Positron Emission Tomography/Computed Tomography In Locally Advanced Breast Cancer

IntroductIon

Breast cancer is the most commonly diagnosed cancer in women. About 5–10% of newly diagnosed breast cancer cases present with locally advanced disease [1, 2]. Locally advanced breast cancer (LABC) is characterized by a primary tumor larger than 5 cm, skin or chest wall involvement and/or the presence of fixed axillary lymph node metastases. LABC has a higher incidence of locoregional recurrence and distant metastases, which causes a poor prognosis [3, 4]. Nowadays neoadjuvant chemotherapy (NACT) before surgery is increasingly used in the management of LABC. NACT has been used in patients with LABC to reduce the tumor volume, which allows breast-conserving surgery or operability for previously inope­rable breast cancer patients, and to eliminate occult distant metastases [5–7]. However, there has been no significant improvement in prognosis with the use of NACT [8, 9]. On the other hand, early determination of patients who do not respond to NACT allows them to be protected from unnecessary toxic effects. Diffe­rent treatment choices can be applied to these patients.

Generally, the Response Evaluation Criteria in Solid Tumors (RECIST) [10] has been used to evaluate the response to treatment. This criteria is based on anatomic imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), which are used to measure the maximum tumor diameter. Response criteria is defined as a decrease in the tumor diameter of at least 30% [10]. However, several cycles of chemotherapy are necessary for the cytotoxic effect which will cause a reduction in the size of the tumour. It is not possible to evaluate the chemosensitivity in the early stage by RECIST criteria.

In the evaluation of response to chemotherapy, the use of functional imaging such as positron emission tomography (PET) is useful to overcome the limitations of anatomic imaging modalities. PET with fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) is used in various cancers for staging, evaluating the response to treatment and also restaging when there is suspicion of recurrence [11]. The use of CT, particularly with hybrid PET/CT systems, increases the success of functional evaluation. Nowadays there are studies with promising results that early stage response to chemotherapy can be evaluated and more correct staging can be applied to LABC patients with the use of PET/CT systems with FDG [12–15]. This review aimed to examine the contribution and significance of the use of FDG PET/CT in the evaluation of LABC patients and also to consider the clinical contribution of blood flow and tumour proliferation agents which will be used more frequently in the near future.

PrImary stagIng

Correct staging of breast cancer is important in deciding the most appropriate therapy option. However, systemic staging is not indicated for early breast cancer in the absence of symptoms. FDG PET and PET/CT are not recommended for routine staging of breast cancer particularly in the early stage because of low sensitivity in detecting small lesions and moderately increased uptake in primary tumor [16].

In the axillary staging of cases with small primary tumours, PET sensitivity has been found to have a limited value of approximately 20% [17–19]. In the differentiation in terms of sentinel lymph node dissection of patients with clinically negative lymph nodes, FDG PET is not sufficiently accurate [20, 21]. However, FDG PET/CT is a good method for the evaluation of the spread of the disease in cases with locally advanced disease who will undergo NACT [22]. It can identify unsuspected regional nodal disease and/or distant metastases when used in addition to standard staging modalities [16]. Today FDG PET is the most sensitive method to identify parasternal and mediastinal metastatic lymph nodes, which are detected more frequently in LABC.

EvaluatIon of therapy response

The routine application for LABC patients is NACT and then surgery. The tumour response following NACT has prognostic significance for disease-free survival and overall survival time [22]. Patients in whom full response is observed macroscopically following chemotherapy have a significantly better prognosis than patients with residual disease [23]. In addition, those with minimal residual disease have a significantly longer disease-free survival and overall survival than those with gross residual disease [22, 23]. Clinical response is observed in approximately 70% of patients following NACT, while partial or full pathological response is seen in 20–30% of patients [2, 22, 24]. No definite relationship has been found between pathological response and clinical response. Even if there is no clinical response due to the presence of scar tissue, full pathological response may be seen because of the disappearance of tumour cells. Clinical examination alone is not reliable in the evaluation of response to chemotherapy [25, 26].

Changes in tumour size are measured by anatomic imaging methods, such as CT, MRI and ultrasonography (USG), which are currently used in the evaluation of response to therapy. A reduction in tumour size of at least 30% is the acceptable criteria for response [10]. ­However, to be able to see a tumour response radiologically, several cycles of chemotherapy are ne­ce­s­­sary. It does not seem to be possible by radiological imaging me­thods to predict response to therapy in the early stage and thus avoid unecessary chemotherapy application. The relationship between radiological tumour response and pathological response is weak. Anatomic imaging methods do not allow for the diffe­rentiation of viable tumour tissue and fibrotic tissue [27].

Functional imaging with FDG-PET may give an idea about the metabolic tumour cell response before anatomical response occurs [24]. FDG-PET is especially useful in the determination of metabolically active tumours which will primarily benefit from NACT [15]. Following a few cycles of chemotherapy, reduction in FDG uptake is a strong indicator for response [15]. To evaluate response to therapy in breast cancer, PET images taken in different cycles are evaluated; basal, early-therapy (after the first cycle of therapy), mid-therapy and post-therapy [12–14, 28–31]. PET sensitivity and specificity for the evaluation of response to therapy has been reported in literature at wide ranges of 39–100% and 74–100%, respectively. This can be explained by the patients included in studies not being homogenous, not performing PET scans with standard protocols, using different SUV cutoff values in the evaluation and using different pathological criteria [28]. Rousseau et al. investigated the efficacy of FDG-PET for evaluating early response to NACT in 64 patients with stage II and III breast cancer, the FDG-PET scans were taken after the 1^st, 2^nd, 3^rd and 4^th courses of chemotherapy and they reported that early response to NACT may be best evaluated after two courses of chemotherapy [14]. Similarly, Kumar et al. reported that after the second cycle of NACT in LABC patients, those responding to therapy can be differentiated from non-responders [28]. In the same study, results of PET/CT, clinical examination and CT findings were compared and the accuracy rates were found to be 87; 39 and 56% respectively. As PET/CT allows for metabolic/functional evaluation, it has been reported that PET/CT can give an idea of response to therapy before the onset of structural changes which can be determined by anatomic ima­ging methods [28]. It has been emphasised that clinical examination results are not sufficient due to the changes in breast tissue after chemotherapy [28]. In predicting the pathological response following NACT, FDG uptake changes measured in midtherapy PET/CT are mainly used. Generally, a 50% or greater reduction in midtherapy FDG uptake has been accepted as a indicator of response to NACT in studies [28–35]. However, many different cutoff values for percentage SUV changes have been reported, with threshold values varying between 20–88% to be used in the differentiation of responders [12–14, 29, 30]. Kumar et al. accepted a 50% reduction in basal SUV as the SUV cutoff value to differentiate between responders and non-responders to therapy following 2 cyles of NACT, and found PET sensitivity and specificity as 93% and 75%, respectively [28]. In a study by Rousseau et al., a 60% reduction in basal SUV was accepted as the threshold value, and PET sensitivity and specificity following 2 cycles of chemotherapy was reported as 89 and 95%, respectively [14]. One of the critical points in the evlauation of response to therapy with FDG PET is the fact that there is a relationship between the observation of FDG uptake and the pre­sence of residual disease or alive tumour cells, but the absence of FDG uptake is not always a true indicator of full pathological response [29, 36, 37]. This is especially true for axillary lymph node metastasis and the sensitivity of PET for evaluation of axillary nodule metastasis in the post-therapy period is low [38].

Other PET radiopharmaceuticals, apart from FDG, used in the evaluation of response following chemotherapy include the tumour blood flow tracer, ¹⁵O-water and the tumour proliferation agent, ¹⁸F-fluoro-L-thymidine (FLT). Although there are a relatively limited number of studies related to these agents, in studies using ¹⁵O-water to evaluate tumour blood flow, it has been reported that in patients with no significant reduction in tumour blood flow following treatment, there was an increase in recurrence risk and mortality rates [39]. Tumour blood flow and metabolism are known to show considerable variations in LABC patients [32, 34, 39]. It has been reported that the flow-metabolism mismatch (high FDG metabolism in proportion to blood flow) observed in tumours in the pre-treatment period is related to treatment resistance and increased risk of early relapse [34, 40]. In a study by Specht et al., evaluating tumour metabolism and blood flow changes following treatment according to the tumour subtype in 71 LABC patients, flow-metabolism mismatch was more often seen in triple negative (oestrogen receptor, progesterone receptor, and HER2-negative) breast cancer patients and this was reported to indicate a poor response to therapy [41].

The PET agent currently used in the evaluation of tumour proliferation is ¹⁸F-FLT. Thymidine uptake is a specific indicator of tumour cell proliferation. In primary and metastatic breast cancers, large primary tumours with metastatic axillary lymph nodes in particular, are defined by increased FLT uptake [42]. It has been reported that the effect of chemotherapy can be predicted by FLT-PET two weeks after one cycle of chemotherapy has been completed [43]. High glucose metabolism is not always correlated with increased tumour proliferation [44]. Therefore, an increased number of studies which evaluate tumour glucose metabolism and cellular proliferation together would be helpful to predict response to chemotherapy for different tumour characteristics.

RestagIng

The correct evaluation of the spread of the disease is important in the choice of a more effective treatment strategy and to obtain successful results. FDG-PET has great importance in defining the correct treatment method in recurrent or advanced breast cancer patients [44]. Raised tumour markers in particular may detect recurrence, apart from occult disease, in suspicious cases or where conventional methods or physical examination results are negative [45, 46]. It is useful in previously treated or symptomatic breast cancer patients for the differentiation of secondary effects with locoregional recurrence of radiotherapy or surgery [44, 47]. In cases where there is suspicion of locoregional recurrence, the determination of the internal mammarian node is a facilitating factor for the spread of the disease to a wider area [48, 49]. In the determination of the internal mammarian node, PET sensitivity and specificity have been found to be 85 and 90%, respectively, and CT sensitivity and specificity 50 and 83%, respectively [50]. It is known that locoregional recurrence and distant metastasis are seen more often in LABC. One of the most frequent areas of metastasis in breast cancer is the bones [44]. Although bone scintigraphy is a sensitive method of determining bone metastases, it is not sufficient to detect purely osteolystic or lesions confined to the bone marrow cavity [51]. FDG PET seems to be an adequate method in the determination of osteolytic metastases [52]. This shows the complementary role of bone scintigraphy and FDG PET in the determination of bone metastasis in breast cancer.

ConclusIons

The role of PET/CT in LABC can be summarised under 4 headings. Firstly, that FDG-PET and ­­PET/CT are not recommended for routine staging of breast cancer, particularly in the early stage. However, FDG PET/CT is a useful method to evaluate the extent of the disease in patients with LABC. It can identify unsuspected regional nodal disease such as parasternal and mediastinal lymph nodes which are detected more frequently in LABC. Secondly, NACT has become the standard therapy modality for patients with LABC. Tumour response following NACT has prognostic importance for disease-free survival and overall survival duration. Functional imaging with FDG-PET can indicate the tumour cell response before the radiological tumour response can be detected. A reduction in FDG uptake following a few cycles of chemotherapy is a strong indicator of response. Thirdly, apart from tumour glucose metabolism, the evaluation of blood flow and cell proliferation together may provide more information about the response to chemotherapy and tumour biology. Lastly, FDG PET is generally more sensitive than conventional methods in the determination of locoregional recurrence and distant metastases. It is therefore an appropriate method which can be used for the accurate determination of the spread of the disease.

ConflIct of Interest

There is no conflict of interest.

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