Bedrosian, I.

Abstract Background: Standard treatment for ductal carcinoma in situ (DCIS) consists of surgery, often followed by adjuvant radiation therapy or endocrine therapy. This current approach is thought to represent overtreatment for some patients. This study was undertaken to determine whether an alternate approach of primary endocrine therapy alone could result in measurable radiographic changes in unresected estrogen receptor (ER)-positive DCIS. Methods: A phase II open-label single arm multi-center cooperative group trial (CALGB 40903) was conducted for postmenopausal patients diagnosed with ER-positive DCIS. All eligible patients underwent baseline mammography and MRI, followed by 6 months of preoperative therapy with letrozole. Follow up breast MRI was obtained at 3 and 6 months of treatment. The primary endpoint was change in total MRI volume of DCIS enhancement from baseline to 3 months and from baseline to 6 months. Secondary endpoints were change in MRI maximum diameter over baseline and change in mammographic extent of disease over baseline. Endpoints were analyzed via 2-sided paired t-tests (a=0.05). Results: From 8/1/12 to 2/1/16 108 patients were enrolled; Of the 77 patients who completed letrozole treatment per protocol, 66 patients were assessable. 2 additional patients who did not complete treatment per protocol were considered assessable and thus included in the analysis for a total of 68 patients. Median age of the cohort was 62.7 years. DCIS nuclear grade was low in 10% of patients, intermediate in 49%, and high in 40%. 82% of patients had ER-positive, PR-positive DCIS. The total mean MRI volume decreased from baseline to 3 months by 1.93 cm3 (p<0.001) and from baseline to 6 months by 1.82 cm3 (p<0.001). There was no significant difference in tumor volume between 3 and 6 months. Mean total mammographic tumor diameter decreased from baseline to 6 months by 3.31 mm2 (p=0.078). Conclusions: In a cohort of postmenopausal women treated with 6 months of preoperative endocrine therapy for ER-positive DCIS, MRI volume decreased markedly by 3 months, while mammographic extent of disease was not altered significantly. Correlation of imaging changes with pathology and baseline biomarkers will be conducted. These results will help determine whether MRI could be an effective modality for monitoring treatment response in some patients treated with primary endocrine therapy for ER-positive DCIS. Citation Format: Hwang ES, Duong S, Bedrosian I, Allred J, Wisner D, Hyslop T, Caudle A, Guenther J, Hudis C, Winer E, Esserman L, Hylton N. Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-05.

Abstract Background Surgical planning and local-regional treatment of breast cancer relies on accurate assessment of disease extent including the primary tumor size and the presence/absence of multiple tumor foci. As a staging modality for breast cancer, MRI has shown high sensitivity for detection of additional foci of diseases within the index breast. However, the impact of preoperative breast MRI on reducing re-excision rates and improving local control is less clear. Data from the COMICE trial in the UK suggested that routine use of pre-operative breast MRI did not alter rates of re-excision; however issues have been raised about the lack of quality standards for the MR imaging that may have resulted in the negative results of this trial. Retrospective data suggest that local recurrence is not impacted by use of breast MRI. In concert with data showing no improvement in clinical outcomes of breast cancer patients, concerns have been raised that routine use of preoperative breast MRI is associated with increased rates of mastectomy and delays to surgery. Therefore, the application of MRI for preoperative surgical staging remains controversial. In order to address this ongoing controversy, a joint effort has been launched by ACOSOG and ACRIN for a prospective clinical trial focused on evaluating the impact of preoperative breast MRI on clinically relevant patient outcomes. An important part of this collaboration is implementation of standards of how MRI findings should be clinically managed and used to direct localization methods and surgical planning, thereby creating guidelines for subsequent patient intervention. Trial design/eligibility criteria: A prospective multicenter trial will include women eligible for BCT by standard criteria and randomized between current standard of care, clinical examination and mammography (+/− ultrasound) and the same plus preoperative breast MRI. The study will focus on women at the highest risk of local recurrence: ER/PR/HER-2 negative (triple negative) and HER-2 amplified breast cancers. Specific aims: To compare the rates of local recurrence following breast conserving therapy in a cohort randomized to preoperative staging with mammography or mammography plus breast MRI. Additionally, a comparison of rates of re-operation, time to local recurrence, survival outcomes, contralateral breast cancer rates, rates of multicentric disease and other secondary aims will be performed. Costs and quality of life measures will also be investigated. Statistical methods: A stratified logrank test and Cox partial likelihood score test will be used to assess whether the distribution of LR times differs with respect to diagnostic work-up approach having adjusted for tumor stage. Cox modeling with the Cox partial likelihood score test will be used to examine the strength of association between these time to event distributions and such additional potential prognostic factors as menopausal status, chemotherapy, radiation therapy, ER, PR, number of positive lymph nodes, HER-2/neu expression, Nottingham grade, and Ki-67 expression. Target Accrual: 556 patients Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-06.

Abstract Purpose: Emerging data from cooperative group trials suggests that not all patients with a positive SLN require completion axillary lymph node dissection (ALND). The controversy regarding who will benefit from additional nodal clearance continues, suggesting a need for improved tools to predict non-SLN involvement. We hypothesized that the size of a SLN metastasis evaluated as a continuous variable would be an important predictor of non-SLN involvement. The goal of this study was to determine clinicopathologic factors including SLN metastasis size that predicted non-SLN involvement and to use these factors to construct an improved predictive nomogram. Methods: Using a prospective database, we identified 509 patients with invasive breast cancer from 1996 - 2007 with a positive SLN who underwent ALND. Patients receiving neoadjuvant therapy were excluded. Clinicopathologic data including age, primary tumor size, presence of multifocal disease, histology (invasive ductal vs. invasive lobular vs. mixed invasive), tumor grade, estrogen receptor, progesterone receptor, and HER2/neu status, presence of lymphovascular invasion (LVI), the number of SLNs identified, number of positive SLNs, the maximum SLN metastasis size and the presence of extranodal extension were recorded. For SLNs described only as containing isolated tumor cells, size was recorded as 0.1 mm. Univariate and multivariate logistic regression analyses were performed to identify factors predictive of positive non-SLNs. Using these variables, a nomogram was constructed and subsequently validated using an external cohort of 464 patients. Results: On univariate analysis, the following factors were predictive of positive non-SLNs: number of SLN identified (p<.001), number of positive SLN (p<.001), maximum SLN metastasis size (p<.001), extranodal extension (p<.001), primary tumor size (p=.001), LVI (p=.019) and histology (p=.034). On multivariate analysis, all factors remained significant at the 5% level except LVI. A nomogram was created using these variables. When applied to an external cohort, the nomogram was accurate and discriminating with an area under the receiver operating characteristic curve of .73 (95% CI: .68 - .77). Conclusions: SLN metastasis size is predictive for identifying additional disease in the axilla. These data have been incorporated into a nomogram that accurately predicts the likelihood of having additional, non-SLN metastasis suggesting that routine reporting of the SLN metastasis size would assist with clinical decision making regarding the need to perform a completion ALND. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-08.