Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIAL.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.

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.

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.

Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy--results from ACRIN 6657/I-SPY TRIAL.

PURPOSE: To compare magnetic resonance (MR) imaging findings and clinical assessment for prediction of pathologic response to neoadjuvant chemotherapy (NACT) in patients with stage II or III breast cancer. MATERIALS AND METHODS: The HIPAA-compliant protocol and the informed consent process were approved by the American College of Radiology Institutional Review Board and local-site institutional review boards. Women with invasive breast cancer of 3 cm or greater undergoing NACT with an anthracycline-based regimen, with or without a taxane, were enrolled between May 2002 and March 2006. MR imaging was performed before NACT (first examination), after one cycle of anthracyline-based treatment (second examination), between the anthracycline-based regimen and taxane (third examination), and after all chemotherapy and prior to surgery (fourth examination). MR imaging assessment included measurements of tumor longest diameter and volume and peak signal enhancement ratio. Clinical size was also recorded at each time point. Change in clinical and MR imaging predictor variables were compared for the ability to predict pathologic complete response (pCR) and residual cancer burden (RCB). Univariate and multivariate random-effects logistic regression models were used to characterize the ability of tumor response measurements to predict pathologic outcome, with area under the receiver operating characteristic curve (AUC) used as a summary statistic. RESULTS: Data in 216 women (age range, 26-68 years) with two or more imaging time points were analyzed. For prediction of both pCR and RCB, MR imaging size measurements were superior to clinical examination at all time points, with tumor volume change showing the greatest relative benefit at the second MR imaging examination. AUC differences between MR imaging volume and clinical size predictors at the early, mid-, and posttreatment time points, respectively, were 0.14, 0.09, and 0.02 for prediction of pCR and 0.09, 0.07, and 0.05 for prediction of RCB. In multivariate analysis, the AUC for predicting pCR at the second imaging examination increased from 0.70 for volume alone to 0.73 when all four predictor variables were used. Additional predictive value was gained with adjustments for age and race. CONCLUSION: MR imaging findings are a stronger predictor of pathologic response to NACT than clinical assessment, with the greatest advantage observed with the use of volumetric measurement of tumor response early in treatment.

Accuracy of breast magnetic resonance imaging in predicting pathologic response in patients treated with neoadjuvant chemotherapy.

BACKGROUND: Prior studies of the ability of magnetic resonance imaging (MRI) to predict pathologic response to neoadjuvant chemotherapy have shown conflicting results that vary depending on baseline molecular characteristics. This study examines the ability of MRI to predict pathologic complete response (pCR) and explores the influence of tumor molecular profiles on MRI sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). METHODS: Eighty-one patients with invasive breast cancer treated with neoadjuvantsystemic therapy between 2002 and 2009 who were imaged with breast MRI pre- and post-treatment were reviewed. Patient, tumor, and treatment characteristics were recorded. Comparisons of molecular subsets and their influence on MRI sensitivity, specificity, PPV, and NPV were made using χ(2)contingency tables. RESULTS: The sensitivity, specificity, PPV, and NPV of MRI for predicting pCR for the total group were 92%, 50%, 74%, and 80%, respectively. Patients had the following molecular subtypes: 33/81 (41%) HR+Her2-, 23/81 (28%) HR+/-Her2 +, and 25/81(31%) triple receptor negative (TN). Molecular subtype did not demonstrate a significant correlation of radiographic and pathologic response, although MRI NPV was highest in the TN subset (100%) followed by those with HR+/-Her2+ disease (87.5%). Multivariate analysis did not show that tumor characteristics (estrogen receptor status, progesterone receptor status, HER2 status) or neoadjuvant treatment (doxorubicin, cyclophosphamide, paclitaxel versus other or trastuzumab) had any effect on MRI sensitivity or specificity. CONCLUSIONS: In patients receiving neoadjuvant systemic therapy for invasive breast cancer, molecular subtype and systemic regimen administered did not significantly influence the sensitivity, specificity, PPV, or NPV of MRI in predicting pathologic response.

Pilot trial of preoperative (neoadjuvant) letrozole in combination with bevacizumab in postmenopausal women with newly diagnosed estrogen receptor- or progesterone receptor-positive breast cancer.

INTRODUCTION: Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of antiestrogen adjuvant therapy. We designed a pilot study to assess the feasibility and short-term efficacy of neoadjuvant letrozole and bevacizumab (anti-VEGF) in postmenopausal women with stage II and III estrogen receptor/progesterone receptor-positive breast cancer. PATIENTS AND METHODS: Patients were treated with a neoadjuvant regimen of letrozole orally 2.5 mg/day and bevacizumab intravenously 15 mg/kg every 3 weeks for a total of 24 weeks before the surgical treatment of their breast cancer. Patients were followed for toxicity at 3-week intervals, and tumor assessment (a physical examination and ultrasound) was performed at 6-week intervals. Positron emission tomography (PET) scans were performed before therapy and 6 weeks after the initiation of therapy. RESULTS: Twenty-five evaluable patients were treated. The regimen was well-tolerated, except in 2 patients who were taken off the study for difficulties controlling their hypertension. An objective clinical response occurred in 17 of 25 patients (68%), including 16% complete responses (CRs) and 52% partial responses. The 4 patients with clinical CRs manifested pathologic CRs in their breasts (16%), although 1 patient had residual tumor cells in her axillary nodes. Eight of 25 patients (32%) attained stage 0 or 1 status. The PET scan response at 6 weeks correlated with clinical CRs and breast pathologic CRs at 24 weeks (P < .0036). CONCLUSION: Combination neoadjuvant therapy with letrozole and bevacizumab was well-tolerated and resulted in impressive clinical and pathologic responses. The Translational Breast Cancer Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.

Specimen radiographs assist in identifying and assessing resection margins of occult breast carcinomas.

For carcinoma specimens with non-grossly identifiable lesions such as microcalcifications, difficulties may be encountered in locating these abnormalities and sampling the margins that are at risk. This is magnified in the case of skin-sparing procedures where the margin is a much greater surface area and is the operation of choice in patients with diffuse microcalcifications and/or multifocal in situ disease. The objective of this study was to determine the efficacy of specimen radiographs of mastectomy in identifying occult carcinoma associated with microcalcifications and assessing the resection margins. We reviewed the histology and corresponding specimen radiographs of 16 patients with diffuse and widespread microcalcifications and who underwent skin-sparing mastectomy. After the specimens were serially sectioned, specimen radiographs of each section of the specimens were obtained with digital mammography equipment. Findings in the specimen radiographs were used to direct the histologic sampling of the specimens. On gross examination, two (12.5%) mastectomy specimens had identifiable discreet masses; the lesions were 4 and 7 mm, respectively. Histologic examination revealed the presence of carcinoma in 13 (81%) cases; seven with both infiltrating and in situ carcinoma and six with in situ carcinoma alone. The remaining three patients demonstrated only changes of biopsy site without any residual carcinoma. Microcalcifications were associated with in situ carcinoma in all malignant cases. Among the 12 cases with microcalcifications present at or within 2 mm of the margins, in situ carcinoma was present at the margins in three cases and located within 2 mm of the margins in two cases. All margins were negative in all cases with microcalcifications that were at least 1 cm away from the resection margins. The average number of tissue blocks examined was 16.6 +/- 5.4. The average number of tissue blocks sampled among randomly selected mastectomy specimens was 15.2 +/- 5.4. There was no statistically significant difference in the number of blocks between mastectomy cases with specimen radiographs taken and those without (t-test). Our study suggests that specimen radiographs may assist in identifying occult breast carcinoma associated with microcalcifications and assessing the resection margins without increased sampling.

Three-dimensional changes in upper airways of patients with obstructive sleep apnea following maxillomandibular advancement.

PURPOSE: The purpose of this study was to analyze the morphologic changes of the airway in obstructive sleep apnea (OSA) patients by helical computed tomography (CT) scanning following maxillomandibular advancement (MMA) surgery. MATERIALS AND METHODS: Twenty consecutive OSA patients treated with MMA from 2000 to 2003 at the University of Alabama at Birmingham Hospital and diagnosed by polysomnography (PSG) were included in this study. The criteria for this study were MMA surgery, pre- and postoperative helical CT scan, and PSG. Lateral (LAT) and anterioposterior (AP) airway dimensions were measured from the level of the hard palate to the hyoid using helical CT scans. RESULTS: There was enlargement of LAT and AP diameters for all patients at all levels. LAT dimensions were enhanced greater than AP in the retroglossal region. CONCLUSION: MMA results in significant increase in both AP and LAT airway dimensions.

Ultrasound detection of bone erosions in rheumatoid arthritis: a comparison to routine radiographs of the hands and feet.

PURPOSE: To determine if ultrasound (US) of selected joints in the hands and feet can detect more erosions than radiography and establish the presence of erosive disease in patients with rheumatoid arthritis (RA). METHODS: Eighty joints in ten patients with RA and 40 joints in five healthy control subjects, who were age, gender and ethnicity-matched to the patients with arthritis, were prospectively studied with radiographs and sonography. Conventional radiographs of the hands and feet were obtained. US examinations of the 2nd and 5th metacarpal-phalangeal (MCP) joints of the hands, and the 1st and 5th metatarsal-phalangeal (MTP) joints of the feet were performed. Radiographs and US exams were independently graded for the presence of erosions. RESULTS: None of the control subjects had erosions. US detected erosions in 17/80, and radiographs detected erosions in 6/80 joints assessed with both modalities. US detected all erosions seen by radiographs in these selected joints. Erosive disease was present in the radiographs of seven of ten RA patients. US established erosive disease in eight of ten RA patients. US determined erosive disease in two of the three patients without radiographic erosions. CONCLUSIONS: US of the MTP and MCP joints in RA can detect erosions not seen with radiography and may be complementary to radiography in establishing the presence of erosive disease in early RA.