Optimized breast MRI functional tumor volume as a biomarker of recurrence-free survival following neoadjuvant chemotherapy

SYSTEMIC CHEMOTHERAPY for locally advanced breast cancer has become the mainstay of treatment because of its correlation with improved survival and reduced overall morbidity (1). Although preoperative, neoadjuvant, compared to postoperative chemotherapy does not result in a survival benefit, it does confer the advantage of increasing the possibility for breast-conserving surgery (2). Neoadjuvant chemotherapy (NACT) provides the further advantage of allowing the primary tumor response to be monitored during treatment. Multiple clinical trials have demonstrated that the response of the primary tumor to NACT correlates with patient survival (3–5), suggesting that tumor response may be an important prognostic indicator. Tumor response is most accurately determined by assessing the presence or stratifying the degree of residual cancer that remains in the breast at the completion of neoadjuvant therapy and at the time of definitive surgical resection (6). Several noninvasive methods for assessing response to NACT have been evaluated, including clinical exam, mammography, and ultrasound. In the past, clinical exam was most commonly used to assess response during NACT. However, in recent decades primary breast tumor response to NACT has been shown to be more accurately assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as compared with clinical exam, mammography, or ultrasound (7,8). MRI measurements have been strongly correlated with the standard of reference of histologic response (8). Only a moderate correlation between clinical exam, mammography, and ultras2ound has been shown with pathologic measurements of tumor after surgical resection (9). Limited literature has been published on sonography alone in assessing response to NACT; however, a recent study showed a lack of correlation of both sonographic 3D and unidimensional measurements of tumor with pathologic outcome (10). PET (positron emission tomography) has also been evaluated in the evaluation of response to neoadjuvant therapy, with changes in size, vascularity, and tumor metabolism highly correlated between 18F-FDG-PET (fluorodeoxyglucose-PET) and DCE-MRI (11). In addition, it has been demonstrated that changes in PET values in patients with locally advanced breast cancer is associated with outcome, with lack of decrease in SUV (standardized uptake value), the measurement of radiotracer uptake in patient’s tumors compared to background, from baseline to mid-treatment carrying an elevated mortality risk (12). One technique that has been shown to accurately characterize functional tumor volume (FTV) uses quantitative breast MRI parameters, the signal enhancement ratio (SER) and percent enhancement (PE), that both can be measured from standard clinical breast MR images. Multiple studies have evaluated MRI as a marker of response, using predefined criteria as imaging predictors. A previous study published by our group (13) used a specific PE threshold of 70% to define tumor volume and found that when MRI was compared to clinical breast examination, tumor size at pathology, and number of positive lymph nodes, MRI tumor volume was the stronger predictor of recurrence-free survival (RFS). More recent work by Yi et al (14) in patients receiving NACT determined that smaller reduction in tumor size and smaller reduction in washout kinetics over the course of treatment was associated with worse RFS and overall survival. However, the group did not evaluate the effects of varying thresholds in their evaluation. Similarly, Heldahl et al (15) found that total enhancing volume as measured on pre-treatment MRIs in 32 patients undergoing NACT was associated with survival. However, percent enhancement thresholds were not varied in their study. The specific aim of our study was to evaluate how enhancement thresholds influence the performance of functional volumetric tumor measurements and to determine the optimal PE and SER thresholds for predicting recurrence-free survival (RFS) in patients with breast cancer undergoing NACT, for whom 6–10 years of survival data was available. RFS was used as the endpoint to determine if patients had relapsed during the study period.