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.

Impact of Muscle Measures on Outcome in Patients Receiving Endocrine Therapy for Metastatic Breast Cancer: Analysis of ECOG-ACRIN E2112.

BACKGROUND: Observational data investigating the relationship between body habitus and outcomes in breast cancer have been variable and inconsistent, largely centered in the curative setting and focused on weight-based metrics. This study evaluated the impact of muscle measures on outcomes in patients with metastatic breast cancer receiving endocrine-based therapy. METHODS: Baseline CT scans were collected from ECOG-ACRIN E2112, a randomized phase III placebo-controlled study of exemestane with or without entinostat. A CT cross-sectional image at the L3 level was extracted to obtain skeletal muscle mass and attenuation. Low muscle mass (LMM) was defined as skeletal muscle index <41 cm2/m2 and low muscle attenuation (LMA) as muscle density <25 HU or <33 HU if overweight/obese by body mass index (BMI). Multivariable Cox proportional hazard models determined the association between LMM or LMA and progression-free survival (PFS) and overall survival (OS). Correlations between LMM, LMA, and patient-reported outcomes were determined using 2-sample t tests. RESULTS: Analyzable CT scans and follow-up data were available for 540 of 608 patients. LMM was present in 39% (n=212) of patients and LMA in 56% (n=301). Those with LMA were more likely to have obesity and worse performance status. LMM was not associated with survival (PFS hazard ratio [HR]: 1.13, P=.23; OS HR: 1.05, P=.68), nor was LMA (PFS HR: 1.01, P=.93; OS HR: 1.00, P=.99). BMI was not associated with survival. LMA, but not LMM, was associated with increased frequency of patient-reported muscle aches. CONCLUSIONS: Both low muscle mass and density are prevalent in patients with hormone receptor-positive metastatic breast cancer. Muscle measures correlated with obesity and performance status; however, neither muscle mass nor attenuation were associated with prognosis. Further work is needed to refine body composition measurements and select optimal cutoffs with meaningful endpoints in specific breast cancer populations, particularly those living with metastatic disease.

The GIANT trial (ECOG-ACRIN EA2186) methods paper: A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer - defining a new treatment option for older vulnerable patients.

INTRODUCTION: Pancreatic cancer is the fourth leading cause of cancer-related death in the US with an increasing incidence in older adults (OA) over age 70. There are currently no treatment guidelines for OA with metastatic pancreatic cancer (mPCA) and selecting a chemotherapy regimen for these patients is subjective, based largely on chronologic age and performance status (PS). Geriatric screening tools provide a more objective and accurate evaluation of a patient's overall health but have not yet been validated in patient selection for mPCA treatment. This study aims to elucidate the optimal chemotherapy treatment of vulnerable OA with mPCA and understand the geriatric factors that affect outcomes in this population. METHODS/DESIGN: The GIANT (ECOG-ACRIN EA2186) study is multicenter, randomized phase II trial enrolling patients over age 70 with newly diagnosed mPCA. This study utilizes a screening geriatric assessment (GA) which characterizes patients as fit, vulnerable, or frail. Patients with mild abnormalities in functional status and/or cognition, moderate comorbidities, or over age 80 are considered vulnerable. Enrolled patients are randomized to one of two dose-reduced treatment regimens (gemcitabine/nab-paclitaxel every other week, or dose-reduced 5-fluoruracil (5FU)/ liposomal irinotecan (nal-IRI) every other week). GA and quality of life (QoL) evaluations are completed prior to treatment initiation and at each disease evaluation. Overall survival (OS) is the primary endpoint, with secondary endpoints including progression free survival (PFS) and objective response rate (ORR). Enrolled patients will be stratified by age (70-74 vs ≥75) and ECOG PS (0-1 vs 2). Additional endpoints of interest for OA include evaluation of risk factors identified through GA, QoL evaluation, and toxicities of interest for older adults. Correlative studies include assessment of pro-inflammatory biomarkers of aging in the blood (IL-6, CRP) and imaging evaluation of sarcopenia as predictors of treatment tolerance. DISCUSSION: The GIANT study is the first randomized, prospective national trial evaluating vulnerable OA with mPCA aimed at developing a tailored treatment approach for this patient population. This trial has the potential to establish a new way of objectively selecting vulnerable OA with mPCA for modified treatment and to establish a new standard of care in this growing patient population. TRIAL REGISTRATION: This trial is registered with ClinicalTrial.gov Identifier NCT04233866.

Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways.

SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in the airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments have not been fully characterized using matched samples from large cohorts. Gene expression data from 793 nasal and 1673 bronchial brushes obtained from individuals participating in lung cancer screening or diagnostic workup revealed that smoking status (current versus former) was the only clinical factor significantly and reproducibly associated with VE gene expression. The expression of ACE2 and TMPRSS2 was higher in smokers in the bronchus but not in the nose. scRNA-seq of nasal brushings indicated that ACE2 co-expressed genes were highly expressed in club and C15orf48+ secretory cells while TMPRSS2 co-expressed genes were highly expressed in keratinizing epithelial cells. In contrast, these ACE2 and TMPRSS2 modules were highly expressed in goblet cells in scRNA-seq from bronchial brushings. Cell-type deconvolution of the gene expression data confirmed that smoking increased the abundance of several secretory cell populations in the bronchus, but only goblet cells in the nose. The association of ACE2 and TMPRSS2 with smoking in the bronchus is due to their high expression in goblet cells which increase in abundance in current smoker airways. In contrast, in the nose, these genes are not predominantly expressed in cell populations modulated by smoking. In individuals with elevated lung cancer risk, smoking-induced VE gene expression changes in the nose likely have minimal impact on SARS-CoV-2 infection, but in the bronchus, smoking may lead to higher viral loads and more severe disease.

Impact of Alternate b-Value Combinations and Metrics on the Predictive Performance and Repeatability of Diffusion-Weighted MRI in Breast Cancer Treatment: Results from the ECOG-ACRIN A6698 Trial.

In diffusion-weighted MRI (DW-MRI), choice of b-value influences apparent diffusion coefficient (ADC) values by probing different aspects of the tissue microenvironment. As a secondary analysis of the multicenter ECOG-ACRIN A6698 trial, the purpose of this study was to investigate the impact of alternate b-value combinations on the performance and repeatability of tumor ADC as a predictive marker of breast cancer treatment response. The final analysis included 210 women who underwent standardized 4-b-value DW-MRI (b = 0/100/600/800 s/mm2) at multiple timepoints during neoadjuvant chemotherapy treatment and a subset (n = 71) who underwent test−retest scans. Centralized tumor ADC and perfusion fraction (fp) measures were performed using variable b-value combinations. Prediction of pathologic complete response (pCR) based on the mid-treatment/12-week percent change in each metric was estimated by area under the receiver operating characteristic curve (AUC). Repeatability was estimated by within-subject coefficient of variation (wCV). Results show that two-b-value ADC calculations provided non-inferior predictive value to four-b-value ADC calculations overall (AUCs = 0.60−0.61 versus AUC = 0.60) and for HR+/HER2− cancers where ADC was most predictive (AUCs = 0.75−0.78 versus AUC = 0.76), p < 0.05. Using two b-values (0/600 or 0/800 s/mm2) did not reduce ADC repeatability over the four-b-value calculation (wCVs = 4.9−5.2% versus 5.4%). The alternate metrics ADCfast (b ≤ 100 s/mm2), ADCslow (b ≥ 100 s/mm2), and fp did not improve predictive performance (AUCs = 0.54−0.60, p = 0.08−0.81), and ADCfast and fp demonstrated the lowest repeatability (wCVs = 6.71% and 12.4%, respectively). In conclusion, breast tumor ADC calculated using a simple two-b-value approach can provide comparable predictive value and repeatability to full four-b-value measurements as a marker of treatment response.

Smoking Modulates Different Secretory Subpopulations Expressing SARS-CoV-2 Entry Genes in the Nasal and Bronchial Airways.

Background : SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments has not been fully characterized using matched samples from large cohorts. Results : Gene expression data from 793 nasal and 1,673 bronchial brushes obtained from individuals participating in lung cancer screening or diagnostic workup revealed that smoking was the only clinical factor significantly and reproducibly associated with VE gene expression. ACE2 and TMPRSS2 expression were higher in smokers in the bronchus but not in the nose. scRNA-seq of nasal brushings indicated that ACE2 co-expressed genes were highly expressed in club and C15orf48 + secretory cells while TMPRSS2 co-expressed genes were highly expressed in keratinizing epithelial cells. In contrast, these ACE2 and TMPRSS2 modules were highly expressed in goblet cells in scRNA-seq from bronchial brushings. Cell-type deconvolution of the RNA-seq confirmed that smoking increased the abundance of several secretory cell populations in the bronchus, but only goblet cells in the nose. Conclusions : The association of ACE2 and TMPRSS2 with smoking in the bronchus is due to their high expression in goblet cells which increase in abundance in current smoker airways. In contrast, in the nose these genes are not predominantly expressed in cell populations modulated by smoking. Smoking-induced VE gene expression changes in the nose likely has minimal impact on SARS-CoV-2 infection, but in the bronchus, smoking may lead to higher viral loads and more severe disease.

A simple assessment of lung nodule location for reduction in unnecessary invasive procedures.

BACKGROUND: CT screening for lung cancer results in a significant mortality reduction but is complicated by invasive procedures performed for evaluation of the many detected benign nodules. The purpose of this study was to evaluate measures of nodule location within the lung as predictors of malignancy. METHODS: We analyzed images and data from 3,483 participants in the National Lung Screening Trial (NLST). All nodules (4-20 mm) were characterized by 3D geospatial location using a Cartesian coordinate system and evaluated in logistic regression analysis. Model development and probability cutpoint selection was performed in the NLST testing set. The Geospatial test was then validated in the NLST testing set, and subsequently replicated in a new cohort of 147 participants from The Detection of Early Lung Cancer Among Military Personnel (DECAMP) Consortium. RESULTS: The Geospatial Test, consisting of the superior-inferior distance (Z distance), nodule diameter, and radial distance (carina to nodule) performed well in both the NLST validation set (AUC 0.85) and the DECAMP replication cohort (AUC 0.75). A negative Geospatial Test resulted in a less than 2% risk of cancer across all nodule diameters. The Geospatial Test correctly reclassified 19.7% of indeterminate nodules with a diameter over 6mm as benign, while only incorrectly classifying 1% of cancerous nodules as benign. In contrast, the parsimonious Brock Model applied to the same group of nodules correctly reclassified 64.5% of indeterminate nodules as benign but resulted in misclassification of a cancer as benign in 18.2% of the cases. Applying the Geospatial test would result in reducing invasive procedures performed for benign lesions by 11.3% with a low rate of misclassification (1.3%). In contrast, the Brock model applied to the same group of patients results in decreasing invasive procedures for benign lesion by 39.0% but misclassifying 21.1% of cancers as benign. CONCLUSIONS: Utilizing information about geospatial location within the lung improves risk assessment for indeterminate lung nodules and may reduce unnecessary procedures. TRIAL REGISTRATION: NCT00047385, NCT01785342.

Distinguishing Smoking-Related Lung Disease Phenotypes Via Imaging and Molecular Features.

BACKGROUND: Chronic tobacco smoke exposure results in a broad range of lung pathologies including emphysema, airway disease and parenchymal fibrosis as well as a multitude of extra-pulmonary comorbidities. Prior work using CT imaging has identified several clinically relevant subgroups of smoking related lung disease, but these investigations have generally lacked organ specific molecular correlates. RESEARCH QUESTION: Can CT imaging be used to identify clinical phenotypes of smoking related lung disease that have specific bronchial epithelial gene expression patterns to better understand disease pathogenesis? STUDY DESIGN AND METHODS: Using K-means clustering, we clustered participants from the COPDGene study (n = 5,273) based on CT imaging characteristics and then evaluated their clinical phenotypes. These clusters were replicated in the Detection of Early Lung Cancer Among Military Personnel (DECAMP) cohort (n = 360), and were further characterized using bronchial epithelial gene expression. RESULTS: Three clusters (preserved, interstitial predominant and emphysema predominant) were identified. Compared to the preserved cluster, the interstitial and emphysema clusters had worse lung function, exercise capacity and quality of life. In longitudinal follow-up, individuals from the emphysema group had greater declines in exercise capacity and lung function, more emphysema, more exacerbations, and higher mortality. Similarly, genes involved in inflammatory pathways (tumor necrosis factor-α, interferon-ß) are more highly expressed in bronchial epithelial cells from individuals in the emphysema cluster, while genes associated with T-cell related biology are decreased in these samples. Samples from individuals in the interstitial cluster generally had intermediate levels of expression of these genes. INTERPRETATION: Using quantitative CT imaging, we identified three groups of individuals in older ever-smokers that replicate in two cohorts. Airway gene expression differences between the three groups suggests increased levels of inflammation in the most severe clinical phenotype, possibly mediated by the tumor necrosis factor-α and interferon-ß pathways. CLINICAL TRIAL REGISTRATION: COPDGene (NCT00608764), DECAMP-1 (NCT01785342), DECAMP-2 (NCT02504697).

Value of dynamic contrast perfusion MRI to predict early response to bevacizumab in newly diagnosed glioblastoma: results from ACRIN 6686 multicenter trial.

BACKGROUND: In Radiation Therapy Oncology Group (RTOG) 0825, a phase III trial of standard therapy with bevacizumab or without (placebo) in newly diagnosed glioblastoma, 44 patients underwent dynamic contrast enhanced (DCE) and/or dynamic susceptibility contrast (DSC) MRI in the American College of Radiology Imaging Network (ACRIN) trial 6686. The association between early changes in relative cerebral blood volume (rCBV) and volume transfer constant (Ktrans) with overall survival (OS) was evaluated. METHODS: MRI was performed at postop baseline (S0), immediately before (S1), 1 day after (S2), and 7 weeks after (S3) bevacizumab or placebo initiation. Mean normalized and standardized rCBV (nRCBV, sRCBV) and Ktrans were measured within contrast-enhancing lesion. Wilcoxon rank sum tests compared parameter changes from S1-S2 and S1-S3. Association with OS and progression-free survival (PFS) were determined using Kaplan-Meier and log-rank tests. Treatment response for groups stratified by pretreatment nRCBV (S0, S1) was explored. The intraclass correlation coefficient and repeatability coefficient for the placebo arm (S1-S2) were used to assess repeatability. RESULTS: Evaluable were 27-36 datasets per time point. Significant differences between treatment arms were found for changes in nRCBV and sRCBV from S1-S2 and S1-S3, and in Ktrans for S1-S3. Improved PFS (P = 0.05) but not OS (P = 0.46) was observed. High pretreatment rCBV predicted improved OS for bevacizumab-treated patients. Based on the intraclass correlation coefficient, sRCBV (0.92) was more repeatable than nRCBV (0.71) and Ktrans (0.75), consistent with repeatability coefficient values. CONCLUSIONS: Bevacizumab significantly changes rCBV but not Ktrans as early as 1 day posttreatment in newly diagnosed glioblastoma unrelated to outcomes. Improvements in clinical trial design to maximize rCBV benefit are indicated.

Repeatability and Reproducibility of ADC Histogram Metrics from the ACRIN 6698 Breast Cancer Therapy Response Trial.

Mean tumor apparent diffusion coefficient (ADC) of breast cancer showed excellent repeatability but only moderate predictive power for breast cancer therapy response in the ACRIN 6698 multicenter imaging trial. Previous single-center studies have shown improved predictive performance for alternative ADC histogram metrics related to low ADC dense tumor volume. Using test/retest (TT/RT) 4 b-value diffusion-weighted imaging acquisitions from pretreatment or early-treatment time-points on 71 ACRIN 6698 patients, we evaluated repeatability for ADC histogram metrics to establish confidence intervals and inform predictive models for future therapy response analysis. Histograms were generated using regions of interest (ROIs) defined separately for TT and RT diffusion-weighted imaging. TT/RT repeatability and intra- and inter-reader reproducibility (on a 20-patient subset) were evaluated using wCV and Bland-Altman limits of agreement for histogram percentiles, low-ADC dense tumor volumes, and fractional volumes (normalized to total histogram volume). Pearson correlation was used to reveal connections between metrics and ROI variability across the sample cohort. Low percentiles (15th and 25th) were highly repeatable and reproducible, wCV < 8.1%, comparable to mean ADC values previously reported. Volumetric metrics had higher wCV values in all cases, with fractional volumes somewhat better but at least 3 times higher than percentile wCVs. These metrics appear most sensitive to ADC changes around a threshold of 1.2 µm2/ms. Volumetric results were moderately to strongly correlated with ROI size. In conclusion, Lower histogram percentiles have comparable repeatability to mean ADC, while ADC-thresholded volumetric measures currently have poor repeatability but may benefit from improvements in ROI techniques.

Detection of early lung cancer among military personnel (DECAMP) consortium: study protocols.

BACKGROUND: Lung cancer is the leading cause of cancer-related death due in large part to our inability to diagnose it at an early and potentially curable stage. Screening for lung cancer via low dose computed tomographic (LDCT) imaging has been demonstrated to improve mortality but also results in a high rate of false positive tests. The identification and application of non-invasive molecular biomarkers that improve the performance of CT imaging for the detection of lung cancer in high risk individuals would aid in clinical decision-making, eliminate the need for unnecessary LDCT follow-up, and further refine the screening criteria for an already large high-risk population. METHODS: The Detection of Early Lung Cancer Among Military Personnel (DECAMP) consortium is conducting two multicenter prospective studies with the goals of developing an integrated panel of both airway and blood-based molecular biomarkers that discriminate benign and malignant indeterminate nodules detected on CT scan as well as predict the future development of lung cancer in high-risk individuals. To achieve these goals, DECAMP is compiling an extensive array of biospecimens including nasal brushings, serum, plasma and intrathoracic airway samples (bronchial brushings and bronchial biopsies) from normal-appearing airway epithelium. DISCUSSION: This bank of samples is the foundation for multiple DECAMP efforts focused on the identification of those at greatest risk of developing lung cancer as well as the discrimination of benign and malignant pulmonary nodules. The clinical, imaging and biospecimen repositories will serve as a resource for the biomedical community and their investigation of the molecular basis of chronic respiratory disease. TRIAL REGISTRATION: Retrospectively registered as NCT01785342 - DECAMP-1: Diagnosis and Surveillance of Indeterminate Pulmonary Nodules (DECAMP-1). Date of Registration: February 7, 2013. Retrospectively registered as NCT02504697 - DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2). Date of Registration: July 22, 2015.

Test-retest repeatability and reproducibility of ADC measures by breast DWI: Results from the ACRIN 6698 trial.

BACKGROUND: Quantitative diffusion-weighted imaging (DWI) MRI is a promising technique for cancer characterization and treatment monitoring. Knowledge of the reproducibility of DWI metrics in breast tumors is necessary to apply DWI as a clinical biomarker. PURPOSE: To evaluate the repeatability and reproducibility of breast tumor apparent diffusion coefficient (ADC) in a multi-institution clinical trial setting, using standardized DWI protocols and quality assurance (QA) procedures. STUDY TYPE: Prospective. SUBJECTS: In all, 89 women from nine institutions undergoing neoadjuvant chemotherapy for invasive breast cancer. FIELD STRENGTH/SEQUENCE: DWI was acquired before and after patient repositioning using a four b-value, single-shot echo-planar sequence at 1.5T or 3.0T. ASSESSMENT: A QA procedure by trained operators assessed artifacts, fat suppression, and signal-to-noise ratio, and determine study analyzability. Mean tumor ADC was measured via manual segmentation of the multislice tumor region referencing DWI and contrast-enhanced images. Twenty cases were evaluated multiple times to assess intra- and interoperator variability. Segmentation similarity was assessed via the Sørenson-Dice similarity coefficient. STATISTICAL TESTS: Repeatability and reproducibility were evaluated using within-subject coefficient of variation (wCV), intraclass correlation coefficient (ICC), agreement index (AI), and repeatability coefficient (RC). Correlations were measured by Pearson's correlation coefficients. RESULTS: In all, 71 cases (80%) passed QA evaluation: 44 at 1.5T, 27 at 3.0T; 60 pretreatment, 11 after 3 weeks of taxane-based treatment. ADC repeatability was excellent: wCV = 4.8% (95% confidence interval [CI] 4.0, 5.7%), ICC = 0.97 (95% CI 0.95, 0.98), AI = 0.83 (95% CI 0.76, 0.87), and RC = 0.16 * 10-3 mm2 /sec (95% CI 0.13, 0.19). The results were similar across field strengths and timepoint subgroups. Reproducibility was excellent: interreader ICC = 0.92 (95% CI 0.80, 0.97) and intrareader ICC = 0.91 (95% CI 0.78, 0.96). DATA CONCLUSION: Breast tumor ADC can be measured with excellent repeatability and reproducibility in a multi-institution setting using a standardized protocol and QA procedure. Improvements to DWI image quality could reduce loss of data in clinical trials. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1617-1628.

Diffusion-weighted MRI Findings Predict Pathologic Response in Neoadjuvant Treatment of Breast Cancer: The ACRIN 6698 Multicenter Trial.

Purpose To determine if the change in tumor apparent diffusion coefficient (ADC) at diffusion-weighted (DW) MRI is predictive of pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancer. Materials and Methods In this prospective multicenter study, 272 consecutive women with breast cancer were enrolled at 10 institutions (from August 2012 to January 2015) and were randomized to treatment with 12 weekly doses of paclitaxel (with or without an experimental agent), followed by 12 weeks of treatment with four cycles of anthracycline. Each woman underwent breast DW MRI before treatment, at early treatment (3 weeks), at midtreatment (12 weeks), and after treatment. Percentage change in tumor ADC from that before treatment (ΔADC) was measured at each time point. Performance for predicting pCR was assessed by using the area under the receiver operating characteristic curve (AUC) for the overall cohort and according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. Results The final analysis included 242 patients with evaluable serial imaging data, with a mean age of 48 years ± 10 (standard deviation); 99 patients had HR-positive (hereafter, HR+)/HER2-negative (hereafter, HER2-) disease, 77 patients had HR-/HER2- disease, 42 patients had HR+/HER2+ disease, and 24 patients had HR-/HER2+ disease. Eighty (33%) of 242 patients experienced pCR. Overall, ΔADC was moderately predictive of pCR at midtreatment/12 weeks (AUC = 0.60; 95% confidence interval [CI]: 0.52, 0.68; P = .017) and after treatment (AUC = 0.61; 95% CI: 0.52, 0.69; P = .013). Across the four disease subtypes, midtreatment ΔADC was predictive only for HR+/HER2- tumors (AUC = 0.76; 95% CI: 0.62, 0.89; P < .001). In a test subset, a model combining tumor subtype and midtreatment ΔADC improved predictive performance (AUC = 0.72; 95% CI: 0.61, 0.83) over ΔADC alone (AUC = 0.57; 95% CI: 0.44, 0.70; P = .032.). Conclusion After 12 weeks of therapy, change in breast tumor apparent diffusion coefficient at MRI predicts complete pathologic response to neoadjuvant chemotherapy. © RSNA, 2018 Online supplemental material is available for this article.

MRI, Clinical Examination, and Mammography for Preoperative Assessment of Residual Disease and Pathologic Complete Response After Neoadjuvant Chemotherapy for Breast Cancer: ACRIN 6657 Trial.

OBJECTIVE: The objective of our study was to determine the accuracy of preoperative measurements for detecting pathologic complete response (CR) and assessing residual disease after neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer. SUBJECTS AND METHODS: The American College of Radiology Imaging Network 6657 Trial prospectively enrolled women with ≥ 3 cm invasive breast cancer receiving NACT. Preoperative measurements of residual disease included longest diameter by mammography, MRI, and clinical examination and functional volume on MRI. The accuracy of preoperative measurements for detecting pathologic CR and the association with final pathology size were assessed for all lesions, separately for single masses and nonmass enhancements (NMEs), multiple masses, and lesions without ductal carcinoma in situ (DCIS). RESULTS: In the 138 women with all four preoperative measures, longest diameter by MRI showed the highest accuracy for detecting pathologic CR for all lesions and NME (AUC = 0.76 and 0.84, respectively). There was little difference across preoperative measurements in the accuracy of detecting pathologic CR for single masses (AUC = 0.69-0.72). Longest diameter by MRI and longest diameter by clinical examination showed moderate ability for detecting pathologic CR for multiple masses (AUC = 0.78 and 0.74), and longest diameter by MRI and longest diameter by mammography showed moderate ability for detecting pathologic CR for tumors without DCIS (AUC = 0.74 and 0.71). In subjects with residual disease, longest diameter by MRI exhibited the strongest association with pathology size for all lesions and single masses (r = 0.33 and 0.47). Associations between preoperative measures and pathology results were not significantly influenced by tumor subtype or mammographic density. CONCLUSION: Our results indicate that measurement of longest diameter by MRI is more accurate than by mammography and clinical examination for preoperative assessment of tumor residua after NACT and may improve surgical planning.

Prognostic value of contrast enhancement and FLAIR for survival in newly diagnosed glioblastoma treated with and without bevacizumab: results from ACRIN 6686.

Background: ACRIN 6686/RTOG 0825 was a phase III trial of conventional chemoradiation plus adjuvant temozolomide with bevacizumab or without (placebo) in newly diagnosed glioblastoma. This study investigated whether changes in contrast-enhancing and fluid attenuated inversion recovery (FLAIR)-hyperintense tumor assessed by central reading prognosticate overall survival (OS). Methods: Two hundred eighty-four patients (171 men; median age 57 y, range 19-79; 159 on bevacizumab) had MRI at post-op (baseline) and pre-cycle 4 of adjuvant temozolomide (22 wk post chemoradiation initiation). Four central readers measured bidimensional lesion enhancement (2D-T1) and FLAIR hyperintensity at both time points. Changes from baseline to pre-cycle 4 for both markers were dichotomized (increasing vs non-increasing). Cox proportional hazards model and Kaplan-Meier survival estimates were used for inference. Results: Adjusting for treatment, increasing 2D-T1 (n = 262, hazard ratio [HR] = 2.07, 95% CI: 1.48-2.91, P < 0.0001) and FLAIR (n = 273, HR = 1.75, 95% CI: 1.26-2.41, P = 0.0008) significantly predicted worse OS. Median OS (days) was significantly shorter for patients with increasing versus non-increasing 2D-T1 for both bevacizumab (443 vs 535, P = 0.004) and placebo (526 vs 887, P = 0.001). Median OS was significantly shorter for patients with increasing versus non-increasing FLAIR for placebo (595 vs 872, P = 0.001), and trended similarly for bevacizumab (499 vs 535, P = 0.0935). Adjusting for 2D-T1 and treatment, increasing FLAIR represented significantly higher risk for death (HR = 1.59 [1.11-2.26], P = 0.01). Conclusion: Increased 2D-T1 significantly predicts worse OS in both treatment groups, implying absence of a substantial proportion of pseudoprogression 22 weeks after initiation of standard therapy. FLAIR adds value beyond 2D-T1 in predicting OS, potentially addressing the pseudoresponse effect by substratifying bevacizumab-treated patients with non-increasing 2D-T1.

CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study.

Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial.Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons.Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (P = 0.028), while BF achieves borderline significance (P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3-6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status (P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS.Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684-91. ©2017 AACR.

Utility of PET/CT to Evaluate Retroperitoneal Lymph Node Metastasis in High-Risk Endometrial Cancer: Results of ACRIN 6671/GOG 0233 Trial.

Purpose To assess the diagnostic accuracy of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with diagnostic contrast material-enhanced computed tomography (CT) in detecting lymph node (LN) metastasis in high-risk endometrial cancer. Materials and Methods This prospective multicenter HIPAA-compliant study had institutional review board approval, and all participants gave written informed consent. Data were accrued between January 2010 and June 2013. Patients underwent PET/CT and pelvic and abdominal lymphadenectomy. Two hundred seven of 215 enrolled patients had PET/CT and pathologic examination results for the abdomen and pelvis. Mean patient age was 62.7 years ± 9.6 (standard deviation). Data in all 23 patients with a positive abdominal examination and in 26 randomly selected patients with a negative abdominal examination were used for this central reader study. Seven independent blinded readers reviewed diagnostic CT and PET/CT results in different sessions 1 month apart. Accuracy was calculated at the participant level, correlating abdominal (right and left para-aortic and common iliac) and pelvic (right and left external iliac and obturator) LN regions with pathologic results, respecting laterality. Reader-average sensitivities, specificities, and areas under the receiver operating characteristic curve (AUCs) of PET/CT and diagnostic CT were compared. Power calculation was for sensitivity and specificity in the abdomen. Results Sensitivities of PET/CT versus diagnostic CT for the detection of LN metastasis were 0.65 (95% confidence interval [CI]: 0.57, 0.72) versus 0.50 (95% CI: 0.43, 0.58) (P = .01) in the abdomen and 0.65 (95% CI: 0.57, 0.72) versus 0.48 (95% CI: 0.41, 0.56) (P = .004) in the pelvis. Corresponding specificities were 0.88 (95% CI: 0.83, 0.92) versus 0.93 (95% CI: 0.89, 0.96) (P = .11) and 0.93 (95% CI: 0.86, 0.96) versus 0.89 (95% CI: 0.82, 0.94) (P = .27), and AUCs were 0.78 (95% CI: 0.66, 0.89) versus 0.74 (95% CI: 0.63, 0.86) (P = .39) and 0.82 (95% CI: 0.71, 0.92) versus 0.73 (95% CI: 0.63, 0.84) (P = .02). Conclusion FDG PET/CT has satisfactory diagnostic accuracy in the detection of abdominal LN metastasis in high-risk endometrial cancer. Compared with diagnostic CT alone, addition of PET to diagnostic CT significantly increased sensitivity in both the abdomen and pelvis while maintaining high specificity. © RSNA, 2017 Online supplemental material is available for this article.

Utility of PET-CT to evaluate retroperitoneal lymph node metastasis in advanced cervical cancer: Results of ACRIN6671/GOG0233 trial.

OBJECTIVE: To assess if FDG PET combined with diagnostic CT improves diagnostic CT accuracy to detect lymph node (LN) metastasis in advanced cervical cancer. METHODS: A prospective HIPAA compliant ACRIN/GOG multicenter trial was conducted. Patients underwent concurrent diagnostic contrast-enhanced CT (DCT) and PET and pelvic/abdominal lymphadenectomy. Seven independent blinded readers reviewed PET-DCT and DCT one-month apart. Reference standard was surgically removed LN pathology. Accuracy values were calculated at participant level, correlating abdominal (right and left para-aortic/common iliac) and pelvic (right and left external iliac/obturator) LN regions with pathology, respecting laterality. Reader average sensitivities/specificities of PET-DCT vs. DCT were compared with generalized linear mixed models, and AUCs with Obuchowski's method. RESULTS: One hundred fifty-three patients had PET-DCT and pathology. Forty-three of 153 patients had metastasis to abdominal LNs. Sample size calculation required review of the first 40 abdominal positive and 40 randomly selected abdominal negative studies. Patients were 24 to 74years (48.9±10.6) old. Mean sensitivities of PET-DCT/DCT for detection of LN metastasis in abdomen were 0.50 (CI: 0.44, 0.56) and 0.42 (CI: 0.36, 0.48) (p=0.052) and in pelvis 0.83 (CI: 0.78, 0.87) and 0.79 (CI: 0.73, 0.83) (p=0.15). Corresponding specificities were 0.85 (CI: 0.80, 0.89) and 0.89 (CI: 0.84, 0.92) (p=0.21) and 0.63 (CI: 0.54, 0.70) and 0.62 (CI: 0.53, 0.69) (p=0.83). Mean AUC values were 0.70 (CI: 0.61, 0.79) and 0.68 (CI: 0.59, 0.77) (p=0.43) and 0.80 (CI: 0.71, 0.88) and 0.76 (CI: 0.67, 0.85) (p=0.21) respectively. CONCLUSION: Addition of PET to DCT resulted in statistically borderline increase in sensitivity to detect LN metastasis in abdomen in advanced cervical cancer.

Neoadjuvant Chemotherapy for Breast Cancer: Functional Tumor Volume by MR Imaging Predicts Recurrence-free Survival-Results from the ACRIN 6657/CALGB 150007 I-SPY 1 TRIAL.

PURPOSE: To evaluate volumetric magnetic resonance (MR) imaging for predicting recurrence-free survival (RFS) after neoadjuvant chemotherapy (NACT) of breast cancer and to consider its predictive performance relative to pathologic complete response (PCR). MATERIALS AND METHODS: This HIPAA-compliant prospective multicenter study was approved by institutional review boards with written informed consent. Women with breast tumors 3 cm or larger scheduled for NACT underwent dynamic contrast-enhanced MR imaging before treatment (examination 1), after one cycle (examination 2), midtherapy (examination 3), and before surgery (examination 4). Functional tumor volume (FTV), computed from MR images by using enhancement thresholds, and change from baseline (ΔFTV) were measured after one cycle and before surgery. Association of RFS with FTV was assessed by Cox regression and compared with association of RFS with PCR and residual cancer burden (RCB), while controlling for age, race, and hormone receptor (HR)/ human epidermal growth factor receptor type 2 (HER2) status. Predictive performance of models was evaluated by C statistics. RESULTS: Female patients (n = 162) with FTV and RFS were included. At univariate analysis, FTV2, FTV4, and ΔFTV4 had significant association with RFS, as did HR/HER2 status and RCB class. PCR approached significance at univariate analysis and was not significant at multivariate analysis. At univariate analysis, FTV2 and RCB class had the strongest predictive performance (C statistic = 0.67; 95% confidence interval [CI]: 0.58, 0.76), greater than for FTV4 (0.64; 95% CI: 0.53, 0.74) and PCR (0.57; 95% CI: 0.39, 0.74). At multivariate analysis, a model with FTV2, ΔFTV2, RCB class, HR/HER2 status, age, and race had the highest C statistic (0.72; 95% CI: 0.60, 0.84). CONCLUSION: Breast tumor FTV measured by MR imaging is a strong predictor of RFS, even in the presence of PCR and RCB class. Models combining MR imaging, histopathology, and breast cancer subtype demonstrated the strongest predictive performance in this study.

Utility of preoperative ferumoxtran-10 MRI to evaluate retroperitoneal lymph node metastasis in advanced cervical cancer: Results of ACRIN 6671/GOG 0233.

RATIONALE AND OBJECTIVES: To assess if ferumoxtran-10 (f-10) improves accuracy of MRI to detect lymph node (LN) metastasis in advanced cervical cancer. MATERIALS AND METHODS: F-10 MRI component of an IRB approved HIPAA compliant ACRIN/GOG trial was analyzed. Patients underwent f-10 MRI followed by extra-peritoneal or laparoscopic pelvic and abdominal lymphadenectomy. F-10-sensitive sequences were T2* GRE sequences with TE of 12 and 21. Seven independent blinded readers reviewed f-10-insensitive sequences and all sequences in different sessions. Region correlations were performed between pathology and MRI for eight abdomen and pelvis regions. Sensitivity and specificity were calculated at participant level. Reference standard is based on pathology result of surgically removed LNs. RESULTS: Among 43 women enrolled in the trial between September 2007 and November 2009, 33 women (mean age 49 ±11 years old) with advanced cervical cancer (12 IB2, 3 IIA, 15 IIB and 3 IIIB, 29 squamous cell carcinomas, 32 grade 2 or 3) were evaluable. Based on histopathology, LN metastasis was 39% in abdomen and 70% in pelvis. Sensitivity of all sequence review in pelvis, abdomen, and combined were 83%, 60%, and 86%, compared with 78%, 54%, and 80% for f-10 insensitive sequences (P: 0.24, 0.44 and 0.14, respectively). Mean diameter of the largest positive focus on histopathology was 13.7 mm in abdomen and 18.8 mm in pelvis (P = 0.018). Specificities of all sequence review in pelvis, abdomen, and combined were 48%, 75%, and 43%, compared with 75%, 83%, and 73% (P: 0.003, 0.14, 0.002 respectively) for f-10 insensitive sequences. CONCLUSION: Addition of f-10 increased MRI sensitivity to detect LN metastasis in advanced cervical cancer. Increased sensitivity did not reach statistical significance and was at the expense of lower specificity.