Diagnostic Performance of Point-of-Care Apparent Diffusion Coefficient Measures to Reduce Biopsy in Breast Lesions at MRI: Clinical Validation.

Background The Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group multicenter A6702 trial identified an optimal apparent diffusion coefficient (ADC) cutoff to potentially reduce biopsies by 21% without affecting sensitivity. Whether this performance can be achieved in clinical settings has not yet been established. Purpose To validate the performance of point-of-care ADC measurements with the A6702 trial ADC cutoff for reducing unnecessary biopsies in lesions detected at breast MRI. Materials and Methods Consecutive breast MRI examinations performed from May 2015 to January 2019 at a single medical center and showing biopsy-confirmed Breast Imaging Reporting and Data System category 4 or 5 lesions, without ipsilateral cancer, were identified. Point-of-care lesion ADC measurements collected at clinical interpretation were retrospectively evaluated. MRI examinations included axial T2-weighted, diffusion-weighted, and dynamic contrast-enhanced sequences. Sensitivity and biopsy reduction rates were calculated by applying the A6702 optimal (ADC, 1.53 × 10-3 mm2/sec) and alternate conservative (1.68 × 10-3 mm2/sec) cutoffs. Lesion pathologic outcomes were the reference standard. To assess reproducibility, one radiologist repeated ADC measurements, and agreement was summarized using the intraclass correlation coefficient. Results A total of 240 lesions in 201 women (mean age, 49 years ± 13 [SD]) with pathologic outcomes (63 malignant and 177 benign) were included. Applying the optimal ADC cutoff produced an overall biopsy reduction rate of 15.8% (38 of 240 lesions [95% CI: 11.2, 20.9]), with a sensitivity of 92.1% (58 of 63 lesions [95% CI: 82.4, 97.4]; sensitivity was 97.2% [35 of 36 lesions] [95% CI: 82.7, 99.6] for invasive cancers). Results were similar for screening versus diagnostic examinations (P = .92 and .40, respectively). Sensitivity was higher for masses than for nonmass enhancements (NMEs) (100% vs 85.3%; P = .009). Applying the conservative ADC cutoff achieved a sensitivity of 95.2% (60 of 63 lesions [95% CI: 86.7, 99.0]), with a biopsy reduction rate of 10.4% (25 of 240 lesions [95% CI: 6.7, 14.5]). Repeated single-reader measurements showed good agreement with clinical ADCs (intraclass correlation coefficient, 0.72 [95% CI: 0.58, 0.81]). Conclusion This study validated the clinical use of ADC cutoffs to reduce MRI-prompted biopsies by up to 16%, with a suggested tradeoff of lowered sensitivity for in situ and microinvasive disease manifesting as NME. Clinical trial registration no. NCT02022579 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.

Breast Multiparametric MRI for Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer: The BMMR2 Challenge.

Purpose To describe the design, conduct, and results of the Breast Multiparametric MRI for prediction of neoadjuvant chemotherapy Response (BMMR2) challenge. Materials and Methods The BMMR2 computational challenge opened on May 28, 2021, and closed on December 21, 2021. The goal of the challenge was to identify image-based markers derived from multiparametric breast MRI, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI, along with clinical data for predicting pathologic complete response (pCR) following neoadjuvant treatment. Data included 573 breast MRI studies from 191 women (mean age [±SD], 48.9 years ± 10.56) in the I-SPY 2/American College of Radiology Imaging Network (ACRIN) 6698 trial (ClinicalTrials.gov: NCT01042379). The challenge cohort was split into training (60%) and test (40%) sets, with teams blinded to test set pCR outcomes. Prediction performance was evaluated by area under the receiver operating characteristic curve (AUC) and compared with the benchmark established from the ACRIN 6698 primary analysis. Results Eight teams submitted final predictions. Entries from three teams had point estimators of AUC that were higher than the benchmark performance (AUC, 0.782 [95% CI: 0.670, 0.893], with AUCs of 0.803 [95% CI: 0.702, 0.904], 0.838 [95% CI: 0.748, 0.928], and 0.840 [95% CI: 0.748, 0.932]). A variety of approaches were used, ranging from extraction of individual features to deep learning and artificial intelligence methods, incorporating DCE and DWI alone or in combination. Conclusion The BMMR2 challenge identified several models with high predictive performance, which may further expand the value of multiparametric breast MRI as an early marker of treatment response. Clinical trial registration no. NCT01042379 Keywords: MRI, Breast, Tumor Response Supplemental material is available for this article. © RSNA, 2024.

The ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): Results from the OSIPI-Dynamic Contrast-Enhanced challenge.

PURPOSE: K trans $$ {K}^{\mathrm{trans}} $$ has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for K trans $$ {K}^{\mathrm{trans}} $$ quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging-Dynamic Contrast-Enhanced (OSIPI-DCE) challenge was designed to benchmark methods to better help the efforts to standardize K trans $$ {K}^{\mathrm{trans}} $$ measurement. METHODS: A framework was created to evaluate K trans $$ {K}^{\mathrm{trans}} $$ values produced by DCE-MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for K trans $$ {K}^{\mathrm{trans}} $$ quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' K trans $$ {K}^{\mathrm{trans}} $$ values, the applied software, and a standard operating procedure. These were evaluated using the proposed OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score defined with accuracy, repeatability, and reproducibility components. RESULTS: Across the 10 received submissions, the OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0-1 = lowest-highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in K trans $$ {K}^{\mathrm{trans}} $$ analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility. CONCLUSIONS: This study reports results from the OSIPI-DCE challenge and highlights the high inter-software variability within K trans $$ {K}^{\mathrm{trans}} $$ estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real-world clinical setting, many of these tools may perform differently with different benchmarking methodology.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer.

PURPOSE: To investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer. METHODS: Patients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated. RESULTS: Thirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31-66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS. CONCLUSION: Mid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

Associations of Multiparametric Breast MRI Features, Tumor-Infiltrating Lymphocytes, and Immune Gene Signature Scores Following a Single Dose of Trastuzumab in HER2-Positive Early-Stage Breast Cancer.

Dynamic biomarkers that permit the real-time monitoring of the tumor microenvironment response to therapy are an unmet need in breast cancer. Breast magnetic resonance imaging (MRI) has demonstrated value as a predictor of pathologic complete response and may reflect immune cell changes in the tumor microenvironment. The purpose of this pilot study was to investigate the value of breast MRI features as early markers of treatment-induced immune response. Fourteen patients with early HER2+ breast cancer were enrolled in a window-of-opportunity study where a single dose of trastuzumab was administered and both tissue and MRIs were obtained at the pre- and post-treatment stages. Functional diffusion-weighted and dynamic contrast-enhanced MRI tumor measures were compared with tumor-infiltrating lymphocytes (TILs) and RNA immune signature scores. Both the pre-treatment apparent diffusion coefficient (ADC) and the change in peak percent enhancement (DPE) were associated with increased tumor-infiltrating lymphocytes with trastuzumab therapy (r = -0.67 and -0.69, p < 0.01 and p < 0.01, respectively). Low pre-treatment ADC and a greater decrease in PE in response to treatment were also associated with immune-activated tumor microenvironments as defined by RNA immune signatures. Breast MRI features hold promise as biomarkers of early immune response to treatment in HER2+ breast cancer.

Mathematical modelling of the dynamics of image-informed tumor habitats in a murine model of glioma.

Tumors exhibit high molecular, phenotypic, and physiological heterogeneity. In this effort, we employ quantitative magnetic resonance imaging (MRI) data to capture this heterogeneity through imaging-based subregions or "habitats" in a murine model of glioma. We then demonstrate the ability to model and predict the growth of the habitats using coupled ordinary differential equations (ODEs) in the presence and absence of radiotherapy. Female Wistar rats (N = 21) were inoculated intracranially with 106 C6 glioma cells, a subset of which received 20 Gy (N = 5) or 40 Gy (N = 8) of radiation. All rats underwent diffusion-weighted and dynamic contrast-enhanced MRI at up to seven time points. All MRI data at each visit were subsequently clustered using k-means to identify physiological tumor habitats. A family of four models consisting of three coupled ODEs were developed and calibrated to the habitat time series of control and treated rats and evaluated for predictive capability. The Akaike Information Criterion was used for model selection, and the normalized sum-of-square-error (SSE) was used to evaluate goodness-of-fit in model calibration and prediction. Three tumor habitats with significantly different imaging data characteristics (p < 0.05) were identified: high-vascularity high-cellularity, low-vascularity high-cellularity, and low-vascularity low-cellularity. Model selection resulted in a five-parameter model whose predictions of habitat dynamics yielded SSEs that were similar to the SSEs from the calibrated model. It is thus feasible to mathematically describe habitat dynamics in a preclinical model of glioma using biology-based ODEs, showing promise for forecasting heterogeneous tumor behavior.

Analysis of simplicial complexes to determine when to sample for quantitative DCE MRI of the breast.

PURPOSE: A method is presented to select the optimal time points at which to measure DCE-MRI signal intensities, leaving time in the MR exam for high-spatial resolution image acquisition. THEORY: Simplicial complexes are generated from the Kety-Tofts model pharmacokinetic parameters Ktrans and ve . A geometric search selects optimal time points for accurate estimation of perfusion parameters. METHODS: The DCE-MRI data acquired in women with invasive breast cancer (N = 27) were used to retrospectively compare parameter maps fit to full and subsampled time courses. Simplicial complexes were generated for a fixed range of Kety-Tofts model parameters and for the parameter ranges weighted by estimates from the fully sampled data. The largest-area manifolds determined the optimal three time points for each case. Simulations were performed along with retrospectively subsampled data fits. The agreement was computed between the model parameters fit to three points and those fit to all points. RESULTS: The optimal three-point sample times were from the data-informed simplicial complex analysis and determined to be 65, 204, and 393 s after arrival of the contrast agent to breast tissue. In the patient data, tumor-median parameter values fit using all points and the three selected time points agreed with concordance correlation coefficients of 0.97 for Ktrans and 0.67 for ve . CONCLUSION: It is possible to accurately estimate pharmacokinetic parameters from three properly selected time points inserted into a clinical DCE-MRI breast exam. This technique can provide guidance on when to capture images for quantitative data between high-spatial-resolution DCE-MRI images.

Quantifying Tumor Heterogeneity via MRI Habitats to Characterize Microenvironmental Alterations in HER2+ Breast Cancer.

This study identifies physiological habitats using quantitative magnetic resonance imaging (MRI) to elucidate intertumoral differences and characterize microenvironmental response to targeted and cytotoxic therapy. BT-474 human epidermal growth factor receptor 2 (HER2+) breast tumors were imaged before and during treatment (trastuzumab, paclitaxel) with diffusion-weighted MRI and dynamic contrast-enhanced MRI to measure tumor cellularity and vascularity, respectively. Tumors were stained for anti-CD31, anti-ɑSMA, anti-CD45, anti-F4/80, anti-pimonidazole, and H&E. MRI data was clustered to identify and label each habitat in terms of vascularity and cellularity. Pre-treatment habitat composition was used stratify tumors into two "tumor imaging phenotypes" (Type 1, Type 2). Type 1 tumors showed significantly higher percent tumor volume of the high-vascularity high-cellularity (HV-HC) habitat compared to Type 2 tumors, and significantly lower volume of low-vascularity high-cellularity (LV-HC) and low-vascularity low-cellularity (LV-LC) habitats. Tumor phenotypes showed significant differences in treatment response, in both changes in tumor volume and physiological composition. Significant positive correlations were found between histological stains and tumor habitats. These findings suggest that the differential baseline imaging phenotypes can predict response to therapy. Specifically, the Type 1 phenotype indicates increased sensitivity to targeted or cytotoxic therapy compared to Type 2 tumors.

Longitudinal FRET Imaging of Glucose and Lactate Dynamics and Response to Therapy in Breast Cancer Cells.

PURPOSE: The reprogramming of cellular metabolism is a hallmark of cancer. The ability to noninvasively assay glucose and lactate concentrations in cancer cells would improve our understanding of the dynamic changes in metabolic activity accompanying tumor initiation, progression, and response to therapy. Unfortunately, common approaches for measuring these nutrient levels are invasive or interrupt cell growth. This study transfected FRET reporters quantifying glucose and lactate concentration into breast cancer cell lines to study nutrient dynamics and response to therapy. PROCEDURES: Two FRET reporters, one assaying glucose concentration and one assaying lactate concentration, were stably transfected into the MDA-MB-231 breast cancer cell line. Correlation between FRET measurements and ligand concentration were measured using a confocal microscope and a cell imaging plate reader. Longitudinal changes in glucose and lactate concentration were measured in response to treatment with CoCl2, cytochalasin B, and phloretin which, respectively, induce hypoxia, block glucose uptake, and block glucose and lactate transport. RESULTS: The FRET ratio from the glucose and lactate reporters increased with increasing concentration of the corresponding ligand (p < 0.005 and p < 0.05, respectively). The FRET ratio from both reporters was found to decrease over time for high initial concentrations of the ligand (p < 0.01). Significant differences in the FRET ratio corresponding to metabolic inhibition were found when cells were treated with glucose/lactate transporter inhibitors. CONCLUSIONS: FRET reporters can track intracellular glucose and lactate dynamics in cancer cells, providing insight into tumor metabolism and response to therapy over time.

Quantitative multiparametric MRI predicts response to neoadjuvant therapy in the community setting.

BACKGROUND: The purpose of this study was to determine whether advanced quantitative magnetic resonance imaging (MRI) can be deployed outside of large, research-oriented academic hospitals and into community care settings to predict eventual pathological complete response (pCR) to neoadjuvant therapy (NAT) in patients with locally advanced breast cancer. METHODS: Patients with stage II/III breast cancer (N = 28) were enrolled in a multicenter study performed in community radiology settings. Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW)-MRI data were acquired at four time points during the course of NAT. Estimates of the vascular perfusion and permeability, as assessed by the volume transfer rate (Ktrans) using the Patlak model, were generated from the DCE-MRI data while estimates of cell density, as assessed by the apparent diffusion coefficient (ADC), were calculated from DW-MRI data. Tumor volume was calculated using semi-automatic segmentation and combined with Ktrans and ADC to yield bulk tumor blood flow and cellularity, respectively. The percent change in quantitative parameters at each MRI scan was calculated and compared to pathological response at the time of surgery. The predictive accuracy of each MRI parameter at different time points was quantified using receiver operating characteristic curves. RESULTS: Tumor size and quantitative MRI parameters were similar at baseline between groups that achieved pCR (n = 8) and those that did not (n = 20). Patients achieving a pCR had a larger decline in volume and cellularity than those who did not achieve pCR after one cycle of NAT (p < 0.05). At the third and fourth MRI, changes in tumor volume, Ktrans, ADC, cellularity, and bulk tumor flow from baseline (pre-treatment) were all significantly greater (p < 0.05) in the cohort who achieved pCR compared to those patients with non-pCR. CONCLUSIONS: Quantitative analysis of DCE-MRI and DW-MRI can be implemented in the community care setting to accurately predict the response of breast cancer to NAT. Dissemination of quantitative MRI into the community setting allows for the incorporation of these parameters into the standard of care and increases the number of clinical community sites able to participate in novel drug trials that require quantitative MRI.

Quantitative magnetic resonance imaging and tumor forecasting of breast cancer patients in the community setting.

This protocol describes a complete data acquisition, analysis and computational forecasting pipeline for employing quantitative MRI data to predict the response of locally advanced breast cancer to neoadjuvant therapy in a community-based care setting. The methodology has previously been successfully applied to a heterogeneous patient population. The protocol details how to acquire the necessary images followed by registration, segmentation, quantitative perfusion and diffusion analysis, model calibration, and prediction. The data collection portion of the protocol requires ~25 min of scanning, postprocessing requires 2-3 h, and the model calibration and prediction components require ~10 h per patient depending on tumor size. The response of individual breast cancer patients to neoadjuvant therapy is forecast by application of a biophysical, reaction-diffusion mathematical model to these data. Successful application of the protocol results in coregistered MRI data from at least two scan visits that quantifies an individual tumor's size, cellularity and vascular properties. This enables a spatially resolved prediction of how a particular patient's tumor will respond to therapy. Expertise in image acquisition and analysis, as well as the numerical solution of partial differential equations, is required to carry out this protocol.

Characterizing Errors in Pharmacokinetic Parameters from Analyzing Quantitative Abbreviated DCE-MRI Data in Breast Cancer.

This study characterizes the error that results when performing quantitative analysis of abbreviated dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data of the breast with the Standard Kety-Tofts (SKT) model and its Patlak variant. More specifically, we used simulations and patient data to determine the accuracy with which abbreviated time course data could reproduce the pharmacokinetic parameters, Ktrans (volume transfer constant) and ve (extravascular/extracellular volume fraction), when compared to the full time course data. SKT analysis of simulated abbreviated time courses (ATCs) based on the imaging parameters from two available datasets (collected with a 3T MRI scanner) at a temporal resolution of 15 s (N = 15) and 7.23 s (N = 15) found a concordance correlation coefficient (CCC) greater than 0.80 for ATCs of length 3.0 and 2.5 min, respectively, for the Ktrans parameter. Analysis of the experimental data found that at least 90% of patients met this CCC cut-off of 0.80 for the ATCs of the aforementioned lengths. Patlak analysis of experimental data found that 80% of patients from the 15 s resolution dataset and 90% of patients from the 7.27 s resolution dataset met the 0.80 CCC cut-off for ATC lengths of 1.25 and 1.09 min, respectively. This study provides evidence for both the feasibility and potential utility of performing a quantitative analysis of abbreviated breast DCE-MRI in conjunction with acquisition of current standard-of-care high resolution scans without significant loss of information in the community setting.

Integrating Quantitative Assays with Biologically Based Mathematical Modeling for Predictive Oncology.

We provide an overview on the use of biological assays to calibrate and initialize mechanism-based models of cancer phenomena. Although artificial intelligence methods currently dominate the landscape in computational oncology, mathematical models that seek to explicitly incorporate biological mechanisms into their formalism are of increasing interest. These models can guide experimental design and provide insights into the underlying mechanisms of cancer progression. Historically, these models have included a myriad of parameters that have been difficult to quantify in biologically relevant systems, limiting their practical insights. Recently, however, there has been much interest calibrating biologically based models with the quantitative measurements available from (for example) RNA sequencing, time-resolved microscopy, and in vivo imaging. In this contribution, we summarize how a variety of experimental methods quantify tumor characteristics from the molecular to tissue scales and describe how such data can be directly integrated with mechanism-based models to improve predictions of tumor growth and treatment response.

Evaluating patient-specific neoadjuvant regimens for breast cancer via a mathematical model constrained by quantitative magnetic resonance imaging data.

The ability to accurately predict response and then rigorously optimize a therapeutic regimen on a patient-specific basis, would transform oncology. Toward this end, we have developed an experimental-mathematical framework that integrates quantitative magnetic resonance imaging (MRI) data into a biophysical model to predict patient-specific treatment response of locally advanced breast cancer to neoadjuvant therapy. Diffusion-weighted and dynamic contrast-enhanced MRI data is collected prior to therapy, after 1 cycle of therapy, and at the completion of the first therapeutic regimen. The model is initialized and calibrated with the first 2 patient-specific MRI data sets to predict response at the third, which is then compared to patient outcomes (N = 18). The model's predictions for total cellularity, total volume, and the longest axis at the completion of the regimen are significant within expected measurement precision (P< 0.05) and strongly correlated with measured response (P < 0.01). Further, we use the model to investigate, in silico, a range of (practical) alternative treatment plans to achieve the greatest possible tumor control for each individual in a subgroup of patients (N = 13). The model identifies alternative dosing strategies predicted to achieve greater tumor control compared to the standard of care for 12 of 13 patients (P < 0.01). In summary, a predictive, mechanism-based mathematical model has demonstrated the ability to identify alternative treatment regimens that are forecasted to outperform the therapeutic regimens the patients clinically. This has important implications for clinical trial design with the opportunity to alter oncology care in the future.