Imaging features of triple negative breast cancer and the effect of BRCA mutations

Abstract

Objective

The purpose of this study is to review the mammographic and the ultrasound features of triple negative breast cancer (TNBC) patients and to investigate the potential effect of BRCA mutations on the imaging features of these patients.

Methods

One hundred and seven patients with TNBC were enrolled in a retrospective study following IRB approval and approval of waiver of informed consent. BRCA mutations were assessed using genetic testing. Imaging features on mammography and ultrasound (US) as well as pathology and clinical information were retrospectively reviewed and characterized according to the BI-RADS lexicon (5th edition). The relationships between BRCA mutations and the imaging findings were examined.

Results

TNBC commonly presented as an irregular mass with obscured margins on mammography and as an irregular hypoechoic mass with microlobulated or angular margins on US. Approximately two thirds of TNBC cases had a parallel orientation and approximately one third had posterior enhancement, features often associated with benign masses. There was no statistically significant difference in the mammographic and the US features of BRCA positive and BRCA negative triple negative tumors.

Conclusion

TNBC may have a parallel orientation and posterior enhancement, which are features often seen with benign masses. BRCA mutations do not affect the imaging features of triple negative breast tumors.

INTRODUCTION

Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer that does not express estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 (HER2/neu) and is associated with aggressive histology and a poor clinical prognosis [1, 2]. TNBC lacks effective targeted therapies such as endocrine therapies and anti-HER2 antibodies, such as trastuzumab, and TNBC is associated with the p53 gene and BRCA mutations [3, 4].

TNBCs have been reported to appear as irregular masses with no calcifications on mammography and irregular hypoechogenicity on ultrasound (US) [5]. The relationship between BRCA mutations and the imaging features of TNBCs, however, has not yet been studied. In this study, we review the mammographic and the US features of TNBC and we investigate the potential effect of BRCA mutations on the imaging features of TNBC.

METHODS AND MATERIALS

Patient selection

All women diagnosed with TNBC who had undergone genetic testing for the BRCA 1 and the BRCA 2 mutations at a single institution between February 1, 1997 and December 1, 2012 were reviewed to be included in the study. One hundred and seven patients with TNBC were enrolled in a retrospective study following IRB approval and approval of waiver of informed consent. Imaging features on mammography and US as well as pathology and clinical information were retrospectively reviewed by 3 board certified radiologists with fellowship training in breast imaging and characterized according to the BI-RADS lexicon (5th edition) [6]. In patients with multifocal or multicentric disease, reviewers attributed their findings to the largest finding. The radiologists reviewing the images were blinded to the BRCA status of the patients. The imaging features of TNBCs and the relationships between BRCA mutations and the imaging findings were examined.

Statistical analysis

Statistical differences in the imaging findings between patients with BRCA positive and BRCA negative TNBCs were determined using the chi-squared test. Multivariate analysis of these differences was conducted using binary logistic regression. P values less than 0.05 were considered statistically significant.

RESULTS

This retrospective study analyzed TNBC in young premenopausal patients between 19 to 41 years of age. Eighty of 107 patients underwent mammography and US; 12 had mammography only and 15 had US only. TNBC was seen in the upper outer quadrant in 61% and in the posterior third of the breast in 47% of cases. In 31% (33/107), TNBC was multifocal, and 7% (8/107) had multicentric cancer.

In 72/92 patients (78%), a mass was visualized on mammography. An irregular shape was seen in 69% (50/72) (Figure 1). Obscured margins were seen in 54% (39/72). Suspicious microcalcifications were seen in 21% (19/92). Architectural distortion was noted in 12% (11/92) and an asymmetry was noted in 13% (12/92).

Fig. 1. 38-year-old woman with a palpable anterior left breast mass.

A) The left craniocaudal mammogram shows an irregular mass with indistinct margins (arrow). B) The left lateromedial mammogram shows the mass (arrow) in the upper breast. C) Left breast extended field of view ultrasound shows an irregular hypoechoic mass with posterior shadowing. The patient was a BRCA1 mutation carrier. Ultrasound-guided biopsy of the left breast mass showed poorly differentiated triple negative invasive ductal carcinoma.

On US, a mass was visualized in 99% (94/95). An irregular shape was seen in 80% (76/95) (Figures 2–3). A parallel orientation was noted in 66% (63/95). Microlobulated was the most common margin feature (38%, 36/95) followed by angular (33%, 31/95). Circumscribed margins were noted in 12% (11/95) of the cases. Tumors were hypoechoic in 77% (73/95) of cases. Thirty-six percent (34/95) had no posterior enhancement or shadowing and 36% had posterior enhancement (Figure 4), 21% (20/95) had combined enhancement and shadowing, and 9% (9/95) had shadowing. Color Doppler was performed in 92 patients, and increased vascularity (mostly central, 60%) was seen in 63% (58/92).

Fig. 2. 36-year-old woman with a palpable abnormality in the upper outer left breast.

A) The left craniocaudal mammogram shows an irregular mass (arrow) with indistinct margins, corresponding to the palpable abnormality (triangle). B) The left mediolateral oblique mammogram shows an irregular high density mass (arrow) with spiculated margins, corresponding to the palpable abnormality. C) Transverse left breast ultrasound in the 1:00 region shows an irregular hypoechoic mass corresponding to the palpable abnormality. The patient was BRCA negative. Ultrasound-guided biopsy of the left breast 1:00 mass revealed triple negative high grade invasive ductal carcinoma.

Fig. 3. 37-year-old woman with a palpable abnormality in the upper outer right breast.

Transverse right breast ultrasound shows an irregular hypoechoic mass in the 10:00 region with some posterior shadowing. The patient had a BRCA1 mutation. Ultrasound-guided biopsy in the right breast at 10:00 showed triple negative intermediate and high grade invasive ductal carcinoma along with ductal carcinoma in situ.

Fig. 4. 37-year-old woman with a palpable abnormality in the upper outer right breast.

A) The right craniocaudal spot compression mammogram shows an oval high density mass (arrow) B) The right lateromedial mammogram shows the oval mass (arrow) with circumscribed margins. C) Transverse right breast ultrasound at 10:00 shows the oval mass with internal cystic spaces, circumscribed margins and posterior enhancement. D) Longitudinal right breast ultrasound at 10:00 shows the circumscribed oval hypoechoic mass with an isoechoic posterior component and posterior enhancement. The patient had a BRCA1 mutation. Ultrasound-guided biopsy of the right breast 10:00 mass revealed triple negative poorly differentiated invasive ductal carcinoma.

BRCA mutations were detected in 43 of 107 patients (40%): 37 with BRCA1 (86%) and 6 with BRCA2 (14%) mutations. The median age at the time of diagnosis was 35 years in both groups (range: 19–41 years). The median tumor size was 2.4 cm (range: 1–9 cm) in the BRCA positive tumors and 2.8 cm (range: 1–12 cm) in the BRCA negative tumors. On mammography, cancers in both groups commonly presented as an irregular mass (p=0.43) with obscured margins (p=0.85) and no calcifications (p=0.22). On US, cancers in both groups commonly presented as hypoechoic (p=0.30) and irregular (p=0.21) masses with a parallel orientation (p=0.93). In BRCA positive tumors, angular margins were the most common margin feature and seen in 36% (15/43). In BRCA negative tumors, microlobulated margins were the most common margin feature and seen in 45% (24/64, p= 0.2). Posterior enhancement was seen in 33% (14/43) of BRCA positive tumors (Figure 5) and in 35% (22/64) of BRCA negative tumors (p=0.20). There was no statistically significant difference in the mammographic and the US features of BRCA positive tumors versus BRCA negative tumors (Table 1).

Fig. 5. 37-year-old woman undergoing ultrasound to evaluate a mass seen in the upper outer right breast on mammography.

A) Longitudinal right breast ultrasound in the 10:00 region shows a hypoechoic oval mass (arrow) with a parallel orientation, anterior to a prepectoral silicone implant, correlating with a mass seen on mammography. The sonographic appearance of the mass simulates that of a benign process, such as a fibroadenoma. The patient had a BRCA1 mutation. B) Right breast ultrasound-guided core biopsy was performed on the 10:00 hypoechoic oval mass (short arrow) with a parallel orientation and posterior enhancement. The core biopsy was performed with an 18-gauge needle (long arrow). Pathology showed poorly differentiated triple negative invasive ductal carcinoma.

Table 1.

Imaging features of BRCA positive and negative TNBCs

Patients (n=107)		BRCA Positive (n=43)	BRCA Negative (n=64)	P Value
Age		35 (19–41)	35 (19–41)	n/a
Tumor Size		2.4 cm (1–9 cm)	2.8 cm (1–12 cm)
US Features	Tumor Presentation	Hypoechoic and irregular mass (31, 74%)	Hypoechoic and irregular mass (43, 67%)	0.22
	Vascularity	Internal (15, 35%)	Internal (20, 31%)	0.5
	Orientation	Parallel (27, 63%)	Parallel (36, 56%)	0.93
	Margin Features	Angular (15, 36%)	Microlobulated (24, 45%)	0.2
	Posterior Enhancement	14, 33%	22, 35%	0.2
Mammo graphic Features	Tumor Presentation	Irregular mass (20, 46%)	Irregular mass (30, 47%)	0.43
	Margin Features	Obscured margins (14, 35%)	Obscured margins (23, 37%)	0.85
	Calcifications	10, 23%	9, 14%	0.22

DISCUSSION

The mammographic findings among TNBC patients in our study were most commonly a mass (78%) with no calcifications (80%) and obscured margins (54%) and irregular shape (69%). In a study by Krizmanich et al of 207 patients with TNBC, masses without calcifications were seen in 58% of the cases with ill-defined (47%) or spiculated (20%) margins and irregular shapes (49%) on mammography [7]. A recent study on the mammographic features of TNBCs in young premenopausal women revealed masses in all cases with a lower frequency of calcifications (15%) compared to HER2 positive (67%) and estrogen receptor positive (61%) cancers [8]. Dogan et al retrospectively reviewed the imaging findings of 44 patients with TNBC. They reported masses (58.1%) and focal asymmetries (21%) as the most common presentation of TNBC on mammography. Sixty percent of masses were round or oval, and 32% had circumscribed margins [9]. Several other studies suggested an irregular mass without calcifications with ill-defined margins as the most common appearance of TNBC on mammography [5, 8, 10].

US features among TNBC patients in our study were most commonly an irregular hypoechoic mass with microlobulated (38%) or angular (33%) margins and increased vascularity. Approximately two thirds of TNBC cases had a parallel orientation and approximately one third had posterior enhancement. The study by Krizmanich et al reported hypoechoic or complex masses with irregular shapes and non-circumscribed margins as the most common features of TNBC on US [7]. Parallel orientation with no posterior acoustic features was also noted in 58% of the cases in that study [7]. The study by Dogan et al reported abnormal sonographic findings in 93% of TNBC patients. Approximately 16% of TNBC masses in the study by Dogan et al had BI-RADS sonographic features that favored the diagnosis of a benign condition including round or oval shape, circumscribed margins, and posterior acoustic enhancement [9]. Hypoechoic masses with an irregular shape and indistinct margins were the most common US features reported in studies on TNBCs [5, 8–10]. US has been reported to be negative in 14–20% of cases with TNBC [5, 8–10].

Women with BRCA 1 and BRCA 2 gene mutations have an increased risk of developing breast cancer. By the age of 70 years, these women have a 56–83% risk of developing breast cancer [11]. The cumulative incidence of breast cancer in BRCA 1 mutation carriers is 2% by age 20 years, 12% by age 40 years, 30% by age 50 years, and 44% by age 60 years [12]. It has also been reported that the tumor growth rate of BRCA mutation carriers is twice that of non-carriers [13]. Current research supports breast screening with a combination of MRI and mammography starting at the age of 30 years for BRCA 1 and BRCA 2 mutation carriers.

TNBC has a close association with mutations in the BRCA pathway. Among newly diagnosed breast cancer patients, fewer than 10% have a mutation in the BRCA1 or BRCA2 genes, while more than 16% of TNBC patients are identified with BRCA mutations and women with early-onset TNBC are candidates for genetic testing for BRCA mutations, even in the absence of a family history of breast or ovarian cancer [14–16].

BRCA-associated breast malignancies have been shown to have imaging features that are commonly seen in benign lesions. The most frequently described mammographic feature of BRCA-associated breast cancers is a round mass with sharp, well-defined margins and no malignant calcifications [17, 18]. BRCA associated breast malignancies often appear as round, well circumscribed, hypoechoic, and homogeneous masses on US with enhanced sound transmission, resembling benign lesions, particularly fibroadenomas [19, 20]. In a recent study, the most common MRI characteristics in BRCA positive breast cancers were described as linear or focal non mass-like enhancements [21].

No prior studies have evaluated the imaging features of BRCA positive breast cancers among patients with TNBC. Our study revealed no statistically significant differences in the mammographic and the US features of BRCA positive tumors versus BRCA negative tumors in patients with TNBC. No comparison was made between BRCA1 versus BRCA 2 mutation carriers in our studied population due to the small number of BRCA2 positive patients.

Limitations of our study included the relatively small number of patients and the retrospective nature of our analysis. Another limitation was that our study focused on mammography and US and did not review MRI findings. In addition, the initial imaging examination of approximately 50% of the studied patients were from outside facilities.

In conclusion, using the BI-RADS lexicon, TNBC commonly presented as an irregular mass with obscured margins on mammography and as an irregular hypoechoic mass with microlobulated or angular margins on US. Approximately two thirds of TNBC cases had a parallel orientation and approximately one third had posterior enhancement, features often associated with benign masses. Our study did not find any statistically significant difference in the mammographic and the US features of BRCA positive and BRCA negative TNBCs. Future studies analyzing MRI features and studies with radiomics may help us to identify differences in BRCA positive and BRCA negative TNBCs.