The value of dynamic contrast-enhanced MRI in the diagnosis and management of triple-negative breast cancer

Breast cancer is undoubtedly the world’s most frequent cancer among women. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that does not express estrogen, progesterone, or human epidermal growth factor receptors, yet its imaging is considered a challenge to radiologists having imprecise features. In this study, we aimed at defining the MRI characteristics of triple-negative breast cancer to validate its impact on management. Most of the TNBCs in this study showed malignant pattern kinetic curves (types II and III), 87/104 (83.7%), and P value 0.673 (not significant), and regarding the type of lesion enhancement, 104/172 cases (60.5%) showed mass enhancement compared to 52/172 (30.2%) non-mass enhancement and 16/172 (9.3%) focus enhancement, P value 0.185 (not significant). As for the internal enhancement pattern of mass lesions, rim internal enhancement was predominant in TNBC mass lesions, 48/104 (46.2%), as well as intratumoral bright signal intensity on T2-weighted images, 108/172 (62.8%), P value 0.001 (highly significant). Triple-negative breast cancers (TNBC) are larger, better defined, and more necrotic than conventional cancers. On MRI, necrosis yields high T2-weighted signal intensity.


Background
Breast cancer (BC) is without a doubt the world's most frequent cancer among women, and it is the commonest reason of cancer related death in women globaly [1].
Triple-negative breast cancer (TNBC) is a subtype of breast cancer which does not express estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). They represent nearly 12-26% of total breast cancers, and are coupled with an extra aggressive clinical course and poor prognosis. They have an elevated rate of local recurrence and metastatic disease, with a 5-year survival of more or less 75% [2,3]. The frequency of TNBC is high in younger, habitually premenopausal women [4,5].
Imaging of TNBC is considered a diagnostic challenge to breast radiologists. On mammography and ultrasound, triple-negative cancer shows imprecise characteristics that can imitate lesions with benign features [6]. Patients with TNBC are commonly youthful with BRCA gene mutation, and they have dense breasts which additionally lowers mammographic sensitivity and specificity. The speedy progression of the TNBC which is not coupled with architectural distortions makes early detection of the disease exceptionally hard [7].
Breast MRI screening is beneficial for patients with high-risk and those with occult breast carcinoma, which has a rather higher prevalence of TNBC [8,9]. MRI shows malignant characteristics that might not be recognized using mammography or ultrasound; consequently, it is considered of higher precision in detecting the local extent of disease in recently diagnosed breast cancer [6,10]. TNBC presented quite a lot of MRI predictors on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); these could be valuable in identifying TNBC from other breast cancer subtypes [5].
Neo-adjuvant chemotherapy (NAC) has been the customary treatment for locally advanced breast cancer. It is mostly designed to decrease the tumor size, thus allowing breast-conserving surgery. Other privileges of NAC are that systemic therapy may be started earlier, and it permits evaluation of a patient's response to chemotherapy [11].
Therefore, the aim of this work is to assess the DCE-MRI features of triple-negative breast cancer and to validate its impact on management.

Methods
The study is a retrospective study in which we analyzed the contrast-enhanced MRI morphology descriptors and kinematic curve in 100 patients with triple-negative breast cancer.

Data collection
Demographic and clinical data including patient's name, age, clinical presentation, family history, and histopathological diagnosis as well as imaging data including breast ultrasound and mammography were compiled.

MRI protocol
Dynamic MR imaging was performed with high field strength (1.5 T MRI system) [Panorama; Philips Medical Systems, Netherland] using a bilateral breast surface coil with the patient in the prone position. Total study time ranged from 30 to 45 min. No sedation was used. ▪ Comfort of the patients was ensured, and they were asked to remain still during the whole examination.

Imaging acquisition protocol
A-Cases were examined first by pre-contrast sequences: Axial T1-weighted turbo spin echo (TR/TE = 500/ 5.3 msec), sagittal and axial T2-weighted images using turbo spin echo (TR/TE = 120/4.9 msec), axial short time inversion recovery (STIR) (TR/TE = 80/ 6.5 msec), and a pre-contrast fat-saturated T2weighted pulse sequence. B-Contrast-enhanced sequences/series: A bolus of contrast was injected manually intravenous, and enhanced images were obtained immediately after contrast agent injection. C-Post processing: Subtraction was used to highlight the enhancing features in the image. 1. Quantitative analysis was done by using time/ signal intensity curve. A color overlay map was displayed, indicating regions of threshold enhancement.
2. The maximum intensity projection (MIP) was performed to demonstrate the distribution of disease in the breast in relation to the skin, nipple, chest wall, and large vessels.

Image analysis
Magnetic resonance images were reviewed by two radiologists in the same setting and the final diagnosis was reached by their agreement (in consensus). The findings of dynamic contrast-enhanced MRI study were evaluated in accordance with the ACR BI-RADS MRI Lexicon, 2013, that includes two major categories of descriptors: morphology and enhancement kinetics.

Morphology descriptors
Enhancing lesions were categorized as focus, mass, and non-mass enhancement.

Associated features
Associated findings with or without enhancement include nipple retraction (when the areola is distorted more than nipple, might be circumferential pulling in but the nipple usually visible unless it is very late stage) or inversion (slit-like and can be averted often results from duct ectasia or fibrosis), skin retraction, thickening or invasion, lymphadenopathy, pectoral muscle invasion and chest wall invasion, architectural distortion, high signal intensity in ducts on unenhanced images, abnormal signal void, hematoma, edema, and cysts were reported.

Signs of spread of malignancy
On the MR images of the breast, spreading to the axillary region, other lymph nodes, the chest wall muscles, the ribs, the adjacent pleura and lung, or overlying skin was reported.

Kinetic enhancement curve assessment
Three enhancement patterns were identified on the basis of the time/signal intensity curve: types I, II, and III. All patients were assigned a BI-RADS category [6] according to the ACR MRI BI-RADS lexicon.

Statistical analysis
The data was summarized using number and percentage for qualitative variables, mean, and SD for normally distributed quantitative variables.
Comparison between groups was done using chisquare test for qualitative variables and independent t test for quantitative variables. P value less than or equal to 0.05 was considered statistical significant, and 0.01 or less considered highly significant.

Results
The study included 100 patients with 172 pathologically proved TNBC.

Age
Ages of TNBC patients ranged from 24 to 60 years (mean age 44.04 ± SD).

Discussion
Although TNBC accounts for a fairly little minority of breast cancer cases, it is responsible for a quite large share of breast cancer deaths, due to the commonly aggressive clinical course and the lack of successful targeted therapies [7,12]. Triple-negative phenotype is characterized by distinct clinical, histopathological, and molecular characteristics, and is associated with the development of recurrence, distant metastases, and a poorer prognosis; therefore, better understanding of the imaging features of TN cancers, especially at MRI, provides an imaging biomarker with clinical implications.
This study aimed to determine the dynamic contrastenhanced magnetic resonance imaging features of TN breast cancers in addition to MRI features that are more frequent with triple-negative breast cancer subtypes such as round shape mass lesion, mass with rim enhancement in post contrast images, and intratumoral bright signal intensity on T2-weighted images, while still maintaining other DCE-MRI parameters commonly seen with other breast cancer subtypes as distribution of fibroglandular tissue (FGT) and BPE, mass margin, non-mass enhancement distribution and enhancement pattern, lymph nodes status, and types of kinetic curves.
In this study, the patients' age ranged from 24 to 60 years (mean age 44.04 ± SD) which agrees with Li and Han [9] as well as Schmadeka et al. [13] who stated that TNBC more commonly affects youthful patients (< 50 years).
104/172 (60.5%) of our cases presented as mass lesions. This goes in concordance with Dogan et al. [17], Li and Han [9], and Osman et al. [5] who stated that TNBC most often presents as mass enhancement.
As regards the shape of mass lesions in this study, 40/ 104 (38.5%) were rounded or oval in shape and 64/104 (61.5%) were irregular in shape; however, Sung et al. [4] found that the majority of TNBC lesions were lobulated and Ivanac et al. [18] as well as Osman et al. [5] found most TNBC were rounded and or oval masses.
We found that most masses had irregular or speculated margins (72/104, 69.2%) while 32/104 (30.8%) had smooth (circumscribed) margins compared to those of Uematsu et al. [19] whose findings which showed that 39% of the TNBCs had smooth margins. On the other hand, Youk et al. [6] and Osman et al. [5] reported that a smooth mass margin tended to be prominently associated with TNBC.
The majority of TNBC mass lesions demonstrated areas of high T2 intratumoral signal intensity (108/172, 62.8%). Our result is compatible with Sung et al. [4] and Osman et al. [5] who stated that high T2 signal intensity was significantly associated with TN cancer and that intratumoral high signal intensity on unenhanced fat suppressed T2-weighted images corresponded morphologically and pathologically to intratumoral necrosis.
Most of the patients in this study showed malignant pattern kinetic curves (types II and III), (87/104, 83.3%) This result is similar to many studies as Chen et al. [21], Dogan et al. [17], and Youk et al. [6] and unlike Uematsu et al. [19] that reported a persistent enhancement pattern was significantly associated with TNBC.
In this study, TNBC were diagnosed by DCE-MRI in all cases, and this coincides with previous studies such as Dogan et al. [17] who studied the characteristics of TNBC by mammography, ultrasound, and MR imaging; TNBC were detected by MRI in all cases and in 91% and 93% of cases by mammography and ultrasound, respectively. Also, Schmadeka et al. [13] suggested that MRI is the most sensitive (99-100%).

Conclusion
In conclusion, in this study, TNBC presented several characteristic MRI features on DCE-MRI such as multiple lesions, mass enhancing type, irregular shape, not circumscribed margin, rim enhancement, high T2 signal intensity, and malignant kinetic curve pattern.