Triple-Negative Breast Cancer: Multimodality Appearance

Triple-negative breast cancer (TNBC) represents about 15–20% of all breast cancers and often presents as an aggressive cancer with poor prognosis compared to other forms of breast cancer. This article will review the clinical manifestations, imaging features, pathology correlation, treatment and management, and prognosis of TNBC. While mammography and ultrasound can be used to diagnose TNBC, MRI is the most accurate and sensitive modality to detect TNBC at nearly 100% sensitivity. Contrast-enhanced breast MRI is the optimal imaging study for assessing response to neoadjuvant chemotherapy and can be used to tailor systemic therapy. Understanding the imaging appearance of TNBC is imperative to diagnose TNBC accurately and to help guide management.


Introduction
Triple-negative breast cancer (TNBC) is a subgroup of breast cancer without estrogen, progesterone, or human epidermal growth factor receptors. TNBC represents 15-20% of invasive breast cancers and usually constitute a high histologic grade. TNBC is highly associated with BRCA, and in particular BRCA1 [1]. Greater than 75% of tumors arising in women carrying a BRCA1 mutation have a triple-negative and/or a basal-like phenotype (see Pathology section) [2]. TNBC also occurs more frequently in young black and Hispanic women [1]. Additional risk factors for TNBC are similar to other breast cancers and include earlier menarche, higher body-mass index during reproductive years, higher parity, and lower lifetime duration of breast-feeding [2].

Clinical Presentation
The typical clinical presentation of TNBC is a palpable mass. TNBC can initially present as a higher-grade cancer and have an aggressive clinical course compared to other types of breast cancer. There is also a higher rate of distant metastatic disease and shorter mean time to distant metastatic disease. There are limited therapies given its lack of endocrine receptor expression. Due to its aggressive course, high rates of recurrence, and limited therapeutic options, TNBC tends to portend a poor prognosis and higher mortality with residual disease compared to non-TNBC [3]. The first three to five years after diagnosis shows the most decrease in survival but afterwards, distant relapse is less common compared to other types of breast cancer [2]. In fact, relapse is more common in patients with ER-positive cancers than ER-negative cancers after 10 years [2]. Fig. 1 A 38-year-old woman with a palpable lump in the right breast and spontaneous bloody nipple discharge. A Right MLO and CC views demonstrate a high density irregular ill-defined mass in the right breast upper inner quadrant which correlates to the palpable abnormality. B Ultrasound demonstrates an irregular hypoechoic complex solid and cystic mass in the right breast at 1 o'clock located 3 cm from the nipple. C Ultrasound of the axilla shows a lymph node measuring 12 9 8 9 11 mm in the right breast with an increased cortical thickness of 8 mm. D MR demonstrates an oval enhancing mass with irregular margins containing a biopsy microclip measuring 23 9 18 9 20 mm at 1:00, upper inner quadrant, 3 cm from nipple. Pre-contrast MR image demonstrates ductal proteinaceous debris/blood products in the subareolar region, which likely correlates with bloody nipple discharge Fig. 2 32-year-old woman with a 4-month-old baby presents with shortness of breast while pushing the stroller. A Frontal chest radiograph demonstrates bilateral lower lung predominant nodules. Chest CT was recommended. B Lung and soft tissue window axial chest CT images demonstrate a heterogeneous left breast soft tissue mass (*) with numerous bilateral lung nodules, suspicious for metastatic breast carcinoma. Patient was subsequently referred to breast imaging. C Bilateral CC and MLO mammographic views demonstrate an irregular obscured mass with few punctate microcalcifications in the left breast at 6:00 subareolar region. D Ultrasound images demonstrate an irregular mass with ill-defined margins, which was assigned a BIRADS 5 classification. This was biopsied and found to be a metastatic pregnancy-associated TNBC. E MR images demonstrate a large, rim-enhancing heterogeneous mass with indistinct margins. Kinetic curve analysis showed a rapid initial uptake with a delayed washout phase. This mass abuts the pectoralis major muscle, which demonstrates increased vascularity, suspicious for invasion. Note that there are few enhancing satellite lesions surrounding the main mass

Imaging Modalities
Mammography TNBC may lack suspicious mammographic features such as suspicious calcifications, so mammography may be suboptimal for initial diagnostic evaluation. Associated calcifications are more commonly seen in postmenopausal patients with TNBC compared to premenopausal patients [4 • ]. Rapid progression of cancer may bypass the in situ stage often detected with mammography. TNBC on mammography often appears as an irregular mass that is ill-defined, spiculated, or with obscured margins but can also present as a round mass, particularly in premenopausal patients [4 • , 5]. Microlobulated margins are depicted more commonly in premenopausal patients with TNBC, whereas spiculated margins are more commonly seen in postmenopausal patients [4 • ].

Ultrasound
Ultrasound offers improved sensitivity compared to mammography. The sensitivity for TNBC is 92%-100%. TNBC can still demonstrate features on ultrasound that overlap with other benign entities, which may delay diagnosis. Ultrasound features include hypoechogenicity or complex echogenicity, irregular shape, ill-defined and non-circumscribed margins, abrupt surface boundary, and no significant posterior acoustic features [5]. TNBC may also present with round or oval shape and parallel orientation, which is a feature often associated with benign masses such as fibroadenomas [5].

MRI
MRI is the most accurate and sensitive modality to detect TNBC at nearly 100% sensitivity. Features of TNBC on MRI include intra-tumoral T2 hyperintense signal, smooth mass margin, post-contrast rim enhancement, and persistent enhancement pattern on kinetic imaging [6 •• , 7]. In particular, rim enhancement is the most accurate predictor of ER status and therefore may be the most useful imaging feature on MR to identify TNBC [6 •• ]. T2 hyperintense signal within the tumor corresponds to necrosis, which is a prognostic factor in invasive breast cancer. Enhancement pattern on kinetic imaging may not necessarily demonstrate the initial rapid enhancement with washout commonly associated with malignancy, likely due to the heterogeneity of TNBC [4 • , 6 •• ]. It is also important to note that mass lesion type, particularly smooth or circumscribed masses, which are typically deemed benign morphologic features can also be suggestive of TNBC [6 •• ]. In addition to contrast enhancement, diffusion-weighted parameters may also function as early biomarkers of response in TNBC [8]. Contrast-enhanced breast MRI is the optimal imaging study for assessing response to neo-adjuvant chemotherapy and can be used to tailor systemic therapy [7]. Figure 1 demonstrates an example of TNBC showing the imaging features on mammography, ultrasound, and MRI.

Pregnancy or Postpartum-Associated TNBC
Pregnancy or postpartum-associated TNBC can be due to hormonal changes and immunosuppression. This represents an increased diagnostic challenge given increased postpartum and/or lactational breast density. Breast involution can assist growth of existing tumor cells. Pregnancy or postpartum-associated TNBC tends to be more aggressive, with a high tumor nuclear grade, poor differentiation, and larger tumor size [9]. There is often also more associated Fig. 3 TNBC invasive ductal carcinoma lymphovascular invasion. Given these characteristics, pregnancy or postpartum-associated TNBC tends to portend a poorer clinical outcome and disease-free survival with a higher mortality rate [9]. An example of pregnancy or postpartum-associated TNBC is shown in Fig. 2.

Pathology
The complex heterogeneous nature of TNBCs is indicated by its various subtypes demonstrating various pathological behavior and outcome [10,11]. Lehmann et al. classified TNBC into six distinct subtypes, and then reclassified into now four subtypes in 2016, based on gene expression analysis, which include two basal-like subtypes, mesenchymal, and luminal androgen receptor [11][12][13]. The basal-like subtypes typically demonstrate epidermal growth factor receptor and basal cyto-keratins such as CK5/6, CK14 and CK17 [10]. Luminal androgen receptor subtype expresses more androgen receptors [10]. TNBC also demonstrates high expression of p53 and Ki67 proliferation [10].
While TNBC and basal-like breast cancer are often considered synonymous, basal-like tumors comprise the majority of TNBCs, not all basal-like tumors have the triple-negative phenotype [2,12]. TNBCs with the basal subtype tend to show a higher mitotic index, increased proliferative activity, and poorer outcome [12].
An example of TNBC invasive ductal carcinoma on pathology are demonstrated in Fig. 3.

Treatment
Because TNBC tumors lack a therapeutic target, the mainstay of treatment often involves systemic cytotoxic chemotherapy. Unlike other breast cancer types, there is no standard form of chemotherapy for TNBC [14 •• ]. MRI features, specifically homogeneous enhancement and concentric tumor shrinkage pattern, can be used to predict chemotherapy efficacy and pathologic complete response on surgical pathology [7].These features are also important in determining the extent of surgical excision [7]. Of note, intra-tumoral necrosis typically associated with TNBC did not seem to be associated with response to neoadjuvant systemic therapy [15]. Pathologic complete response guides adjuvant chemotherapy approach and is correlated with longer survival [7]. On the other hand, for the majority of patients who still have residual disease after treatment, the outcome remains relatively poor [2].
Targeted immune agents are a new treatment option. A study in 2021 demonstrated that an antibody-drug conjugate (ADC), sacituzumab govite, can significantly prolong progression-free and overall survival compared to singleagent chemotherapy [16]. Additionally, use of pembrolizumab and atezolizumab, both of which are programmed-death (PD) inhibitors, in combination with standard neoadjuvant chemotherapy results in higher complete pathologic response rate compared to neoadjuvant chemotherapy alone [17,18]. Currently, inhibitors of poly(adenosine diphosphate-ribose) polymerase (PARP), the enzyme that plays a role in base-excision repair following DNA damage, is one of the emerging novel targeted therapies for TNBC [2, 14 •• ]. These include olaparib, veliparib, niraparib, rucaparib and talazoparib [14 •• ]. Additional novel targeted therapies include androgen receptor (AR)-targeted therapy, such as enzalutamide, abiraterone acetate and seviteronel, and AKT inhibition [14 •• , 19].
An example of biopsy-proven TNBC treated with chemotherapy is shown in Fig. 4.

Conclusions
Familiarity with TNBC and a high level of suspicious for this entity helps aid prompt recognition and accurate diagnosis of TNBC, which is crucial given its more aggressive clinical course and poorer outcome compared to other breast cancers.
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