Ayelet Shai

Statins, aspirin and risk of thromboembolic events in ovarian cancer patients

OBJECTIVES Studies suggest that statins and low dose aspirin reduce risk of VTEs in the general population. We aimed to study the effect of these drugs on the incidence of VTEs in patients with ovarian cancer. METHODS Patients diagnosed with ovarian cancer between 2000 and 2011 were identified through the Clalit Health Services (CHS) chronic disease registry. Data were extracted from CHS database and from computerized pharmacy records. Use of medications was analyzed as a time dependent covariate in a Cox regression model. RESULTS Of 1746 patients 175 (10%) had a VTE during a median follow up of 3.13 years. 83 patients (5.6%) had a VTE within 2 years of diagnosis of ovarian cancer. Use of chemotherapy and stage 3 and 4 at presentation were associated with an increased risk for VTEs. Statins were used by 43.5% of the patients, and 32.3% used aspirin. Aspirin use was associated with a marginally significant reduction in incidence of VTEs within 2 years of diagnosis, HR 0.423 (95% CI 0.182-1.012, p-value 0.053). Statin use was not associated with risk of VTEs. CONCLUSION This is the first study looking at the effect of statins and aspirin on the incidence of VTEs in ovarian cancer patients. In our cohort, statins did not decrease the risk for a VTE and aspirin use was associated with a reduced risk which was marginally significant. Our results might be explained by use of low potency statins and by alternate mechanisms for VTE formation in cancer patients.

The effect of metabolic comorbidities and commonly used drugs on the prognosis of patients with ovarian cancer

BACKGROUND Diabetes mellitus is associated with an increased risk of recurrence in patients with ovarian cancer. Retrospective studies suggested that the use of statins, metformin and beta blockers is associated with improved prognosis in these patients. Patients with diabetes often suffer from hypertension and are usually treated concomitantly by several classes of drugs. Our aim was to assess the independent contribution of diabetes mellitus and hypertension and of the use of aspirin, statins, metformin and beta blockers on the risk of ovarian cancer recurrence and mortality. METHODS Files of ovarian cancer patients treated between 2000 and 2012 were retrospectively reviewed. Data regarding disease characteristics, presence of diabetes mellitus and hypertension, recurrence and death were extracted. The use of drugs was assessed using the Clalit Health Services (CHS) pharmacy records. RESULTS 143 patients treated by debulking surgery and platinum based chemotherapy were included. Median age was 62.5, 22 (15.4%) had diabetes mellitus, 61 (42.7%) had chronic hypertension. Statins were used by 43 (30%) patients, 31 (21.7%) used aspirin, 25 (17.5%) used beta blockers and 12 (8.4%) used metformin. In multivariate analysis diabetes mellitus was associated with a shorter recurrence free survival (RFS) and the use of aspirin and metformin was associated with a prolonged RFS in this cohort. Overall survival (OS) was longer in patients using aspirin and shorter in patients with hypertension. CONCLUSIONS Our data suggests that metabolic comorbidities and commonly used drugs are associated with the prognosis of patients with ovarian cancer. Additional trials are needed to confirm these observations and test therapeutic interventions.

MicroRNA regulation of progesterone receptor in breast cancer

Hormone receptor status is of significant value when deciding on anti-estrogenic adjuvant therapy for breast cancer tumors. However, while estrogen receptor (ER) regulation was intensively studied, the regulation of progesterone receptor (PR) levels has not been extensively investigated. MicroRNAs (miRNAs, miRs) are post-transcriptional negative regulators of gene expression involved in diverse cellular processes. The aim of this study was to identify miRNAs that regulate PR in breast cancer.We mapped potential miRNA binding sites for miR-181a, miR-23a and miR-26b on PR mRNA and demonstrated a direct regulation of PR by these three miRNAs by in-vitro Luciferase binding assays. Over-expression of each miRNA in MCF-7 cells resulted in a reduction in the expression levels of PR mRNA. Then, expression levels of these miRNAs were measured in Formalin-Fixed, Paraffin-Embedded (FFPE) samples of 29 ER-positive breast cancer tumors and adjacent normal breast tissues. A significant reciprocal correlation between PR mRNA and the miRNA levels were identified suggesting a role for miR-181a, miR-23a and miR-26b in PR regulation in breast cancer. Moreover, the average expression fold-changes of the three miRNAs between cancerous and normal tissues displayed an opposite trend when analyzing according to Immuno-histochemistry(IHC) status. Furthermore, miR-181a and miR-26b were found to be over-expressed in most tumor tissues supporting their role in ER-positive breast cancer development. We conclude that miR-181a, miR-23a and miR-26b act as negative regulators of PR expression in ER-positive breast cancer. The diagnostic and prognostic potential of these miRNAs in breast cancer should be further evaluated.

FDG PET/CT differentiating two malignant tumors in the same patient

remain [5]. In patients with an intact GTV a “suitable margin” is given by the radiation oncologist to account for microscopic spread of disease (or the CTV). Literature for the extent of this margin (derived from pathological series, imaging data, wisdom earned from pattern of recurrences) is limited for most sites [6]. In brief, the gun of radiation delivery is reasonably precise, but the issue of target definition remains ever controversial. To conclude, the biology, behaviour and even the correct radiology interpretation of cancer is far from understood. Defining targets and treating them, both in the context of medical as well as radiation oncology is challenging. The oncology community has made some preliminary progress towards the goal of real targeted therapy. But as readily evident, it is not the time to celebrate but to introspect. If needed, we should redefine our priorities and concepts, even if it means beginning afresh in some areas. We are yet so far from understanding cancer and its mystic ways. And real targeted therapy is not even on the anvil yet. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

Abstract P1-15-13: Short term toxicity of intra-operative radiotherapy for patients with breast cancer treated at a single center

Introduction: Intra-operative radiotherapy (IORT) is increasingly being used for the treatment of low risk breast cancer. In the randomized TARGIT trial, late toxicity was not different between patients treated with IORT and external beam radiotherapy. Early toxicity of IORT has not been fully characterized. Methods: IORT with one dose of 20 Gy using the Intrabeam© device has been offered as an alternative to standard treatment as part of a single center prospective single arm trial. Patients over 60 years with clinically node negative, For the present study information regarding complications occurring within the first year after surgery was analyzed. Patients treated between 2006 and 2012 were included in this analysis. Results: 393 patients were treated from 2006 – 2012. 4 were lost to follow up. Median age was 70 years (55-90) and median clinical tumor size was 1.2 cm (5-30). 102 patients (26.2%) had a complication. Infections were most frequent. Misdiagnosis of radiation dermatitis as infection in some cases cannot be excluded. Clinically meaningful seromas occurred in 10.2% of patient and 8.2% had a wound dehiscence, possibly related to rupture of pre-existing seromas. 18 patients (4.6%) had a grade 3 complication. 2 patients (0.5%) had grade 4 radiation induced skin necrosis of small size and both resolved within 4 months. All other complications resolved completely (table 1). Risk factors for complications in this cohort will also be presented. Conclusions: Intra-operative radiotherapy was associated with a relatively high rate of clinically meaningful seromas and wound dehiscence and rare small size skin necrosis. Most complications were mild – moderate. 5% of patients experienced grade 3 or 4 complications, and all resolved completely. Further study of the factors predisposing to severe complications is warranted. Citation Format: Ayelet Shai, Maoz Zur, Michelle Leviov, Arie Bitterman, Shiloni Eitan, Mariana Steiner. Short term toxicity of intra-operative radiotherapy for patients with breast cancer treated at a single center [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-13.