Breast cancer (BC) is a heterogeneous disease of significant social importance. For many years, it has been the most common malignant tumour in women in Poland and in many countries throughout the world. The incidence of BC in women over 30 is systematically increasing. In Poland in 2018, according to the National Cancer Registry, there were 18,869 cases of BC in women and 154 in men. At the same time, a total of 6,895 and 75 deaths were recorded for women and men, respectively(1). The neoplasm is characterised by a varied clinical course and a wide spectrum of morphological images in radiological studies. In recent years, there have been many developments in terms of the knowledge base, diagnostic methods, and new therapeutic options for breast cancer. Currently, BC treatment consists of a comprehensive approach to the diagnostic and therapeutic processes. Three main imaging methods are used in the diagnosis of BC: ultrasonography (US), mammography (MMG), and magnetic resonance imaging (MRI)(2). Each of these methods plays a special role in diagnostics. Ultrasonography is used mainly in young women and those with glandular or mixed breast structure. Contemporary breast US means not only mapping the morphology of focal lesions and their surroundings but also involves a combination of additional techniques such as sonoelastography (SE) and colour Doppler (CD). These techniques allow an increase in the accuracy of imaging and qualification of patients for biopsy or observation(3). Early diagnosis of BC and knowledge of its oncological characteristics on the basis of biopsy findings facilitate the choice of optimal therapy, including surgical treatment which, in selected cases, is preceded by neoadjuvant chemotherapy (NAC). Treatment of early BC is complex and includes a combination of surgical methods (breast conserving therapy, BCT), radiotherapy, systemic therapies (chemotherapy, hormone therapy, molecularly targeted therapies), and adjunctive therapy in various sequences(2). The use of predictive biomarkers such as the histological type of BC (invasive or preinvasive forms), the expression of ER/PgR (estrogen receptor (ER) and progesterone receptor), Ki67 (proliferation index) and HER2 (human epidermal growth factor receptor 2), genomic signatures, if available, stage of the primary tumour, condition of the axillary lymph nodes, and patient’s preferences, affect the choice and sequence of therapies. These methods, especially systemic treatment, have undergone significant changes over the years. NAC, first introduced in 1970, has been used in locally advanced breast cancer (LABC) and inflammatory BC to reduce tumour size and improve the radical nature of surgical treatment, including BCT.
Currently, decisions regarding neoadjuvant treatment should be based on the anticipated sensitivity to particular types of treatment, the benefits of their use, and the individual risk of relapse. Additionally, short-term and longterm toxicity, the biological age of the patients, and their general health and comorbidities should be considered. In the current recommendations of all scientific oncological societies, neoadjuvant chemotherapy is recommended not only in locoregional advanced breast cancer but also in the early stages of the following subtypes: triple-negative breast cancer (TNBC) and in combination with molecularly targeted treatment in the subtypes with the presence of HER2 receptors (luminal B HER2 positive and HER2 positive non-luminal subtypes)(3). NAC can also be used in cases of HER2 negative luminal B cancer with low expression of hormone receptors, high grade (G3), and in young individuals (≤35 years of age), stage II or III(2).
The aim of this study is to present the differential patterns of various subtypes of breast cancer in ultrasound examination based on a review of the literature.
A unique challenge for both radiologists and oncologists is presented by TNBC and HER2+ subtypes. TNBC represents 10–15% of the four immunohistochemical subtypes of BC and frequently occurs in young women who are not yet included in the screening programme. In comparison with the other forms, they are characterised by an aggressive clinical course and heterogeneous response to treatment, with a significantly more frequent occurrence of high malignancy grade (G3) and more frequent mutation of the
For the treatment of TNBC, NAC has been the only standard preoperative systemic treatment to date(2,8). The reason for heterogeneous response to treatment may be the differential gene expression profile (including
Despite the therapies used, there is no targeted treatment for the subgroup of TNBC patients, as opposed to the HER2+ group. The reason for varied responses to treatment may be the altered gene expression profiles in different TNBC subtypes and in the surrounding stroma. These differences may be reflected by microRNAs (miRNAs) released outside the tumour microenvironment(12).
In imaging studies (US and MMG), this subtype often mimics benign lesions (no acoustic shadow effect behind the lesion and sparse vascularisation). In studies on US imaging features of TNBC subtypes, a characteristic pattern of features has been described. Yang
On the other hand, Li
Zhang L
Overexpression of HER2 occurs in 15–25% of invasive BC and is associated with a poor prognosis. On the other hand, HER2+ cancers are characterised by a favourable response to targeted therapies(20). HER2 overexpression is associated with increased cell proliferation, cell survival, mobility and invasiveness, and neoangiogenesis due to increased production of vascular endothelial growth factor(21). For this reason, HER2+ carcinomas have a different clinical course and show different features on imaging studies. Molecularly targeted therapy in combination with chemotherapy in patients with HER2 overexpression/ amplification in tumours greater than 1 cm reduces the risk of recurrence and mortality by approximately half, compared to chemotherapy alone, and translates into a 9% gain in 10-year OS(22, 23, 24).
In view of cardiotoxicity, anti-HER2 treatment is not used in combination with anthracyclines. In patients receiving sequential treatment, it begins with chemotherapy according to the AC (Adriamycin, Cyclophosphamide) regimen – 4 courses, then continues with trastuzumab with taxanes(2). In special cases of low risk early BC with tumours <1 cm, encouraging results were obtained when taxanes were used with trastuzumab alone(25). In cases of preoperative treatment, in patients with poor prognostic factors, dual anti-HER2 blockade in combination with chemotherapy results in a higher percentage of pCR than that obtained by chemotherapy with trastuzumab only. The NeoSphere study demonstrated the superiority of the pertuzumab-trastuzumab combination with docetaxel compared to other anti-HER2 combinations with docetaxel. However, the study did not show any effect on disease-free survival (DFS)(26). Based on the pooled analysis (CTNeoBC), it seems that the achievement of pCR after preoperative treatment translates into a better prognosis for these patients, but the analysis covered the full spectrum of different types of BC(27).
A recently reported pooled analysis confirmed the association of pCR with long-term treatment outcomes, although traditional factors of poor prognosis are still relevant even after pCR has been obtained. Hence treatment with adjuvant anti-HER2 with trastuzumab(28) should be continued.
If pCR is not achieved after preoperative treatment, the use of trastuzumab emtansine (T-DM1) in adjuvant treatment reduces the relative risk of recurrence or death by half. However, this therapeutic option is not yet reimbursed in Poland(29).
Several studies have shown that HER2+ cancers are characterised by a higher prevalence of calcifications. In Algazzar’s study(30), calcifications in HER2+ tumours were present in 70% compared to the HER2- group, in which calcifications were observed in 25.5% of lesions (
In contrast, another feature associated with HER2+ lesions is the multifocality of tumours; it was shown that unifocal tumours were more common in HER2- than in HER2+ subtypes (92.5% vs. 36.4%, respectively,
Luminal breast cancer is an ER-positive type of tumour that accounts for almost 70% of all BC cases in Western populations(36). Luminal A tumours are characterised by high expression of the ER and PR (PR- greater than or equal to 20%), lack of HER2 overexpression or amplification, and Ki-67 proliferation index less than 20%. In this subtype, ER transcription factors activate genes whose expression is characteristic of the luminal epithelium that lines the mammary ducts(37). Additionally, these tumours show low expression of genes related to cell proliferation. Clinically, these cancers are mostly low grade, slow growing, and associated with the best prognosis. They are less sensitive to chemotherapy, and patients benefit more from primary hormone therapy. In general, hormone therapies are used as complementary treatments. In some cases, postmenopausal patients may receive NAC for 4–8 months prior to surgery or until a maximum response is achieved, and continued postoperatively. Aromatase inhibitors are more effective than tamoxifen in reducing tumour size and enabling breast-conserving surgery(38, 39, 40). A good response to preoperative hormone therapy, as expressed by a decrease in Ki67 or the preoperative prognostic index (PEPI), may, in combination with other clinical factors, guide the selection of patients with a favourable prognosis, not requiring adjuvant chemotherapy(41, 42, 43).
In contrast to the A subtype, the prognosis in cases of luminal B tumours is worse, and these tumours have a higher malignancy grade. They are characterised by the expression of ER, low level (<20%) or no expression of PR, the presence or absence of HER2 overexpression, and a higher fraction of Ki67 (>20%). Additionally, they have a high expression of genes related to proliferation, and lower expression of genes and proteins typical of luminal epithelium, such as PR and FOXA (but not of ER, which serves to distinguish luminal from non-luminal cancer types)(44,45). Indications for chemotherapy should include both the risk of recurrence and patient preferences. It could be considered in the absence of response to hormonotherapy and in selected cases of luminal B BC, especially with a high proliferation index, as well as in patients with additional risk factors. In luminal B cancers overexpressing HER2, the principles for the treatment of HER2+ BC are applied, and after surgery, treatment with trastuzumab and hormonotherapy is continued(2).
On imaging examinations, luminal A subtype show some features, the knowledge of which can improve the diagnostic process. On MMG, luminal A and B cancers are far more likely to present as spiculated lesions in comparison with other subtypes(46). Publications describing this subtype in US studies(19) showed that luminal A cancers statistically more frequently show echogenic halo and acoustic shadow or no effect behind the lesion. An example of this type is presented in Fig. 3.
Histologically, the echogenic halo corresponds to tumour cells infiltrating adipose tissue and interlacing connective tissue fibres. According to the literature, echogenic halomay correspond to very fine, densely packed spicules that are too small to be visualised accurately. A thick, fuzzy, hyperechoic halo may also be a manifestation of peritumoral oedema resulting from inflammation or lymphatic outflow obstruction; in such cases the halo is visible superficially between the tumour and the skin, following the physiological direction of lymph drainage(47).
Tumours showing acoustic shadow are characterised by increased desmoplasia. This is because the slow growth of the tumour allows the surrounding stroma to induce the mobilisation of fibroblasts and inflammatory cells, and the proliferation of vascular structures, which leads to fibrosis(14). The acoustic shadow effect results from the reflection of the ultrasound beam or its attenuation by the neoplasm containing a significant connective/fibrous component(47). The shadow may not be visible behind the entire lesion but only part of it. In a 2019 paper by Liu H.
Luminal B subtype of BC on ultrasound is characterised by increased vascularity and lack of halo(19). An example of this type is presented in Fig. 4. The lack of halo suggests a higher incidence of recurrence and a high histological grade(32). Subtypes with the presence of HER2 overexpression are also characterised by increased neovasularisation.
The authors of this paper wanted to draw attention to differential patterns of various subtypes of breast cancer, especially aggressive ones, such as TNBC and HER2+. Additionally, multiparametric US analysis of BC features is helpful in detecting aggressive subtypes, assigning the appropriate BIRADS classification category, and referring patients for biopsies.