Citations

Significance In this work we report on the previously uncharacterized clinical and biological role for EGFL7 in acute myeloid leukemia (AML). Patients with increased EGFL7 mRNA expression had lower complete remission rates and shorter overall and event-free survival, demonstrating the clinical relevance of EGFL7 expression in cytogenetically normal AML. Our results show that AML blasts are able to synthesize and secrete EGFL7 protein, promoting autocrine blast cell growth. Inhibition of EGFL7 results in decreased proliferation and induces apoptosis of AML cells. Taken together, our data provide the rationale for targeting EGFL7 using blocking antibodies as a therapy for patients with AML.

Abstract Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints. Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550). Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127–37. ©2017 AACR.

101 Background: Diabetes mellitus (DM) has been associated with an increased risk of mortality among patients with many types of cancers. The aim of this case-control study was to determine the impact of DM on short-term overall survival in prostate cancer patients, and to examine the impact of prostate cancer on glycemic control in DM. Methods: 276 patients with newly diagnosed prostate cancer from 2007-2014 with DM were identified from the Institutional Cancer Registry and matched to 276 prostate cancer patients without DM according to age and year of prostate cancer diagnosis. The file was linked to the electronic medical record to obtain information on DM and cancer therapies, and laboratory results. Results: The mean age of the entire prostate cancer cohort was 72 years, most (93%) were white, the most common Gleason score (in 52%) was 7, and the majority (56%) were tumor stage 2. No differences in age, race/ethnicity, Gleason score, or tumor stage were detected between patients with and without DM, although DM patients had higher body mass index (P = .031). Among those with DM the mean hemoglobin A1c (HbA1c) was 6.7%. In Kaplan-Meier survival analysis (median follow-up time of 43.7 months), 5-year overall survival was estimated at 88% for DM patients versus 93% in non-DM patients. Hazard ratio (for matched pairs) was 1.64 (95% CI: 0.77-3.46, P = .20). Moreover, mean HbA1c and glucose values among DM cases did not significantly change over 1 year (P ≥ .13). Mean glucose among DM patients was significantly (p < 0.01) higher compared to non-DM patients. Conclusions: DM did not adversely impact survival in prostate cancer patients. In addition, prostate cancer or its treatment does not appear to affect glycemic control. Both patients and their providers can be reassured that the two concurrent diagnoses do not adversely interact to worsen short term outcomes.

55 Background: The aim of this retrospective study was to examine the overall survival (OS) of metastatic breast cancer patients over a decade and assess for any differences with respect to age, tumor characteristics, and ECOG status. Methods: Data on metastatic breast cancer cases from 1999-2010 were retrieved from the institutional cancer registry and linked to electronic medical records. Through chart review of 240 metastatic breast cancer cases, we determined hormone receptor (HR), HER2/neu (HER2), ECOG, age at diagnosis of metastatic cancer and mortality data. Kaplan-Meier survival curves for OS were used and compared between HR status, HER2 status, ECOG, and age at diagnosis using log-rank regression and Cox Regression analysis was performed to control for these variables. A 95% confidence interval (CI) was used. Results: The median OS of the sampled cases was 2.2 years (CI: 1.8-2.5 years). Analysis for overall survival by pre-determined age groups demonstrated no significant difference between the age groups (p value 0.46), but did yield a statistical difference based on ECOG status (p value 0.0001). Cox regression analysis showed consistent findings where survival was significantly affected by HR, HER2 status and ECOG but not age (HR: p value <0.0001; HER2: p value 0.0132; ECOG: p value <0.0001; age at diagnosis: p value 0.8462). Analysis for OS based on HR yielded a median survival of 1.4 years (CI: 0.9-1.6 years) for HR negative and 2.5 years (CI: 2.2-3.0 years) for HR positive (p value 0.0018). HER2 yielded a median survival of 1.8 years (CI: 1.4-2.3 years) for no amplification and 3.0 years (CI: 2.5 - 3.4 years) for amplification (p-value 0.0043). HR negative, HER2 non-amplified tumors had the poorest median OS at 0.7 years (CI: 0.5 - 1.1 years) whereas those tumors with HR positive, HER2 amplified had the best median OS at 3.0 years (CI: 2.5 - 4.7 years) with a p value < 0.0001. Conclusions: In this retrospective analysis, there was no significant survival difference with respect to age. Age continued to have no significant effect on survival when adjusting for ECOG, hormone status, and HER2/neu status. Those factors that did act as determinants of survival were ECOG status, hormone status and HER2/neu status of the tumor.

137 Background: Diabetes has been associated with an increased risk of mortality among patients with many types of cancers. Methods: We performed a case-control study of 109 breast cancer patients to determine the impact of diabetes on disease recurrence and survival. These 109 patients diagnosed with invasive breast cancer during 2007-2011 with diabetes were identified from the institutional Cancer Registry and matched to 109 breast cancer patients without diabetes according to age, race/ethnicity and year of diagnosis. Statistical tests included paired t-tests, McNemar’s tests, and stratified Cox regression. Results: The median ages of those with and without diabetes were 68 years, and 91% in both groups were white (both matched). Patients with and without diabetes were not significantly different in terms of tumor grade, cancer stage, estrogen or progesterone receptor status, HER2 neu status, marital and employment status, smoking use, use of adjuvant chemotherapy, and steroid treatment (all P >.4). Patients with diabetes reported less use of alcohol (50% vs 64%, P=.04), and had greater BMI (79% overweight/obese vs 58%, P= .002). Survival analysis demonstrated no differences in survival from initial breast cancer diagnosis (HR=1.25, 95% CI 0.49-3.17) with median follow-up of 2.2 years (range 0.1-4.9), and no differences in recurrence-free survival (HR=1.00, 95% CI 0.14-7.10) though very few deaths and recurrences were observed. Within the diabetes group, 96 (88%) had type 2 diabetes and 97/106 (92%, 3 unknown) had diabetes pre-existing to cancer diagnosis. Initial diabetes therapy included diet (33, 30%), oral therapy (48, 44%), insulin (21, 19%), or oral+insulin (6, 6%). 7 patients required a change in diabetes therapy within 1 year of cancer diagnosis with 3 patients starting insulin. 32/70 (46%) with available lab data had 1 or more A1C >/=7 within 1 year of cancer diagnosis. Conclusions: In this retrospective, carefully matched case-control study, we developed a comprehensive profile of the patient population with newly diagnosed breast cancer and diabetes. Diabetes did not appear to impact mortality or recurrence-free survival based on descriptive estimates in this small breast cancer cohort.

710 Background: Leptomeningeal metastasis (LM) has been described as a rare form of metastatic disease progression in colorectal cancer (CRC). There remains a paucity of literature with regards to the course and management of LM in CRC. The aim of this study was to estimate the incidence of LM in CRC patients seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. Methods: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. Results: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. One patient also had a lung adenocarcinoma diagnosed during initial staging for the CRC primary. Median overall survival after CRC diagnosis was 25.7 months (range 4.7-74.8). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range 1-68.1). All patients had MRI findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, 1 with both. One of three CSF analyses at the time of LM workup was positive for malignant cells; all had elevated protein. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in two cases. Seven patients (78%) had palliative radiotherapy (RT) for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. No patients underwent intrathecal chemotherapy. Median survival after LM diagnosis was 7 weeks (range 2-39). Conclusions: The diagnosis of LM is an exceedingly rare development in the natural course of CRC. It continues to confer an extremely poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving RT to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy. The most common presentation of EMPD is the vulva followed by perianal involvement. Most cases are localized to the dermis with treatment focused on surgery, topical treatment or radiotherapy. Recurrence is frequent despite therapies utilized. Metastatic extramammary Paget disease is uncommon and, as such, standard treatment guidelines do not exist. This study sought to evaluate the treatment regimens and outcomes of patients treated at a Mayo Clinic Center from 1998-2012. Cancer registry inquiry revealed 261 patients with report advanced Paget disease during these years. Ten cases of metastatic EPMD were identified with sufficient documentation for review. This review reveals support for utilizing localized radiation therapy for bulky disease sequentially with systemic chemotherapy consisting of carboplatin and paclitaxel or irinotecan. Further studies are necessary to define the optimal treatment regimen.

Background Light chain amyloidosis (AL) is associated with high mortality, especially in patients with advanced cardiovascular involvement. It is caused by toxicity of misfolded light chain proteins ( LC ) in vascular, cardiac, and other tissues. There is no treatment to reverse LC tissue toxicity. We tested the hypothesis that nanoliposomes composed of monosialoganglioside, phosphatidylcholine, and cholesterol (GM1 ganglioside–containing nanoliposomes [ NLGM 1]) can protect against LC ‐induced human microvascular dysfunction and assess mechanisms behind the protective effect. Methods and Results The dilator responses of ex vivo abdominal adipose arterioles from human participants without AL to acetylcholine and papaverine were measured before and after exposure to LC (20 μg/mL) with or without NLGM 1 (1:10 ratio for LC : NLGM 1 mass). Human umbilical vein endothelial cells were exposed for 18 to 20 hours to vehicle, LC with or without NLGM 1, or NLGM 1 and compared for oxidative and nitrative stress response and cellular viability. LC impaired arteriole dilator response to acetylcholine, which was restored by co‐treatment with NLGM 1. LC decreased endothelial cell nitric oxide production and cell viability while increasing superoxide and peroxynitrite; these adverse effects were reversed by NLGM 1. NLGM 1 increased endothelial cell protein expression of antioxidant enzymes heme oxygenase 1 and NAD (P)H quinone dehydrogenase 1 and increased nuclear factor, erythroid 2 like 2 (Nrf‐2) protein. Nrf‐2 gene knockdown reduced antioxidant stress response and reversed the protective effects of NLGM 1. Conclusions NLGM1 protects against LC ‐induced human microvascular endothelial dysfunction through increased nitric oxide bioavailability and reduced oxidative and nitrative stress mediated by Nrf‐2–dependent antioxidant stress response. These findings point to a potential novel therapeutic approach for light chain amyloidosis.