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Breast Imaging |
1 From the Ctr for Magnetic Resonance Research (S.M., P.J.B., E.H.B., M.G.), Dept of Radiology (S.M., P.J.B., E.H.B., L.I.E., M.T.N., T.H.E., M.G.), Cancer Ctr (R.L.B., D.Y., M.G.), Dept of Pathology/Laboratory Medicine (E.G.), Dept of Surgery (T.M.T.), and Dept of Medicine (D.Y.), Univ of Minnesota School of Medicine, 2021 Sixth St SE, Minneapolis, MN 55455. From the 2003 RSNA scientific assembly. Received Aug 19, 2003; revision requested Oct 31; revision received Jan 14, 2004; accepted Feb 16. Supported by DOD Breast Cancer Research Program DAMD 17–01-1–0331, NIH grants RR08079, CA92004, RR00400, and PHS Cancer Ctr Support Grant P30 CA77398, the Lillian Quist-Joyce Henline Chair in Biomedical Research, and the Tickle Family Land Grant Chair in Breast Cancer Research. Address correspondence to M.G. (e-mail: gar@cmrr.umn.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Sixteen women with biopsy-confirmed locally advanced breast cancer scheduled to undergo doxorubicin-based PST were recruited. Magnetic resonance (MR) imaging and spectroscopy were performed at 4 T prior to treatment, within 24 hours after the first dose, and after the fourth dose. Lesion size was assessed by using gadolinium-enhanced MR imaging. Lesion tCho concentration was quantified by using single-voxel hydrogen 1 MR spectroscopy. Statistical analysis was performed by using the Pearson correlation coefficient and the Wilcoxon rank sum test.
RESULTS: Fourteen of 16 patients completed the protocol. In one patient, the level of tCho was not measurable because of unfavorable lesion morphology for MR spectroscopy voxel placement. Of the remaining 13 patients, four had inflammatory breast cancer, six had invasive ductal carcinoma, two had invasive lobular carcinoma, and one had mixed invasive ductal and lobular carcinoma. On the basis of the Response Evaluation Criteria in Solid Tumors, eight of 13 patients had an objective response and five had no response. The change in concentration of tCho from baseline to within 24 hours after the first dose of PST showed significant positive correlation with the change in lesion size (R = 0.79, P = .001). Change in tCho concentration within 24 hours after first dose was significantly different between patients with objective response and those with no response (P = .007).
CONCLUSION: These results suggest that the change in tCho concentration between baseline and 24 hours after the first dose of PST can serve as an indicator for predicting clinical response to doxorubicin-based chemotherapy in locally advanced breast cancer.
© RSNA, 2004
Index terms: Breast neoplasms, MR, 00.12145 • Breast neoplasms, therapy, 00.32 • Chemotherapy • Magnetic resonance (MR), spectroscopy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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There are currently no standardized criteria that can individually enable detection of early response to PST. Conventional modalities such as physical examination, ultrasonography (US), and mammography vary in reliability for measuring tumor response (5–8). Magnetic resonance (MR) imaging is increasingly being used to evaluate locally advanced breast cancer defined as invasive carcinoma 2 cm or larger in longest diameter (LD) with or without inflammatory features. With respect to treatment monitoring, study results have shown correlation between specific MR findings and clinical response. Changes in lesion size, neoplastic phenotype, dynamic contrast enhancement, and extraction flow product all correlate with clinical response (9–15). However, changes in lesion size or dynamic contrast enhancement measured with MR imaging are not detected until at least 6 weeks following PST (13). The ability to immediately detect response to a specific chemotherapeutic regimen would be ideal, since it would allow for optimal individualization of chemotherapeutic regimens for patients, with the goal of obtaining a pathologic complete response.
Recently there has been an interest in the use of hydrogen 1 (1H) MR spectroscopy for the detection and monitoring of breast cancer. With the use of 1H MR spectroscopy, it has been shown that neoplastic breast tissue contains elevated levels of choline-containing compounds (tCho) that yield a signal at a chemical shift of 3.2 ppm (16–20). One group of researchers has shown that changes in the tCho signal occur in patients with breast cancer who receive PST (21). Results of other studies have shown a correlation between the change in tCho signal and clinical response in patients with extracranial lymphomas and germ cell tumors (22) and in pediatric gliomas (23).
1H MR spectroscopy of the breast is technically challenging because sensitivity can be limiting and spectral artifacts can occur. Because of the heterogeneous distribution of fat and glandular tissue in the breast, 1H spectra of the breast often contain large lipid signals that give rise to contaminant peaks around 3.2 ppm. Fortunately, these artifactual peaks, which are also known as sidebands, can be suppressed by using a recently developed technique called echo-time averaging (24). In addition, treatment monitoring requires implementation of a method to quantify spectra. Previous studies at a lower magnetic field strength (1.5 T) were based on the hypothesis that tCho signal is detectable only in malignant breast tissue (20). However, with the increased sensitivity at a high field strength (4 T), it has been shown that tCho signal is also detectable in benign lesions and normal fibroglandular breast tissue (25).
We hypothesized that an early decrease in the concentration of tCho could allow us to identify an early response to PST. Thus, the purpose of our study was to determine if changes in tCho concentration from before PST to within 24 hours after PST predict clinical response in patients with locally advanced breast cancer.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Patients underwent MR imaging and MR spectroscopy prior to treatment, within 24 hours after the first dose of AC (day 2), and after the fourth dose of AC (prior to surgery). Patients had the option of returning for additional imaging examinations after the second and third doses of AC. Patients underwent baseline imaging and spectroscopy at a median of 2 days (range, 1–21 days) prior to the first dose of AC, and the final imaging and spectroscopy examination was performed at a median of 3 days (range, 1–8 days) after the fourth dose. After undergoing four cycles of AC treatment, one patient continued treatment with four cycles of paclitaxel (Bristol-Myers Squibb, Princeton, NJ) and underwent additional imaging and spectroscopy examinations after the second and fourth doses of paclitaxel.
MR Imaging and MR Spectroscopy Techniques
All measurements were performed with a 4-T research imager that consisted of a 90-cm bore magnet (4T-900; Oxford Magnet Technology, Oxfordshire, England) with a clinical gradient system (Sonata; Siemens, Erlangen, Germany) interfaced with an imaging spectrometer (Unity Inova; Varian, Palo Alto, Calif). The gradient system was capable of 40 mT/m and a 400-µsec rise time. Several single-breast quadrature transmit-receive radiofrequency surface coils of similar design were used to accommodate different breast sizes (26). The coils were mounted onto a custom-built patient table designed for unilateral prone breast studies. Patients were placed in the prone position with the breast centered horizontally in the magnet. After scout images were acquired to verify proper positioning, the coil was manually tuned and matched. A high-spatial-resolution three-dimensional fast low-angle shot image with fat suppression (repetition time msec/echo time msec, 13.5/4.1; matrix, 256 x 256 x 64; field of view, 14–18 cm; flip angle, 30°) and a fast two-dimensional multisection fast low-angle shot image with fat suppression (390/5.1; matrix, 256 x 128; 30 sections; section thickness, 2.5 mm; field of view, 14–18 cm; flip angle, 90°) were acquired prior to injection of 0.1 mmol of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) per kilogram of body weight. Five sets of two-dimensional images were acquired immediately after injection; this was followed by a second three-dimensional image acquisition. Both image sets were analyzed by using our own image processing software developed with Matlab (Mathworks, Natick, Mass) to select voxels for MR spectroscopy with the patient still in the magnet bore.
Voxel placement was usually performed jointly by at least two of the authors (S.M., P.J.B., E.H.B., or M.G.). In a few instances, the physician alone (S.M. or E.H.B., each with at least 6 months of experience in breast MR imaging) performed the voxel placement. Criteria for voxel selection included lesion architecture, lesion size (
2 cm in LD), dynamic contrast material uptake, and prior clinical information obtained from mammographic or US images. Voxels were planned to maximize coverage of the lesion and to minimize inclusion of adipose tissue. Voxels that were planned at imaging examinations following PST were placed to cover the same portion of the lesion covered at the baseline examination. If the lesion changed in size, the voxel was adjusted accordingly. Single-voxel 1H MR spectroscopy was performed with a technique known as localization with adiabatic selective refocusing (27). MR spectroscopy data were acquired by using 4096 complex points and 6-kHz spectral width. Each spectroscopy measurement began with a calibration of the localized B1 field strength, followed by 30–60 seconds of manual adjustment of the linear shims. A fully relaxed single-shot unsuppressed spectrum was acquired to measure the water and lipid signals. The radiofrequency power was then manually adjusted to suppress the water signal by using the variable pulse power and optimized relaxation delays technique (28). The metabolite spectrum was acquired by using echo-time averaging, with an echo time of 45–196 msec in increments of 64 or 128 and a repetition time of 3 seconds (24). Each free induction decay signal was individually saved—no averaging was performed until processing. Levels of tCho were quantified by fitting a Voigt lineshape model to the data and by using the unsuppressed water signal as an internal reference (25). All tCho measurements were recorded in millimoles per kilogram of water.
Data and Statistical Analyses
Statistical analysis was performed by using a software package (version 8.02 for Windows; SAS, Cary, NC). Lesion size was measured from the high-spatial-resolution three-dimensional subtraction image that was obtained by subtracting the baseline three-dimensional image from the contrast material–enhanced three-dimensional image. The variable used to characterize lesion size was the LD. LDs measured at baseline and after the fourth dose of AC are represented by the variables LD0 and LDf, respectively. Derived variables included LD after the fourth dose of AC normalized to baseline and expressed as a percentage (%LDf) as follows: %LDf = (LDf/LD0) · 100, and the change in LD from baseline to after the fourth dose expressed as a percentage (%
LDf) as follows: %LDf = {(LDf – LD0)/LD0} · 100.
Concentrations of tCho at baseline, within 24 hours after the first dose of AC, and after the fourth dose of AC are represented by the variables [tCho]0, [tCho]24, and [tCho]f, respectively. Derived variables included the tCho concentration at 24 hours after the first dose normalized to baseline and expressed as a percentage (%[tCho]24) as follows: %[tCho]24 = ([tCho]24/[tCho]0) · 100, and the change in tCho level from baseline to 24 hours after the first dose expressed as a percentage (%[tCho]24) as follows: %[tCho]24 = {([tCho]24 – [tCho]0)/ [tCho]0} · 100.
With the Response Evaluation Criteria in Solid Tumors (RECIST) classification system (29), patients were categorized into one of two groups: objective responders or nonresponders. Objective responders were patients who had %LDf less than or equal to –30%. Nonresponders were patients who had %LDf greater than –30%. The association between the %[tCho]24 and the %LDf was calculated by using the Pearson correlation coefficient (30). The comparison between the %[tCho]24 and patient response and the comparison of [tCho]0 between objective responders and nonresponders were calculated by using the Wilcoxon rank sum test (31).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The Table lists the lesion size, concentration of tCho, diagnosis, clinical response, and estrogen and progesterone receptor status in the 13 patients who completed the protocol. The median age of the patient group was 46 years (range, 31–70 years). Of these 13 patients, eight were premenopausal, of whom five had a prior history of using oral contraceptives. Five patients were postmenopausal, of whom two were undergoing hormone replacement therapy. Histologic diagnosis was obtained by using US-guided needle core biopsy in 11 patients and by using mammographic stereotactic-guided biopsy in two patients. Invasive ductal carcinoma was diagnosed in six patients, four of whom also had ductal carcinoma in situ. Invasive lobular carcinoma was diagnosed in two patients, one of whom also had ductal carcinoma in situ and the other of whom also had both ductal carcinoma and lobular carcinoma in situ. Inflammatory breast cancer was diagnosed in four patients, one of whom also had ductal carcinoma in situ and another of whom also had lobular carcinoma in situ. Both invasive ductal and invasive lobular carcinoma were diagnosed in one patient. Eight patients were estrogen receptor–positive and five were progesterone receptor–positive. Three patients had additional breast lesions with an LD at baseline of less than 2 cm. Because these additional lesions did not fit the voxel selection criteria for MR spectroscopy, they were not evaluated.
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Objective Response
Eight of 13 patients experienced an objective response with diminished lesion size. The median %LDf was –56% (range, –35% to –100%), and the median %[tCho]24 was –30% (range, –16% to –100%). All eight patients who were objective responders had a tCho concentration that was greater at baseline than within 24 hours after the first dose, which was in turn greater than or equal to the concentration after the fourth dose of AC ([tCho]0 > [tCho]24 [tCho]f)(Table). Figure 1 shows [tCho]24 and LDf as a percentage of the baseline measurement for objective responders.
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[tCho]24 was –20%, and it was predicted that the patient would have an objective response. After the fourth dose of AC (day 64), tCho level decreased to 0.9 mmol/kg and LD was 1.7 cm. On the basis of the %LDf, which was –58%, we classified the patient as an objective responder. This patient had palpable lymphadenopathy. Since treatment with paclitaxel is regarded as standard therapy for node-positive patients (32), this patient continued with PST with paclitaxel prior to surgery. Twenty-four hours after the second dose of paclitaxel, tCho concentration increased to 4.1 mmol/kg and LD remained at 1.7 cm. Although not shown in the figure, LD after the fourth dose of paclitaxel remained at 1.7 cm, whereas tCho concentration increased to 4.8 mmol/kg.
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LDf was –13% (range, 0% to –23%) and the median %[tCho]24 was 13% (range, 0% to 50%). All five patients who were nonresponders had a tCho concentration at baseline that was less than or equal to that measured within 24 hours after the first dose. In comparison with tCho concentration at baseline, tCho concentration after fourth dose was lower in two patients, higher in two patients, and equal in one patient (Table). Figure 3 shows [tCho]24 and LDf as a percentage of the baseline for nonresponders.
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[tCho]24 was 50% and it was predicted that the patient would be a nonresponder. After the fourth dose of AC (day 65), tCho level was 0.9 mmol/kg and LD was 2.7 cm. On the basis of %LDf of only –7%, this patient was classified as a nonresponder.
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[tCho]24 and %LDf[tCho]24 and %LDf was found (R = 0.79, P = .001). Figure 5 shows a graph of the correlation between %[tCho]24 and %LDf. Each patient was categorized (objective responder or nonresponder) based on RECIST. All five patients who were nonresponders had a %[tCho]24 value that was greater than or equal to 0. All eight patients who had an objective response had a %[tCho]24 value that was less than 0. The %[tCho]24 was significantly different between objective responders and nonresponders (Wilcoxon rank sum test, P = .007).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Overall, patients who were objective responders had a higher tCho level at baseline than did patients who were nonresponders. All patients who were objective responders had a lower tCho level within 24 hours after first dose than they did at baseline, and, in lesions with measurable tCho at 24 hours, a further decrease in tCho concentration was observed after the fourth dose of AC. Perhaps the immediate decrease in tCho concentration 24 hours after the first dose of AC reflects inhibition of cellular proliferation and the acute cytotoxic effect of chemotherapy. All patients who were nonresponders had either no change or a higher tCho level 24 hours after first dose than they did at baseline. This may be related to the fact that certain breast neoplasms exhibit de novo resistance to chemotherapy and, as a result, PST with the AC regimen would have no effect on the proliferating neoplastic cells.
It is expected that quantitative 1H MR spectroscopy will not only improve the accuracy of MR imaging in depicting breast cancer, but as shown here, it may be used with MR imaging to assess response to PST early in the course of treatment. In a study similar to ours, one group of researchers found that in a majority of patients who underwent PST for breast cancer, there was a disappearance or a decrease in tCho signal (21). However, authors of this earlier study did not categorize which patients had a change in tCho signal nor did they describe when the change in the signal occurred. In another study in which 1H MR spectroscopy was used to evaluate treatment response in pediatric gliomas, the ratio of tCho signals from tumor and normal white matter was measured (23). In brain tumors that responded clinically, there was a decrease in the tCho ratio, whereas in patients who did not respond, there was no change or an increase in the tCho ratio.
The precise mechanisms as to why neoplastic tissues exhibit elevated tCho levels still remain unclear. It has been proposed that increased phosphocholine, the primary metabolite responsible for the tCho signal in neoplastic tissue, is a result of increased synthesis of membranes by replicating cells. Elevated tCho levels may reflect a change in the balance between biosynthetic and catabolic pathways in which tCho serve as both precursors and catabolites (33). Other researchers have observed that the predominant intracellular mechanism responsible for the augmented levels of phosphocholine is caused by upregulation of choline kinase (34).
Although no PST regimen other than AC was considered in our study, it is interesting to note the pattern of change in tCho concentration in the patient who continued treatment with four doses of paclitaxel prior to surgery. Despite the fact that this individual was an objective responder to AC, the patient did not respond to paclitaxel. Between the last dose of AC and the second dose of paclitaxel, the patient’s tCho concentration increased by 355%, from 0.9 to 4.1 mmol/kg, whereas the lesion size did not change. The lesion size, even after the fourth dose of paclitaxel, remained at 1.7 cm, while the tCho concentration increased further by 17%, from 4.1 to 4.8 mmol/kg. It is reasonable to assume that early changes seen at 1H MR spectroscopy may even be used in predicting clinical response between different regimens. Although the findings of this study showed that the change in tCho level was an early marker for response to the specific cytotoxic agent AC, further work is needed to determine whether early prediction is possible with other agents.
Among all objective responders in our study, the smallest change in tCho level 24 hours after the first dose was a decrease of 16%. The ability to predict response depends on having sufficient accuracy and reproducibility in the MR spectroscopy measurement, and thus future studies with multiple baseline spectra are needed to establish the variance of tCho concentration measurements. We believe the accuracy of a tCho concentration measurement is limited primarily by signal-to-noise ratio, which has been shown to increase at least linearly with magnetic field strength (35,36). Thus, the 4-T imager used in our study offered a substantial advantage over 1.5-T imagers. Further studies are needed to determine whether 1.5-T machines can provide the signal-to-noise ratio necessary to measure tCho accurately. However, newer 3-T clinical imagers are expected to perform similarly to the 4-T research imager used in our study. An additional limitation of MR spectroscopy is the inability to predict clinical response in breast cancers that are small, diffuse, or irregularly shaped. Because of signal-to-noise ratio limitations, tCho levels in voxels less than 1 cm3 may be difficult to measure accurately. Fortunately, the minimum voxel size used for monitoring response to PST will typically be greater than 1 cm3, since tumors must be at least 2 cm in LD (stage II or greater) to be eligible for PST according to current criteria. Breast tumors with thin or linear morphology can pose a problem for the spectroscopist planning the voxel, particularly when intense lipid signals are contained in the voxel (24). For example, data from one patient were excluded from the analysis because of an inability to plan a suitable voxel for tCho measurements at baseline and following PST. At baseline, the MR image revealed a diffuse, linearly shaped mass. Because of the thin conformation of this lesion, it was not possible to place a rectangular voxel containing less than 33% fat by volume, as required by the quantification method (25).
The observation of consistent trends in the changes in tCho levels between objective responders and nonresponders suggests that in vivo 1H MR spectroscopy, when used with MR imaging, may be a sensitive indicator in predicting clinical response as early as 24 hours after the first dose of PST. The use of MR spectroscopy to monitor patients undergoing PST appears to offer a means to detect the presence of viable and/or proliferating neoplastic cells. With the possibility of early prediction comes the benefit of immediate assessment in tailoring an effective regimen for individual patients. Perhaps early changes seen with 1H MR spectroscopy in patients who undergo PST may even serve as an indicator of risk for recurrent or metastatic breast cancer. Furthermore, the opportunity for such early prediction will be useful to researchers seeking to evaluate new drugs for PST and may help to elucidate the mechanisms of multi-drug resistance in breast cancer.
These promising findings were obtained in a small group of patients, and, thus, a prospective study of a larger patient series is needed. A larger study may also provide information about the possibility of using MR spectroscopy to predict when a patient is expected to have a pathologic complete response. To our knowledge, this is the first report in which quantitative tCho measurements were made with in vivo 1H MR spectroscopy for the purpose of predicting clinical response to PST in breast cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, S.M., P.J.B., M.G.; study concepts and design, D.Y., M.G.; literature research, S.M., P.J.B.; clinical studies, S.M., P.J.B., E.H.B., L.I.E., M.G.; data acquisition, S.M., P.J.B., E.H.B., M.G.; data analysis/interpretation, all authors; statistical analysis, S.M., P.J.B., R.L.B.; manuscript preparation, S.M., M.G.; manuscript definition of intellectual content and editing, S.M., P.J.B., D.Y., M.G.; manuscript revision/review and final version approval, all authors
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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= tCho level 24 hours after first dose, normalized to baseline and expressed as a percentage (%[tCho]24), 
= LD after fourth dose, normalized to baseline and expressed as a percentage (%LDf). LD and tCho level pairs from individual patients are indicated by connecting lines. All objective responders had tCho concentration at 24 hours that was less than that at baseline.
represents one of eight objective responders, and each 
represents one of five nonresponders. There is a significant positive correlation between the change in tCho level 24 hours after the first dose (%