Diagnostic accuracy of MRI to evaluate tumour response and residual tumour size after neoadjuvant chemotherapy in breast cancer patients

A total of 91 patients with invasive breast cancer (92 carcinomas) were included in this institutional retrospective study. All patients were diagnosed by core needle biopsy between October 2006 and June 2013. All patients were treated with NAC followed by surgical treatment and underwent MRI before and after NAC for monitoring tumour response to treatment. Considering the Helsinki Declaration principles, the Institutional Research Ethics Committee approved this study (No. 2015/059).

According to the results of the initial diagnostic biopsy, tumours were classified into 5 molecular subtypes based on immunohistochemical characteristics of breast cancer30 (hormone receptor status, human epidermal growth factor receptor 2 (HER2) status and level of expression of ki-67). Estrogen receptor (ER) and progesterone receptor (PR) were considered positive if ≥ 10% of tumour cell nuclei stained positive. Hormone receptors (HR) were considered positive when the ER, PR, or both were positive. HER2 tumours scoring 3+ (intense homogeneous membranous staining in ≥ 10% of tumour cells) were considered positive. In case of 2+ scores (moderate complete membranous staining in ≥ 10% of tumour cells), the technique of fluorescent in situ hybridization was used to determine HER2 gene amplification. Samples with scores 0 to 1+ were considered negative. The cut-off of ki-67 expression level was set at 14%, to determine whether the cell proliferation index was high (≥ 14%) or low (≤ 14%). The five categories of molecular subtypes were: luminal A-like subtype (HR positive, HER2 negative, ki-67 ≤ 14%), luminal B/HER2-negative-like subtype (HR positive, HER2 negative, ki-67 > 14%), luminal B/HER2-positive-like subtype (HR positive, HER2 positive), HER2-positive-like subtype (HR negative, HER2 positive) and triple negative subtype (HR negative, HER2 negative).

The treatment plan was chosen by oncologists and explained to every patient. The initial evaluation of patients before NAC included a complete medical history, physical examination, complete blood work, chest X-ray, CT scan and bone scan. Clip titanium was placed in the tumour bed in all patients before starting chemotherapy, to identify the area of the primary tumour at the time of surgery. All patients with HER2-positive cancers received trastuzumab-based regimen as neoadjuvant therapy.

Tumour size was measured on the last MRI performed after completing NAC. The studies were done on a 1.5 T MRI scanner (Best, The Netherlands). The patient was placed in a prone position. Protocol in space-occupying lesions in the breast includes an axial T1-weighted sequence (TR: 494 msec, TE: 8 msec, number of acquired signals: 2, slice thickness: 3 mm, interval: 0.3 mm) and T2-weighted sequence (TR: 5000 msec, TE: 120 msec, number of acquired signals: 2, slice thickness: 3 mm, interval: 0.3 mm), followed by 3D T1-weighted fast spoiled gradient-echo dynamic sequence, selective excitation of water, (TR: 23 msec, TE: 5.7 msec, angle: 20^o, slice thickness: 2 mm) acquiring 6 series, one pre-contrast series and five consecutive post-contrast series at 90-second intervals. Contrast agent (Gd-DOTA, DOTAREM, Guerbet) was administered using a bolus injection (2 mL/s) at a dose of 0.1 mmol/kg followed by a bolus of saline solution (20 mL). All images are analysed at a workstation. Subtraction images between the without contrast stage and the 2^nd-3^rd-4^th-5^th post-contrast phase were obtained, which were interpreted with the help of specific programs for the analysis of contrast enhancement and time-signal intensity curves.

Assessment of response was based on changes in tumour size in the MRI contrast sequences. Tumour size was calculated by summing the maximum diameters of tumour enhancement on axial slices of MRI, as the Response Evaluation Criteria in Solid Tumours (RECIST). The absence of a clear enhancement indicates no residual cancer. The final response was defined as the change in size between the pre-treatment and post-treatment MRI. Response categories, based on radiological examination with contrast MRI, were classified as: (1) imaging complete response on MRI (iCR: no evidence of residual disease on posttreatment MRI); and (2) non-iCR: residual disease on posttreatment MRI.

Pathologic measurement of the tumour size was used as the “gold standard” and compared to the MRI-measured residual tumour size. Samples for histopathological examination were cut into 5 mm slices, fixed in 10 % neutral-buffered formalin, trying to identify any lesion that corresponded with invasive carcinoma. If the tumour lesion was evident, it was included in its entirety for morphological study with hematoxylin and eosin (H&E). If no evident tumour was found, the clip marker was identified, and slides from the block containing the marker as well as the adjacent blocks were examined. Tumour response after NAC was classified as (1) pCR: no residual invasive tumour in the breast on final pathology; and (2) non-pCR: presence of residual invasive cancer on final pathology. If any residual invasive disease, pathologic tumour size was determined by measuring the longest dimension of a sample stained with H&E and the number of blocks in which invasive tumour was detected.

A descriptive analysis of the variables included in the study was performed. Continuous variables were expressed as mean and standard deviation, and categorical variables were expressed as absolute values and percentages with their estimated 95% confidence interval. Comparison of means was performed using Student’s t test or Mann-Whitney test and analysis of variance or Kruskal-Wallis test, as appropriate after checking normality with the Kolmogorov-Smirnov test. Association of qualitative variables was estimated using the Chi-square test. Pearson correlation analysis was used to compare the MRI-measured and pathological tumour sizes. Linear regression model was used to analyse the diagnostic accuracy of MRI. P ≤ 0.05 was considered significant. Basic statistical indicators to assess the accuracy of MRI in detecting residual disease after NAC were calculated. The efficacy of MRI was measured by the predictive values. True negative (TN) was defined as negative in both MRI and pathology; true positive (TP) was defined as positive in both MRI and pathology; false negative (FN) was defined as negative on MRI and positive on pathology; and false positive (FP) was defined as positive on MRI and negative on pathology. To assess the accuracy of MRI in detecting residual disease, sensitivity: TP / (TP + FN), specificity: TN / (TN + FP), positive predictive value (PPV): TP / (TP + FP), negative predictive value (NPV): TN / (TN + FN), and overall accuracy: (VN + VP) / (TP + TN + FP + FN) were calculated. Analyses were performed using IBM SPSS Statistics version 19.

Tumour responses to NAC were compared based on the results obtained by MRI and pathological examination. MRI showed complete remission in 38 cases (41.3%) and residual disease in 54 cases (58.7%). The pathological study showed a pCR in 28 cases (30.4%) and invasive residual tumour was found in 64 samples (69.6%).The diagnostic performance of MRI for detecting residual tumour is summarized in Table 2. The sensitivity of MRI for detecting residual disease after NAC was 75% (48/64) and the specificity was 78.57% (22/28). The PPV (accuracy of MRI for detecting residual disease) was 88.89% (48/54). The NPV (accuracy of MRI in predicting pCR) was 57.89% (22/38). The overall accuracy of MRI was 76.09% (70/92). MRI showed FN diagnoses in 25% cases (16/64).

It was possible to compare the residual tumour size determined by MRI and pathological examination in 89 of the 92 cases of the study. In 3 cases it was not possible to determine the pathologic tumour size due to the presence of scattered residual multifocal disease. The mean residual tumour size determined by MRI after NAC was 1.44 cm. The final pathologic tumour size was 1.53 cm. The two measurements are correlated forwardly significantly (r = 0.648, p < 0.001) (Figure 1). The mean discrepancy between the two measures was 0.96 cm. The discrepancy was less than 1 cm in 57 cases (64.04%).

Figure 1.

Linear regression models were performed to find clinicopathological predictors of the diagnostic accuracy of MRI based on the absolute difference between the MRI-measured and pathologic residual tumour size (Table 3). The strongest predictor was tumour grade (p < 0.001). The mean absolute discrepancy was significantly lower in the group of high-grade tumours. In addition, the HR status was associated significantly with the diagnostic accuracy of MRI, observing a lower discrepancy in the group of non-luminal tumours (p = 0.033). Baseline tumour size was kept in the limit of significance, with a lower discrepancy in the group with baseline tumour size ≤ 5 cm. The age, histological type and HER2 status were not associated with the diagnostic accuracy of MRI. Triple negative subtype showed the smallest difference between the two measurements (Figure 2), although no statistically significant difference regarding the molecular phenotype of the tumour (p = 0.055). After a multivariate linear regression analysis, tumour grade (p = 0.001) and baseline tumour size (p = 0.030) remained significant independent predictors of MRI accuracy (Table 4).

Figure 2.

Discrepancy between MRI-measured and pathologic residual tumour size, based on molecular subtypes.