breast density was evaluated using the Breast Imaging Reporting and Data System (BI-RADS) classification of the American College of Radiology. The BI-RADS breast density was read by the radiologist at each screening center. The BI-RADS classification has been used to categorize breast density in the Korean National Cancer Screening Program since 2009. The BI-RADS mammographic breast density comprises 4 categories: 1 indicates almost entirely fat, 2 indicates scattered fibroglandular densities, 3 indicates heterogeneously dense tissue, and 4 indicates extremely dense tissue.

Measurement of BMI
During health examinations, height and weight were measured by trained nurses and used to calculate BMI. This study used the BMI cutoff points according to the World Health Organization Asia-Pacific classification. 16 Body mass index was categorized into the following 4 groups: underweight (<18.5), normal weight (18.5 to <23.0), overweight (23.0 to <27.5), and obese (Ն27.5).

Measurement of Other Covariates
Information on other covariates was collected using standardized questionnaires during health examination and cancer screening. The questionnaires were distributed by nurses and self-reported by participants. The questionnaires measured information regarding health behaviors, including drinking, smoking, physical activity, family history of cancer and other major chronic diseases, and the reproductive physiological processes of all of the participants. In our analysis, we considered the following factors as covariates: participants' age at screening, history of smoking, number of days of alcohol consumption per week, family history of breast cancer among first-degree relatives, history of benign breast disease, age at menarche, number of children, duration of breastfeeding, history of breastfeeding, use of oral contraceptives, and history of hormone replacement therapy.

Statistical Analysis
Statistical analysis was performed from June 1 to July 15, 2021. The study end point was the development of breast cancer. The association among BMI levels, BI-RADS breast density categories, and breast cancer risk was presented in terms of relative risks (RRs) using Poisson regression models, considering the rare events of breast cancer. The associations between BMI and breast cancer risk according to BI-RADS density classification and between BI-RADS density classification and breast cancer risk according to BMI were also evaluated. In addition, the combined associations of BMI and the BI-RADS density classification with breast cancer risk were presented using a Poisson regression model. All analyses were stratified by menopausal status and adjusted for the covariates as mentioned.
The interactions between breast density classification and BMI on the additive and multiplicative scales were examined in association with breast cancer risk. The additive interactions were assessed using relative excess risk due to interaction (RERI), which was computed as RERI RR = RR 11 − RR 10 − RR 01 + 1. An RERI value of 0 indicated no additive interaction, a positive value indicated a super-additive or positive interaction, and a negative value indicated a subadditive (negative) interaction. The multiplicative interactions were assessed using the ratio of RRs: RR 11 /(RR 10 × RR 01 ). A multiplicative interaction value of more than 1 indicated a positive interaction, while a multiplicative interaction value of less than 1 indicated a negative interaction. 17 Additive interaction is present when the combined association of BMI and breast density is larger than the sum of the individual associations. Multiplicative interaction was estimated to evaluate whether the combined association of BMI and breast density with breast cancer risk was larger than the product estimated association of BMI alone and breast density alone. 17 A 2-sided P < .05 was considered statistically significant. The analyses were performed using SAS, version 9.4 (SAS Institute Inc).

Associations of BMI With Breast Cancer Risk According to Breast Density
Among premenopausal women, no significant association between BMI and the risk of breast cancer was found in any of the BI-RADS categories after adjusting for other covariates (Figure 3; eTable 3 in the Supplement). However, among postmenopausal women, a high BMI was associated with a subsequent increased risk of breast cancer in total and across all breast density categories after adjusting for other potential confounders. Among postmenopausal women in BI-RADS category 1, those with obesity had a 2.45-fold (95% CI, 1.87-3.21) increased risk of breast cancer relative to women in the underweight category. Among postmenopausal women in high BI-RADS categories, a high level of obesity was associated with an increased risk of breast cancer compared with being underweight; however, the strength of the association was low among women with high breast density.

Combined Associations of Breast Density and BMI With Breast Cancer Risk
Among premenopausal women, those in BI-RADS categories 1 and 2 did not show significant associations with breast cancer risk, irrespective of obesity status, compared with those in BI-RADS category 1 who were in the underweight category (

Discussion
This population-based cohort study found that breast density was independently associated with breast cancer risk for premenopausal and postmenopausal women; however, obesity was associated with breast cancer risk only for postmenopausal women. Considering the combined associations of breast density and obesity, women with obesity in BI-RADS category 4 showed the highest risk of breast cancer among both premenopausal and postmenopausal women, which was 2-fold higher for premenopausal women and 6-fold higher for postmenopausal women than that for women in BI-RADS category 1 who were in the underweight category. A positive synergistic association in terms of additive interaction was suggested in both groups, especially for postmenopausal women. This study confirmed the association between dense breast tissue and increased breast cancer risk previously found in other populations 2,8,18 and for Korean women. 3,19 Although increased adiposity was not associated with premenopausal breast cancer risk, it showed a strong association with an increased risk of postmenopausal breast cancer, which was also found in our study. 20,21 Previous studies on the interactive associations between breast density and BMI with breast cancer risk provide mixed evidence. A case-control study found that women with a breast density of 76% to 100% had a 5-fold higher risk of breast cancer than those with a breast density of 0% to 10%; moreover, breast density had a significant multiplicative interaction with BMI. 22 Other case-control studies in the US 12 and Japan 23 also reported that breast density was associated with an increased risk of premenopausal and postmenopausal breast cancers, and the association was strong in women with overweight or obesity, showing a multiplicative interaction. In contrast, no multiplicative interaction association between breast density and BMI with breast cancer risk was reported in a pooled analysis of 4 case-control studies 6 and a study on postmenopausal women from the Nurses' Health Study. 8 A recent nested case-control study reported that the combination of overweight or obesity and elevated breast density was associated with a higher risk of premenopausal breast cancer. 9 In particular, a high association was found with estrogen receptor-negative subtypes (odds ratio, 2.17; 95% CI, 1.50-3.16); however, no interactions between breast density and BMI were

Strengths and Limitations
This study has some strengths, including its large national cohort design and prospective ascertainment of breast cancer development. Most previous studies have investigated the interaction between BMI and breast density using a multiplicative approach. However, considering that additive interactions would be relevant for assessing the public health effect of an interaction, 17 the positive additive interaction for both premenopausal and postmenopausal women found in our study might be informative. To our knowledge, this study is the first to comprehensively investigate the combined association of breast density and BMI with breast cancer risk among women in Asian countries based on population-based breast screening settings, considering both additive and multiplicative interactions. Thus, this study provides evidence from real-world data on breast cancer risk, and the findings are generalizable to East Asian women, who tend to have a higher breast density than Western women. 29 In addition, given the consistent findings from this study with previous studies conducted in Western countries, 9,12 our results could also be applied to Western populations of women with increasing obesity.
This study also has some limitations. It included a population of women aged 40 years or older, which prevented us from examining breast cancer risk in younger groups. Furthermore, breast density was subjectively interpreted. Although the BI-RADS classification has been widely used for breast density classification, the results might vary depending on the ability and experience of

Conclusions
This study found that elevated breast density and having overweight or obesity are independently associated with an increased risk of breast cancer and interact synergistically to augment breast cancer risk for both premenopausal and postmenopausal women in terms of additive interactions. In addition, strong multiplicative interaction associations of BMI and breast density with breast cancer risk were found for postmenopausal women. Recent work suggests that notification of breast density should be combined with breast cancer risk to identify women at the highest risk so that they can undergo supplemental imaging screening and engage in discussions with their health care professionals. 34,35 Our findings suggest that breast density notification should be provided not as a stand-alone risk factor but as an adjunct factor with BMI for risk stratification in population-based mammographic screening settings for public health significance.