The diagnostic test accuracy of magnetic resonance imaging (MRI) was compared with that of 18F-fluoro-2-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging in assessment of response to neoadjuvant chemotherapy (NAC) in breast cancer. In the intra-NAC setting, FDG-PET/CT imaging outperformed MRI with fairly similar pooled sensitivity and higher specificity. However, MRI appeared to have higher diagnostic accuracy than FDG-PET/CT imaging when performed after the completion of NAC, with significantly higher sensitivity.
Keywords: Magnetic resonance imaging, 18F-fluoro-2-glucose-positron emission tomography/computed tomography, Breast cancer, Neoadjuvant chemotherapy, Meta-analysis
Abstract
Introduction.
This study compared the diagnostic test accuracy of magnetic resonance imaging (MRI) with that of 18F-fluoro-2-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging in assessment of response to neoadjuvant chemotherapy (NAC) in breast cancer.
Methods.
A systematic search was performed in PubMed and EMBASE (last updated in June 2015). Studies investigating the performance of MRI and FDG-PET or FDG-PET/CT imaging during or after completion of NAC in patients with histologically proven breast cancer were eligible for inclusion. We considered only studies reporting a direct comparison between these imaging modalities to establish precise summary estimates in the same setting of patients. Pathologic response was considered as the reference standard. Two authors independently screened and selected studies that met the inclusion criteria and extracted the data.
Results.
A total of 10 studies were included. The pooled estimates of sensitivity and specificity across all included studies were 0.71 and 0.77 for FDG-PET/CT (n = 535) and 0.88 and 0.55 for MRI (n = 492), respectively. Studies were subgrouped according to the time of therapy assessment. In the intra-NAC setting, FDG-PET/CT imaging outperformed MRI with fairly similar pooled sensitivity (0.91 vs. 0.89) and higher specificity (0.69 vs. 0.42). However, MRI appeared to have higher diagnostic accuracy than FDG-PET/CT imaging when performed after the completion of NAC, with significantly higher sensitivity (0.88 vs. 0.57).
Conclusion.
Analysis of the available studies of patients with breast cancer indicates that the timing of imaging for NAC-response assessment exerts a major influence on the estimates of diagnostic accuracy. FDG-PET/CT imaging outperformed MRI in intra-NAC assessment, whereas the overall performance of MRI was higher after completion of NAC, before surgery.
Implications for Practice:
The timing of therapy assessment imaging exerts a major influence on overall estimates of diagnostic accuracy. 18F-fluoro-2-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) imaging outperformed magnetic resonance imaging (MRI) in intra-neoadjuvant chemotherapy assessment with fairly similar pooled sensitivity and higher specificity. However, MRI appeared to be more accurate than FDG-PET/CT in predicting pathologic response when used in the post-therapy setting.
Introduction
Neoadjuvant chemotherapy (NAC) has been increasingly used in the management of patients with breast cancer [1, 2] and is well established in patients with locally advanced breast cancer. When successful, NAC enables the patient to undergo breast-conserving surgery rather than mastectomy, by reducing the size of the tumor [3]. The effectiveness of NAC is an important consideration in the management breast cancer. Early and accurate prediction of tumor response to NAC may help in individualizing a treatment regimen and avoiding ineffective chemotherapy [3–5].
Patients who achieve a pathologic complete response (pCR) following NAC are expected to have improved outcomes compared with those who do not [6]. The accurate preoperative assessment of residual tumor may guide surgical resection when negative margins are achieved and allows a less-invasive surgical procedure in those with pCR. The postoperative histopathologic evaluation remains the gold standard for NAC therapeutic response assessment in breast cancer [7]. Although several studies have attempted to determine the optimum imaging modality to evaluate the response to NAC before surgery, there is still debate surrounding the most accurate imaging for early detection of pathologic complete response [3, 4].
Various conventional imaging modalities are used in the preoperative setting, including mammography, ultrasound, and magnetic resonance imaging (MRI). MRI has been shown to correlate better with pathologic breast tumor size [8, 9]. MRI has been increasingly used and recommended as an accurate imaging for NAC response evaluation in patients with operable breast cancer [10, 11]. However, a potential limitation of MRI imaging is its inability to distinguish viable tumor tissue from fibrotic scar tissue. Recent studies have proposed an evolving role for 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging in early assessment of tumor response [3, 12]. FDG-PET/CT imaging is able to quantitatively assess metabolic changes in tumors, which occur much earlier in the course of a tumor’s response to chemotherapy [13]. These metabolic indices may not always agree with the dynamic contrast-enhanced MRI parameters such as blood flow and microvascular permeability [13]. In particular, the change in standardized uptake value measurement on FDG-PET/CT imaging has been shown to be a relatively accurate predictor of pathologic response after NAC in patients with breast cancer [3, 12, 14].
Currently, there is no clear consensus regarding the comparative effectiveness of MRI and FDG-PET/CT imaging for accurate response assessment to NAC in patients with breast cancer. Although several studies investigated the diagnostic performance of either MRI or FDG-PET/CT imaging alone in therapy response assessment of breast cancer, there is high heterogeneity in methodological designs used in these studies [1, 3, 4, 13]. A number of recent accuracy studies compared the ability of the imaging parameters of both MRI and FDG-PET/CT in predicting response to NAC in breast cancer in the same setting of patients [1, 13–19]. However, the varying results and relatively small patient population in most of these studies make the comparison of MRI and FDG-PET/CT imaging inconclusive.
The purpose of this meta-analysis was to compare the diagnostic performance of MRI and FDG-PET or FDG-PET/CT imaging in predicting response to NAC in patients with breast cancer. We considered only studies reporting a direct comparison between these imaging modalities, to establish precise summary estimates of diagnostic accuracy for MRI and FDG-PET/CT imaging in the therapy assessment workup of patients with breast cancer treated with NAC.
Materials and Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed for performing the current systematic review and meta-analysis.
Search Strategy
Systematic electronic searches of the PubMed and EMBASE libraries were performed to identify relevant published studies comparing the diagnostic performance of FDG-PET/CT scanning and MRI for evaluation of pathologic response to neoadjuvant chemotherapy in patients with breast cancer. The search strategy was based on the following combination of key words: (a) “PET” or “Positron emission tomography” or “positron emission tomography and computed tomography “or “FDG” or “18 f fluorodeoxyglucose”; (b) “MRI” or “magnetic resonance imaging”; (c) “breast cancer OR “locally advanced breast cancer” or “breast carcinoma” or “breast neoplasia”; (d) “neoadjuvant” or “primary” or “preoperative” or “response” or “induction”; (e) “sensitivity” or “specificity” or “diagnostic accuracy”.
We used a comprehensive search strategy without any restrictions on date, language, or country of origin. The search was updated on June 17, 2015, without a beginning date limit.
Criteria for Considering Studies for This Review
Studies investigating the performance of imaging for evaluating response to NAC in patients with histologically proven breast cancer were eligible for inclusion if (a) the imaging response was monitored with both MRI and FDG-PET or FDG-PET/CT imaging during or after completion of treatment; (b) the criteria to classify the imaging results as positive or negative were recorded; (c) postoperative pathologic result (pCR vs. non-pCR) was considered as the reference standard; and (d) enough data were reported to extract the number of true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) results.
Selection of Studies, Data Extraction and Management
All records identified from the electronic search were reviewed independently by two authors. Review articles, editorials, case reports, and irrelevant citations were excluded in the initial assessment. Full texts of the remaining articles were then retrieved and analyzed by two authors for final inclusion. When the full text was not available, we contacted authors for the potentially eligible abstracts, requesting them to provide the relevant information necessary to resolve the uncertainty [20, 21]. We minimized patient overlap by only selecting the most recent published study when more than one paper was published from the same institution [22].
Two authors independently extracted the following data: bibliographic information, patient characteristics, histopathology result, receptor status of tumor, type of NAC, index test characteristics, timing of scans, imaging response interpretation criteria, reference standard, and the prevalence of pCR. The number of TP, FP, TN, and FN scans were extracted from each included study to construct 2 × 2 contingency tables. The diagnostic performance of both MRI and FDG-PET/CT imaging for predicting residual disease was assessed by cross-relating index test results and the reference standards. All data extracted by two review authors were compared in each step, and any discrepancies were resolved through discussion or by a third author.
Assessment of Methodological Quality
The methodological qualities of the eligible studies were assessed using a modified version of the QUADAS tool (QUADAS-2; University of Bristol, Bristol, U.K., http://www.bristol.ac.uk/social-community-medicine/projects/quadas/quadas-2/) as recommended by Cochrane Collaborations. The tool consists of four domains covering “patient selection,” “index test,” “reference standard,” and “flow and timing.” Each domain appraises the risk of bias and applicability of the study through a series of questions. Two authors independently assessed study quality. Disagreements were mediated by consensus.
Statistical Analysis and Data Synthesis
We used 2 × 2 contingency tables to calculate sensitivity and specificity for each index test in all included studies using RevMan 5.3 (ReviewManager, 2013; The Cochrane Collaboration, London, U.K., http://tech.cochrane.org/revman/). The coupled forest plots and the summary receiver operator characteristic (SROC) curves were created to display the variations in the results of the individual studies. To quantify the degree of heterogeneity in studies, an I2 index was measured. I2 lies between 0 and 100 and the respective values around 0, 25, 50, and 75 indicate no, low, moderate, and high heterogeneity, respectively, among studies [23]. SROC space is defined by sensitivity (y-axis) and specificity (x-axis), respectively, and each data point represents one particular study. The pooled sensitivity and specificity with 95% confidence intervals (CIs) were estimated by CMA software (Comprehensive Meta-analysis, 2013; Biostat, Englewood, NJ, https://www.meta-analysis.com). The random-effects models were used for synthesizing meta-analytic data to deal with the anticipated heterogeneity. We further performed a subgroup analysis according to the time of assessment (intra-NAC vs. post-NAC).
Results
Literature Search
Details of the study selection process for the meta-analysis are shown in Figure 1. A total of 370 exclusive records were identified through a comprehensive PubMed and EMBASE library search, of which 346 were excluded by initial screening of titles and abstracts. To assess the eligibility of the remaining 24 records, we retrieved the corresponding full texts (21 articles) or contacted the study authors (3 abstracts) for additional information. Ultimately, a total of 10 studies met our inclusion criteria [12–21].
Figure 1.
Study flow diagram.
Abbreviations: FDG, 18F-fluoro-2-glucose; MRI, magnetic resonance imaging; PET, positron emission tomography.
Study Characteristics and Methodological Quality Assessment
The study design, patient characteristics and treatment, index test, imaging, and pathologic response assessment classification of the included studies are summarized in Tables 1 and 2.
Table 1.
The characteristics of the included studies
Table 2.
Additional characteristics of the included studies
Among the 10 included studies, 6 were prospective and 4 were retrospective. All studies compared the diagnostic performance of FDG-PET/CT imaging and MRI in NAC-response assessment of breast cancer. Seven studies used FDG-PET/CT imaging as an index test and three studies used FDG-PET imaging. In all studies except one, the index tests were performed both at baseline and during or after completion of NAC therapy. Three studies investigated the performance of interim-NAC imaging (between two and four cycles), and seven investigated the performance of imaging after completion of NAC and before surgery.
In all studies, the treatment was NAC followed by a surgical resection of breast cancer (breast conserving or mastectomy). Patients were treated with different courses and cycles of NAC among the studies. The result of postsurgical pathologic response (pCR vs. non-pCR) was considered as a reference standard. The index test was interpreted as positive or negative according to the authors’ definition in each study, and the details were summarized in Table 2. The risk of bias and the applicability concerns among the included studies according to the QUADAS-2 domains is shown in supplemental online Figure 1.
Findings
Figure 2 shows the paired forest plot for sensitivity and specificity of MRI compared with FDG-PET/CT imaging. The sensitivity of MRI across the included studies ranged from 0.64 to 1.0, whereas specificity ranged from 0.21 to 1.0. The pooled estimates of sensitivity and specificity for MRI were 0.88 (95% CI: 0.76–0.95) and 0.55 (95% CI: 0.41–0.68), respectively.
Figure 2.
Forest plot of sensitivity and specificity of therapy assessment by FDG-PET/CT imaging and MRI in patients with breast cancer who were treated with neoadjuvant chemotherapy, across individual studies.
Abbreviations: CI, confidence interval; CT, computed tomography; FDG, 18F-fluoro-2-glucose; FN, false negative; FP, false positive; MRI, magnetic resonance imaging; PET, positron emission tomography; TN, true negative; TP, true positive.
The sensitivity of FDG-PET or FDG-PET/CT imaging across the included studies ranged from 0.21 to 0.93, whereas specificity ranged from 0.33 to 1.0. The pooled estimates of sensitivity and specificity of FDG-PET or FDG-PET/CT imaging for detection of residual disease after NAC therapy were 0.71 (95% CI: 0.52–0.85) and 0.77 (95% CI: 0.58–0.89), respectively. The pooled estimates of sensitivity were significantly higher in those studies that used combined FDG-PET/CT imaging compared with those using FDG-PET imaging alone (Table 3). The sensitivity and specificity values displayed moderate to high heterogeneity across the included studies (Fig. 2; Table 3).
Table 3.
Pooled estimates of sensitivity and specificity of MRI and FDG-PET/CT in detection of residual disease after neoadjuvant chemotherapy of breast cancer
Figure 3 illustrates the sensitivity and specificity of the individual studies in a SROC space for FDG-PET or FDG-PET/CT imaging and MRI. Figure 3A shows that the overall diagnostic accuracy of MRI was higher than the FDG-PET or FDG-PET/CT imaging, because its curve dominates across all specificity values. After excluding studies using FDG-PET imaging alone, the SROC curve analysis depicts fairly similar performance for FDG-PET/CT imaging and MRI (Fig. 3B).
Figure 3.
Summary receiver operator characteristic curve analysis outlines diagnostic performance of MRI versus FDG PET or PET/CT imaging in all studies. Sizes of points indicate the sample size in each study. (A): MRI versus FDG-PET/CT imaging. (B): MRI versus FDG-PET imaging versus FDG-PET/CT imaging.
Abbreviations: CT, computed tomography; FDG, 18F-fluoro-2-glucose; MRI, magnetic resonance imaging; PET, positron emission tomography.
Furthermore, studies were subgrouped according to the time of therapy assessment (i.e., whether it was performed during [intra-NAC] or after [post-NAC] the completion of NAC scans).
The pooled sensitivity for MRI was fairly similar, both in intra-NAC (0.89; 95% CI: 0.66–0.97) and post-NAC assessment (0.88; 95% CI: 0.71–0.96). However, the specificity of MRI improved when it was performed after completion of NAC compared with intra-NAC assessment (0.63 [95% CI: 0.51–0.74] vs. 0.42 [95% CI: 0.20–0.68]). In comparison with MRI, our subgroup analysis indicated that FDG-PET/CT imaging showed similar sensitivity (0.91; 95% CI: 0.86–0.95) and higher specificity (0.69; 95% CI: 0.25–0.93) during intra-NAC therapy assessment of tumor response. The diagnostic performance of FDG-PET/CT imaging appeared to be higher in intra-NAC therapy assessment but lower when performed after completion of NAC, when compared with MRI (Fig. 4). The results of the subgroup analysis are summarized in Table 3.
Figure 4.
Summary receiver operator characteristic curve analysis outlines the diagnostic performance of MRI versus FDG-PET/CT imaging in intra-neoadjuvant chemotherapy (NAC) assessment (A) and post-NAC assessment (B).
Abbreviations: CT, computed tomography; FDG, 18F-fluoro-2-glucose; MRI, magnetic resonance imaging; PET, positron emission tomography.
Discussion
Locally advanced breast cancer is often treated with a combined modality approach including preoperative NAC followed by surgery and radiation [1]. Assessment of the presence or absence of residual tumor after NAC could substantially impact the subsequent management, guiding the extent of surgery, and possibly minimizing the morbidity in patients with breast cancer [1, 15, 24]. According to the current guideline, surgery is required after NAC to obtain local control by removing the residual tumor and affected nodes, allowing for definitive assessment of the response to NAC. However, preoperative assessment of patients who achieve pCR allows less-invasive surgery, particularly in terms of the node. In addition, a precise method of assessing tumor response could assist the clinician to alter the NAC regimen early in the course of treatment in patients who have not achieved pCR after NAC [25].
Several studies have evaluated the role of different imaging parameters in predicting pathologic response to NAC and identifying nonresponders earlier among patients with breast cancer [3, 4, 9, 12]. Both FDG-PET/CT imaging and MRI are used for assessing the response to NAC. We conducted a comprehensive meta-analysis, restricting our inclusion criteria to only those studies that made direct comparisons between FDG-PET or FDG-PET/CT imaging and MRI in the same patient population with breast cancer. The results of our study have the potential to provide clinicians with further insight into the usefulness of FDG-PET/CT imaging and MRI in monitoring treatment responses to NAC in patients with breast cancer.
The pooled result of all 10 studies included in our analysis showed that MRI has higher sensitivity (88% vs. 71%) but lower specificity (55% vs. 77%) than FDG-PET imaging alone or FDG-PET/CT imaging in detecting residual disease after NAC. There was moderate to high heterogeneity in the reported values of sensitivity and specificity among the included studies for both imaging modalities. According to the result of the SROC curves, MRI is more accurate than FDG-PET/CT imaging for predicting pathologic response to NAC in patients with breast cancer. However, after excluding studies that performed PET imaging alone, FDG-PET/CT imaging and MRI appear to have comparable accuracy in predicting therapy response assessment (Fig. 2).
A previous meta-analysis including 17 studies and 781 subjects (10 FDG-PET/CT imaging, 7 FDG-PET imaging) indicated that FDG-PET/CT imaging has reasonable performance for evaluation of response to NAC, with a pooled sensitivity of 0.84 (95% CI: 0.80–0.88) and specificity of 0.71% (95% CI: 0.67–0.76) [3]. In their study, there were no statistically significant differences between FDG-PET/CT imaging and PET imaging in SROC analysis, although the accuracy of FDG-PET/CT imaging was higher than that of PET imaging alone [3]. Another meta-analysis, which included 25 studies, reported a pooled sensitivity of 0.63 (95% CI: 0.56–0.70) and specificity of 0.91 (95% CI: 90.89–0.92) for MRI in predicting pathologic complete response to NAC [26]. They reported the response-based diagnostic performance and defined sensitivity as the ability to identify patients achieving pCR after NAC. In the present study, we defined sensitivity as the ability to detect residual tumor after NAC. Thus, different definitions used to calculate sensitivity and specificity should be considered in interpretation and comparison of the outcomes.
There is currently no consensus on the optimal timing of imaging for response assessment to NAC, although several studies attempted to investigate the optimum time point. Imaging response assessment can be performed at different time intervals during NAC (e.g., at baseline and after 1–2 cycles) or after completion of NAC and shortly before surgery. To address this, we performed a subgroup analysis and dichotomized the studies into intra-NAC and post-NAC assessment groups. Our results showed that in the intra-NAC setting, FDG-PET/CT imaging outperformed MRI in predicting pathologic response, with fairly similar pooled sensitivity (91% for PET/CT imaging and 89% for MRI) and higher specificity (69% for PET/CT imaging and 42% for MRI). However, in the post-NAC setting, MRI appears to have significantly higher sensitivity (63% vs. 80%) but lower specificity (88% vs. 57%) than FDG-PET/CT imaging. Considering MRI alone, we found that the specificity partially improved when MRI is performed after completion of NAC without a loss in the sensitivity. This suggests that post-NAC may be a more appropriate time to perform MRI than during the treatment course. A possible explanation may be that the anatomic imaging studies do not account for differentiation between viable tumor and fibrotic scar tissue, particularly in the early course of treatment [13]. Furthermore, there is a considerable delay between the time when chemotherapy is initiated and the time when tumor shrinkage is actually seen [27].
On the other hand, PET imaging could potentially be useful to differentiate responders from nonresponders early in the course of chemotherapy. Several studies corroborated the high accuracy of FDG-PET/CT imaging in monitoring early response to NAC [27–32]. A recent study with 107 patients with breast cancer who had sequential FDG-PET/CT imaging at baseline and during NAC (n = 270 scans) suggested that FDG-PET/CT imaging after 3 cycles of NAC appears to be optimally predictive of pCR compared with the earlier time (after 1 cycle of NAC) in triple-negative tumors [33]. However, FDG-PET/CT imaging was not found to be significantly associated with pCR in HER-2-positive tumors. Furthermore, the study indicated that intra-NAC assessment with FDG-PET/CT imaging (between two and four cycles) showed considerably higher sensitivity than post-NAC assessment with partially lower specificity. Arguably, this may be a more valuable time to assess patients’ treatment regimen, if needed, to avoid ineffective chemotherapy. However, the result of subgroup analysis in our study must be interpreted with caution because only three studies with heterogeneity among them have been included.
In addition, recent studies showed that therapy response monitoring in patients with breast cancer is considerably dependent on the receptor status of the tumors. The performance of imaging techniques was shown to differ markedly among different breast cancer subtypes [12, 34, 35]. A previous study of 188 patients with breast cancer with baseline and interim MRI suggested that MRI during NAC was effective in triple-negative or HER-2-positive disease but not in “estrogen receptor (ER)-positive/HER-2 negative” patients [34]. A recent study of 169 patients with breast cancer with baseline and interim FDG-PET/CT imaging suggested that the quantitative PET indexes that are correlated best with pathologic response vary by breast cancer phenotype. Changes in the maximum standardized uptake value (SUVmax) or total lesion glycolysis were best correlated with response to NAC in triple-negative and “ER-positive/HER-2 negative” breast cancers, while absolute SUVmax was more useful for response assessment in HER-2-positive breast cancers [35]. In this setting, one of the limitations of our study is that we were unable to perform subgroup analysis based on receptor subtypes, because a limited number of studies with different histology and receptor status were included.
Another limitation of this study is the lack of consensus on the defined criteria and cut points used for response evaluation across included studies. A previous meta-analysis investigated the potential variables that could affect MRI performance in NAC-response assessment of breast cancer. The specificity of MRI was found to be lower when test negativity thresholds were more stringent. Accuracy estimates were also varied according to the definition of pCR: They were lower in “standard” pCR definitions than “near-pCR” definitions [4]. This emphasizes the need for a standardized method to determine a response definition and to further strengthen comparative research in this field.
Conclusion
This meta-analysis of the available studies with MRI and FDG-PET/CT imaging for neoadjuvant chemotherapy-response assessment indicates that the overall performance of MRI is more accurate than FDG-PET/CT imaging in predicting pathologic response when used in post-therapy setting, whereas FDG-PET/CT imaging outperformed MRI in intratherapy settings. The timing of the therapy assessment imaging exerts a major influence on overall estimates of diagnostic accuracy.
See http://www.TheOncologist.com for supplemental material available online.
Supplementary Material
Author Contributions
Conception/Design: Sara Sheikhbahaei, Rathan M. Subramaniam
Provision of study material or patients: Sara Sheikhbahaei, Tyler J. Trahan, Rathan M. Subramaniam
Collection and/or assembly of data: Sara Sheikhbahaei, Tyler J. Trahan, Jennifer Xiao
Data analysis and interpretation: Sara Sheikhbahaei, Rathan M. Subramaniam
Manuscript writing: Sara Sheikhbahaei, Tyler J. Trahan, Jennifer Xiao, Mehdi Taghipour, Esther Mena, Roisin M. Connolly, Rathan M. Subramaniam
Final approval of manuscript: Sara Sheikhbahaei, Tyler J. Trahan, Jennifer Xiao, Mehdi Taghipour, Esther Mena, Roisin M. Connolly, Rathan M. Subramaniam
Disclosures
Roisin M. Connolly: Novartis, Genentech, Merrimack, Clovis Oncology, Puma Biotech (RF); Rathan M. Subramaniam: GE Healthcare, Philips Healthcare (C/A), Bayer HealthCare (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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