Evaluation of MRI accuracy after primary systemic therapy in breast cancer patients considering tumor biology: optimizing the surgical planning

A total of 204 patients with primary operable breast cancer treated with PST from October 2006 to September 2016 were included in this retrospective study. MRI was performed before and after PST to evaluate tumor response and residual tumor extent. A clip marker was placed at the tumor site prior to PST for surgical detection of the tumor bed. Patients with luminal A-like tumors were excluded due to their worse response to PST. Furthermore, in our previous study, the tumor size discrepancy between MRI and pathology was higher in this tumor subtype.16

Breast cancer was classified into 5 approximate subtypes based on tumor characteristics using immunohistochemistry (HR status, HER2 status and ki-67 status). The five categories of tumor subtypes were: luminal A-like, luminal B-like (HER2-negative), luminal B-like (HER2-positive), HER2 positive (non-luminal) and TN subtype.17 The cutoff of ki-67 expression level was established at 20% to distinguish between luminal A-like and luminal B-like (HER2-negative) subtypes, so that a threshold of ≥ 20% was indicative of high ki-67 status.

62.2% of patients received an anthracycline/taxane-based PST. All HER2-positive breast cancer patients except one received trastuzumab-based PST (36.3%), in combination with an anthracycline/taxane-based regimen. Three patients received a nanoparticle albumin-bound paclitaxel regimen (1.5%).

Residual tumor extent after PST was measured by MRI as the longest dimension of the enhancing lesion. MRI examinations were performed with patients in prone position using a 1.5T MRI scanner (Best, The Netherlands) with breast-surface coils. The protocol included an axial T1-weighted sequence (repetition time [TR]: 494 msec, echo time [TE]: 8 msec, number of acquired signals: 2, slice thickness: 3 mm, interval: 0.03 mm) and T2-weighted sequence (TR: 5000 msec, TE: 120 msec, number of acquired signals: 2, slice thickness: 3 mm, interval: 0.03 mm), followed by diffusion-weighted images performed at different b values (b = 0 and b = 1000).

A dynamic study (3D T1-weighted fast spoiled gradient-echo sequence) in the axial plane was performed before and 90, 180, 270, 360 and 450 sec after starting intravenous injection of 0.1 mmol/kg of gadoterate meglumine (Gd-DOTA, DOTAREM, Guerbet) at a rate of 2 mL/s, followed by a 20 mL saline flush.

All images were processed at a workstation for the analysis of contrast enhancement, time-signal intensity curves and restriction to the difussion.

Imaging complete response (iCR) was defined as the absence of a clear enhancement visible on post-treatment MRI. Non-iCR was defined as the presence of any amount of tissue enhancement within the previous tumor bed visible on dynamic MRI after PST.

Surgery was performed within four weeks after completion of the neoadjuvant therapy. BCS was performed when the breast-tumor size index was favorable, considering patient´s preference and multifocality. In non-palpable lesions after PST, a wire-guided resection of the clip containing breast area was performed. All patients undergoing BCS received adjuvant whole-breast irradiation with tangential fields.

All surgical specimens were fixed after gross evaluation in 10% neutral-buffered formalin for 24 hours, and then serially cut into 5 mm thick sections. If residual tumor was clearly visible a gross measurement was made. If no evident tumor was identified, the clip marker placed prior to PST was found, and slides from the block containing the marker as well as the adjacent blocks were microscopically examined. Surgical specimens were stained with hematoxylin and eosin for the histological examination. The largest tumor diameter provided by the pathologist was used in the comparative study. If no invasive cancer was found in the surgical specimen after PST, regardless of the presence of carcinoma in situ, a breast pCR was considered. Negative resection margins were defined as no ink on tumor for invasive carcinoma and 2 mm clean margins for ductal carcinoma in situ.

Analyses were performed using SPSS version 23.0. Descriptive statistics of the variables included in the study were obtained. Continuous variables were expressed as mean (standard deviation) and median (range), and categorical variables were expressed as absolute values and percentages with their estimated 95% confidence interval. Student’s T test or Mann-Whitney U Test were used to compare continuous variables. Moreover, chi-square test or Fisher’s exact test were used to compare categorical variables. Multiple linear regression models were used to identify variables associated with MRI/pathologic tumor size discrepancy. Variables found to be significant on univariate analysis were included for the multivariate analysis. The diagnostic ability of MRI to detect residual disease after PST was quantified by the measures of diagnostic accuracy: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy.

Considering the Helsinki Declaration principles, the Institutional Research Ethics Committee approved this retrospective study (No. 2016/457).

Baseline patient and tumor characteristics for the 204 breast cancer patients are described in Table 1. The median age of the patient cohort was 47 years (range, 30-82 years). Mean initial tumor size determined by MRI was 3.9 cm (72% of patients had T2 tumors). Patients enrolled by tumor subtype were 77 luminal B-like (HER2-negative) (37.7%), 45 luminal B-like (HER2-positive) (22.1%), 30 HER2 positive (non-luminal) (14.7%) and 52 TN (25.5%). The axillary nodal status before PST was positive in 55.4% of cases.

84 patients (41.2%) achieved pCR in the breast after PST. The pCR rates differed significantly among tumor subtypes: 13% for luminal B-like (HER2-negative), 42.2% for luminal B-like (HER2-positive), 76.6% for HER2 positive (non-luminal) and 61.5% for TN. The iCR rate was 56.4% (115/204). The average pathologic tumor size was 1.10 cm and the average tumor size by post-treatment MRI was 1.03 cm.

The diagnostic accuracy of MRI to detect residual invasive disease in the breast for all patients and by tumor subtypes is summarized in Table 2. The overall accuracy was 71.1%. The NPV and PPV were 60.9% and 84.3%, respectively. Among the different tumor subtypes, the highest diagnostic accuracy of MRI was observed in TNBC patients (78.8%). The ability of MRI to predict pCR was highest for the TN and HER2 positive (non-luminal) subtypes (83.9% and 80.9%, respectively).

The mean size difference between post-treatment MRI and pathology was significantly lower in TN tumors as compared with luminal B-like (HER2-negative) tumors (0.45 cm vs. 0.98; p = 0.003) (Figure 1).

Figure 1

The mean discrepancy between residual tumor extent measured on MRI and pathology according to various clinicopathologic factors was determined in 203 patients (Table 3). Pathologic residual tumor size was not available in one case due to the presence of scattered residual multifocal disease in the surgical specimen. On univariable analysis, high tumor grade and baseline tumor size smaller than 5 cm were associated with a higher MRI accuracy. HR status showed marginal significance (p = 0.059), with lower mean discrepancy in HR-negative breast cancers. Age, histological type and HER2 status were not significantly associated with MRI/pathologic tumor size discrepancy. On multi-variable analysis, tumor grade and baseline tumor size were significant and independent predictors of MRI accuracy.

After PST, 166 patients (81.4%) underwent BCS and 38 patients (18.6%) underwent mastectomy. From the BCS subset, 19 patients (11.4%) required re-excision because of positive margins (3 of 19 patients required a salvage mastectomy). Of these 19 patients, 2 (10.5%) had residual invasive disease on the final pathology. The positive margins rate after BCS was higher in patients with HR-positive breast cancer (23.6% for luminal B-like (HER2-negative) and 13.5% for luminal B-like (HER2-positive)) than in patients with HER2 positive (non-luminal) or TNBC (5% and 2.4%, respectively).