OT2-03-06: ACRIN 6698 MR Imaging Biomarkers for Assessment of Breast Cancer Response to Neoadjuvant Chemotherapy: A Sub-Study of the I-SPY 2 TRIAL (Investigation of Serial Studies To Predict Your Therapeutic Response with Imaging And moLecular Analysis).

Abstract

Background Functional MRI techniques may be utilized for characterizing breast tumors and measuring response to neoadjuvant chemotherapy (NAC). Dynamic contrast enhanced (DCE) MRI is the most common functional breast MRI technique. Fitting DCE MRI data to an appropriate pharmacokinetic model allows noninvasive, in vivo measurement of physiological parameters related to tissue perfusion, microvascular permeability, and extracellular/extravascular volume fraction. Diffusion weighted imaging (DWI) MRI is an alternative technique that measures the mobility of water molecules in vivo and is sensitive to tissue characteristics such as cell density, membrane permeability, and microstructure. DWI provides complementary information to DCE MRI about tumor biology and has shown promise for early prediction of response. The master ISPY2 multi-center study is a process targeting the rapid, focused clinical development of paired oncologic therapies and biomarkers. Its framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. As a sub-study, ACRIN 6698 will combine both DCE and DWI MRI data to generate novel imaging biomarkers that correlate with treatment response. The two studies will provide a rich data set that can be used to elucidate molecular pathways and tumor responses to novel investigational drugs with standard chemotherapy. Trial design: ACRIN 6698 will perform advanced DCE and DWI MR imaging as part of the I-SPY TRIAL. The ISPY 2 adaptive therapy design will use different tumor biomarker assays to identify patients with high risk of recurrence. Patients will receive NAC doublet chemotherapy and trastuzumab (if Her2+). Patients will be randomized and stratified into different arms receiving investigational agents of different drug classes. ACRIN 6698 patients will receive four advanced MRI exams (both DCE and DWI) at baseline, early therapy, mid therapy and prior to surgery. Specific aims: The primary aim will determine if the % change in tumor apparent diffusion coefficient (ADC) measured on DWI from baseline to early treatment timepoint is predictive of pathologic complete response (pCR). The secondary aim will determine if the combined measurement of percentage change in tumor ADC on DWI, and percentage change in tumor volume and peak signal enhancement ratio (SER) on DCE MRI is predictive of pCR. Statistical methods: Receiver operating characteristic (ROC) curve and corresponding area under the ROC curves (AUC) for the individual marker, % change in tumor ADC, and % change in tumor volume and peak SER, will be estimated. Linear score of the 3 markers will be derived by fitting the multivariate logistic regression model, where the outcome is a binary variable for pCR and the predictors are the 3 measurements. The ROC curve for the derived linear score will be constructed and its AUC value will be estimated. Target accrual: ACRIN 6698 is open to ISPY 2 sites. The target accrual is 200 of ISPY 2's planned enrollment of 800 participants. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-03-06.

Diffusion-Weighted Breast Magnetic Resonance Imaging

“…As DWI is increasingly gaining acceptance for clinical use for breast imaging applications and currently is being studied in large multi-site trials 9, 10 , it is critical that a standardized and reproducible method for ADC measurement be established that facilitates consistency across readers. Accordingly, we have developed a semi-automated approach to calculate ADC values for breast lesions and normal breast parenchyma.…”

PPV3 of Suspicious Breast MRI Findings

“…Finally, diffusion-weighted imaging and spectroscopy were not performed as it is not standard in our breast MRI protocol. The utility of diffusion imaging has not been determined and is currently under investigation with ACRIN trial 6698 (56).…”

The use of molecular imaging combined with genomic techniques to understand the heterogeneity in cancer metastasis

“…Its subsequent I-SPY2 clinical trial platform targeting the rapid focused clinical development of paired oncologic therapies and biomarkers now uses MR volumes to provide information about response to chemotherapy between regimens-information that cannot otherwise be obtained without surgical resection. 109 Additionally, its sub-study, ACRIN 6698, combines both DCE and DWI MRI data to generate novel imaging biomarkers that may correlate with treatment response, 110 and its results are eagerly awaited. Integration of these imaging biomarkers with genomic profiles of tumours are likely to prove essential for future clinical translation.…”