Introduction
Adjuvant endocrine therapy is the most effective systemic treatment modality for patients with hormone receptor (ER)-positive breast cancer, although many patients experience tumor recurrence during or after completion of endocrine therapy. Identifying factors that can predict disease recurrence early during adjuvant treatment may result in a more tailored strategy for patients likely to be endocrine resistant and may improve their overall outcomes.
Mammographic breast density (MD) is defined by the relative proportion of radiopaque areas, indicating the presence of fibroglandular tissue among the surrounding fatty component of the breast. High MD is associated with increased risk of breast cancer in both Western and Asian women [
1,
2]. The degree of lobular involution is known to have inverse correlation with breast cancer risk as well [
3].
Studies on the efficacy of tamoxifen for chemoprevention of breast cancer in high-risk women have shown that MD is decreased following tamoxifen treatment [
4,
5]. Moreover, 12- to 18-month change in MD was found to be an excellent predictor of response to tamoxifen in the preventive setting [
5]. However, no studies to date have addressed the association between MD reduction and the efficacy of adjuvant endocrine treatment in breast cancer patients. Using quantitative imaging analysis software to assess serial changes in MD, we investigated the association between the degree of MD reduction and long-term breast cancer recurrence in ER-positive breast cancer patients who received adjuvant endocrine therapy.
Discussion
We have shown here that short-term MDR is predictive of long-term outcomes following endocrine therapy in patients with ER-positive breast cancer. Patients who experienced < 5% absolute MDR and those with increased MD after about 1 year of endocrine therapy were at 1.92- and 2.26-fold greater risk of recurrence respectively, than patients with MDR ≥ 10%. This association was also observed when absolute MDR was analyzed as a continuous variable, and when MDRR rather than absolute MDR was assessed.
Regardless of the evolution of anti-estrogen therapy, a substantial proportion of patients with ER-positive breast cancer experience disease recurrence during follow-up. Effective biomarkers are needed to predict endocrine resistance despite ER expression. Many previous investigations have focused on tumor factors associated with endocrine resistance [
6,
7]. The level of MDR resulting from endocrine treatment is a host factor indicating individual susceptibility to endocrine agents. These findings support the hypothesis that host response to adjuvant endocrine therapy may be as important and should be considered in addition to the clinicopathological characteristics of the primary tumor.
Breast density is one of the strongest risk factors for breast cancer development [
8]. A recent study showed that the magnitude of the association of exogenous or endogenous hormone exposure and mammographic density change is related to future risk of breast cancer [
9]. Cuzick
et al. conducted a nested case-control study within the IBIS-I study, a randomized prevention trial of tamoxifen versus placebo to determine the association between tamoxifen-induced density change and breast cancer risk. They showed that the 12- to 18-month change in mammographic breast density is an excellent predictor of tamoxifen efficacy in the preventive setting [
5].
Our findings raise the question of whether treatment strategy should be altered based on change in MD after only one year of endocrine therapy. For the clinical application of individualized therapy, studies are needed to evaluate the ability of shorter-term changes in MD, such as after < 6 months, to predict risk of recurrence, and new treatment strategies also should be tested according to the predicted result.
We also found that factors such as age < 50 years, high preoperative MD, and long interval between the start of endocrine therapy and the second mammogram were significantly associated with high MDR, indicating that a dense breast per se is not a sign of endocrine resistance, and that MD decreases more with prolonged endocrine treatment.
Although MDR was greater in patients < 50 years of age than in those aged ≥ 50 years, the degree of MDR was not associated with recurrence in younger patients. The reason for this is not clear, although it may be due to the complicated hormonal milieu and factors other than endocrine therapy affecting breast density in younger women. The relatively small number of events in patients aged < 50 years (43/680, 7.1%) in our dataset could have affected the statistical significance and further evaluation within a larger dataset is required.
The degree of MDR may differ according to the type of endocrine therapy. Tamoxifen was reported to be associated with an 8% mean absolute reduction in breast density at 1.5 years and a reduction of 14% after 4.5 years [
10,
11]. Raloxifene has been reported to decrease absolute breast density by 1.5% per year [
12]. In a small study involving 54 patients, adjuvant anastrozole had no effect on breast density in the contralateral breast after 6 months and resulted in a 16% relative reduction (
P = 0.08) after 12 months [
13]. Letrozole and exemestane also did not reduce mammographic breast density [
14]. Addition of an aromatase inhibitor to hormone replacement therapy resulted in a significant reduction in breast density [
1]. In a univariate analysis we found that tamoxifen treatment was associated with a higher MDR than treatment with aromatase inhibitors (
P < 0.001). However, an association between MDR and recurrence-free survival was observed in our aromatase inhibitor group.
There is no definite evidence-based mechanism for an association between anti-estrogen therapy, reduced breast density and a better outcome. With aromatase inhibitors, it is possible that reduced density reflects effective circulating estrogen deprivation, and as a result, also affects micro-metastases. Another explanation is the difference in the drug metabolism efficiency of the host. Patients with adequate serum drug concentrations should have a better response and outcome. However, the metabolic mechanism of tamoxifen and aromatase inhibitors must be different. Adherence to a prescribed drug can partly explain the correlation between density change and patient outcome. In premenopausal and perimenopausal women, a good chemotherapy response could cause chemotherapy-induced ovarian failure, and as a result, could reduce breast density and improve disease-free survival. It is unknown, but is less likely that tumor-associated fibroblasts or other stromal cells in the breast might directly affect distant micro-metastatic cancer cells.
We also found that 17.8% of our study subjects had increased MD after endocrine therapy. Similarly, in the preventive tamoxifen study IBIS-1, 11% of patients treated with tamoxifen and 24% given placebo had an increased MD. The mechanism of this increase in MD is unknown. Investigations are needed to determine whether in these women, tamoxifen acts as an estrogen agonist in the breast.
The reproducibility of MD measurement is important, and studies indicate good intraobserver reproducibility with correlation coefficients of 0.92 to 0.96 [
15]. We used Cumulus software, which has been the most widely used for MD measurements in previous studies. Using digital mammographic images, we found that the Pearson correlation coefficient was 0.93.
The major limitation of the study was the absence of data on factors that may be closely associated with breast density, such as body mass index. Because this study was retrospective in design, the timing of follow-up mammography was not uniform, varying from 8 to 20 months after initiation of endocrine therapy. Another limitation was that the study subjects received heterogeneous adjuvant therapy regimens. We also could not determine the degree of ER expression in tumors, a potential major factor affecting resistance to endocrine treatment.
To our knowledge, this study was the first to assess the value of MD change as a predictive surrogate in breast cancer patients receiving adjuvant endocrine therapy. The positive result we obtained warrants larger-scale prospective studies. Basic research to identify the molecular pathways related to endocrine resistance and mammographic density is also needed.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All the authors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. HRK, JMC, NC, and WKM carried out analysis of the imaging profiles of each patient including the Cumulus density measurement. SWH, SAI, and TYK confirmed patients' outcomes of recurrence and the adequacy of endocrine therapy. SKA, HCS, and JMY directly participated in the whole process throughout the research and statistical analysis. HGM and DYN participated in the study design and helped to draft the manuscript. JK measured the percent mammographic density and performed the research. As corresponding author, WSH designed and coordinated the research and provided close guidance throughout the process. All authors read and approved the final manuscript. The authors have been involved in drafting the manuscript or revising it critically for important intellectual content and have all given final approval of the version to be published.