**1. Introduction**

Neoadjuvant chemotherapy (NAC) is currently one of the basic methods of treatment of locally advanced breast cancer [1,2]. The main advantage of NAC use is the possibility of reducing the mass of previously inoperable tumors to allow surgical intervention. In the case of massive ye<sup>t</sup> operable tumors, NAC provides a decrease of their mass to a

**Citation:** Steinhof-Radwa ´nska, K.; Grazy ´ ˙ nska, A.; Lorek, A.; Gisterek, I.; Barczyk-Gutowska, A.; Bobola, A.; Okas, K.; Lelek, Z.; Morawska, I.; Potoczny, J.; et al. Contrast-Enhanced Spectral Mammography Assessment of Patients Treated with Neoadjuvant Chemotherapy for Breast Cancer. *Curr. Oncol.* **2021**, *28*, 3448–3462. https://doi.org/10.3390/ curroncol28050298

Received: 9 August 2021 Accepted: 2 September 2021 Published: 6 September 2021

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size that makes conservative surgical treatment possible. Thus, a better cosmetic effect will be achieved and fewer post-operative complications will be present [3–5]. Besides reducing the tumor mass and enabling thereby offering better conditions for local treatment (breast-conserving therapy (BCT)), NAC provides unique opportunities for in vivo chemotherapeutic evaluation of cancer cells' sensitivity, as well as for the search for new biomarkers of therapeutic response. In addition to locally advanced breast cancers, NAC has applications in some molecular subtypes of breast cancer. It is recommended for the following kinds of cancer patients: hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) low and high risk, human epidermal growth factor receptor 2 positive (HER2+) and triple negative breast cancer (TNBC) of any size and stage. NAC is also a method of choice in cases of inflammatory breast cancer (IBC) [6–8].

Consequently, in the event of poor response and progression of the disease, NAC offers a chance to alter the treatment scheme or refer a specific patient for surgical treatment. Apart from the predictive and prognostic factors known to date, including staging, grading, HER2 status, hormone receptors status, and Ki-67% index, the therapeutic response of the tumor to NAC provides information about the patient's prognosis [9–11]. Achieving complete response (CR) upon completion of neoadjuvant therapy and surgical resection is associated with improved survival rates. CR was approved by the US Food and Drug Administration (FDA) in 2020 as the final point of clinical studies in the neoadjuvant therapy of early breast cancer with high recurrence risk [12]. However, it has to be mentioned that NAC response parameters can differ among patients due to the internal heterogeneity of tumors caused by molecular features, their clinical status, and morphological appearance. It is estimated that approximately 10–35% of female patients diagnosed with breast cancer remain chemotherapy-resistant, while in 5% NAC is completely non-reactive and leads to the disease progression [13]. In cases of such patients, NAC is a method of much lower efficacy: it deteriorates prognosis, delays surgical intervention, and increases the overall cost of therapy. Most recent research indicates its unsatisfactory results in decreasing or removing metastatic sites [11,14,15]. Despite the limitations described above, NAC is widely used in breast cancer therapy. It is estimated that approximately 7–27% of female patients suffering from breast cancer in Europe, the USA, and Australia undergo NAC treatment [2].

Evaluating the tumor response to NAC is key to planning further therapy. Underestimation of residual lesions after NAC can lead to incomplete tumor resection during surgery. This can lead to relapse or a need for reoperation. On the other hand, overestimation may result in overly radical surgical intervention, which can lead to much more serious complications. The gold standard of NAC response analysis is still histopathological examination. However, such examinations are conducted postoperatively. Due to this, it is crucial to determine and find reliable, non-invasive, and effective imaging diagnostic methods to assess NAC response in tumors.

The diagnostic imaging techniques currently used to assess response to NAC are conventional mammography (MG), ultrasound (US), photon emission tomography, and magnetic resonance imaging (MRI) with contrast enhancement (CE-MRI). CE-MRI is considered to be the most effective of these methods [16,17]. Multiple studies have shown that dynamic contrast-enhanced MRI is the optimal imaging tool to determine disease response, with a sensitivity reaching 90%, specificity of 60% to 100%, and accuracy of approximately 91%. However, CE-MRI remains an expensive method with limited access in local diagnostic centers. Patients with contraindications and who are unable to tolerate examination conditions (i.e., claustrophobia, psychic comfort, old-type pacemakers) cannot undergo such examinations [18–22]. Furthermore, some research shows that MRI may under- as well as overestimate the size of residual lesions in 18% of cases [23]. Considering all these aspects, the search for new, more efficient, and potent diagnostic methods is still important.

Contrast-enhanced spectral mammography (CESM) is a novel technique intensively developed in the last few years. This diagnostic method was accepted by the FDA for

clinical use in the United States in 2011. During CESM examination, approximately 2 min after contrast administration (chelated iodine-based X-ray contrast agent), dual-energy mammography is performed. During one examination, two images are acquired: one resembling conventional mammography (low-energy images of equal or noninferior quality to those of standard digital mammography) and another—the subtraction image— demonstrating areas of increased contrast enhancement (like in the case of the CE-MRI that uses Gadolinium-based contrast dose) [24,25]. Another advantage of CESM is that it provides both the anatomical and morphological characteristics of the lesions in the breast and regions of increased neoangiogenesis. CESM is characterized by comparable or even better sensitivity and a higher negative predictive value (NPV) and positive predictive value (PPV). Moreover, in contrast to MRI, CESM allows the visualization of microcalcifications [26,27]. Due to the much shorter examination time, lower costs, higher comfort, and low anxiety involved, patients tend to cooperate more fully and prefer CESM to MRI [28].

Consequently, the use of CESM in the evaluation of response to NAC is justified, bearing in mind the efficiency of this method, which is comparable to CE-MRI. According to the European Society of Breast Cancer (EUSOBI) recommendation in 2017, CESM can be considered as an alternative to contrast-enhanced MRI in the case of contraindications to MRI. CESM is a younger and less-studied technique than MRI. In CESM, there is an extra radiation dose of approximately 20%, but both images—low- and high-energy—still imply an X-ray dose below the recommended dose for mammography. In patients treated with neoadjuvant chemotherapy for breast cancer when a CESM examination is planned, additional MG can be avoided, with the possibility of saving the radiation dose [29].

Therefore, our study aimed to evaluate the effectiveness of low-energy and subtraction CESM images in the detection of CR for neoadjuvant chemotherapy in breast cancer. In addition, we decided to correlate the residual changes assessed with CESM low-energy and subtraction images.

## **2. Materials and Methods**

A total of 63 female patients (mean age of 53.32 ± 9.47 years; ages ranged from 33 to 75 years) were qualified for our retrospective analysis. Between 2016 and 2019 they were put forward for NAC due to breast cancer in the University Clinical Center of the Medical University of Silesia in Katowice, Poland. Inclusion criteria encompassed: a diagnosis of breast cancer (based on core needle biopsy), minimal stage of T1N+, age of more than 18 years, completion of NAC treatment, surgery after NAC, and a complete set of imaging examinations—CESM; ultrasonography (US) of the breast, lymph nodes, and abdomen; and chest X-ray. Exclusion criteria were as follows: known BRCA1 or BRCA2 mutation (to provide the highest radioprotection), pregnancy, anaphylaxis or anaphylactoid reaction to a contrast agen<sup>t</sup> in medical history, e-GFR of less than 60 mL/min, chronic kidney disease in stage 3 or higher, and incomplete NAC. Patients with significant post-biopsy changes (e.g., hemorrhage) affecting image quality were also excluded. A full description of the study group is in Table 1.


**Table 1.** Patients and tumors characteristics.


**Table 1.** *Cont.*

Abbreviations: IDC—invasive ductal carcinoma; ILC—invasive lobular carcinoma; LumA—luminal A breast cancer; LumB—luminal B breast cancer; TNBC—triple-negative breast cancer; TNM—T, N, and M status.

Due to the retrospective nature of this study, the local ethics committee of the Medical University of Silesia repealed the requirement for informed consent (decision number PCN/0022/KB/157/20). All the test procedures were carried out in compliance with the ethical principles of the 1964 Helsinki Declaration and its subsequent amendments.

## *2.1. Neoadjuvant Systemic Therapy*

After the end of breast cancer diagnosis, each patient's final decision concerning the proper treatment was made by the multidisciplinary breast cancer team (BCU) unit, taking into account patients' preferences. Following the decision by the BCU team, 98% of patients received chemotherapy based on anthracyclines and taxanes (for a period of 12 weeks), including 30% in the "dose-dense" regimen. Only one patient did not receive anthracyclines due to a limited dose of anthracyclines in earlier treatment of Hodgkin's disease. Due to the lack of public funding for trastuzumab in this center in the years 2016– 2019 (no drug prescription governmen<sup>t</sup> program), all the cancer patients with positive HER2 were treated outside our center and were not included in this analysis.
