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Dynamic Breast MRI in the Course of Neoadjuvant Chemotherapy

Posted Mar 31, 2010 Updated Apr 7, 2023
By Thomas Schlossbauer MD , Steven Sourbron PhD , Anna Scholz , Marc Mosner MD , Steffen Kahlert MD , Holger Böhm MD , Maximilian Reiser MD , Karin Hellerhoff MD
12 min read

Rationale and Objectives

Basic exploratory data analysis to evaluate enhancement and tumor size (SIZE) in contrast-enhanced breast magnetic resonance imaging (CE-MRI) during chemotherapy. Correlation with histopathology (human epidermal growth factor receptor (HER2/neu) status and estrogen receptor (ER) score).

Materials and Methods

Sixty-five women (mean age 47 ± 10 years) with locally advanced breast cancer (mean SIZE 25 mL) had CE-MRI (three-dimensional fast low angle shot (FLASH); repetition time = 9.1 ms, echo time = 4.8 ms, flip angle (FA) 25°, matrix size 256 × 256 pixels, field of view 350 mm, slice thickness 2 mm, number of slices = 32, one precontrast and five postcontrast series) before and after chemotherapy. Lesion segmentation and subsequent SIZE and enhancement analysis including maximum enhancement (MAX), area under the curve (AUC), time-to-peak (TTP), and maximum upslope (MUS) were performed. Correlation with histopathology (ER score and HER2/neu status).

Results

SIZE reduced significantly during therapy (25 mL vs. 5 mL, P < .0001). AUC, MAX, MUS decreased ( P < .0001), TTP increased ( P < .0001). SIZE and MAX were independent parameters ( r 2 = .22). No correlation ( P > .01) in any of the parameters with either ER score or HER2/neu status was found. HER2/neu score equal 2+pos. or 3+ showed significantly stronger changes in SIZE ( P < .01), MAX ( P < .01) and AUC ( P < .05) compared to lower HER2/neu score (0 to 2+neg.).

Conclusions

From routine MRI protocol and semiquantitative analysis of signal enhancement curves, information about size, and hemodynamic status of tumors under treatment may be extracted. Reduction in size and maximum enhancement were complementary parameters. In the course of therapy, size and enhancement may develop differently in clinically relevant histopathological subgroups.

Neoadjuvant chemotherapy has become the standard of care for patients with locally advanced breast cancer . Therapy aims to achieve a pathological complete response or tumor reduction and increased rates of breast conserving approaches. Different clinical and pathologic staging parameters and biologic tumor markers have been identified to predict the rate of tumor response in the course of neoadjuvant chemotherapy . Therapy response is frequently described as tumor size reduction in B-mode ultrasound and mammography. There are still controversies in clinical practice on the use of contrast-enhanced breast magnetic resonance imaging (CE-MRI) and there is no international reference on breast MRI protocols . Accurate and precise tumor response quantification is critical for monitoring patient therapy and for physician’s decision-making on the patient care (ie, therapy decision regime and follow-up). In current clinical practice, tumor size remains the main parameter used to monitor tumor response to therapy . The size criterion is limited however and provides information on only one aspect of therapy response. Enhanced vessel density is an essential premise for tumor growth. Because of increased vessel density and capillary leakage, invasive cancer shows different contrast-enhancement kinetics compared to the adjacent tissue . In the course of neoadjuvant chemotherapy, the density of tumor vessels may decrease ; therefore, functional parameters are becoming subject of various investigations. Parameters describing tumor perfusion may provide additional information and may allow a better prediction of outcome. Chemotherapeutic treatments are more and more individualized in each patient, and therefore radiological diagnosis can result in therapeutic conclusions of significant importance.

Two distinct approaches have been proposed to measure such hemodynamic parameters with dynamic CE MRI (DCE-MRI) in the breast. High coverage and spatial resolution is essential for lesion detection within glandular parenchyma, and assessment of the lesion’s morphology . In addition, the tumor can be characterized to a certain extent by evaluating the shape of the signal-enhancement curve in the lesion . High temporal resolution (∼1 second) might support a more accurate quantification of perfusion and permeability parameters , but coverage is limited to a small number of slices. To combine the benefits of both alternatives, a dual-bolus protocol has been proposed in which the first bolus is monitored at low temporal resolution for localization and curve-type classification, and the second bolus is measured rapidly at the slice position of the detected lesion(s) to allow for more complete and accurate characterization

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Research design and methods

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Study Population

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Figure 1, Frequencies of different chemotherapeutic treatments. ECT: 4 × epirubicin/cyclophosphamide (90/600 mg/m 2 ) − 4 × paclitaxel (175 mg/m 2 ); TAC: 6 × docetaxel/doxorubicin/cyclophosphamide (75/500/50 mg/m 2 body surface [BS]); EC-DH = 4 × epirubicin/cyclophosphamide (90/600 mg/m 2 BS) − 4 × docetaxel (100 mg/m 2 BS) + Herceptin 8 mg/kg kg (initial 6 mg/kg kg); EC-D: 4 × epirubicin/cyclophosphamide (90/600 mg/m 2 BS) − 4 × docetaxel (100 mg/m 2 BS); E-T-CMF: 3 × epirubicin (150 mg/m 2 BS) − 3 × Paclitaxel (225 mg/m 2 BS) − 3 × cyclophosphamide/methotrexate/5 Fluorouracil (500/40/600 mg/m 2 BS); ETC: 3 × epirubicin (150 mg/m 2 BS) q2w − 3 × Paclitaxel (225 mg/m 2 BS) q2w − 3 × cyclophosphamide (2000 mg/m 2 BS) q2w; FEC-D: 3 × 5-Fluorouracil/epirubicin/cyclophosphamide (500/100/500 mg/m 2 BS) − 3 × Docetaxel (100 mg/m 2 BS); Carb T: Carboplatin area under the curve 5/Paclitaxel 175 mg/m 2 BS.

Figure 2, Plot of tumor sizes, all patients ( n = 65). Mean lesion size estimated from semi-automatic segmentation procedure was 26 mL.

Figure 3, Distribution of histopathologic tumor characteristics. Estrogen receptor score (ER-score), Progesterone receptor score (PR-score), human epidermal growth factor receptor (HER2/neu) score, and grading.

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Imaging and Patient Protocols

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Table 1

MRI Scanning Parameters

STIR T2w TSE Dynamic T1 GE NoS 32 32 32 TR 4920 4000 9.1 TE 68 71 4.8 FA 180 180 25 TI 150 Matrix 512 × 512 512 × 512 256 × 256 ST 4 mm 4 mm 2 mm

MRI, magnetic resonance imaging; NoS, number of slices; TR, repetition time; TE, echo time; FA, flip angle; TI, inversion time; ST, slice thickness; STIR, short TI inversion recovery; TSE, turbo spin echo; GE, gradient echo.

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Postprocessing

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Figure 4, Illustration of the different postprocessing steps. (a) The magnetic resonance signal intensity as a function of time for a single slice. The precontrast image is given on the left, followed by five contrast-enhanced images taken in 90-second intervals. In a first step (b) , the relative signal enhancement (RSE) is calculated for every pixel and every time point. In a second step (c) , color-coded parameter maps are created of three summary parameters: the maximum RSE ( c , left ), the area under the RSE curve ( c , middle ) and the ratio of both ( c , right ). The maximum image is then taken as a basis for tumor region of interest (ROI) definition (d) . A mask is defined automatically as all pixels with a maximum RSE larger than 50% ( d , left ), the tumor is outlined manually on all slices ( d , middle ) and a final tumor ROI is created as the intersection of the manual outline with the mask ( d , right ).

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Figure 5, Illustration of the five parameters calculated on region of interest (ROI) level. The magnetic resonance imaging signal is averaged over all pixels in the ROI derived as in Figure 1 (d), and relative signal enhancement (RSE) is calculated for the ROI (black line) . The following four parameters are then extracted on ROI level: the maximum RSE (MAX), the time to peak RSE (TTP), the area under the RSE curve (AUC), and the maximum RSE upslope (MUS).

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Reproducibility

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Histopathologic Evaluation

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Statistics

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Results

Examples

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Figure 6, Example with reduction in tumor size (SIZE) (−78%) and in maximum enhancement (MAX) (−34%). Subtraction image (before neoadjuvant chemotherapy) and color-coded enhancement images before and after chemotherapy.

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Figure 7, Example with reduction in tumor size (SIZE) (−81%) but an increase in maximum enhancement (MAX) (+12%). Subtraction image (before neoadjuvant chemotherapy) and color-coded enhancement images before and after chemotherapy.

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Figure 8, Relative signal enhancement curves before (triangles) and after (squares) therapy, for a region of interest (ROI) covering the node with suspected malignancy in Figure 7 .

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Reproducibility

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Table 2

Interobserver Variability: Manual Segmentation vs. Semiautomatic Segmentation Technique

Manual Segmentation Semiautomatic Segmentation Observer 1 Observer 2 Observer 1 Observer 2 Mean lesion size (mL) 14 12.8 9 8.9 Correlation ( r 2 ) 0.93 0.98

Mean segmented lesion size described in mL.

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Response to Treatment within Study Population

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Table 3

Changes of Lesion Size in the Course of Chemotherapy (all patients, n = 65)

S_P__P_ Bonferroni Lesion size −1038.5 <.0001 2.6 ∗ 10-19 Perfusion parameters Area under the curve (AUC) −1038.5 <.0001 4.4 ∗ 10-17 Maximum enhancement (ME) −1010.5 <.0001 2.2 ∗ 10-15 Maximum upslope (MUS) −998.5 <.0001 1 ∗ 10-14 AUC/ME −863.5 <.0001 .000000003 Time to maximum 345.5 <.0001 .001

S, intensity of change; P Bonferroni , corrected P values for multivariate analysis.

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Enhancement Parameters and Histopathologic Characteristics

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Figure 9, Change of enhancement parameters in two clinically relevant subgroups. Results are given for three different groups: all patients (black) , patients with HER2/neu status 2+positive/3 + (gray) , and patients with ER 12 (white) .

Table 4

P values of the t -test for the Changes during Therapy in each Parameter

Change during  therapy (HER2/neu 2+pos./3+ vs. HER2/neu 0 to 2+neg.) - P values ( t -test) SIZE MAX AUC MUS TTP AUC/MAX_P_ values .0002 ∗∗ .008 ∗∗ .044 ∗ .32 .58 .59

Patients are subdivided into two subgroups according to HER2/neu status: one group consists of tumors which are expected to show superior response to therapy (HER2/neu 2+pos./3+), the other group consists of all others (HER2/neu 0 to 2+neg.).

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Tumor Size versus Enhancement

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Figure 10, A plot of all measured values for tumor size (SIZE) (horizontal axis) and maximum enhancement (MAX) (vertical axis) shows that both parameters are fully uncorrelated ( r = 0.22). Correlation was calculated from pretherapeutic data.

Figure 11, Overview of the changes in tumor size (SIZE) (horizontal axis) and maximum enhancement (MAX) (vertical axis) for all patients. Data are grouped in the same manner as in Table 4 : White triangles are data from the HER2/neu 0 to 2+negative group, black diamonds from the HER-2/neu 2+positive/3+ group. The circles indicate the location within the population of the two case studies discussed in more detail ( Figs 6 and 7 ).

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Discussion

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Limitations of this Study

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Transfer to Clinical Context

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Academic Radiology, Volume 17, Issue 4
Journals General Radiology
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