The most striking results in our prospective study to understand global breast stiffness in normal and high risk patients, is the significantly higher stiffness of breast tissue in the high-risk (prior breast cancer history or high risk based on lifetime risk of greater than 20%) dense breasted patients compared to the normal risk dense breasted patients. Patients that had prior unilateral post-operative and/or post-treatment related radtaion change did not show a significant difference in MRE parameters between the treated and untreated breast. Our study suggests that the structurally-based (tissue stiffness) risk information obtained from MRE could be used to identify the subset of women with dense breasts most likely to benefit from increased surveillance and serve as a prognostic biomarker in screening breast cancer patients. These differences in stiffness were also seen between high risk and normal risk patients with non-dense breasts, although is less clinically significant as the performance of screening mammography is better in non-dense breasts.
Through translational studies27,28, one biologic explanation for the increased risk of breast cancer in dense breasted patients suggests that increased collagen deposition, tissue tensile strength and collagen structural differences may contribute to increased mammographic density which then is associated with breast cancer initiation4,14,15,29−36. In fact, increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of, and predisposition to breast cancer37,38. Recent studies have shown that organization and stiffness of the collagen matrix are important in mediating tumor growth and invasion3,4,28,39−41. Abnormal changes in the amount and organization of extracellular matrix lead to altered biochemical, physical, and biomechanical properties of tumor-associated ECM that contribute to tumor progression42,43.
In a similar light, a 2002 study investigated the feasibility of MRE to distinguish malignant and benign properties of breast tissue. Analysis of MR elastograms using a 65Hz frequency on 20 female patients with malignant and benign breast lesions and 15 healthy volunteers as the control demonstrated that cancerous growths consistently demonstrated higher elasticity values (greater stiffness) in contrast to surrounding tissue. Malignant breast tumors measured a median stiffness of 15.9 kPa while adjacent breast parenchyma and fatty tissue measured a median of only 2.5 kPa and 2.0 kPa, respectively. Furthermore, the difference in stiffness between malignant and benign tumors were also evident through MRE where benign breast lesions were determined to be at a median value of 7.0 kPa. In fact, quantitatively, the stiffness value of breast carcinomas was, on average, 418% higher than the value of the adjacent tissues, (p < 0.05)44. The differing values of malignant tumors, benign tumors, and surrounding breast tissue illustrates that MRE as an imaging technique is able to accurately differentiate these tissues, and therefore of clinical importance 44–46.
Clinically, we know that over 40% of our breast cancer screening patients have dense breasts47. As a result of relatively new dense breasts notification laws, these patients are now being told that they have dense breast tissue (which could result in decreased sensitivity of mammography screening and increase their risk of breast cancer). Providers are encouraged to discuss these details with patients and where appropriate, offer various forms of supplemental dense breast screening48–50. These supplemental screening examinations can find additional cancers, however, also result in increased false positive results23,51,52. Since the risks and benefits of screening test are functions of each patient’s density features and risk factors, personal screening policies tailored to individuals are necessary and the new paradigm of breast cancer screening. Personalized breast cancer screening algorithms will result in cost efficiencies53–58 and reduced false positive rates. As such, our data is promising whereby imaging biomarker of global breast tissue stiffness could provide an additional component in a clinical decision making tool to guide providers of screening and risk-reduction measures based on patient values and preferences.
In our study we observed a nonsignificant increase in stiffness in both the dense and non-dense breasts. These observed differences with increasing stiffness with density are consistent with other smaller studies59–61, however the lack of a statistical significance is unique in our study. It should be noted that our study had few cases included along the the extreme spectrum of breast densities, fatty (n = 1) and extremely dense (n = 3) in our normal risk cohort, which may be affecting our results of statistical significance. Also it should be noted in our study, we chose to use the central slice as a first step to assess global 3D MRE values and used a 40Hz frequency on a 3T scanner. The region of interest included the central breast tissues, including fatty tissue and breast parenchyma on the slice, sparing the edges. This technique is similar to the annotations drawn and lessons learned on clinical diagnostic liver MRE. Contrast this technique to that of a 2017 study that demonstrated that dense breasts had significantly higher stiffness measurements compared with non-dense breasts (p < 0.0561) the authors used a 60Hz frequency on the 3T scanner which requires less power for penetration. We speculate that the stiffness is highly dependent on the measurement method and the tissues that are covered.
Limitations within our study highlight the need for further inquiry to fill the gaps of current research before implementation in clinical practice. Our study is one of the largest to date, other published breast MRE studies have been performed using a small sample cohort of approximately 20 to 50 patients, limiting the representation of breast tissue density. In addition, the high risk volunteers used for testing the efficacy of MRE had a included those with a personal history breast cancer, making it difficult to extrapolate the results to the general screening population. Thus, future research should aim to encompass a larger set of patients to account for individual differences in breast tissue and a variety of lesion characteristics. Given the current study is based on self- reported family history, we will also plan to calculate lifetime and 5 year risks for patients based on acccepted clinical breast cancer risk models62–64. Doing so, will allow us to have more accurate correlations to lifetime risk rather than the current stratification provided here. Another limitation is the fairly homogenous demographics of the patient population in this study. Therefore adding demographic variation to the population will be of utmost interest given the variations seen in breast density based on racial differences65–67. Also, future studies should include computer-generated volumetric breast density from MG to classify pateints as dense or non dense, given the considerable inter- and intra-reader variability within the mammographic density reporting system68,69.
As more personalized approach within the breast cancer screening regimen develops, further risk stratification using quantitative imaging biomarker of global breast stiffness could inform more effective personalized screening regimens.We anticipate the results of this study and ours will give light to more investigations on how tissue stiffness correlates with breast cancer risk and prognosis. These prior studies and our results provide support for the further study of MRE given its ability to assess the viscoelastic properties of breast tumors and the surrounding tissue 70–72. While the studies on MRE’s application to in vivo breast tissue are limited, this trial substantiates the capabilities of MRE and its potential for a risk stratification tool in women with dense breasts.