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Response monitoring of breast cancer patientsreceiving neoadjuvant chemotherapy using breast MRI – a review of current knowledge

Response monitoring of breast cancer patientsreceiving neoadjuvant chemotherapy using breast MRI... Background: Breast MRI is the most accurate method for evaluating treatment response in breast cancer patients receiving neoadjuvant chemotherapy (NAC). Methods: In this review, the current knowledge with respect to response monitoring of breast cancer patients receiving NAC using MRI is presented. Both standard and more advanced approaches are discussed, including potential pitfalls and future developments. Results: Many parameters have been proposed in the past for early response monitoring of NAC by MRI. Tumour size and volume, and apparent diffusion coefficient values seem most promising and are best validated. However, proper response criteria are still lacking. Breast MRI accuracy for pathologic complete response prediction has moderate sensitivity, but high specificity. Diffusion weighted MR imaging might be able to compensate this shortcoming. However, residual disease assessment after NAC is equally important. Studies have shown that assessment of residual disease by MRI is good, but can be influenced by several factors, such as breast cancer subtype or treatment regimen. Both overestimation and underestimation of residual disease by breast MRI have been reported, and both can have important clinical impact for the individual patient. Conclusion: MRI is the best imaging modality to monitor treatment response in breast cancer patients receiving NAC. However, further research is required to investigate potential confounding factors and its pitfalls. Key words: Breast cancer, breast neoplasm, MRI, pathologic complete response, neoadjuvant chemotherapy Background frequently used. In general, pCR is den fi ed as the absence Neoadjuvant chemotherapy (NAC) is defined as the of any residual invasive tumour cells in the original tumour administration of chemotherapy to treat invasive breast bed. However, the den fi ition of pCR may vary between cancer before any local treatment, such as surgery. At different grading systems, mainly with respect to the first, NAC was used for treatment of locally advanced inclusion or exclusion of any residual ductal carcinoma in breast cancer. Nowadays, NAC is more and more used situ (DCIS) surrounding the culprit region, or with respect in early stages of breast cancer, for example to enable to the presence or absence of any axillary lymph node breast conserving therapy (for patients who were originally metastases. Pathological complete response after NAC scheduled for mastectomy), to enable less complicated has shown to be a prognostic factor for overall better surgery in cases where skin or pectoral muscle is involved survival, but also for disease-free survival and recurrence- (Figure 1), or to achieve better cosmetic results after surgery. free survival [2]. Studies have shown that there is no significant difference Many examinations have been proposed to evaluate in survival or overall disease progression between patients response monitoring in breast cancer patients receiving receiving adjuvant or neoadjuvant chemotherapy [1]. NAC, such as physical examination, mammography, and The use of NAC enables physicians to assess tumour ultrasound. However, their accuracy was only modest [3]. response in vivo. Patients treated with NAC can demonstrate There is increasing evidence that magnetic resonance stable or progressive disease, or remission and even imaging (MRI) is an excellent imaging tool to monitor complete response. Complete response is den fi ed as the response to NAC, for both early response monitoring and absence of any residual breast cancer, and is usually assessed the assessment of residual disease extent. In comparative by pathological analysis of acquired tissue samples. In this studies it has been shown that MRI is superior to physical context, the term ‘pathological complete response’ (pCR) is examination, ultrasound, and mammography in response © 2012 Lobbes et al; licensee Herbert Publications Ltd. This is an open access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0 ),This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 Figure 2. All images are contrast-enhanced, T1-weighted MR images. Top row shows baseline MR examinations, whereas the bottom row shows MR examinations aer co ft mpletion of neoadjuvant chemotherapy. Left column shows an example of complete response, in which the tumour disappeared completely and only the marker clip artifact (arrow) is still visible (Miller and Payne grade 5); middle column shows partial response, with some enhancing residual disease left (Miller and Payne grade 3); right column shows poor response (Miller and Payne grade 2). the reader with an overview of current knowledge and developments, and explore the lacks in knowledge that still remain. Die ff rent techniques for assessing early response in NAC are discussed, as well as the accuracy of MRI to assess residual disease extent and pCR. These issues are illustrated by several examples from everyday clinical practice. Early response monitoring Early response monitoring is considered to be the monitoring of disease changes after the first cycle(s) of NAC treatment. In Figure 1. (A) shows a small irregular mass close to the other words, it is the assessment of disease changes before chest wall with increased enhancement of the pectoral the completion of the entire course of NAC. muscle ascie medially (total ameter 45 mm). Aer ft With respect to early response monitoring, many studies neoadjuvantchemtherapy (B), mass size has not changed have been published, which have been summarized in a significantly, but the enhancement of muscle fascie has disappeared and a fatty line has occured between tumor tissue recent meta-analysis by our study group, and which included and chest wall, thus enabling breast conserving therapy in a a total of 15 studies until January 2012. In this review, a total patient who would otherwise undergo mastectomy. number of 31 potential MR parameters were described [5]. The MRI techniques that were most frequently used were evaluation during NAC [4]. It is able to monitor complete dynamic, contrast-enhanced MRI (DCE-MRI), diffusion response, partial response and poor response (Figure 2). weighted-imaging (DWI), and MR spectroscopy (MRS). Because NAC allows the physicians to monitor disease development in vivo, there is a need for a (preferably non- Dynamic, contrast-enhanced MRI invasive) modality that is able to assess tumour response DCE-MRI is based on the fact that breast cancers possess an during treatment. There is a need for a modality that can increased microvasculature, which is often ‘immature’ and assess response early in treatment (i.e. after only several leaky, resulting in a leakage of contrast agent through the cycles of chemotherapy), but also for a modality that can vessel walls into the interstitium. As a result, breast tumours accurately detect any residual disease left after therapy. show enhancement after contrast administration. In DCE- This review focuses on the role of magnetic resonance MRI, two separate approaches can be identified for early imaging with respect to response monitoring in breast response monitoring in NAC: pharmacokinetic modeling cancer patients receiving NAC. We attempted to provide using ‘ultrafast’ DCE-MRI and ‘standard’ contrast-enhanced 2 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 breast MRI. These techniques can either be performed alone, or combined in a dedicated sequence protocol. For the assessment of different pharmacokinetic parameters, it is mandatory that a MR sequence is used with a very small temporal resolution, usually in the order of several seconds. As a result, spatial resolution is often poor, preventing adequate assessment of lesion morphology. With respect to early response monitoring in NAC, many parameters of pharmacokinetic modeling have been proposed, such as trans K , K , and V . However, there are several characteristics of ep e pharmacokinetic modeling (which are general and not specic fi for the NAC setting) which hamper the widespread use of this Figure 3. A large, irregular mass with skin involvement is visible in approach. For example, the measurement of the arterial input the right breast. Maximum tumour diameter before treatment was function (AIF) can be difficult. The AIF is the concentration- 38 mm (arrow). Maximum tumour diameter aer t ft reatment was 32 time curve of the artery supplying the vascular bed of interest, mm (arrow). This is a diameter reduction of 16%, corresponding which in breast MRI is most commonly the internal mammary to ‘stable disease’ according to RECIST and WHO criteria. artery or aorta. For proper measurement of the AIF, a high Histopathologic analysis showed poor tumour regression, i.e. Miller and Payne grade 2. temporal resolution is essential to capture the inflow and passage of contrast in the blood stream. However, the artery that is used is often located at an important distance from the contrast-enhanced dynamic series [13]. the breast tumour. As a result, temporal resolution is reduced In a study of 216 breast cancer patients, Hylton et al., in order to fit the artery within the field-of-view. This leads evaluated changes in tumour volume and diameter after to an inaccurate assessment of the AIF and pharmacokinetic the first cycles of treatment with NAC. They observed that parameter outcomes. The parameters could also be inuenc fl ed early in treatment, maximum tumour diameter and tumour by the dose and type of the contrast agent used, and by the volume were the best parameters to predict pCR (AUC of method by which the contrast agent is administered. Finally, 0.64 and 0.70, respectively) [4]. In our systematic review, the MR sequence composition can be of inu fl ence on these we found four studies presenting AUC values, which were parameters as well [6,7]. As a result, many variables can be slightly higher and ranged from 0.73 to 0.9 [5]. Similar to the introduced in pharmacokinetic modeling, which make it pharmacokinetic parameters, the majority of the studies difficult to compare different studies. This is probably the did not suggest useful cut off values at which diagnostic most important reason why the use of pharmacokinetic accuracy would be optimal. Only Loo et al., suggested a modeling has not been widely introduced in everyday clinical cut off value of a diameter reduction of 25% between MRI practice after all these years. examinations at baseline and at first follow-up [ 14]. In their meta-analysis, Prevos et al., observed both Although evidence is still rather limited, the measurement significant and non-significant changes in both absolute of tumour volume and diameter seems promising. As an trans and relative values of K K , and V between responders additional advantage over pharmacokinetic modeling ep e and non-responders. In order to be clinically applicable, parameters, clinical breast MRI has been standardized to it would be interesting to learn what the area under the a large extent over the past years. With respect to clinical ROC curve (AUC) would be for these parameters. Based on application, measurement of tumour diameter is perhaps the AUC, a cut off value for absolute or relative changes in the simplest method of (early) response monitoring. the different parameters could be suggested in which the Nonetheless, there are several important limitations to diagnostic accuracy would be optimal. Although several these measurements. trans studies presented AUC values for K and K , this was not With respect to maximum tumour diameter ep trans available for Ve. For K and K , this AUC ranged from 0.6-0.9 measurement, the two most commonly used guidelines [8-11]. Disappointingly, only a single study suggested absolute to assess treatment response are the guidelines of the World -1 and relative cut off values of 0.39 min and 85%, respectively Health Organization (WHO) and the Response Evaluation [12]. Currently, the aforementioned limitations of this technique Criteria for Solid Tumours (RECIST). In the WHO guidelines, and the scant scientific evidence that is currently available four response categories can be identified: (1) complete prevent widespread application in everyday clinical practice. response (CR), in which no more enhancing tumour is As an alternative, ‘standard’ DCE-MRI might be used for early visible; (2) partial response (PR), which is a reduction in response monitoring. In this approach, lesion morphology diameter of ≥50%, (3) progressive disease (PD), which and extent is assessed by evaluating contrast-enhanced, T1- is an increase in tumour diameter of ≥25% and which weighted images using a dedicated breast coil and minimum rarely occurs under NAC; and (4) no changes, which is the field strength of 1.5 Tesla. Additional information can be level between PD and PR [15, 16]. The RECIST criteria also extracted by analyzing the signal-intensity time curves in divide response into four categories: CR is den fi ed as the 3 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 criteria and the variation in methods to determine tumour volumes [16] have prevented widespread use of tumour volume assessment as parameter for treatment response in breast cancer patients receiving NAC. Diffusion-weighted imaging In DWI, the random Brownian movement of water molecules is evaluated using MRI. The free (or restricted) movement of these molecules can be quantified by calculating the apparent diffusion coec ffi ient (ADC). In breast cancer, dense packing of cells results in a restricted movement of water molecules. As a result, the ADC value decreases in DWI. During NAC, cell density of the tumour generally decreases, improving water molecule movement within the tumour. As a consequence, the ADC increases during NAC if a proper response is expected. If ADC values remains stable or even decreases further, it would be suggestive for stable or progressive disease under NAC. Thus, measurement of ADC might be a suitable parameter for evaluating treatment response. In the study by Sharma et al., tumour volume, diameter and ADC value were assessed at each MRI examination. Figure 4. Two examples of cases in which tumour diameter They showed that the percentage change in ADC after the measurement might be challenging. Case (A) shows a round mass with irregular contours at baseline breast MRI. r fi st cycle of treatment was statistically significant between Aer t ft reatment, the mass has reduced and only scattered responders and non-responders, when compared with foci of enhancement are present in the tumour bed. Case tumour volume and diameter. After three cycles of NAC, (B) shows a highly irregular mass with spiculae, which sensitivity and specificity of the ADC-value for distinguishing does not significantly reduce aer t ft reatment. However, the responders and non-responders were 68% and 100%, prominent spiculations might suggest an extensive intraductal component and an accurate tumour diameter measurement is respectively [22]. a study by Fangberget et al., an ADC cut -3 2/s 2 difficult in this case. Interestingly, both cases showed a Miller off value of 1.42x10 mm (at b=750 s/mm ) was suggested and Payne regression grade of 3. as optimal value after four cycles of chemotherapy [23]. This yielded a sensitivity and specificity to distinguish responders and non-responders of 88% and 80%, respectively. A absence of enhancing tumour; PR as a decrease in tumour significant change in ADC in responders after several cycles diameter ≥30%; PD as an increase in tumour diameter ≥20%; of NAC was also observed in a study by Li et al., This change stable disease is considered to be the level between PD and could not be observed in non-responders. However, they PR (Figure 3) [16,17]. However, accurate measurement of did not suggest any kind of cut off value at which diagnostic tumour diameter can be challenging in cases which show accuracy would be optimal [24]. fragmentation of tumour during NAC, or in cases which In summary, several studies have shown the potential show a mass with surrounding areas of so-called non-mass of DWI to predict early response in breast cancer patients like enhancement (which can be associated with a more receiving NAC. However, the number of studies is still limited, extensive intraductal component (Figure 4) [18]. and the size of the various study populations is rather To cope with these difficulties, some studies have small. In addition, the use of DWI has several limitations. suggested the use of tumour volume measurements as For example, DWI has limited spatial resolution and as a treatment response parameter [4,5,16]. However, there are result, small tumour foci might be overlooked. In addition, no well-validated response criteria available for tumour breast cancer subtypes that do not form masses might be volume measurements. Some studies used the surrogate misinterpreted (i.e. ductal carcinoma in situ or invasive parameter of tumour volume measurements that was lobular carcinoma). Furthermore, DWI is a technique that is provided in the RECIST criteria appendix: PR was den fi ed highly sensitive to motion artifacts caused by (in)voluntary as a volume reduction of ≥65%, whereas PD was den fi ed patient movement, resulting in inaccurate ADC values due as an increase in tumour volume of ≥20% [19-21]. For our to imaging mismatch. Finally, DWI sequences can vary study population of interest (i.e. breast cancer patients between vendors and institutions, especially with respect receiving NAC), these response criteria are not validated in to the select b-values in this technique, which inu fl ence the large, multicenter studies and thus should be used with this ADC-value and make it difficult to compare study results limitation in mind. Until today, the lack of proper response between different groups. 4 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 Magnetic resonance spectroscopy In MRS, the molecular composition of a tissue of interest is analyzed by looking at the spectrum of resonances produced by the MR signal. This spectral ‘signature’ is used to diagnose certain metabolic disorders that are associated with tumour cells. The majority of the MR signal arises from fat and water, but small magnetic field differences can be utilized to identify additional metabolites that are present in much smaller concentrations. Relative to normal breast tissue, breast cancers have increased levels of choline-containing compounds (such as phosphocholine, glycerophosphocholine, and free choline). However, these metabolites are present in extremely small concentrations, and cannot be identified separately by MRS. Therefore, the total choline peak (tCho, at 3.2 ppm) is usually Figure 5. (A) shows a large irregular mass with heterogeneous enhancement in the lateral part of the left breast. Aer co ft mpletion of presented [16].In a study by Jagannathan et al., 67 patients with neoadjuvant chemotherapy (B), no residual enhancing tumor is left and breast cancer and 16 healthy controls were evaluated. Using only the signal void of the metal marker clip can be observed (arrow). MRS, they showed that sensitivity and specificity of MRS for Histopathological analysis of the surgical specimen showed pathologic detecting tCho in tumours was 78% and 86%, respectively complete response, i.e. Miller and Payne grade 5. [25]. Baek et al., measured tCho concentration in a study of 35 breast cancer patients receiving NAC. At first follow-up (after median of 20 days, corresponding with 1-2 cycles of NAC), changes in tCho concentrations were not significantly Residual disease extent and pathologic com- different between patients achieving pCR and patients not plete response achieving pCR. However, at second follow-up (median of 69 After completion of all cycles of NAC, MRI can also be days, corresponding to 3-4 cycles of NAC), tCho concentrations used to assess the extent of residual disease, which can decreased by 100% in patients achieving pCR (versus 67% be extremely useful for the surgeon when planning the decrease in patients not achieving pCR, p=0.01) [10]. surgical treatment strategy. It also contains prognostic However, the analysis of the MRS data can be time- information, since the achievement of pCR is associated consuming and there are many technical difficulties in with better long-term survival. However, the latter can assessing the very low concentrations of tCho in vivo. Other be drawn better from the histopathological analysis of confounding factors are the variable fat content within the the surgical specimen. breast, field inhomogeneity caused by air-tissue interfaces and marker clips artifacts (inserted after biopsy) [16]. Until now, Residual disease extent these limitations prevented a widespread clinical use of this After the completion of NAC, residual disease is still present technique to monitor early response in patients receiving NAC. in the majority of patients. PCR is only achieved by 6-15%, for example in anthracycline-based regimens. PCR rate Other parameters can increase up to 30% when taxanes are added [26]. In the recent past, a great many parameters have been Although several recent studies have focused on the introduced to monitor early response in the NAC setting. (early) prediction of pCR by MRI, they failed to provide Next to the aforementioned parameters, these include for information about residual disease (which is still present example early contrast uptake, signal intensity ratio, maximum in the majority of patients receiving NAC). Many studies Gd-DTPA concentration, relative blood volume, relative blood have presented correlation coefficients between size flow, mean transit time, signal intensity time curves, relative measurements assessed by MRI compared to pathological signal enhancement after 3, 12, 17, 90, and 90-450 seconds, tumour size measurement [23,27,42]. In an analysis of R2* value, intrinsic T2* relaxivity, differences in R2* values, these studies, we calculated that the median correlation initial area under the gadolinium curve after 60 seconds coefficient were 0.698, with a range of 0.21-0.982 (Lobbes, (IAUGC ), BI-RADS lexicon descriptors, change in tumour unpublished data). However, most of the studies did not morphology, early enhanced ratio during the first phase sufficiently discuss the agreement between tumour size after contrast administration, maximal enhancement ratio, measurements as assessed by MRI and histopathology. time to maximal enhancement, and peak enhancement ratio Excellent correlation coefficients do not automatically [5]. However, these parameters have only been studied in 1 reflect excellent agreement. or 2 studies with rather limited population sizes. As a result, In summary, the ability of breast MRI to assess residual there is currently no sufficient evidence that any of these disease extent seems adequate, but in the various studies parameters can be used in clinical practice to monitor early on this topic potential confounders for the accuracy of MRI response in patients receiving NAC for breast cancer. were discovered, which are summarized in the ‘Confounding 5 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 potential pitfalls’ paragraph). In contrast, the sensitivity of DWI to predict pCR seems better, albeit at slightly lower specificity. In theory, the combined use of DWI and contrast- enhanced MRI could further improve the accuracy of MRI to predict pCR, since one MR technique might compensate the shortcomings of the other. However, no studies have been published that have demonstrated the added value of both techniques combined. Confounding factors and potential pitfalls Figure 6. Baseline contrast-enhanced T1-weighted MR image Marker artifacts (A), showing a heterogeneously enhancing irregular mass in the left breast with a centrally placed marker clip. Note the During the course of NAC, tumour might regress in diameter adjacent skin thickening. Aer co ft mpletion of neoadjuvant and become more difficult to visualize by imaging. In the chemotherapy (B), the tumour bed reduced slightly, and best case scenario, complete response is observed and limited enhancement was observed in this area. Detailed the tumour is not detectable at all anymore. Therefore, outtake of this area (C) shows the signal void caused by all patients receiving NAC and in which breast-conserving the marker (*), surrounded by two rims of increased signal intensity (arrows). This might suggest or obscure small foci therapy might be considered afterwards should have of residual disease. The configuration of the increased signal their tumour marked. In general, this is done by placing intensity parallel to the signal void suggests a susceptibility a clip, marker or small coil inside the tumour. However, artifact. The final conclusion of this case was ‘probably these clips cause local field inhomogeneities when MRI is complete response, but residual disease cannot be ruled performed, causing susceptibility artifacts in the tumour out’. Histopathologic analysis showed complete pathologic response (Miller and Payne grade 5). bed itself. These artifacts are usually observed as a signal void (which represents the marker itself), surrounded by a rim of increased signal intensity, which is often more factors and potential pitfalls’ paragraph. pronounced than the enhancing fibroglandular tissue or residual disease. However, these small areas of increased Pathologic complete response (pCR) signal intensity might be difficult to distinguish from small Pathologic complete response is defined as the absence foci of residual disease (Figure 6). Subtraction of contrast- of any invasive tumour cells in the surgical specimen, after enhanced MR images might aid in reducing these false the completion of NAC. However, pathological grading positive findings. systems to assess treatment response vary widely, also in their den fi ition of pCR. Breast cancer subtypes and chemotherapy regimen In treatment response monitoring by MRI, the achievement In recent studies, it was observed that the accuracy of of pCR is suggested by the absence of any residual enhancing breast MRI to assess residual disease and predict pCR tumour tissue after contrast administration (Figure 5). At this depended on breast cancer subtypes, but also on the stage, histopathological analysis has not yet been performed chemotherapy regimen that was used. For example, it was and therefore we prefer the term ‘complete radiological observed that MRI was able to predict pCR more accurately response’ in our institution. In a meta-analysis by Yuan et al., in patients having HER2-positive tumours when compared the pooled weighted estimates of sensitivity and specic fi ity to HER2-negative tumours. In the latter case, a higher false- of breast MRI to predict pCR were 0.63 (range 0.56-0.70) and negative rate was observed, especially when receiving 0.91 (range 0.91-0.92), respectively [43]. In a meta-analysis of anti-angiogenic drugs [40,45]. It was also observed that the 34 studies by Wu et al., the ability of both DWI and contrast- average size discrepancy between MRI and pathology was enhanced MRI to predict pCR was evaluated. They found that greater in tumours demonstrating limited Ki-67 staining sensitivity and specificity for contrast-enhanced MRI was when compared to tumours demonstrating increased 0.68 (95% confidence interval (CI) 0.57-0.77) and 0.91 (95% Ki-67 staining [40]. In addition, Loo et al., concluded that CI 0.87-0.94), respectively. For DWI, sensitivity and specificity response monitoring using breast MRI is accurate in were 0.93 (95% CI 0.82-0.97) and 0.82 (95% CI 0.70-0.90), patients having triple-negative or HER2-positive tumours. respectively [44]. The minor variations in these observations However, they found it was inaccurate in ER-positive/HER2- can be explained by the minor differences in inclusion and negative subtypes [46]. Finally, Denis et al., showed that exclusion criteria that were applied in their reviews. residual tumour size was often underestimated by MRI in Based on these critical reviews, it can be concluded that taxane-containing regimens, which is probably caused the accuracy of contrast-enhanced MRI to predict pCR after by the antivascular effects of this type of chemotherapy, NAC has a high specificity, but only moderate sensitivity. which results in less enhancement on contrast-enhanced Several confounding factors were observed that might breast MRI [47]. These findings suggest that breast cancer inu fl ence its accuracy (see also the ‘Confounding factors and subtype and the type of NAC is of inu fl ence on breast MRI 6 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 accuracy. Therefore, larger studies are warranted to further could be continued as planned. Patients that showed only clarify which factors effect MRI’s accuracy and in what way partial response might benefit from a more prolonged (positive or negative). chemotherapy treatment (i.e. more cycles of chemotherapy), in order to achieve a higher pCR rate. In non-responders, Overestimation and underestimation or even progressive disease, one might reconsider surgical In monitoring response to NAC by MRI, both overestimation intervention at an earlier stage in treatment or at least and underestimation were observed in various studies. Both prevent the administration of toxic agents from which the discrepancies can have an important impact on patient care. patient does not benet fi . However, the application of breast Overestimation of tumour size by MRI can be caused by MRI for early response monitoring is still developing at this surrounding sclerosis or necrosis, the presence of multiple moment, and so far, no studies have been published that scattered lesions or foci, reactive inflammation caused by altered their treatment plan based on the breast MRI findings. tumour response and subsequent healing, and the presence The accuracy of breast MRI to predict pathologic complete of accompanying ductal carcinoma in situ [31,48,49]. If the response has a moderate sensitivity, but high specificity. residual tumour size is overestimated, it could alter the surgical DWI might be able to compensate this shortcoming, since treatment plan for the individual patient. It could result in it has higher sensitivity and only slightly lower specificity. unnecessary wide resection margins with subsequent poorer Unfortunately, there are no studies yet that have investigated cosmetic results, but it could also result in a mastectomy the added value of both MR techniques combined. where breast-conserving therapy might still have been However, pCR only occurs in the minority of patients. possible. Residual disease assessment after NAC by MRI might be Underestimation of residual tumour size by MRI can be even more important. Studies have shown that assessment caused by the lack of an ina fl mmatory response surrounding of residual disease by MRI is good, but can be inu fl enced by the tumour (common in regimens containing docetaxel), the several factors, such as breast cancer subtype or treatment antivascular effects of docetaxel, extensive ductal carcinoma regimen. Finally, both overestimation and underestimation in situ component (which may be difficult to identify by of residual disease by breast MRI have been reported in MRI), and partial volume ee ff cts in the case of very small foci the past. Both can have important clinical impact for the of residual disease [27,30,47]. The risk of positive resection individual patient. margins after surgery increases in these cases. Studies have Future studies should further investigate the confounding shown that positive resection margins are associated with variables that could inu fl ence the accuracy of breast MRI increased risk of disease recurrence [50]. In addition, positive during NAC. Researchers should not only focus on single MR resection margins require additional re-excisions or even techniques, but rather explore the added value of combined conversion to mastectomy. This increases health care costs MR techniques that might compensate for the separate due to additional surgeries that need to performed, and shortcomings of the various techniques. However, study the additional hospital admission times that are required designs for these studies should consist of large, multicenter in these cases. trials, since most available studies only included a limited number of patients. Underpowered studies could mask Conclusions and future perspectives important findings which would be statistically significant Currently, breast MRI is considered the most accurate method if the population size was adequately powered. for evaluating treatment response in breast cancer patients Competing interests receiving NAC. Even after several cycles of NAC, changes in The authors declare that they have no competing interests. tumour size, morphology, enhancement and metabolism Author contributions can be observed in vivo. Based on these changes, a great ML, RP, and MS all contributed to this manuscript. Manuscript many parameters have been proposed for early response preparation was performed by ML and MS. Figure monitoring of NAC by MRI. Of these parameters, tumour size preparation was performed by RP. ML and RP provided and volume, and ADC values seem most promising and are the unpublished data presented in this manuscript. All best validated. However, proper response criteria (such as authors read and approved the final manuscript. optimal cut off values) are still lacking for these parameters Publication history and should be investigated in future (larger) studies. Received: 17-Nov-2012 Revised: 08-Dec-2012 It might be assumed that early response monitoring could Accepted: 12-Dec-2012 Published: 19-Dec-2012 be used to change treatment strategy during NAC. In theory, patients that showed a poor response to one chemotherapy References regimen might switch to an alternative one. However, 1. D. 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Response monitoring of breast cancer patientsreceiving neoadjuvant chemotherapy using breast MRI – a review of current knowledge

journal of Cancer Therapeutics and ResearchJan 1, 2012

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10.7243/2049-7962-1-34
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Abstract

Background: Breast MRI is the most accurate method for evaluating treatment response in breast cancer patients receiving neoadjuvant chemotherapy (NAC). Methods: In this review, the current knowledge with respect to response monitoring of breast cancer patients receiving NAC using MRI is presented. Both standard and more advanced approaches are discussed, including potential pitfalls and future developments. Results: Many parameters have been proposed in the past for early response monitoring of NAC by MRI. Tumour size and volume, and apparent diffusion coefficient values seem most promising and are best validated. However, proper response criteria are still lacking. Breast MRI accuracy for pathologic complete response prediction has moderate sensitivity, but high specificity. Diffusion weighted MR imaging might be able to compensate this shortcoming. However, residual disease assessment after NAC is equally important. Studies have shown that assessment of residual disease by MRI is good, but can be influenced by several factors, such as breast cancer subtype or treatment regimen. Both overestimation and underestimation of residual disease by breast MRI have been reported, and both can have important clinical impact for the individual patient. Conclusion: MRI is the best imaging modality to monitor treatment response in breast cancer patients receiving NAC. However, further research is required to investigate potential confounding factors and its pitfalls. Key words: Breast cancer, breast neoplasm, MRI, pathologic complete response, neoadjuvant chemotherapy Background frequently used. In general, pCR is den fi ed as the absence Neoadjuvant chemotherapy (NAC) is defined as the of any residual invasive tumour cells in the original tumour administration of chemotherapy to treat invasive breast bed. However, the den fi ition of pCR may vary between cancer before any local treatment, such as surgery. At different grading systems, mainly with respect to the first, NAC was used for treatment of locally advanced inclusion or exclusion of any residual ductal carcinoma in breast cancer. Nowadays, NAC is more and more used situ (DCIS) surrounding the culprit region, or with respect in early stages of breast cancer, for example to enable to the presence or absence of any axillary lymph node breast conserving therapy (for patients who were originally metastases. Pathological complete response after NAC scheduled for mastectomy), to enable less complicated has shown to be a prognostic factor for overall better surgery in cases where skin or pectoral muscle is involved survival, but also for disease-free survival and recurrence- (Figure 1), or to achieve better cosmetic results after surgery. free survival [2]. Studies have shown that there is no significant difference Many examinations have been proposed to evaluate in survival or overall disease progression between patients response monitoring in breast cancer patients receiving receiving adjuvant or neoadjuvant chemotherapy [1]. NAC, such as physical examination, mammography, and The use of NAC enables physicians to assess tumour ultrasound. However, their accuracy was only modest [3]. response in vivo. Patients treated with NAC can demonstrate There is increasing evidence that magnetic resonance stable or progressive disease, or remission and even imaging (MRI) is an excellent imaging tool to monitor complete response. Complete response is den fi ed as the response to NAC, for both early response monitoring and absence of any residual breast cancer, and is usually assessed the assessment of residual disease extent. In comparative by pathological analysis of acquired tissue samples. In this studies it has been shown that MRI is superior to physical context, the term ‘pathological complete response’ (pCR) is examination, ultrasound, and mammography in response © 2012 Lobbes et al; licensee Herbert Publications Ltd. This is an open access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0 ),This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 Figure 2. All images are contrast-enhanced, T1-weighted MR images. Top row shows baseline MR examinations, whereas the bottom row shows MR examinations aer co ft mpletion of neoadjuvant chemotherapy. Left column shows an example of complete response, in which the tumour disappeared completely and only the marker clip artifact (arrow) is still visible (Miller and Payne grade 5); middle column shows partial response, with some enhancing residual disease left (Miller and Payne grade 3); right column shows poor response (Miller and Payne grade 2). the reader with an overview of current knowledge and developments, and explore the lacks in knowledge that still remain. Die ff rent techniques for assessing early response in NAC are discussed, as well as the accuracy of MRI to assess residual disease extent and pCR. These issues are illustrated by several examples from everyday clinical practice. Early response monitoring Early response monitoring is considered to be the monitoring of disease changes after the first cycle(s) of NAC treatment. In Figure 1. (A) shows a small irregular mass close to the other words, it is the assessment of disease changes before chest wall with increased enhancement of the pectoral the completion of the entire course of NAC. muscle ascie medially (total ameter 45 mm). Aer ft With respect to early response monitoring, many studies neoadjuvantchemtherapy (B), mass size has not changed have been published, which have been summarized in a significantly, but the enhancement of muscle fascie has disappeared and a fatty line has occured between tumor tissue recent meta-analysis by our study group, and which included and chest wall, thus enabling breast conserving therapy in a a total of 15 studies until January 2012. In this review, a total patient who would otherwise undergo mastectomy. number of 31 potential MR parameters were described [5]. The MRI techniques that were most frequently used were evaluation during NAC [4]. It is able to monitor complete dynamic, contrast-enhanced MRI (DCE-MRI), diffusion response, partial response and poor response (Figure 2). weighted-imaging (DWI), and MR spectroscopy (MRS). Because NAC allows the physicians to monitor disease development in vivo, there is a need for a (preferably non- Dynamic, contrast-enhanced MRI invasive) modality that is able to assess tumour response DCE-MRI is based on the fact that breast cancers possess an during treatment. There is a need for a modality that can increased microvasculature, which is often ‘immature’ and assess response early in treatment (i.e. after only several leaky, resulting in a leakage of contrast agent through the cycles of chemotherapy), but also for a modality that can vessel walls into the interstitium. As a result, breast tumours accurately detect any residual disease left after therapy. show enhancement after contrast administration. In DCE- This review focuses on the role of magnetic resonance MRI, two separate approaches can be identified for early imaging with respect to response monitoring in breast response monitoring in NAC: pharmacokinetic modeling cancer patients receiving NAC. We attempted to provide using ‘ultrafast’ DCE-MRI and ‘standard’ contrast-enhanced 2 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 breast MRI. These techniques can either be performed alone, or combined in a dedicated sequence protocol. For the assessment of different pharmacokinetic parameters, it is mandatory that a MR sequence is used with a very small temporal resolution, usually in the order of several seconds. As a result, spatial resolution is often poor, preventing adequate assessment of lesion morphology. With respect to early response monitoring in NAC, many parameters of pharmacokinetic modeling have been proposed, such as trans K , K , and V . However, there are several characteristics of ep e pharmacokinetic modeling (which are general and not specic fi for the NAC setting) which hamper the widespread use of this Figure 3. A large, irregular mass with skin involvement is visible in approach. For example, the measurement of the arterial input the right breast. Maximum tumour diameter before treatment was function (AIF) can be difficult. The AIF is the concentration- 38 mm (arrow). Maximum tumour diameter aer t ft reatment was 32 time curve of the artery supplying the vascular bed of interest, mm (arrow). This is a diameter reduction of 16%, corresponding which in breast MRI is most commonly the internal mammary to ‘stable disease’ according to RECIST and WHO criteria. artery or aorta. For proper measurement of the AIF, a high Histopathologic analysis showed poor tumour regression, i.e. Miller and Payne grade 2. temporal resolution is essential to capture the inflow and passage of contrast in the blood stream. However, the artery that is used is often located at an important distance from the contrast-enhanced dynamic series [13]. the breast tumour. As a result, temporal resolution is reduced In a study of 216 breast cancer patients, Hylton et al., in order to fit the artery within the field-of-view. This leads evaluated changes in tumour volume and diameter after to an inaccurate assessment of the AIF and pharmacokinetic the first cycles of treatment with NAC. They observed that parameter outcomes. The parameters could also be inuenc fl ed early in treatment, maximum tumour diameter and tumour by the dose and type of the contrast agent used, and by the volume were the best parameters to predict pCR (AUC of method by which the contrast agent is administered. Finally, 0.64 and 0.70, respectively) [4]. In our systematic review, the MR sequence composition can be of inu fl ence on these we found four studies presenting AUC values, which were parameters as well [6,7]. As a result, many variables can be slightly higher and ranged from 0.73 to 0.9 [5]. Similar to the introduced in pharmacokinetic modeling, which make it pharmacokinetic parameters, the majority of the studies difficult to compare different studies. This is probably the did not suggest useful cut off values at which diagnostic most important reason why the use of pharmacokinetic accuracy would be optimal. Only Loo et al., suggested a modeling has not been widely introduced in everyday clinical cut off value of a diameter reduction of 25% between MRI practice after all these years. examinations at baseline and at first follow-up [ 14]. In their meta-analysis, Prevos et al., observed both Although evidence is still rather limited, the measurement significant and non-significant changes in both absolute of tumour volume and diameter seems promising. As an trans and relative values of K K , and V between responders additional advantage over pharmacokinetic modeling ep e and non-responders. In order to be clinically applicable, parameters, clinical breast MRI has been standardized to it would be interesting to learn what the area under the a large extent over the past years. With respect to clinical ROC curve (AUC) would be for these parameters. Based on application, measurement of tumour diameter is perhaps the AUC, a cut off value for absolute or relative changes in the simplest method of (early) response monitoring. the different parameters could be suggested in which the Nonetheless, there are several important limitations to diagnostic accuracy would be optimal. Although several these measurements. trans studies presented AUC values for K and K , this was not With respect to maximum tumour diameter ep trans available for Ve. For K and K , this AUC ranged from 0.6-0.9 measurement, the two most commonly used guidelines [8-11]. Disappointingly, only a single study suggested absolute to assess treatment response are the guidelines of the World -1 and relative cut off values of 0.39 min and 85%, respectively Health Organization (WHO) and the Response Evaluation [12]. Currently, the aforementioned limitations of this technique Criteria for Solid Tumours (RECIST). In the WHO guidelines, and the scant scientific evidence that is currently available four response categories can be identified: (1) complete prevent widespread application in everyday clinical practice. response (CR), in which no more enhancing tumour is As an alternative, ‘standard’ DCE-MRI might be used for early visible; (2) partial response (PR), which is a reduction in response monitoring. In this approach, lesion morphology diameter of ≥50%, (3) progressive disease (PD), which and extent is assessed by evaluating contrast-enhanced, T1- is an increase in tumour diameter of ≥25% and which weighted images using a dedicated breast coil and minimum rarely occurs under NAC; and (4) no changes, which is the field strength of 1.5 Tesla. Additional information can be level between PD and PR [15, 16]. The RECIST criteria also extracted by analyzing the signal-intensity time curves in divide response into four categories: CR is den fi ed as the 3 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 criteria and the variation in methods to determine tumour volumes [16] have prevented widespread use of tumour volume assessment as parameter for treatment response in breast cancer patients receiving NAC. Diffusion-weighted imaging In DWI, the random Brownian movement of water molecules is evaluated using MRI. The free (or restricted) movement of these molecules can be quantified by calculating the apparent diffusion coec ffi ient (ADC). In breast cancer, dense packing of cells results in a restricted movement of water molecules. As a result, the ADC value decreases in DWI. During NAC, cell density of the tumour generally decreases, improving water molecule movement within the tumour. As a consequence, the ADC increases during NAC if a proper response is expected. If ADC values remains stable or even decreases further, it would be suggestive for stable or progressive disease under NAC. Thus, measurement of ADC might be a suitable parameter for evaluating treatment response. In the study by Sharma et al., tumour volume, diameter and ADC value were assessed at each MRI examination. Figure 4. Two examples of cases in which tumour diameter They showed that the percentage change in ADC after the measurement might be challenging. Case (A) shows a round mass with irregular contours at baseline breast MRI. r fi st cycle of treatment was statistically significant between Aer t ft reatment, the mass has reduced and only scattered responders and non-responders, when compared with foci of enhancement are present in the tumour bed. Case tumour volume and diameter. After three cycles of NAC, (B) shows a highly irregular mass with spiculae, which sensitivity and specificity of the ADC-value for distinguishing does not significantly reduce aer t ft reatment. However, the responders and non-responders were 68% and 100%, prominent spiculations might suggest an extensive intraductal component and an accurate tumour diameter measurement is respectively [22]. a study by Fangberget et al., an ADC cut -3 2/s 2 difficult in this case. Interestingly, both cases showed a Miller off value of 1.42x10 mm (at b=750 s/mm ) was suggested and Payne regression grade of 3. as optimal value after four cycles of chemotherapy [23]. This yielded a sensitivity and specificity to distinguish responders and non-responders of 88% and 80%, respectively. A absence of enhancing tumour; PR as a decrease in tumour significant change in ADC in responders after several cycles diameter ≥30%; PD as an increase in tumour diameter ≥20%; of NAC was also observed in a study by Li et al., This change stable disease is considered to be the level between PD and could not be observed in non-responders. However, they PR (Figure 3) [16,17]. However, accurate measurement of did not suggest any kind of cut off value at which diagnostic tumour diameter can be challenging in cases which show accuracy would be optimal [24]. fragmentation of tumour during NAC, or in cases which In summary, several studies have shown the potential show a mass with surrounding areas of so-called non-mass of DWI to predict early response in breast cancer patients like enhancement (which can be associated with a more receiving NAC. However, the number of studies is still limited, extensive intraductal component (Figure 4) [18]. and the size of the various study populations is rather To cope with these difficulties, some studies have small. In addition, the use of DWI has several limitations. suggested the use of tumour volume measurements as For example, DWI has limited spatial resolution and as a treatment response parameter [4,5,16]. However, there are result, small tumour foci might be overlooked. In addition, no well-validated response criteria available for tumour breast cancer subtypes that do not form masses might be volume measurements. Some studies used the surrogate misinterpreted (i.e. ductal carcinoma in situ or invasive parameter of tumour volume measurements that was lobular carcinoma). Furthermore, DWI is a technique that is provided in the RECIST criteria appendix: PR was den fi ed highly sensitive to motion artifacts caused by (in)voluntary as a volume reduction of ≥65%, whereas PD was den fi ed patient movement, resulting in inaccurate ADC values due as an increase in tumour volume of ≥20% [19-21]. For our to imaging mismatch. Finally, DWI sequences can vary study population of interest (i.e. breast cancer patients between vendors and institutions, especially with respect receiving NAC), these response criteria are not validated in to the select b-values in this technique, which inu fl ence the large, multicenter studies and thus should be used with this ADC-value and make it difficult to compare study results limitation in mind. Until today, the lack of proper response between different groups. 4 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 Magnetic resonance spectroscopy In MRS, the molecular composition of a tissue of interest is analyzed by looking at the spectrum of resonances produced by the MR signal. This spectral ‘signature’ is used to diagnose certain metabolic disorders that are associated with tumour cells. The majority of the MR signal arises from fat and water, but small magnetic field differences can be utilized to identify additional metabolites that are present in much smaller concentrations. Relative to normal breast tissue, breast cancers have increased levels of choline-containing compounds (such as phosphocholine, glycerophosphocholine, and free choline). However, these metabolites are present in extremely small concentrations, and cannot be identified separately by MRS. Therefore, the total choline peak (tCho, at 3.2 ppm) is usually Figure 5. (A) shows a large irregular mass with heterogeneous enhancement in the lateral part of the left breast. Aer co ft mpletion of presented [16].In a study by Jagannathan et al., 67 patients with neoadjuvant chemotherapy (B), no residual enhancing tumor is left and breast cancer and 16 healthy controls were evaluated. Using only the signal void of the metal marker clip can be observed (arrow). MRS, they showed that sensitivity and specificity of MRS for Histopathological analysis of the surgical specimen showed pathologic detecting tCho in tumours was 78% and 86%, respectively complete response, i.e. Miller and Payne grade 5. [25]. Baek et al., measured tCho concentration in a study of 35 breast cancer patients receiving NAC. At first follow-up (after median of 20 days, corresponding with 1-2 cycles of NAC), changes in tCho concentrations were not significantly Residual disease extent and pathologic com- different between patients achieving pCR and patients not plete response achieving pCR. However, at second follow-up (median of 69 After completion of all cycles of NAC, MRI can also be days, corresponding to 3-4 cycles of NAC), tCho concentrations used to assess the extent of residual disease, which can decreased by 100% in patients achieving pCR (versus 67% be extremely useful for the surgeon when planning the decrease in patients not achieving pCR, p=0.01) [10]. surgical treatment strategy. It also contains prognostic However, the analysis of the MRS data can be time- information, since the achievement of pCR is associated consuming and there are many technical difficulties in with better long-term survival. However, the latter can assessing the very low concentrations of tCho in vivo. Other be drawn better from the histopathological analysis of confounding factors are the variable fat content within the the surgical specimen. breast, field inhomogeneity caused by air-tissue interfaces and marker clips artifacts (inserted after biopsy) [16]. Until now, Residual disease extent these limitations prevented a widespread clinical use of this After the completion of NAC, residual disease is still present technique to monitor early response in patients receiving NAC. in the majority of patients. PCR is only achieved by 6-15%, for example in anthracycline-based regimens. PCR rate Other parameters can increase up to 30% when taxanes are added [26]. In the recent past, a great many parameters have been Although several recent studies have focused on the introduced to monitor early response in the NAC setting. (early) prediction of pCR by MRI, they failed to provide Next to the aforementioned parameters, these include for information about residual disease (which is still present example early contrast uptake, signal intensity ratio, maximum in the majority of patients receiving NAC). Many studies Gd-DTPA concentration, relative blood volume, relative blood have presented correlation coefficients between size flow, mean transit time, signal intensity time curves, relative measurements assessed by MRI compared to pathological signal enhancement after 3, 12, 17, 90, and 90-450 seconds, tumour size measurement [23,27,42]. In an analysis of R2* value, intrinsic T2* relaxivity, differences in R2* values, these studies, we calculated that the median correlation initial area under the gadolinium curve after 60 seconds coefficient were 0.698, with a range of 0.21-0.982 (Lobbes, (IAUGC ), BI-RADS lexicon descriptors, change in tumour unpublished data). However, most of the studies did not morphology, early enhanced ratio during the first phase sufficiently discuss the agreement between tumour size after contrast administration, maximal enhancement ratio, measurements as assessed by MRI and histopathology. time to maximal enhancement, and peak enhancement ratio Excellent correlation coefficients do not automatically [5]. However, these parameters have only been studied in 1 reflect excellent agreement. or 2 studies with rather limited population sizes. As a result, In summary, the ability of breast MRI to assess residual there is currently no sufficient evidence that any of these disease extent seems adequate, but in the various studies parameters can be used in clinical practice to monitor early on this topic potential confounders for the accuracy of MRI response in patients receiving NAC for breast cancer. were discovered, which are summarized in the ‘Confounding 5 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 potential pitfalls’ paragraph). In contrast, the sensitivity of DWI to predict pCR seems better, albeit at slightly lower specificity. In theory, the combined use of DWI and contrast- enhanced MRI could further improve the accuracy of MRI to predict pCR, since one MR technique might compensate the shortcomings of the other. However, no studies have been published that have demonstrated the added value of both techniques combined. Confounding factors and potential pitfalls Figure 6. Baseline contrast-enhanced T1-weighted MR image Marker artifacts (A), showing a heterogeneously enhancing irregular mass in the left breast with a centrally placed marker clip. Note the During the course of NAC, tumour might regress in diameter adjacent skin thickening. Aer co ft mpletion of neoadjuvant and become more difficult to visualize by imaging. In the chemotherapy (B), the tumour bed reduced slightly, and best case scenario, complete response is observed and limited enhancement was observed in this area. Detailed the tumour is not detectable at all anymore. Therefore, outtake of this area (C) shows the signal void caused by all patients receiving NAC and in which breast-conserving the marker (*), surrounded by two rims of increased signal intensity (arrows). This might suggest or obscure small foci therapy might be considered afterwards should have of residual disease. The configuration of the increased signal their tumour marked. In general, this is done by placing intensity parallel to the signal void suggests a susceptibility a clip, marker or small coil inside the tumour. However, artifact. The final conclusion of this case was ‘probably these clips cause local field inhomogeneities when MRI is complete response, but residual disease cannot be ruled performed, causing susceptibility artifacts in the tumour out’. Histopathologic analysis showed complete pathologic response (Miller and Payne grade 5). bed itself. These artifacts are usually observed as a signal void (which represents the marker itself), surrounded by a rim of increased signal intensity, which is often more factors and potential pitfalls’ paragraph. pronounced than the enhancing fibroglandular tissue or residual disease. However, these small areas of increased Pathologic complete response (pCR) signal intensity might be difficult to distinguish from small Pathologic complete response is defined as the absence foci of residual disease (Figure 6). Subtraction of contrast- of any invasive tumour cells in the surgical specimen, after enhanced MR images might aid in reducing these false the completion of NAC. However, pathological grading positive findings. systems to assess treatment response vary widely, also in their den fi ition of pCR. Breast cancer subtypes and chemotherapy regimen In treatment response monitoring by MRI, the achievement In recent studies, it was observed that the accuracy of of pCR is suggested by the absence of any residual enhancing breast MRI to assess residual disease and predict pCR tumour tissue after contrast administration (Figure 5). At this depended on breast cancer subtypes, but also on the stage, histopathological analysis has not yet been performed chemotherapy regimen that was used. For example, it was and therefore we prefer the term ‘complete radiological observed that MRI was able to predict pCR more accurately response’ in our institution. In a meta-analysis by Yuan et al., in patients having HER2-positive tumours when compared the pooled weighted estimates of sensitivity and specic fi ity to HER2-negative tumours. In the latter case, a higher false- of breast MRI to predict pCR were 0.63 (range 0.56-0.70) and negative rate was observed, especially when receiving 0.91 (range 0.91-0.92), respectively [43]. In a meta-analysis of anti-angiogenic drugs [40,45]. It was also observed that the 34 studies by Wu et al., the ability of both DWI and contrast- average size discrepancy between MRI and pathology was enhanced MRI to predict pCR was evaluated. They found that greater in tumours demonstrating limited Ki-67 staining sensitivity and specificity for contrast-enhanced MRI was when compared to tumours demonstrating increased 0.68 (95% confidence interval (CI) 0.57-0.77) and 0.91 (95% Ki-67 staining [40]. In addition, Loo et al., concluded that CI 0.87-0.94), respectively. For DWI, sensitivity and specificity response monitoring using breast MRI is accurate in were 0.93 (95% CI 0.82-0.97) and 0.82 (95% CI 0.70-0.90), patients having triple-negative or HER2-positive tumours. respectively [44]. The minor variations in these observations However, they found it was inaccurate in ER-positive/HER2- can be explained by the minor differences in inclusion and negative subtypes [46]. Finally, Denis et al., showed that exclusion criteria that were applied in their reviews. residual tumour size was often underestimated by MRI in Based on these critical reviews, it can be concluded that taxane-containing regimens, which is probably caused the accuracy of contrast-enhanced MRI to predict pCR after by the antivascular effects of this type of chemotherapy, NAC has a high specificity, but only moderate sensitivity. which results in less enhancement on contrast-enhanced Several confounding factors were observed that might breast MRI [47]. These findings suggest that breast cancer inu fl ence its accuracy (see also the ‘Confounding factors and subtype and the type of NAC is of inu fl ence on breast MRI 6 Lobbes et al. Journal of Cancer Therapeutics & Research 2012, http://www.hoajonline.com/journals/pdf/2049-7962-1-34.pdf doi: 10.7243/2049-7962-1-34 accuracy. Therefore, larger studies are warranted to further could be continued as planned. Patients that showed only clarify which factors effect MRI’s accuracy and in what way partial response might benefit from a more prolonged (positive or negative). chemotherapy treatment (i.e. more cycles of chemotherapy), in order to achieve a higher pCR rate. In non-responders, Overestimation and underestimation or even progressive disease, one might reconsider surgical In monitoring response to NAC by MRI, both overestimation intervention at an earlier stage in treatment or at least and underestimation were observed in various studies. Both prevent the administration of toxic agents from which the discrepancies can have an important impact on patient care. patient does not benet fi . However, the application of breast Overestimation of tumour size by MRI can be caused by MRI for early response monitoring is still developing at this surrounding sclerosis or necrosis, the presence of multiple moment, and so far, no studies have been published that scattered lesions or foci, reactive inflammation caused by altered their treatment plan based on the breast MRI findings. tumour response and subsequent healing, and the presence The accuracy of breast MRI to predict pathologic complete of accompanying ductal carcinoma in situ [31,48,49]. If the response has a moderate sensitivity, but high specificity. residual tumour size is overestimated, it could alter the surgical DWI might be able to compensate this shortcoming, since treatment plan for the individual patient. It could result in it has higher sensitivity and only slightly lower specificity. unnecessary wide resection margins with subsequent poorer Unfortunately, there are no studies yet that have investigated cosmetic results, but it could also result in a mastectomy the added value of both MR techniques combined. where breast-conserving therapy might still have been However, pCR only occurs in the minority of patients. possible. Residual disease assessment after NAC by MRI might be Underestimation of residual tumour size by MRI can be even more important. Studies have shown that assessment caused by the lack of an ina fl mmatory response surrounding of residual disease by MRI is good, but can be inu fl enced by the tumour (common in regimens containing docetaxel), the several factors, such as breast cancer subtype or treatment antivascular effects of docetaxel, extensive ductal carcinoma regimen. Finally, both overestimation and underestimation in situ component (which may be difficult to identify by of residual disease by breast MRI have been reported in MRI), and partial volume ee ff cts in the case of very small foci the past. Both can have important clinical impact for the of residual disease [27,30,47]. The risk of positive resection individual patient. margins after surgery increases in these cases. Studies have Future studies should further investigate the confounding shown that positive resection margins are associated with variables that could inu fl ence the accuracy of breast MRI increased risk of disease recurrence [50]. In addition, positive during NAC. Researchers should not only focus on single MR resection margins require additional re-excisions or even techniques, but rather explore the added value of combined conversion to mastectomy. This increases health care costs MR techniques that might compensate for the separate due to additional surgeries that need to performed, and shortcomings of the various techniques. However, study the additional hospital admission times that are required designs for these studies should consist of large, multicenter in these cases. trials, since most available studies only included a limited number of patients. Underpowered studies could mask Conclusions and future perspectives important findings which would be statistically significant Currently, breast MRI is considered the most accurate method if the population size was adequately powered. for evaluating treatment response in breast cancer patients Competing interests receiving NAC. Even after several cycles of NAC, changes in The authors declare that they have no competing interests. tumour size, morphology, enhancement and metabolism Author contributions can be observed in vivo. Based on these changes, a great ML, RP, and MS all contributed to this manuscript. Manuscript many parameters have been proposed for early response preparation was performed by ML and MS. Figure monitoring of NAC by MRI. Of these parameters, tumour size preparation was performed by RP. ML and RP provided and volume, and ADC values seem most promising and are the unpublished data presented in this manuscript. All best validated. However, proper response criteria (such as authors read and approved the final manuscript. optimal cut off values) are still lacking for these parameters Publication history and should be investigated in future (larger) studies. Received: 17-Nov-2012 Revised: 08-Dec-2012 It might be assumed that early response monitoring could Accepted: 12-Dec-2012 Published: 19-Dec-2012 be used to change treatment strategy during NAC. In theory, patients that showed a poor response to one chemotherapy References regimen might switch to an alternative one. However, 1. D. 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