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Apparent Diffusion Coefficient Value to Evaluate Tumor Response After Neoadjuvant Chemotherapy in Patients with Breast Cancer

Posted Jan 31, 2018 Updated Apr 10, 2023
By Yazmín Aseret Ramírez-Galván MD , Servo Cardona-Huerta MD PhD , Guillermo Elizondo-Riojas MD PhD , Neri Alejro Álvarez-Villalobos MD
12 min read

Rationale and Objectives

This study explored tumor behavior in patients with breast cancer during neoadjuvant chemotherapy (NAC) by sequential measurements of tumor apparent diffusion coefficient (ADC) after each chemotherapy cycle. The aim was to determine if the tumor ADC is useful to differentiate complete pathological response (cPR) from partial pathological response (pPR) during NAC.

Materials and Methods

A total of 16 cases (in 14 patients) with diagnosis of breast cancer eligible to receive NAC were included. There were 70 magnetic resonance imaging examinations performed, 5 for each patient, during NAC cycles. Diffusion-weighted imaging was performed on a 1.5T system (b values of 0 and 700s/mm 2 ). Four ADC ratios between the five MRI examinations were obtained to assess ADC changes during NAC. Absence of invasive breast cancer at surgical specimens (Miller-Payne 5) was considered as cPR and was used as reference for ADC cutoff ratios.

Results

In this study, we were able to differentiate between cPR and pPR, after two cycles of NAC until the end of NAC before surgery (ADC ratios 2–4). The thresholds to differentiate between cPR and pPR of ADC ratios 2, 3, and 4, were 1.14 × 10 −3 mm 2 /s, 1.08 × 10 −3 mm 2 /s, and 1.25 × 10 −3 mm 2 /s, respectively, and have a cross-validated sensitivity and specificity of 79.2%, 79.7% (ADC ratio 2); 100%, 66.7% (ADC ratio 3); and 100%, 83.8% (ADC ratio 4), respectively.

Conclusions

The ADC ratios were useful to differentiate cPR from pPR in breast cancer tumors after NAC. Thus, it may be useful in tailoring treatment in these patients.

Introduction

Neoadjuvant chemotherapy (NAC), also known as primary or preoperatory chemotherapy, is used before surgical treatment. NAC is generally used as a part of conventional treatment in patients with locally advanced breast cancer with the potential to convert unresectable tumors into resectable tumors, to increase the possibility of breast conserving surgery, and also to provide an early management of micro-metastatic disease . In breast cancer, the survival benefit of patients receiving NAC is similar to that observed in patients who receive chemotherapy after surgery. Furthermore, the complete pathological response (cPR) or the absence of residual invasive disease in NAC is considered a favorable long-term predictive indicator or surrogate for survival . Even the measurement of tumor response in vivo to NAC may change the type and number of cycles of proposed chemotherapy .

The development of new anticancer therapies has prompted the search for new tools to assess the response to these therapies . The reference standard for evaluating the effects of new drugs is direct assessment of tumor tissue samples obtained through invasive techniques . In phase 2 and 3 clinical trials, the evaluation of the response to treatment is mainly measured in an indirect and less invasive manner using biological markers .

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Materials and Methods

Patients

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Breast Tumor Marking

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Chemotherapy Regimens

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MRI Acquisition

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Image Postprocessing

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Figure 1, Images of a 49-year-old woman. (a) Magnification of axial DWI before NAC, showing a mass in the union of upper quadrants of the left breast. (b) Magnification of axial DWI after the second cycle of NAC, showing the same mass. (c) Magnification of axial DWI before surgery, showing the same mass. (d) Magnification of axial ADC map before NAC at the same level as in (a) shows one of the three ROIs into the mass with an ADC value of 1.36 × 10 −3 mm 2s. (e) Magnification of axial ADC map after the second cycle of NAC at the same level as in (b) shows one of the three ROIs into the mass with an ADC value of 1.32 × 10 −3 mm 2s. Based on the average of the three ROIs, resulting in an ADC ratio 2 of 1.05 × 10 −3 mm 2s. (f) Magnification of axial ADC map before surgery at the same level as in (c) shows one of the three ROIs into the mass with an ADC value of 1.66 × 10 −3 mm 2s. Based on the average of the three ROIs, resulting in an ADC ratio 4 of 1.25 × 10 −3 mm 2s. The pathological result was infiltrating ductal carcinoma poorly differentiated, classified as triple negative by its immunohistochemical expression. In accordance to the Miller-Payne system, the surgical specimen had a grade 4 with a loss >90% of the neoplastic cells, corresponding to pPR. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; NAC, neoadjuvant chemotherapy; pPR, partial pathological response; ROIs, regions of interest.

Figure 2, Images of a 65-year-old woman. (a) Magnification of axial DWI before NAC, showing a mass in the union of outer quadrants of the right breast. (b) Magnification of axial DWI after the second cycle of NAC, showing the same mass. (c) Magnification of axial DWI before surgery, showing the same mass. (d) Magnification of axial ADC map before NAC at the same level as in (a) shows one of the three ROIs into the mass with an ADC value of 1.07 × 10 −3 mm 2s. (e) Magnification of axial ADC map after the second cycle of NAC at the same level as in (b) shows one of the three ROIs into the mass with an ADC value of 1.66 × 10 −3 mm 2s. Based on the average of the three ROIs, resulting in an ADC ratio 2 of 1.17 × 10 −3 mm 2s. (f) Magnification of axial ADC map before surgery at the same level as in (c) shows one of the three ROIs into the mass with an ADC value of 1.92 × 10 −3 mm 2s. Based on the average of the three ROIs, resulting in an ADC ratio 4 of 1.36 × 10 −3 mm 2s. The pathologic result was infiltrating ductal carcinoma moderately differentiated, classified as Her/2neu by its immunohistochemical expression. In accordance to the Miller-Payne system, the surgical specimen had a grade 5 with no malignant cells identifiable, corresponding to cPR, also was reported a fibrosis area of 4 cm. ADC, apparent diffusion coefficient; cPR, complete pathological response; DWI, diffusion-weighted imaging; NAC, neoadjuvant chemotherapy; ROIs, regions of interest.

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Assessment of Tumor Response

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Data Collection

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Statistical Analysis

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Results

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TABLE 1

Clinicopathological Characteristics of the Population

Characteristic Breast Cancer Cases n = 16

Mean ± SD or n (%) cPR n = 4

Mean (SD) or n (%) pPR n = 12

Mean (SD) or n (%)P Values Age, years mean (SD) 48.5 (7.8) 51.5 (10.3) 47.5 (7.0) .39 Tumor grade, n (%) .99 Grade 2 (moderately differentiated) 11 (68.8) 3 (75) 8 (66.7) Grade 3 (poorly differentiated) 5 (31.3) 1 (25) 4 (33.3) Immunohistochemical expressions of ER, PR, and Her2/neu receptors, n (%) .40 Positive hormonal receptor 7 (43.8) 1 (25) 6 (50) Triple negative 5 (31.3) 1 (25) 4 (33.3) Her2/neu overexpressing 4 (25) 2 (50) 2 (16.7) Ki-67 protein status, n (%) .53 Low proliferation (<20%) 13 (81.3) 4 (100) 9 (75) High proliferation (≥20%) 3 (18.8) 0 (0) 3 (25) MRI tumor size at diagnosis, mm mean (SD) 36.6 (17.6) 41.2 (29.5) 35.1 (13.1) .56 MRI tumor size at diagnosis, n (%) .59 <20 mm 2 (12.5) 1 (25) 1 (8.3) 20–50 mm 11 (68.8) 2 (50) 9 (75) >50 mm 3 (18.8) 1 (25) 2 (16.7) MRI tumor volume at diagnosis, cm 3 mean (SD) 15.9 (16.7) 18.7 (27.5) 15 (13.1) .71 MRI tumor size after second cycle NAC, mm mean (SD) 30 (16.6) 35.5 (27.4) 28.2 (12.5) .64 MRI tumor size after second cycle NAC, n (%) .09 <20 mm 5 (31.3) 2 (50) 3 (25) 20–50 mm 10 (62.5) 1 (25) 9 (75) >50 mm 1 (6.3) 1 (25) 0 (0) MRI tumor volume after second cycle NAC, cm 3 mean (SD) 10.3 (14) 12.8 (19.1) 9.4 (12.8) .69 MRI tumor size after NAC, mm mean (SD) 24.9 (15.9) 32.2 (25.5) 22.4 (11.8) .50 MRI tumor size after NAC, n (%) .16 <20 mm 7 (43.8) 2 (50) 5 (41.7) 20–50 mm 8 (50) 1 (25) 7 (58.3) >50 mm 1 (6.3) 1 (25) 0 (0) MRI tumor volume after NAC, cm 3 mean (SD) 3.36 (3.3) 3.18 (3.6) 3.43 (3.4) .90 Surgical specimen tumor size, mm mean (SD) 16.47 (14.6) 0 (0) 21.9 (12.7) .004 Tumor pathological response Miller-Payne, n (%) .001 Grade 1 (no reduction in overall cellularity) 2 (12.5) 0 (0) 2 (16.7) Grade 3 (30%–90% reduction in tumor cells) 6 (37.5) 0 (0) 6 (50) Grade 4 (>90% loss of tumor cells) 4 (25) 0 (0) 4 (33.3) Grade 5 (no malignant cells identifiable) 4 (25) 4 (100) 0 (0)

cPR, complete pathological response; ER, estrogen receptor; MRI, magnetic resonance imaging; NAC, neoadjuvant chemotherapy; pPR, partial pathological response; PR, progesterone receptor; SD, standard deviation.

P values calculated by Pearson χ 2 test or Fisher exact test for categorical variables and independent Student t test for numerical variables.

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Measures of the ADC Ratios

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TABLE 2

Comparison Chart Between Mean ADC Ratios of cPR and pPR

ADC Ratios cPR n = 4

Mean ± SD pPR n = 12

Mean ± SD_P_ Values ADC ratio 1 1.08 ± 0.04 1.12 ± 0.09 .44 ADC ratio 2 1.30 ± 0.28 1.10 ± 0.10 .25 ADC ratio 3 1.35 ± 0.28 1.10 ± 0.15 .17 ADC ratio 4 1.49 ± 0.20 1.13 ± 0.21 .01

ADC, apparent diffusion coefficient; cPR, complete pathological response; pPR, partial pathological response; SD, standard deviation.

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Figure 3, Box and whisker plot. Box and whisker plot shows the distribution of ADC ratio 4 for cPR and pPR. The median for cPR was 1.47 and for pPR was 1.20, and the minimum and maximum values were 1.29–1.73 for cPR and 0.62–1.43 for pPR. ADC, apparent diffusion coefficient; cPR, complete pathological response; pPR, partial pathological response.

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Cross-validated Analysis

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TABLE 3

Cross-validated Threshold, Sensitivity, Specificity, and AUC

ADC Ratios Threshold (× 10 −3 mm 2 /s) Sensitivity (%) Specificity (%) AUC_P_ Values ADC ratio 1 ≤1.09 85.9 58.6 0.641 .34 ADC ratio 2 >1.14 79.2 79.7 0.807 .03 ADC ratio 3 >1.08 100 66.7 0.826 .01 ADC ratio 4 >1.25 100 83.8 0.938 .0001

ADC, apparent diffusion coefficient; AUC, area under the curve.

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Figure 4, ROC curve. ROC curve shows the diagnostic performance of all ADC ratios. The cross-validated AUC was significant at ADC ratios 2, 3, and 4. ADC, apparent diffusion coefficient; AUC, area under the curve; ROC, receiver operating characteristic curve.

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Discussion

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Acknowledgments

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Academic Radiology, Volume 25, Issue 2
Journals General Radiology
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