Gianmario Sambuceti

18F-FDG PET/CT is a prognostic biomarker in patients affected by bone metastases from breast cancer in comparison with 18F-NaF PET/CT

AIM To compare 18F-FDG PET/CT and 18F-NaF PET/CT with respect to disease prognostication and outcome in patients affected by bone metastases from breast cancer (BC). PATIENTS, METHODS We retrospectively investigated 32 women with BC and documented bone metastases. Semi-quantitative parameters were applied to 18F-FDG PET/CT and 18F-Na PET/CT in order to evaluate disease extent and tumour metabolism. We used time-to-event analyses (Kaplan Meier and COX proportional hazard methods) to estimate progression-free (PFS) and overall survival (OS) in order to assess the independent prognostic value of 18F-FDG PET/CT and 18F-Na PET/CT. RESULTS The sensitivity of 18F-NaF PET/CT (100%) was higher (p < 0.05) than that of 18F-FDG PET/CT (72% and 72%). None of the 18F-FDG PET/CT-negative patients showed disease progression at the end of follow-up. After adjustment for age, Ki-67 levels, presence of visceral metastases, hormone therapy, duration of bone disease and response to first-line therapy, only 18F-FDG SUV mean [HR 15.7, 95% confidence interval (CI) 1.15-214.5] and 18F-FDG whole-body bone metabolic burden (WB-B-MB) (HR 16.9; 95%CI 1.87-152.2) were independently and significantly associated with OS. None of the 18F-NaF PET/CT parameters were associated with OS. None of the conventional clinical prognostic parameters remained significantly associated with OS after the inclusion of PET/CT parameters in the model. CONCLUSION 18F-FDG PET/CT is independently associated with OS in BC patients with bone metastases and its prognostic impact seems to be higher than conventional clinical and biological prognostic factors. Although 18F-NaF PET/CT has a higher diagnostic sensitivity than 18F-FDG PET/CT, it is not independently associated with OS.

Abstract 1182: Metformin affects breast cancer cell growth and disturbs an IGF1/insulin related gene network that correlates with breast cancer progression

Background Obesity and the insulin resistance syndrome are risk factors for breast cancer and might also affect breast cancer progression. The anti-diabetic drug Metformin (METF) reduces the breast cancer risk in diabetic women. Insulin like growth factor 1 (IGF1) and insulin are involved in breast cancer tumorigenesis and progression. We tested the effect of METF on the IGF1/insulin pathway and its involvement in breast cancer progression. Methods We developed a prognostic signature based on IGF1/insulin pathway genes using the Stockholm breast cancer microarray dataset of 149 cases for training and primary validation and the Uppsala dataset of 249 for external validation. The effect of METF on the prognostic gene set identified was tested in vitro on a panel of breast cancer cell lines. METF effects on proliferation and glucose metabolism were analyzed in vitro and in vivo. The insulin receptor substrate 2 (IRS2) was silenced by transfection with shRNA-lentiviral vectors. Xenograft growth, in the presence and absence of METF, was studied and 18FDG-uptake was measured in vitro and in vivo. Results A 15-gene signature (Insulin sensitivity score, ISS) was developed and predicted breast cancer metastasis with an accuracy similar to the Recurrence Score. ISS genes were expressed at variable levels in a breast cancer cell line panel and showed variable responsiveness to METF. The high expression correlation among the ISS genes observed in untreated breast cancer cell lines was lost upon treatment with METF. METF reduced breast cancer cell growth in vitro with IC50 values ranging from 1mM to 25mM. Growth of MDA-MB-231 cells and hyper-invasive subpopulations derived therefrom was reduced in vivo by oral administration of METF to xenografted nude mice. Response to METF in terms of IC50 values correlated with basal expression of the 15 ISS genes with the strongest inverse correlation observed for IRS2. Stable silencing of IRS2 reduced the MDA-231 cell responsiveness to METF in vitro. Discussion METF acts on the insulin/IGF1 axis by disturbing a network of breast cancer progression related genes and appears to depend in its action on the expression of IRS2 that inversely correlates with the sensitivity of cell lines to the drug. The disruption of the ISS gene network is expected to correlate with an effect on breast cancer growth and progression and in fact, mouse xenografts show reduced growth upon treatment with METF. IRS2 appears to be a major mediator of METF effects. Citation Format: Alessia I. Esposito, Adriana Amaro, Giovanna Angelini, Laura Emionite, Alessandra Gennari, Stefano Indraccolo, Davide Maggi, Cecilia Marini, Barabara Salani, Gianmario Sambuceti, Maria Pia Sormani, Ulrich Pfeffer. Metformin affects breast cancer cell growth and disturbs an IGF1/insulin related gene network that correlates with breast cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1182. doi:10.1158/1538-7445.AM2015-1182

PTCA acutely expands perfused myocardial mass and increases flow homogeneity

In absence of collaterals, coronary stenosis produces a pressure drop in the microcirculation which might compromise capillary pressure and physiological blood—tissue exchanges. The present study tests the hypothesis that a derecruitment of vascular units occurs in the post-stenosis territory to maintain capillary pressure constant and that the restoration of a normal distal coronary pressure by PTCA is able to recruit additional myocardium to perfusion. Nine patients with single left coronary vessel disease, no previous myocardial infarct and normal ventricular function, were studied in a single session, before and after successful PTCA and stenting. Flow entering the stenotic vessel (CBF = ml/min, by Doppler catheter and quantitative angiography), and flow per gram of myocardium downstream the stenosis (MBF = ml/min/g of tissue, by the analysis of radioactive Xenon wash-out curves) were simultaneously measured. Perfused tissue was calculated as CBF/MBF and heterogeneity of flow distribution as the ratio between high and low flow sub-compartments estimated by bi-exponential analysis of Xenon curves. Distal coronary pressure was assessed by pressure wire. Heterogeneity of perfusion was also assessed in the remote region perfused by the angio-graphically normal left coronary branch. Distal coronary pressure during balloon occlusion was 21 ± 10 mmHg. PTCA increased CBF following i.e. adenosine from 19.8 ± 16.1 to 48 ± 27 ml/min, coronary flow reserve from 1.5 ± 0.2 to 2.3 ± 0.8 (p < 0.01) and distal coronary pressure from 68 ± 9 to 99 ± 8 at rest, and from 54 ± 10 to 99 ± 10 mmHg during adenosine. Perfused myocardial volume at rest increased from 27 ± 21 to 39 ± 8 g. A strict correlation was found between the increase in distal coronary pressure and the increase in perfused volume after PTCA (r = 0.79, p < 0.001). Flow homogeneity significantly increased following PTCA to the level of the remote region. In conclusion severe coronary stenosis contracts the amount of normally perfused myocardium likely to preserve capillary pressure and flow reserve in the residual perfused vascular units. PTCA expands perfused volume and decreases flow heterogeneity, according to the increase in distal coronary pressure.