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Published online before print May 29, 2003, 10.1148/radiol.2281011303
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(Radiology 2003;228:63-69.)
© RSNA, 2003

Breast Imaging

Invasive Ductal Breast Carcinoma Response to Neoadjuvant Chemotherapy: Noninvasive Monitoring with Functional MR Imaging— Pilot Study1

Jean-Paul Delille, MD, Priscilla J. Slanetz, MD, MPH, Eren D. Yeh, MD, Elkan F. Halpern, PhD, Daniel B. Kopans, MD and Leoncio Garrido, PhD

1 From the NMR Center (J.P.D., L.G.) and Division of Breast Imaging (E.D.Y., E.F.H., D.B.K.), Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass; and Division of Breast Imaging, Department of Radiology, Saint Elizabeth’s Medical Center, 736 Cambridge St, Brighton, MA 02135 (P.J.S.). From the 2000 RSNA scientific assembly. Received July 31, 2001; revision requested September 24; final revision received October 18, 2002; accepted November 5. Supported by the Association pour la Recherche contre le Cancer, Société Française de Radiologie, Institut National de la Santé et de la Recherche Médicale, Massachusetts General Hospital-NMR Center, and RSNA Research and Education Foundation. Address correspondence to P.J.S. (e-mail: priscilla_slanetz@cchcs.org).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To investigate if the extraction flow product (EFP), as determined on dynamic contrast material–enhanced magnetic resonance (MR) images, could be a potential marker of tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.

MATERIALS AND METHODS: Fourteen women with proven breast cancer underwent MR imaging prior to and following neoadjuvant chemotherapy. Dynamic gradient-echo and echo-planar MR images were acquired before and after injection of gadopentetate dimeglumine. Precontrast T1s were measured before EFP maps were calculated by using a multicompartmental model. Mean EFP (EFPmean) and distribution analysis of EFP (EFPcount) were measured in tumors before and after neoadjuvant chemotherapy and were compared with tumor response at MR imaging. The significance of the difference in EFP values between the responders and nonresponders was calculated with a two-tailed Student t test.

RESULTS: EFPmean after neoadjuvant chemotherapy in partial responders and nonresponders was 33 mL · 100 g-1 · min-1 ± 9.8 and 54.2 mL · 100 g-1 · min-1 ± 10.3, respectively (P < .005). EFPmean decreased after neoadjuvant chemotherapy in the responders and nonresponders by 37% ± 30 and -5% ± 35, respectively (P > .05). An increase in EFPmean values was observed only in nonresponders who received taxanes. For regimens without taxanes, EFPmean decreased regardless of the morphologic response. EFPcount decreased for all the responders by 77% ± 33 and increased for all the nonresponders by 45% ± 68 (P < .02).

CONCLUSION: EFPcount appears to provide functional information regarding changes in tumor angiogenesis due to neoadjuvant chemotherapy. Functional MR imaging of the breast may be useful in monitoring tumor response to neoadjuvant chemotherapy.

© RSNA, 2003

Index terms: Breast neoplasms, 00.321, 00.327 • Breast neoplasms, MR, 00.121412, 00.121413, 00.121416, 00.12143, 00.12146 • Chemotherapy • Magnetic resonance (MR), diffusion study, 00.12144 • Magnetic resonance (MR), tissue characterization, 00.12144, 00.12146


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Neoadjuvant chemotherapy was introduced about 2 decades ago to treat patients with locally advanced breast cancer (1–11), which represents approximately 20% of all women who receive a diagnosis of breast cancer (12,13). The main objectives of this approach are to treat distant metastases earlier (8) and to reduce the size of inoperable tumors, thereby enabling conservative breast surgery (14–18). When a pathologically complete response is achieved, patients have increased disease-free and overall survival (19–22).

Methods to monitor response to neoadjuvant chemotherapy might permit (a) detection of resistant tumors, which would allow changes in therapy; and (b) adjustment of timing of surgery to the maximal response. Clinical, mammographic, and ultrasonographic examinations are used in an attempt to monitor tumor response in vivo, but they have been shown to be suboptimal in some cases because of chemotherapy-induced fibrosis (3,8,21,23,24). More recently, contrast material–enhanced magnetic resonance (MR) imaging has been shown to provide quantitative information that reflects early changes in tumors (25) due to chemotherapy (26–31). MR imaging may potentially be able to depict changes associated with the regression of angiogenesis after chemotherapy. Hulka et al (32,33) reported correlation of the extraction flow product (EFP), a measure of blood flow and microvascular permeability, with neoangiogenic activity. The purpose of our study was to investigate if the EFP, as determined on dynamic contrast-enhanced MR images, could be a potential marker of tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Subjects
The study cohort included 14 consecutive women (mean age, 46.3 years; age range, 28–61 years) with locally advanced breast cancer who were treated with neoadjuvant chemotherapy and surgery at a tertiary referral academic center between February and November 1999. The research study was approved by the hospital’s subcommittee on human studies, and written informed consent was obtained from all patients. Nine women were premenopausal, and five were postmenopausal. Histologic examination was performed by means of core needle biopsy (n = 13) or incisional biopsy (n = 1), and a nonferromagnetic clip was inserted in the center of each tumor. All patients had invasive ductal carcinomas (grades 2–3 of 3), four of which were associated with ductal carcinoma in situ (grades 1–3 of 3). Estrogen and progesterone receptors were positive in six and seven patients, respectively. An overexpression of the oncogene HER-2/neu was detected in eight patients. One patient did not undergo receptor and HER-2/neu determination. All patients underwent MR imaging prior to and following completion of neoadjuvant chemotherapy.

All patients received the first cycle of neoadjuvant chemotherapy a median of 4 days (range, 0–24 days) after the initial MR study. The chemotherapeutic regimens lasted a median of 77 days (range, 63–168 days): cyclophosphamide-doxorubicin for 63 days (n = 5), herceptin-paclitaxel for 77 days (n = 4), cyclophosphamide-doxorubicin-docetaxel for 85 days (range, 63–105 days; n = 3), and cyclophosphamide-methotrexate-fluorouracyl for 168 days (n = 1). One patient received a cyclophosphamide-doxorubicin regimen for 62 days, then paclitaxel for a total of 139 days (n = 1). The median delay between the end of treatment and posttreatment MR imaging was 8 days (range, 1–53 days). The median delay between posttreatment MR imaging and surgery was 45 days (range, 3–102 days); in four women in whom additional chemotherapy was given, surgery and final pathologic examination were delayed by 102, 89, 56, and 48 days, respectively. Lumpectomy was performed in nine patients, and in one of them, modified radical mastectomy was required because of margins positive for tumor at reexcision. Five patients underwent modified radical mastectomy. In one of these five women, lumpectomy was proposed, but the patient requested mastectomy.

MR Imaging
MR imaging of the breast was performed with a 1.5-T MR imager with a dedicated breast coil (Signa; GE Medical Systems, Milwaukee, Wis). An intravenous catheter was placed in an antecubital vein before imaging and was connected to a power injector (MedRad, Pittsburgh, Pa) containing gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ). Localization with a gradient-echo (repetition time msec/echo time msec, 18/5) sequence was performed, followed by a transverse fast spin-echo (3,500/17, 165) acquisition. After manual shimming in the volume of interest, a three-dimensional spoiled gradient-echo (23/6; flip angle, 30°; one signal acquired) sequence was used to acquire high-spatial-resolution MR images. Fat suppression was performed by using a binomial water-selective pulse. The matrix size was 512 x 256, with a field of view ranging from 28 to 35 cm. To accommodate different breast sizes and to ensure full coverage of the volume of interest, 60 sections with a 2.0–2.7-mm thickness were acquired with a voxel size ranging from 0.5 x 1.0 x 2.0 mm to 0.7 x 1.4 x 2.7 mm.

The functional MR imaging protocol included two successive echo-planar spin-echo acquisitions: (a) Prior to administration of the contrast agent, T1 of breast tissue was measured with an echo-planar inversion-recovery (6,000/30; inversion time ranging from 50 to 1,400 msec, with 10 steps of 150 msec; one signal acquired) sequence. The matrix size was 128 x 128, with a field of view varying between 35 and 40 cm. Seventeen to 19 sections with a 5–7-mm thickness and a gap of 1.5 mm were acquired. The voxel size ranged from 2.7 x 2.7 x 5.0 mm to 3.1 x 3.1 x 7.0 mm. (b) The tissue contrast material uptake was monitored before, during, and after administration with an echo-planar inversion-recovery (8,000/30) sequence. A fixed inversion time of 160 msec was used to minimize the contribution of fat to the total MR signal. The other parameters were the same as those used for T1 mapping. Twenty-six images were acquired at 8-second intervals during a total imaging time of 3 minutes 29 seconds. Five to seven images were acquired before an intravenous bolus of gadopentate dimeglumine was administered (0.1 mmol per kilogram of body weight at 3.5 mL/sec). Immediately after data acquisition with the echo-planar inversion-recovery sequence, a second set of contrast-enhanced high-spatial-resolution MR images was acquired by using a fat-suppressed three-dimensional spoiled gradient-echo MR sequence with the parameters used before injection.

Image Analysis
Morphologic analysis was performed before and after treatment on contrast-enhanced three-dimensional spoiled gradient-echo high-spatial-resolution MR images. The tumor volume was calculated by one radiologist (J.P.D.) from the surface of the tumor measured on each section in which the tumor was visible. If fat suppression was poor, subtraction of the precontrast images from the postcontrast images was performed to help improve delineation of the tumor boundary.

The echo-planar inversion-recovery data were used to calculate the T1 maps on a pixel-by-pixel basis by using a standard three-parameter fit. The dynamic echo-planar inversion-recovery data provided tissue signal intensity changes as a function of time that were converted into R1, taking into consideration the previous T1 calculations. Then, tissue R1 changes in each pixel were converted into time-concentration curves by using the R1 of gadopentate dimeglumine (4.5 sec-1 · mmol/L-1 at 37°C). Assuming a multicompartmental physiologic model of the tissue contrast material uptake (34) and an average arterial input function weighted by patient weight, EFP maps were calculated from the time-concentration curves by using a linear-fitting algorithm (32).

EFP values measured in voxels with low signal-to-noise ratio or rate of contrast material uptake below 0.2 mmol/L · sec-1 were excluded from the final EFP maps. Regions with EFP values above the threshold of 25 mL · 100 g-1 · min-1 were labeled as suspicious and highlighted on color-coded maps. Tumors were identified on fat-suppressed three-dimensional spoiled gradient-echo MR images by an experienced breast MR radiologist (P.J.S, E.D.Y.) and were compared with those on the functional maps (J.P.D.). Mean T1, mean EFP values (EFPmean), and peak of EFP (EFPpeak) were measured inside a region of interest (ROI) drawn over the whole tumor and the parenchyma of the contralateral breast on four sections centered around the nipple. Distribution analysis of the EFP values (EFPcount) was performed (35) by counting pixels with EFP values ≥ 25 mL · 100 g-1 · min-1 inside an ROI drawn around each tumor, including surrounding breast parenchyma and/or fat but excluding any vessels. For each patient, an ROI was drawn around the tumor with maximal dimensions (pre- or posttreatment), and the distribution analysis was performed over constant areas between pre- and posttreatment cases. If tumor shrinkage due to treatment allowed surrounding large vessels to be included in the ROI, these vessels were manually removed.

Assessment of Tumor Response
Morphologic response was determined according to published criteria involving changes in tumor volume after chemotherapy (36). Complete response indicated disappearance of the primary tumor. Partial response indicated a volume reduction of at least 65%. Progressive disease indicated a volume increase of at least 73%. Stable disease corresponded to neither partial response nor progressive disease criteria.

The pathologic response to treatment was assessed at examination of postsurgical tumor specimens. Patients with no evidence of residual tumor after treatment were classified as pathologically complete responders. Patients with morphologic response but with residual tumors were classified as pathologically partial responders.

Comparison of Functional MR Imaging with Response
EFPmean values obtained at the end of treatment were compared between the morphologic responders and the nonresponders. Relative percentage changes in EFPmean, EFPpeak, and EFPcount were recorded as (EFPinitial - EFPfinal)/EFPinitial, where EFPinitial and EFPfinal are the values obtained before and after treatment, respectively. For qualitative analysis, a decrease in the relative change of EFP was recorded as a functional response, and an increase as a nonfunctional response. All functional data were compared with the morphologic response and the pathologic findings.

Statistical Analysis
The significance of the difference in EFP values between the responders and nonresponders was calculated by using a two-tailed Student t test (Statview, version 5.0; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Morphologic Response and Pathologic Findings
Before treatment, the median of the tumor volumes was 22.0 cm3 (range, 6.2–109.7 cm3). After treatment, the median tumor volumes for the responders and nonresponders were 0.7 cm3 (range, 0–25.0 cm3) and 21.1 cm3 (range, 5.1–146.3 cm3), respectively.

According to the morphologic changes assessed with tumor volume measurements, there were two morphologically complete responders, seven partial responders, four patients with stable disease, and one with progressive disease (Table 1). For the two complete responders, one patient was a pathologically complete responder, with an inflammatory infiltrate over 8 x 8 cm. The other patient had multiple remaining microscopic foci of invasive ductal carcinoma associated with ductal carcinoma in situ, spanning 5 cm at pathologic examination. For the seven partial responses, five patients showed residual invasive ductal carcinoma with a maximal dimension ranging from 0.6 to 6.0 cm. Associated ductal carcinoma in situ was seen in two patients. One patient with partial response showed fibrocystic changes over 6.5 x 5.5 cm and was classified as a pathologically complete responder. Another patient with partial response showed residual ductal carcinoma in situ. The pathologic findings in four patients with stable disease showed invasive ductal carcinoma associated with ductal carcinoma in situ, with a maximal dimension between 1.5 and 4.5 cm. For the patient classified as having progressive disease, the pathologic findings showed a diffuse fibrosis with invasive ductal carcinoma and ductal carcinoma in situ.


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  		TABLE 1. Chemotherapy Regimen, Tumor Volume, Morphologic Response, Tumor EFP, Pathologic Findings, and Prognostic Factors

 
Functional MR Imaging
EFPmean and EFPpeak measured after treatment are summarized in Table 1. By definition, tumor EFP was not measurable at the end of treatment in the two patients with complete responses. EFPmean in tissue where the tumor was located prior to treatment was measured at 5 mL · 100 g-1 · min-1 ± 1.3 (SD) in one patient with complete response and was not measurable in the other because of very low contrast-to-noise ratio or low rate of contrast material uptake (< 0.2 mmol/L · sec-1). EFPmean measured in tumors after treatment in the partial responders (n = 7) and nonresponders (stable disease, n = 4; progressive disease, n = 1) was 33 mL · 100 g-1 · min-1 ± 9.8 and 54.2 mL · 100 g-1 · min-1 ± 10.3, respectively (P < .005) (Fig 1), and EFPpeak was 59.4 mL · 100 g-1 · min-1 ± 30.4 and 97.4 mL · 100 g-1 · min-1 ± 24.8, respectively (P < .05).



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  		Figure 1. Bar graph shows postchemotherapy EFPmean (gray bars; error bars indicate SDs) in the responders and nonresponders (P < .005).

 
Eight patients underwent functional MR imaging before and after treatment. Relative changes in EFPmean, EFPpeak, and EFPcount are summarized in Table 2. Before treatment, all tumors were visible on EFP maps. EFPmean for the responders and nonresponders was 61.2 mL · 100 g-1 · min-1 ± 16.2 and 56 mL · 100 g-1 · min-1 ± 19.3, respectively (P > .05), and EFPpeak was 90 mL · 100 g-1 · min-1 ± 22.9 and 100.5 mL · 100 g-1 · min-1 ± 41.9, respectively (P > .05). The relative decrease in EFPmean between measurements obtained before and after treatment in the responders and nonresponders was 37% ± 30 and -5% ± 35, respectively (P > .05). The relative decrease in EFPpeak was 26% ± 4 and -13% ± 46, respectively (P > .05). EFPmean increased only for the nonresponders with regimens that included taxanes. For regimens without taxanes, EFPmean decreased regardless of the morphologic response. EFPcount was determined for the eight patients who underwent functional MR imaging. Void pixels with very low signal-to-noise ratio or very slow contrast material uptake corresponded to an average of 2.2% of the ROIs before treatment and 2.7% after treatment. For the patient with complete response, the quantitative analysis showed a decrease of EFPcount by 96% once all large vessels located inside the ROI after treatment (due to tumor shrinkage) were manually excluded.


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  		TABLE 2. Relative Percentage Changes in EFPmean, EFPpeak, and EFPcount as a Function of the Morphologic Response and Pathologic Findings

 
After treatment, EFPcount decreased for all the responders (complete response, n = 1; partial response, n = 3) by an average of 77% ± 33 and increased for all the nonresponders (stable disease, n = 3; progressive disease, n = 1) by an average of 45% ± 68 (P < .02) (Fig 2). Qualitative analyses of changes in EFPcount and EFPmean are summarized in Table 3.



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  		Figure 2. Plot shows relative percentage changes in the ratio of EFPcount measured before and after treatment. A significant difference is observed between the responders and nonresponders (P < .02). pCR = pathologically complete responders ({bullet}), pPR = pathologically partial responders ({circ}), mNR = morphologic nonresponders (X), * = two patients with the same response.

 

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  		TABLE 3. Qualitative Analysis of Functional MR Imaging: Relative Percentage Changes in EFPmean and EFPcount versus Morphologic and Pathologic Responses

 
EFPmean measured in the contralateral breast tissue before and after treatment was 9.2 mL · 100 g-1 · min-1 ± 8.1 and 4.8 mL · 100 g-1 · min-1 ± 1.5 (P > .05), respectively. The T1s measured in tumor before and after treatment were 901 msec ± 281 and 1,101 msec ± 139 (P > .05), respectively, and T1s in normal breast tissue before and after treatment were 931 msec ± 243 and 1,034 msec ± 142 (P > .05), respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Since neoadjuvant chemotherapy is receiving increased attention for management of locally advanced breast cancer, tools to monitor tumor response are desirable to permit optimization of the chemotherapy course and the timing of surgery. Conventional methods used to monitor response have limitations. Chemotherapy-induced fibrosis can be difficult to differentiate from residual disease at physical examination and conventional imaging (3,8,21,23,24). Residual tumor burden can potentially be overestimated at clinical examination; morphologic response has been shown to be assessed more accurately by using dynamic contrast-enhanced MR imaging (26,31).

Dynamic information from MR contrast agent kinetic analysis appears to be useful in the assessment of tumor response to neoadjuvant chemotherapy (25) (Fig 3). Since the initial T1 affects signal intensity and hence the dynamic characterization of a lesion, it is recommended that the initial T1 be measured to reduce the interpatient and interlesion variability in dynamic tumor imaging (37). In the present study, the initial T1 in tumors was relatively higher after treatment, but the difference was not significant.



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  		Figure 3a. Images show a lesion in the inner right breast (arrows). (a) Gradient-echo MR image and (b) T1 map calculated from echo-planar inversion-recovery (inversion time, 8 msec) MR images before contrast material injection. (c, d) Dynamic echo-planar inversion-recovery (inversion time, 160 msec) MR images obtained (c) before and (d) 12 seconds after contrast material injection with an area of signal loss in the inner right breast. (e) EFP color-encoded map calculated from the T1 map and dynamic echo-planar acquisitions shows an area with high EFP values in the inner right breast parenchyma. (f) Gradient-echo MR image obtained at the equilibrium of contrast material injection shows right breast tumor enhancement and bilateral small areas of physiologic focal enhancement. Invasive ductal carcinoma was proven at pathologic examination.

 


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  		Figure 3b. Images show a lesion in the inner right breast (arrows). (a) Gradient-echo MR image and (b) T1 map calculated from echo-planar inversion-recovery (inversion time, 8 msec) MR images before contrast material injection. (c, d) Dynamic echo-planar inversion-recovery (inversion time, 160 msec) MR images obtained (c) before and (d) 12 seconds after contrast material injection with an area of signal loss in the inner right breast. (e) EFP color-encoded map calculated from the T1 map and dynamic echo-planar acquisitions shows an area with high EFP values in the inner right breast parenchyma. (f) Gradient-echo MR image obtained at the equilibrium of contrast material injection shows right breast tumor enhancement and bilateral small areas of physiologic focal enhancement. Invasive ductal carcinoma was proven at pathologic examination.

 


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  		Figure 3c. Images show a lesion in the inner right breast (arrows). (a) Gradient-echo MR image and (b) T1 map calculated from echo-planar inversion-recovery (inversion time, 8 msec) MR images before contrast material injection. (c, d) Dynamic echo-planar inversion-recovery (inversion time, 160 msec) MR images obtained (c) before and (d) 12 seconds after contrast material injection with an area of signal loss in the inner right breast. (e) EFP color-encoded map calculated from the T1 map and dynamic echo-planar acquisitions shows an area with high EFP values in the inner right breast parenchyma. (f) Gradient-echo MR image obtained at the equilibrium of contrast material injection shows right breast tumor enhancement and bilateral small areas of physiologic focal enhancement. Invasive ductal carcinoma was proven at pathologic examination.

 


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  		Figure 3d. Images show a lesion in the inner right breast (arrows). (a) Gradient-echo MR image and (b) T1 map calculated from echo-planar inversion-recovery (inversion time, 8 msec) MR images before contrast material injection. (c, d) Dynamic echo-planar inversion-recovery (inversion time, 160 msec) MR images obtained (c) before and (d) 12 seconds after contrast material injection with an area of signal loss in the inner right breast. (e) EFP color-encoded map calculated from the T1 map and dynamic echo-planar acquisitions shows an area with high EFP values in the inner right breast parenchyma. (f) Gradient-echo MR image obtained at the equilibrium of contrast material injection shows right breast tumor enhancement and bilateral small areas of physiologic focal enhancement. Invasive ductal carcinoma was proven at pathologic examination.

 


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  		Figure 3e. Images show a lesion in the inner right breast (arrows). (a) Gradient-echo MR image and (b) T1 map calculated from echo-planar inversion-recovery (inversion time, 8 msec) MR images before contrast material injection. (c, d) Dynamic echo-planar inversion-recovery (inversion time, 160 msec) MR images obtained (c) before and (d) 12 seconds after contrast material injection with an area of signal loss in the inner right breast. (e) EFP color-encoded map calculated from the T1 map and dynamic echo-planar acquisitions shows an area with high EFP values in the inner right breast parenchyma. (f) Gradient-echo MR image obtained at the equilibrium of contrast material injection shows right breast tumor enhancement and bilateral small areas of physiologic focal enhancement. Invasive ductal carcinoma was proven at pathologic examination.

 


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  		Figure 3f. Images show a lesion in the inner right breast (arrows). (a) Gradient-echo MR image and (b) T1 map calculated from echo-planar inversion-recovery (inversion time, 8 msec) MR images before contrast material injection. (c, d) Dynamic echo-planar inversion-recovery (inversion time, 160 msec) MR images obtained (c) before and (d) 12 seconds after contrast material injection with an area of signal loss in the inner right breast. (e) EFP color-encoded map calculated from the T1 map and dynamic echo-planar acquisitions shows an area with high EFP values in the inner right breast parenchyma. (f) Gradient-echo MR image obtained at the equilibrium of contrast material injection shows right breast tumor enhancement and bilateral small areas of physiologic focal enhancement. Invasive ductal carcinoma was proven at pathologic examination.

 
Correlation of functional data, such as EFP, with angiogenesis has been established previously by Hulka et al (32,33). If such correlation between microvessel density and EFP exists, tumors with high EFP values would likely be aggressive tumors and would be expected to be less responsive to chemotherapy. In the present study, however, EFPmean, EFPpeak, and EFPcount measured before treatment were not able to predict the responders and the nonresponders (P > .05). In contrast, values of EFPmean and EFPpeak obtained after neoadjuvant chemotherapy were significantly different (P < .005 and P < .05, respectively) between the morphologically partial responders and the nonresponders. When no residual tumor is present at pathologic examination, EFPmean is close to the threshold for biopsy (25 mL · 100 g-1 · min-1) or is too low to be measured accurately because of a very low contrast-to-noise ratio or very slow rate of contrast medium uptake.

Local inflammation and remaining neovascularization may account for a delayed normalization of EFP. Partial volume effect with small lesions may result in low EFPmean, as well as the absence of visible tumors on spoiled gradient-echo MR images. Because initially large tumors become small enough to be undetectable with conventional and/or functional MR imaging, missing small lesions is not expected to have a substantial effect on surgical strategy. Furthermore, it has been demonstrated that the absence of macroscopic residual tumor or the presence of microscopic residual tumor smaller than 1 cm3 is predictive of prolonged disease-free and overall survival (15,19,38).

Although EFPmean and EFPpeak values obtained after treatment were significantly different between the partial responders and nonresponders, the individual relative percentage changes in EFPmean and EFPpeak were not statistically different between the partial responders and nonresponders (P > .05). This is likely related to the fact that EFPmean is not correlated to tumor volume changes and is an average of the values of EFP over the entire active tumor, regardless if the value of any pixel is below or above the threshold of suspicion. The use of EFPmean and EFPpeak do not allow quantification of tumor response for the complete responders. Qualitative analysis may be performed, however, because if EFPmean measured in the tissue where the tumor was located is below the threshold for suspicious lesions, it can reasonably be concluded to be a functional response. EFPpeak reflects the value of EFP in 1 pixel over the whole tumor. This parameter appears very sensitive in the search for residual tumor activity and therefore is not adapted for monitoring tumor response. In contrast, EFPcount is measured by using the distribution analysis of EFP values and reflects the binary changes in the distribution of a population of pixels by counting pixels above the threshold of suspicion. Thus, this semiqualitative method of analysis is better suited to analysis of specific functional changes related to the evolution of neoangiogenesis and combines morphologic information, since the number of pixels in the tumor are counted.

In our sample of patients, distribution analysis allowed us to individually distinguish the morphologic responders from the nonresponders, regardless of the chemotherapy agents used (P < .02). Relative percentage changes in EFPcount showed a response of 97.5% ± 2.1 in two patients with a pathologically complete response, a response of 55.5% ± 37.5 in two patients with a pathologically partial response, and an absence of response of 45% ± 68 in four patients who were nonresponders. The sample of patients is too small to allow statistical analysis, but these results support the need for further study to assess the potential of distribution analysis of relative changes in EFP for early prediction of morphologic and possibly pathologic responses.

Additionally, the use of distribution analysis gives the opportunity to draw an ROI away from the border of the tumor while including the surrounding tissue, which reduces the operator variability related to the delineation of the boundary between the tumor and the healthy tissue when measuring EFPmean. Errors related to ROI drawing are well known, and different strategies may be used to minimize these errors, including semiautomated ROI analysis (39). However, such analyses are profiled to select most enhancing pixels, which is most likely not appropriate for monitoring tumor response, as demonstrated by our results obtained with EFPpeak.

Changes in EFP appear to be dependent on the chemotherapeutic regimens. Docetaxel may contribute to increased uptake of contrast material by the tumor by inducing a capillary protein leakage due to an increase in vascular permeability (40). This hypothesis is supported by the increase in EFPmean observed only for nonresponders with regimens that include taxanes. In the absence of residual tumor at pathologic examination, EFP values decreased, but the final value was above the threshold for biopsy. This may be explained by increased capillary permeability induced by taxanes, in addition to residual neovascularization. In mice, it has been demonstrated that taxanes induce a significant early increase in tumor vessel diameter (41). Thus, EFP measurements may have great potential to predict early tumor response by showing an early increase in EFP values. For patients who do not receive taxanes, the decrease in EFPmean may be explained by the direct antiangiogenic effect of chemotherapy on the proliferation of neovessels (42).

This pilot study presents several limitations, principally the small population of women with locally advanced breast cancer treated with neoadjuvant chemotherapy and the variety of regimens of neoadjuvant chemotherapy used. In four patients, prolonged treatment increased the delay between MR imaging and pathologic analysis, and this may theoretically impair the direct comparison between MR imaging data and pathologic findings.

In conclusion, the results of this pilot study show that noninvasive EFP measurements obtained with dynamic contrast-enhanced MR imaging may provide in vivo functional information regarding changes in tumor angiogenesis due to neoadjuvant chemotherapy. When distribution analysis is performed, individual EFP change within the tumors is correlated with the tumor morphologic response after a complete course of neoadjuvant chemotherapy. These results support the need to conduct further studies to assess the value of functional MR imaging in the prediction of early in vivo morphologic and pathologic tumor response during the course of specific regimens of neoadjuvant chemotherapy.


   ACKNOWLEDGMENTS
 
The authors thank Mary T. Foley, RT, Terry Campbell, RT, and Tina Chaves, AB, for assistance with data acquisition.


   FOOTNOTES
 
Abbreviations: EFP = extraction flow product, EFPcount = distribution analysis of EFP, EFPmean = mean EFP, EFPpeak = peak of EFP, ROI = region of interest

Author contributions: Guarantors of integrity of entire study, J.P.D., P.J.S., E.D.Y.; study concepts, J.P.D., P.J.S., L.G.; study design, J.P.D., P.J.S., D.B.K.; literature research, J.P.D.; clinical studies, P.J.S., E.D.Y., D.B.K.; data acquisition, J.P.D., P.J.S., E.D.Y.; data analysis/interpretation, E.H., J.P.D., P.J.S., E.D.Y.; statistical analysis, E.H., J.P.D., L.G.; manuscript preparation, J.P.D., P.J.S.; manuscript definition of intellectual content and editing, J.P.D., P.J.S., L.G.; manuscript revision/review and final version approval, J.P.D., P.J.S.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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