McDonough, Michelle

604 Background: Many patients with localized breast cancer undergo breast conservation therapy. Partial breast irradiation (PBI) is a technique that reduces irradiated tissue volume and decreases treatment time. Appropriate patient selection for this technique is critical. We studied the influence of pre-operative breast MRI on patient selection for PBI. Methods: Between 05/04 and 05/05, 231 women with newly diagnosed breast cancer underwent pre-operative bilateral breast MRI (median age = 64, range 34 to 89). Following initial clinico-pathologic review, patients were deemed to be eligible for PBI based on the NSABP B39 protocol if they satisfied its inclusion criteria (tumor size ≤3 cm, ≤3 positive nodes, negative surgical margins, lack of multicentric disease), derived through physical examination, mammography and/or ultrasonography. Breast MRI scans of all patients deemed eligible for PBI by these criteria were then reviewed to determine the impact of the MRI findings on their eligibility for PBI. Only patients who had pathological assessment to correlate with the MRI findings were included in the analysis. Results: Based on the NSABP B39 inclusion criteria, 186 patients (81%) were considered to be appropriate candidates for PBI without influence from MRI findings. Of these 186 women, MRI findings led to pathologically proven additional disease that altered the recommendations for PBI in 26 patients (14%). Mammographically occult, biopsy proven multicentic disease was detected in the ipsilateral breast in 13 patients (7%), whereas 5 women (2.7%) had mammographically occult, biopsy proven multicentric disease in the contralateral breast. In 8 patients (4.3%), pathological assessment confirmed more extensive local disease than was detected by breast MRI. Conclusions: Up to 14% of patients initially deemed eligible for PBI were later found to be ineligible because of breast MRI findings. Ipsilateral multicentric disease was identified in 7%, contralateral disease was discovered in 2.7%, and more extensive local disease was noted in 4.3%. Bilateral breast MRI complements other imaging modalities in determining eligibility for PBI by identifying mammographically occult disease in patients for whom PBI may be inappropriate. No significant financial relationships to disclose.

Abstract Background: Targeting immune checkpoint programmed death receptor 1 (PD-1)/PD-L1 pathway has shown promising clinical activity with some preliminary association of clinical benefit with PD-L1 expression on tumors. Recent preclinical and clinical studies highlight the beneficial immunomodulatory potential of epigenetic therapy. Entinostat is a class I specific histone deacetylase inhibitor (HDACi). A promising preclinical study showed that entinostat in combination with immune checkpoint blockade agent can eradicate modestly immunogenic breast tumors in mice via reduction in immunosuppressive myeloid-derived suppressor cells. In this study, we investigated the effects of entinostat on expression of immune-related genes in breast cancer cells to further explore the potential mechanism of its combined activity. Method: Gene expression was assessed on Nanostring platform using the nCounter GX Human ImmunologyV2 panel comprised of 594 immune-related and 15 reference genes. Gene expression was normalized to the internal positive controls and reference genes using nSolver2.0 software. Hormone receptor-positive (HR+) breast cancer (MCF-7 and T47D) and triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and Hs578T) were used for the analysis. Gene expression analysis was performed on control and after 24-hour treatment of entinostat at clinically relevant 125 and 500 nM concentrations. Results: Overall, a greater number of immune-related genes were induced > 2 fold with entinostat at 125 and 500 nM in TNBC compared to HR+: 77 and 118 genes in MDA-MB-231, 80 and 147 genes in Hs578T, 20 and 64 genes in MCF-7, and 73 and 72 genes in T47D, respectively. In particular, MHC class I (HLA-A, HLA-B, HLA-C) and II (HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DQB2, HLA-DRA, and HLA-DRB1) genes were induced by entinostat in a dose dependent manner (range 1.5-22.44 fold). These inductions were observed in both HR+ and TNBC cell lines. Interestingly, we found higher baseline expression and a several fold increase in PD-L1 expression in TNBC. PD-L1 mRNA expression increased by 1.74 and 2.14 fold in MDA-MB-231 and 3 and 9.6 fold in Hs578T with 125 and 500 nM treatment, respectively. Corresponding increase in PD-L1 protein expression after entinostat treatment was also observed. In contrast, there appeared to be no significant changes in PD-L1 expression after entinostat treatment in MCF-7 and T47D. Furthermore, we also identified 21 genes that were differentially induced by entinostat in TNBC but not in HR+. These genes include PTPN22, ARG2, CISH, IL17A, ICAM2, KIR3DL1, CXCR3, TLR2, CFD, CCR5, IL13, LILRA3, IL8, TNFRSF9, DPP4, MR1, SELPLG, PTGS2, IL1B, CD3D, and MBL2. No significant change in PDL2 expression was observed in any of the cell lines. Conclusion: Our data suggest that entinostat induces immune-related genes involved in antigen presentation in both ER+ and TNBC cells, potentially increasing the immunogenicity of these tumors. Given the significant induction of PD-L1 expression with entinostat in TNBC, our preclinical data provides support for further investigation of entinostat in combination with anti-PD1 or anti-PD-L1 in this subtype of breast cancer. Citation Format: Chumsri S, Necela BM, Ordentlich P, Advani P, Moreno-Aspitia A, McLaughlin SA, Geiger X, McDonough M, Vallow LA, Perez EA, Thompson EA. Immunomodulatory effects of entinostat on PD-L1 and MHC class I and II in different subtypes of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-04-02.

Abstract Background: Imaging biomarkers of cellular division offer promise as non-invasive measures of tumor response. 3’-deoxy-3’[18F]-fluorothymidine ([18F]-FLT) positron emission tomography (PET) imaging generally correlates with pathology-based measurements of cancer proliferation, especially the Ki67 score. Though clinical studies have associated changes in [18F]-FLT uptake with therapeutic response, clinical studies validating its ability to assess cell proliferation are comparatively lacking. The goal of this study was to determine quantitative relationships between [18F]-FLT compared with molecular and cellular metrics of proliferation during treatment for locally advanced breast cancer (LABC). Methods: Baseline [18F]−FLT-PET scans were obtained prior to the initiation of chemotherapy for LABC from patients enrolled at several academic oncology study sites. MRI scans, and transmission CT scans were obtained. Core needle biopsies were obtained to determine Ki-67 indices using immuno-histochemistry and to assess an mRNA signature based measurement of proliferation. Prospectively specified quantitative relationships between PET, Ki67 immunohistochemistry and the mRNA signature were evaluated using image-matched tumor specimens. Correlations between volumetric MRI changes and pathologic responses were evaluated in a post-hoc exploratory analysis. Results: Motivated by the hypothesis that effective chemotherapies should decrease tumor cell proliferation, FLT-PET was compared with biomarkers of proliferation including Ki67 and the mRNA signature during neoadjuvant treatment for LABC. [18F]-FLT correlated both with the Ki67 labeling index (SUVmean r = 0.53) and with the proliferation signature (SUVmean r = 0.7), validating the principle of thymidine analogue imaging. However, variability in the [18F]-FLT PET and tumor cell proliferation measures likely contributed to correlations less than pre-specified target values considered appropriate for clinical use (r > 0.78). Moreover, none of the proliferation biomarkers predicted pathologic complete responses at the end of neoadjuvant therapy ∼16 weeks after the 3 week response scan. In contrast, an evaluation of change in tumor volume measured by MRI after 3 weeks of therapy confirmed its superior ability to predict pCR and tumor re-staging. Conclusion: With large numbers of cancer drugs entering therapeutic pipelines, early efficacy measures remain critical for drug development. The 3-4 month neoadjuvant treatment paradigm for LABC offers unique opportunities for drug evaluation. Functional imaging using [18F]-FLT has been advanced as an assessor of cellular proliferation, potentially offering a non-invasive approach to response evaluation. While [18F]-FLT generally correlated with proliferation, its lack of association with patient responses likely limit its clinical utility. On the other hand, the predictive value of MRI offers unique opportunities for future trial designs and confirms previous reports (1). 1. N. M. Hylton et al., Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy. Radiology 263, 663 (2012). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-11.

Purpose. Women with ductal carcinomain situ(DCIS) are often candidates for breast-conserving therapy, and one option for radiation treatment is partial breast irradiation (PBI). This study evaluates the use of preoperative breast magnetic resonance imaging (MRI) for PBI selection in DCIS patients.Methods. Between 2002 and 2009, 136 women with newly diagnosed DCIS underwent a preoperative bilateral breast MRI at Mayo Clinic in Florida. One hundred seventeen women were deemed eligible for PBI by the NSABP B-39 (National Surgical Adjuvant Breast and Bowel Project, Protocol B-39) inclusion criteria using physical examination, mammogram, and/or ultrasound. MRIs were reviewed for their impact on patient eligibility, and findings were pathologically confirmed.Results. Of the 117 patients, 23 (20%) were found ineligible because of pathologically proven MRI findings. MRI detected additional ipsilateral breast cancer in 21 (18%) patients. Of these women, 15 (13%) had more extensive disease than originally noted before MRI, and 6 (5%) had multicentric disease in the ipsilateral breast. In addition, contralateral breast cancer was detected in 4 (4%).Conclusions. Preoperative breast MRI altered the PBI recommendations for 20% of women. Bilateral breast MRI should be an integral part of the preoperative evaluation of all patients with DCIS being considered for PBI.

Abstract Abstract #4018 Background: Preoperative breast magnetic resonance imaging (MRI) has been shown to identify occult breast disease in women with newly diagnosed breast cancer. We sought to determine the accuracy of MRI in predicting the actual pathologic tumor size in women with newly diagnosed breast cancer.
 Methods: Preoperative breast MRI was reviewed in 460 women with newly diagnosed breast cancer. The size in terms of maximum tumor dimension, of 476 incident breast cancers on MRI were recorded and correlated with the actual pathologic size upon surgical resection. The correlation of size from MRI to pathology was determined. The size discrepancy was analyzed in relation to tumor size and histology.
 Results: MRI demonstrated 476 breast cancers (460 in the ipsilateral breast and 16 with concurrent contralateral breast cancer). Median age was 62 with a range of 25 to 91. The T stages of the population included T0 in 19% of the women, 60% had T1 lesions, 18% had T2 lesions and 3% were T3 or T4. The histology consisted of DCIS alone in 20%, infiltrating ductal in 74% and infiltrating lobular in 6%. Pre-operative MRI was unable to define an enhancing lesion usually due to hematoma following core needle biopsy in 9.8% (47/476). MRI described the size of the incident lesion in 90% (429/476). The mean difference in size between the preoperative MRI and the actual pathologic size for the entire group was 2.4 mm. MRI underestimated tumor size in only 3% of cases. The mean difference according to T stage and histology between MRI and actual pathologic size is listed in Table 1. The percentage of difference between MRI size and pathologic size for the entire group is presented in Table 2.
 
 
 
 Discussion: The mean difference in tumor size estimated by preoperative MRI in women with newly diagnosed breast cancer was within 5 mm of the actual pathologic size in 68% of patients. MRI was accurate in predicting T stage with no significant difference in relation to histology or T stage. This analysis further clarifies the role of preoperative MRI in surgical and treatment planning. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4018.