Carina Signori's research while affiliated with Penn State Hershey Medical Center and Penn State College of Medicine and other places

Preclinical data indicate that omega-3 fatty acids (n-3FA) potentiate the chemopreventive effect of the antiestrogen (AE) Tamoxifen against mammary carcinogenesis. The role of n-3FA in breast cancer prevention in humans is controversial. Pre-clinical and epidemiologic data suggest that n-3FA may be preferentially protective in obese subjects. To directly test the protective effect of n-3FA against breast cancer, we conducted a two-year, open label randomized clinical trial in 266 healthy postmenopausal women (50% normal weight, 30% overweight, 20% obese) with high breast density (BD) (≥25%) detected on their routine screening mammograms. Eligible women were randomized to one of the following five groups 1) No treatment, Control; 2) Raloxifene 60 mg; 3) Raloxifene 30 mg; 4) n-3FA Lovaza 4 gm and 5) Lovaza 4 gm plus Raloxifene 30 mg. The two-year change in BD, a validated biomarker of breast cancer risk was the primary endpoint of the study. In subset analysis, we tested the pre-specified hypothesis that Body Mass Index (BMI) influences the relationship between plasma n-3FA on BD. While none of the interventions affected BD in the intention to treat analysis, increase in plasma DHA was associated with a decrease in absolute breast density but only in participants with BMI >29. Our results suggest that obese women may preferentially experience breast cancer risk reduction from n-3FA administration.

Our preclinical data indicate that n-3FA potentiate the chemopreventive effects of the antiestrogen (AE) Tamoxifen against mammary tumorigenesis induced by 1-methyl-1-nitrosourea in female Sprague Dawley rats.(A. Manni et al. Int. J. of Cancer 2014; 134:1549).To test the clinical impact of this approach we conducted a randomized clinical trial in healthy postmenopausal women at increased risk of breast cancer based on BD ≥ 25% detected at their routine annual screening mammogram. Out of 784 eligible subjects, 266 women were randomly assigned to one of the following groups 1) Control 2) The AE Raloxifene 60mg 3) Raloxifene 30mg 4) Lovaza 4g (the FDA approved n-3FA formulation containing EPA + DHA), 5) Lovaza 4gm plus Raloxifene 30mg. The rationale for choosing a dose of Raloxifene half the conventional dose of 60mg to be tested in combination was in the attempt to reduce toxicity while preserving antitumor action as supported by our preclinical studies with Tamoxifen (A. Manni et al. Canc. Prev. Res 2010; 3:322). The groups were comparable with regard to baseline demographics including age, BMI, parity, age at first child birth, family history of breast cancer, and history of prior breast biopsies. The duration of the intervention was 2 years and the change in breast density at year one and two was the primary endpoint. Breast density, a well established biomarker of breast cancer risk, was measured by the volumetric method using the Volpara software. Two hundred and fourteen women (∼80%) completed the trial. Compliance was excellent as assessed by pill counts (>95%) and plasma fatty acid analysis using gas chromatography-flame ionization (GC-FID) detection which showed the expected rise in n-3FA levels in the groups receiving Lovaza. Toxicity was minimal with vasomotor symptoms being more frequent in the groups receiving Raloxifene (13.2% with 30mg and 22.6% with 60mg) and gastrointestinal events more frequent in the combination group. No subject experienced thromboembolic events. The combination group exhibited the most beneficial changes in lipid panel with reduction in LDL (low density lipoprotein) cholesterol, triglyceride and increase in HDL (high density lipoprotein) cholesterol. Compared to control, none of the interventions significantly affected percent or absolute breast density at either year one or two. Our results indicate that in this group of healthy postmenopausal women the combination of Lovaza and Raloxifene at less than the conventional dose (e.g. 30mg), while feasible and well tolerated did not reduce breast cancer risk as assessed by a decrease in breast density. (This work has been funded by Susan G. Komen for the Cure, KG081632). Citation Format: Narinder Sandhu, Susann E. Schetter, Jason Liao, Terryl J. Hartman, John P. Richie, Karam El-Bayoumy, Bogdan Prokopczyk, Cindy DuBrock, Carina Signori, Christopher Hamilton, Laurence M. Demers, Andrea Manni. Randomized clinical trial testing the efficacy of the combination of omega-3-fatty acids (n-3FA) and the antiestrogen raloxifene in reducing breast density (BD) in postmenopausal women. [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 1904. doi:10.1158/1538-7445.AM2015-1904

Percent breast density (PBD), a commonly used biomarker of breast cancer risk (BCR), is confounded by the influence of non-dense breast tissue on its measurement and factors, such as BMI, which have an impact on non-dense tissue. Consequently, BMI, a potent BCR factor, is, paradoxically, negatively correlated with PBD. We propose that absolute breast density (ABD) is a more accurate biomarker of BCR. We used a volumetric method to compare the correlation between PBD and ABD with baseline demographics and dietary and physical activity variables in a group of 169 postmenopausal women enrolled in a clinical trial prior to any intervention. As expected, a strong negative correlation between PBD and BMI was observed (Rho = -0.5, p < 5e(-12)). In contrast, we observed a strong, previously not well established, positive correlation of BMI with ABD (Rho = 0.41, p < 2.5e(-8)), which supports the use of ABD as a more accurate indicator of BCR. Correction of PBD by BMI did not frequently provide the same information as ABD. In addition, because of the strong influence of BMI on ABD, many correlations between dietary variables and ABD did not emerge, until adjustment was made for BMI. ABD corrected by BMI should be the gold standard BD measurement. These findings identify the optimal measurement of BD when testing the influence of an intervention on BD as a biomarker of BCR.

Background: Lenalidomide is an immunomodulatory drug frequently used for treatment of patients with multiple myeloma and myelodysplastic syndromes. This report presents a rare case of lenalidomide-associated hepatotoxicity and reviews the available literature. Case report: A 67-year-old male with multiple myeloma was hospitalized with nausea, vomiting and jaundice, while treated with a second three-week course of lenalidomide. The patient was found to have acutely elevated bilirubin, alkaline phosphatase, AST and ALT. He also had acute on chronic renal function impairment. Serology for viral hepatitis, abdominal ultrasound, magnetic resonance cholangiopancreatography and hepatobiliary scan revealed no abnormalities. Lenalidomide was stopped, resulting in subsequent (8 days) clinical improvement and normalization of the liver abnormalities. The RUCAM causality assessment score was 8, consistent with probable lenalidomide-associated hepatotoxicity. Literature review revealed four other published cases of lenalidomide-associated hepatotoxicity with clinical presentation varying between cholestatic-, hepatocellular- or mixed-pattern of liver injury. All patients had clinical and laboratory improvement soon after lenalidomide discontinuation. Renal function impairment was present in 3 of the 5 reported cases. The exact mechanism of lenalidomide-associated liver injury remains unclear as only 2 patients had liver biopsies without specific findings. Conclusion: Physicians should be aware of the potential for lenalidomide-associated hepatotoxicity, particularly in patients with underlying renal insufficiency.

The antiestrogen, Raloxifene (Ral) is an effective breast cancer chemopreventive agent. Omega-3 fatty acids (n-3FA) may inhibit mammary carcinogenesis. On the basis of their mechanisms of action, we test the hypothesis that a combination of n-3FA and Ral may be superior in reducing select biomarkers of breast cancer risk in women. Postmenopausal women at increased risk for breast cancer (breast density ≥ 25%) were randomized to: (1) no intervention; (2) Ral 60 mg; (3) Ral 30 mg; (4) n-3FA (Lovaza) 4 g and (5) Lovaza 4 g+Ral 30 mg for 2 years. Reduction in breast density is the primary end point of the study. We report preliminary data on feasibility, compliance and changes in secondary end points related to IGF-I signaling, estrogen metabolism, oxidative stress and inflammation in the first group of 46 women who completed 1 year of the study. All interventions were well tolerated with excellent compliance (96 ± 1% overall) by pill count and also supported by the expected rise in both serum n-3FA and n-3FA/Omega-6 fatty acids (n-6FA) ratio in women randomized to groups 4 and 5 (P<0.05). Lovaza decreased serum triglycerides and increased high-density lipoprotein (HDL) cholesterol compared with control (P<0.05 for both). Ral reduced serum IGF-1 in a dose-dependent manner (P<0.05) while Lovaza did not. Lovaza had no effect on IGF-1 or IGFBP-3. None of the other biomarkers were affected by our treatment. The combination of Lovaza and Ral is a feasible strategy that may be recommended in future breast cancer chemoprevention trials.

The antiestrogen, Raloxifene (Ral), is an effective breast cancer chemopreventive agent. Literature data appears to support a protective role of omega-3 fatty acids (n-3FA) against mammary carcinogenesis. On the basis of their mechanisms of action, this trial tests for the first time the hypothesis that a combination of antiestrogens and n-3FA may be superior in reducing select biomarkers of breast cancer risk in women. This combination with n-3FA may also allow a lower dose of Ral to be effective with less adverse events. Healthy postmenopausal women at increased risk for breast cancer (based on breast density β25%) were randomized into five groups: 1) No intervention; 2) Ral 60 mg; 3) Ral 30 mg; 4) n-3FA (Lovaza) 4 gm; and 5) Lovaza 4 gm + Ral 30 mg for two years. While the primary endpoint of our clinical trial is a reduction in breast density, an established risk factor for breast cancer, we are also examining the effects of the individual and combined administration of Ral and n-3FA on several biomarkers thought to be potentially involved in mammary carcinogenesis. We report preliminary data on the first 46 women who complete one year of the study for feasibility, compliance, and changes in secondary endpoints related to IGF-I signaling (IGF-1, IGF-BP3), estrogen metabolism (2OHE1, 16αOH1), oxidative stress (8-OH-dG, GSH, 8-isoprostane) and inflammation (IL-6, CRP). Anthropometric measurements (including weight, BMI and waist to hip ratio) were followed at each visit. Dietary and physical activity data were monitored with food frequency and physical activity questionnaires. Plasma fatty acid analysis in the Lovaza groups were compared to the control group to ensure compliance; lipid analysis was also performed. All interventions were well tolerated with excellent compliance (96 ± 1% overall) by pill count and also supported by the expected rise at twelve months in both serum n-3FA and n-3FA/n-6FA ratio (48% and 40%, respectively) in both groups receiving Lovaza (p<0.05). Despite normal lipid values at baseline, Lovaza decreased serum triglycerides (15% in group 4 and 22% in group 5; p<0.05) and increased HDL cholesterol (7% in group 4 and 14% in group 5; p<0.05) compared to control. Ral reduced serum IGF-1 (6.5% in group 3 and 26% in group 2; p<0.05) and the ratio of IGF-1/IGF-BP3 (14% in group 3, 23% in group 2; p<0.05) compared to control in a dose-dependent fashion. Lovaza had no effect on IGF-1 or IGF-BP3. None of the other biomarkers were affected by our treatment. These results suggest that the combination of n-3 FA and Ral is a feasible strategy that may be recommended in future breast cancer chemoprevention trials. (Work supported by Susan G. Komen for the Cure Grant no. KG081632) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3556. doi:1538-7445.AM2012-3556

Despite the perception that omega-3 fatty acids (n-3 FA) protect against breast cancer, epidemiologic studies have yielded inconsistent results. Although preclinical data have been, in general, more supportive of a protective effect of n-3 FA on breast cancer, inconsistencies still remain, which preclude definite conclusions or in-depth mechanistic investigations despite 30 years of research in this area. In this review, we discuss key variables that may account for inconsistencies of results across preclinical studies and provide recommendations for future experiments testing the chemopreventive effect of n-3 FAs in breast cancer, as part of a multiagent approach under rigorously controlled conditions.

e11036 Background: Prevention represents the most effective approach to reducing mortality from breast cancer. To translate our preclinical findings in this regard we are conducting a 2-year randomized clinical trial in healthy postmenopausal women with increased breast cancer risk based on breast density (>25%). Methods: We are studying the effects of omega-3 fatty acids (FA) alone and in combination with raloxifene on several biomarkers including those of inflammation (CRP, IL-6), estrogen metabolism (2-hydroxyestrone, 16-α-hydroxyestrone), oxidative status (glutathione [GSH]), IGF-1 signaling (IGF-1, IGFBP-3) and plasma FA. Our study consists of 5 groups: (1) no intervention; (2) raloxifene 60mg; (3) raloxifene 30mg; (4) omega-3-acid ethyl esters (Lovaza) 4g; (5) raloxifene 30mg + Lovaza 4g. We report here preliminary findings from the first 46 women after 1 year. Results: Raloxifene reduced serum IGF-1 (12% in Group 3 and 20% in Group 2) compared to control (Group 1) in a dose-dependent fashion (p=0.0...

Obesity as well as bariatric surgery may increase the risk for vitamin D deficiency. We retrospectively compared vitamin D levels in obese patients (n = 123) prior to bariatric surgery and 1 year postoperatively. We also evaluated parathyroid hormone levels (PTH) 1 year after surgery. A higher percentage of patients had baseline vitamin D deficiency (86%), defined as 25-hydroxy vitamin D <32 ng/mL, compared with the 1-year (post-surgical) levels, (70%; p < 0.001). Body mass index (BMI) inversely correlated with vitamin D deficiency at baseline (r = -0.3, p = 0.06) and at the postoperative follow-up (r = -0.2, p = 0.013). One third of the postoperative population had secondary hyperparathyroidism, defined by a serum PTH level >62 pg/mL; however, postoperative PTH and vitamin D levels were unrelated (r = -0.001, p = 0.994). Pre- and postoperative vitamin D levels were inversely correlated with BMI. Secondary hyperparathyroidism was observed in 33% of patients postoperatively; however, this did not correlate with vitamin D.