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Impact of statin therapy on survival in epithelial ovarian cancer
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Gynecologic Oncology 111 (2008) 102 – 105 www.elsevier.com/locate/ygyno
Impact of statin therapy on survival in epithelial ovarian cancer R. Geoffrey Elmore, Yevgeniya Ioffe, Daniel R. Scoles, Beth Y. Karlan, Andrew J. Li ⁎ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA Received 9 April 2008
Abstract Objective. 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, are common therapeutic agents in the management of dyslipidemias. Epidemiologic and pharmacologic data also suggest statins have an effect on cancer biology. We sought to determine the association between use of statins and epithelial ovarian cancer survival, disease progression, and clinico-pathologic factors. Methods. After IRB approval, we performed a retrospective review of all patients with advanced stage (III/IV) epithelial ovarian or primary peritoneal cancer undergoing primary cytoreductive surgery by a gynecologist oncologist between 6/1996 and 6/2001. Abstracted data included statin use at time of initial cytoreductive surgery, as well as clinico-pathologic factors and survival. Statistical analysis included Fisher's exact test, Kaplan–Meier survival, and Cox regression analyses. Results. 126 patients met criteria for review. Seventeen (14%) patients were undergoing concurrent statin therapy at time of initial cytoreductive surgery. Statin users were statistically older (median age 67 years, versus 60 years for non-users, p = 0.002) and had a greater incidence of diabetes mellitus (18% versus 3% in non-users, p = 0.03). Of the entire cohort, 21 patients (17%) were suboptimally cytoreduced after initial surgery, with residual disease N 1 cm; statin use did not correlate with incidence of optimal resection (p = 0.3). Median progression-free survival for statin users was 24 months, compared to 16 months for statin non-users (p = 0.007). Similarly, overall survival was significantly longer for statin users (62 months) compared to statin non-users (46 months, p = 0.04). Multivariable analysis identified statin use as an independent positive prognostic factor, after controlling for age, stage, grade, and suboptimal cytoreduction (p = 0.02). Conclusions. These data indicate statin use in patients diagnosed with epithelial ovarian cancer is associated with improved survival, and suggest a potential suppressive impact of HMG-CoA reductase inhibitors on tumor biology. Studies are proposed to explore the molecular mechanisms underlying these clinical observations. © 2008 Elsevier Inc. All rights reserved. Keywords: Statins; Ovarian cancer
Introduction Cardiovascular disease continues to be the leading cause of death in the United States, and the role of dyslipidemias in its pathogenesis is well documented. In the United States, the incidence of elevated total cholesterol in women has been shown to be greater than 50% [1]. 3-hydroxy-3-methyl-glutarylCoA (HMG-CoA) reductase inhibitors, commonly referred to as statins, have gained recognition as an effective and potent interventional strategy in lowering low-density lipoprotein (LDL) cholesterol and triglycerides and raising high-density ⁎ Corresponding author. Fax: +1 310 423 0155. E-mail address: [email protected] (A.J. Li). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.06.007
lipoprotein (HDL). Early studies have shown statins to be effective in both primary and secondary prevention of coronary heart disease, myocardial infarction, stroke, and peripheral artery disease [2–6]. Furthermore, recent studies suggest aggressive statin regimens may even induce regression of severe coronary artery disease [7]. Expectedly, the rate of statin use among high-risk patients in the United States has risen from 4% in 1992 to 19% in 2002 [8]. Statins inhibit HMG-CoA reductase, an enzyme upstream in the mevalonate biosynthesis pathway. Subsequent inhibition of the coupling of farnesyl moieties to the intermediate protein pyrophosphate in the cholesterol pathway, known as isoprenylation, also affect several other proteins dependent on prenylation for their activity. These include Ras, nuclear lamins,
R.G. Elmore et al. / Gynecologic Oncology 111 (2008) 102–105 Table 1 Clinico-pathologic characteristics of statin users and non-users at time of initial cytoreductive therapy Statin user (n = 17) Median age (years) 67 Stage IV 3 (18%) Grade 3 17 (100%) Papillary serous histology 16 (94%) Suboptimal cytoreduction 1 (6%)
103
Kaplan–Meier survival, and Cox regression analyses. A p value of less than 0.05 was considered to be statistically significant.
Statin non-user (n = 109)
p
Results
60 12 (11%) 100 (92%) 98 (90%) 21 (19%)
0.002 n.s. n.s. n.s. n.s.
One hundred twenty six patients met criteria suitable for review. The mean age of the entire cohort was 61 years (range 35–89). The majority of patients had stage III (111, or 88%) and grade 3 disease (117, or 93%) with papillary serous histology (114, or 90%). One hundred four patients (83%) underwent optimal cytoreductive surgery at initial exploration to residual disease less than 1 cm. Seventeen (14%) patients were on statin therapy at time of initial cytoreductive surgery, and statins used included lovastatin, simvastatin, atorvastatin, fluvastatin, and pravastatin. For purposes of comparison, we divided the cohort into statin users and non-statin users. Incidence of stage IV and grade 3 disease as well as papillary serous histology were evenly matched. While only 6% of statin users underwent suboptimal resection at initial surgery, compared to 19% who underwent suboptimal resection in non-statin users, this difference was not statistically different (Table 1). However, age was significantly higher in patients on statin therapy (67 years) than on non-users (60 years, p = 0.002). Dyslipidemias may be associated with co-morbid medical conditions that could potentially affect survival. In this cohort, overall incidence of co-morbidities was relatively low; 32 patients (25%) reported a concurrent history of hypertension, 10 (8%) reported a history of coronary artery disease, and 6 (5%) reported a history of diabetes mellitus. There were no statistical differences between incidence of hypertension (24 versus 26%) or coronary artery disease (12 versus 14%) between statin users and non-statin users. Furthermore, incidence of obesity, as measured by mean body mass index, was similar for statin users and non-statin users (23.9 kg/m2 versus 24.3, respectively; range, 16.5–47.7). However, 18% of statin users demonstrated a concurrent diagnosis of diabetes mellitus. This compares to a 3% incidence of diabetes in non-statin users, which was statistically different (p = 0.007; Table 2). To examine the influence of preoperative statin use on disease progression and overall survival, we performed Kaplan–Meier survival analyses. Using the log-rank test, a statistical difference in time to recurrence was observed for statin users (median progression-free survival of 24 months) compared to statin non-users (16 months, p = 0.007; Fig. 1). A statistically significant difference was also identified for overall
transducin g, rhodopsin kinase, Rho, and all of the heterotrimeric and small G proteins [9]. As these proteins are also implicated in the development and progression of several human cancers, there is significant interest in exploring a potential role of statins in chemoprevention and therapeutic strategies. Pursuant to these findings, several epidemiologic studies have identified a potential protective effect of these medications on cancer risk. Specifically, case-control and meta-analysis studies indicate that the risks of breast, colorectal, prostate, and skin cancers appear modestly decreased in patients on certain statin therapies [10–14]. While other investigators have reported conflicting results, Farwell et al. recently examined a relatively large and older patient cohort of 25,594 statin users with a significantly longer median follow-up time. Compared to the referent group, the risk of cancer incidence was 24–26% less among patients using statins [15]. Emerging data also suggest a potential effect of statin use on tumor biology. Studies have reported a decreased risk of advanced stage prostate cancer with statin therapy, and initiation of statin use post breast cancer diagnosis was found to decrease rates of recurrence [16,17]. As Ras, Rho, and G proteins may also function in gynecologic malignancies, we hypothesized that statin use confers a protective effect in women with advanced stage epithelial ovarian cancers. Our objectives were to examine associations between statin use at time of initial cytoreductive surgery and clinico-pathologic prognostic factors, as well as to determine the impact of statin use on progression-free and overall survival. Materials and methods After Institutional Review Board approval, we queried our Gynecologic Oncology database at Cedars-Sinai Medical Center for consecutive patients with advanced stage (III or IV) epithelial ovarian or primary peritoneal carcinoma between 1996 and 2001. Patients must have undergone primary cytoreductive surgery by 1 of 5 gynecologic oncologists followed by at least six cycles of platinum-based chemotherapy. Type and length of chemotherapeutic or surgical interventions following disease recurrence were given at the discretion of the treating gynecologic oncologist. Patients with non-epithelial tumor histologies, borderline tumors, synchronous uterine and ovarian malignancies, and patients who underwent neoadjuvant chemotherapy were excluded from review. Medical records for all eligible patients were reviewed and abstracted data included statin use at time of initial cytoreductive surgery, clinico-pathologic factors, and time to disease recurrence and death. Medication records were taken from the patient's preoperative history and physical, and data were confirmed from routine preoperative nursing evaluations. The specific statin formulation was also recorded. For statistical considerations, the cohort was divided into statin users and statin non-users. Data were analyzed using Fisher's exact test, Chi square,
Table 2 Co-morbid medical conditions in statin users and non-users Statin user (n = 17) Hypertension 4 (24%) Coronary artery disease 2 (12%) Mean body mass index (kg/m2) 23.9 Diabetes mellitus 3 (18%)
Statin non-user (n = 109)
p
28 (26%) 15 (14%) 24.3 3 (3%)
n.s. n.s. n.s. 0.01
104
R.G. Elmore et al. / Gynecologic Oncology 111 (2008) 102–105 Table 3 Univariate analysis of potential prognostic factors of survival
Age Diabetes mellitus Grade Stage Suboptimal cytoreduction Statin use
Fig. 1. Effect of statin use on progression-free survival. Median progression-free survival was significantly longer in the statin cohort (24 months), compared to the non-statin cohort (16 months, p = 0.007).
p
Relative risk
Confidence interval
n.s. n.s. n.s. 0.06 0.009 0.004
0.99 0.62 1.64 1.68 1.90 0.43
0.97–1.01 0.23–1.70 0.76–3.55 0.97–2.91 1.17–3.07 0.28–0.82
optimal cytoreductive surgery, only statin use at preoperative surgery retained significance as an independent positive prognostic factor (relative risk 0.45, p = 0.02; Table 4). Discussion
survival, with median survival 62 months for statin users, compared to 46 months for statin non-users (p = 0.039; Fig. 2). While statin users demonstrated improved survival, they were as a group older and had a greater incidence of diabetes compared to statin non-users. To determine if these two factors, as well as other established clinical-pathologic prognosticators, affected survival, we initially performed univariate analyses on the entire cohort. Despite the initial differences observed for age and diabetes, they did not influence survival. Similarly, grade was not an important prognosticator in this cohort. However, stage did approach statistical significance as a univariate predictor of survival (p = 0.06). Suboptimal cytoreduction, as expected, was a significant predictor of poor survival (p = 0.009). Statin use remained significant as a positive univariate prognosticator (p = 0.004; Table 3). In order to determine the independent prognostic impact of statin use in this cohort, we performed multivariate Cox regression analyses on the entire cohort. Established prognostic factors as well as statin use at time of initial cytoreductive surgery were included in the analysis. Diabetes was not found to influence survival on univariate studies and therefore excluded in this analysis. After controlling for age, stage, grade, and
We have hypothesized that statin use confers a protective effect in women with epithelial ovarian cancers. To test this hypothesis, we retrospectively examined a cohort of women with advanced stage disease, and found that despite greater age and higher incidence of diabetes, statin use at the time of initial cytoreductive surgery was associated with improved progression-free and overall survival. In this study, statin use also retained significance as an independent positive prognostic factor. Our data are consistent with several studies published in breast, skin, colorectal, and prostate cancer research indicating that statin use may have a favorable effect on the natural course of neoplasias. The exact mechanisms by which statins exert anti-tumor effects are currently not well established, and the study of the interaction of these agents on intracellular processes is the focus of significant on-going research. Several in vitro studies demonstrate that statins inhibit tumor growth and induce apoptosis in a variety of malignant cell lines, including melanoma, glioma, neuroblastoma, and epithelial ovarian [18–21]. While there is a relative paucity of data examining the influence of statins specific to ovarian cancer biology, studies in other tumor types suggest that the observed antitumor effects may result from inhibition of angiogenesis. For example, pravastatin was found to induce a dose-dependent decrease in the proliferative activity of human umbilical vein endothelial cells, and inhibited tube formation on Matrigel and adhesion to extracellular matrix [22]. Similarly, simvastatin was shown to inhibit signaling by vascular endothelial growth factor (VEGF), AKT, and focal adhesion kinase, three RhoA-
Table 4 Multivariable Cox proportional hazard analysis of potential prognostic factors on survival
Fig. 2. Effect of statin use on overall survival. Overall survival was significantly longer in the statin cohort (62 months) compared to the non-statin cohort (46 months, p = 0.05).
Variable
Risk ratio
95% confidence interval
p value
Age Stage Grade Optimal cytoreduction Statin use
1.00 1.42 1.81 1.53 0.45
0.98–1.01 0.80–2.51 0.81–4.05 0.92–2.53 0.23–0.88
n.s. n.s. n.s. n.s. 0.02
R.G. Elmore et al. / Gynecologic Oncology 111 (2008) 102–105
dependent pathways known to be involved in angiogenesis [23]. Simvastatin has also been observed to inhibit TNF-alphainduced NF-kappa B activation, with correlation of downregulated gene products that mediate cell proliferation (cyclin D1, cyclooxygenase-2), survival (Bcl-2), invasion (matrix metalloproteinase-9), and angiogenesis (VEGF) [24]. Chemosensitivity assays also indicate statins may potentiate platinumand taxane-induced cell death in a synergistic manner, with enhanced cell cycle arrest, inhibition of cell migration and invasion, and increased apoptosis [25–27]. Taken together, these data suggest statins may effect tumor biology through several antiangiogenic mechanisms applicable to ovarian cancer as well. Our study is limited by its retrospective nature, relatively small study cohort, and examination of patients from only one institution. Furthermore, complete data was not available regarding length of statin use, and we did not have access to serum to determine actual levels of lipoproteins. Although these findings are exploratory, this is the first study to suggest statins may have a role in epithelial ovarian cancer biology. Confirmation studies in a separate, larger cohort of women with ovarian cancer are underway, as are examinations of potential molecular mechanisms that may be responsible for these clinical observations. Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgment This study was supported by the Ovarian Cancer Research Fund (AJL). References [1] Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total cholesterol concentrations and awareness, treatment and control of hypercholesterolemia among US adults. Circulation 2003;107:2185–9. [2] Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005–16. [3] Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615–22. [4] Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent events Trial investigators. New Engl J Med 1996;335:1001–9. [5] Ford ES, Giles WH. Serum C-reactive protein and self-reported stroke: findings from the Third National Health and Nutrition Examination Survey. Arteroscler Thromb Vasc Biol 2000;20:1052–6. [6] Herrmann J, Lerman A, Baumgart D, et al. Preprocedural statin medication reduces the extent of periprocedural non-Q-wave myocardial infarction. Circulation 2002;106:2180–3.
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[7] Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297: 499–508. [8] Ma J, Sehgal NL, Ayanian JZ, Stafford RS. National trends in statin use by coronary heart disease risk category. PLoS Medicine 2005;2:434–40. [9] Graaf, M.R., Richel, D.J., van Noorden, C.J., Guchelaar, H.J., Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. 2004; 30: 609–41. [10] Pocobelli G, Newcomb PA, Trentham-Dietz A, Titus-Ernstoff L, Hampton JM, Egan KM. Statin use and risk of breast cancer. Cancer 2007;112: 27–33. [11] Bonovas S, Filioussi K, Flordellis CS, Sitaras NM. Statins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol 2007;25:3462–8. [12] Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Cholesterol-lowering drugs and prostate cancer risk: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2007;16:2226–32. [13] Freeman SR, Drake AL, Heilig LF, et al. Statins, fibrates, and melanoma risk: a systematic review and meta-analysis. J Natl Cancer Inst 2006;98:1538–46. [14] Cauley JA, McTiernan A, Rodabough RJ, et al. Statin use and breast cancer: prospective results from the Women's Health Initiative. J Natl Cancer Inst 2006;98:700–7. [15] Farwell WR, Scranton RE, Lawler EV, et al. The association between statins and cancer incidence in a veterans population. J Natl Cancer Inst 2008;100:134–9. [16] Platz EA, Leitzmann MF, Visvanathan K, et al. Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst 2006;98:1819–25. [17] Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat 2007 Epub. [18] Shellman YG, Ribble D, Miller L, et al. Lovastatin-induced apoptosis in human melanoma cell lines. Melanoma Res 2005;15:83–9. [19] Koyuturk M, Ersoz M, Altiok N. Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Cancer Lett 2004;370:212–7. [20] Girgert R, Vogt Y, Becke D, et al. Growth inhibition of neuroblastoma cells by lovastatin and L-ascorbic acid is based on different mechanisms. Cancer Lett 1999;137:167–72. [21] Melichar B, Ferrandina G, Verschraegen CF, Loercher A, Abbruzzese JL, Freedman RS. Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines. Clin Cancer Res 1998;4:3069–76. [22] Asakage M, Tsuno NH, Kitayama J, et al. 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on G1 cell cycle arrest. Anticancer Drugs 2004;15:625–32. [23] Park HJ, Kong D, Irula-Arispe L, Begley U, Tang D, Galper JB. 3hydroxy-3methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. Circ Res 2002;91:143–50. [24] Ahn KS, Sethi G, Aggrawal BB. Simvastatin potentiates TNF-alphainduced apoptosis through the down-regulation of NF-kappaB-dependent antiapoptotic gene products. J Immunol 2007;178:2507–16. [25] Holstein SA, Hohl RJ. Synergistic interaction of lovastatin and paclitaxel in human cancer cells. Molec Cancer Therapeutics 2001;1:141–9. [26] Fromigue O, Hamidouche Z, Marie PJ. Statin-induced inhibition of HMGCoA reductase sensitizes human osteosarcoma cells to anticancer drugs. J Pharmacol Exp Ther 2008 epub. [27] Kozar K, Kaminski R, Legat M, Kopec M, Nowis D, Skierski JS, Koronkiewicz M, Jakóbisiak M, Golab J. Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin. Int J Oncol 2004;24:1149–57.
Gynecologic Oncology 111 (2008) 102 – 105 www.elsevier.com/locate/ygyno
Impact of statin therapy on survival in epithelial ovarian cancer R. Geoffrey Elmore, Yevgeniya Ioffe, Daniel R. Scoles, Beth Y. Karlan, Andrew J. Li ⁎ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA Received 9 April 2008
Abstract Objective. 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, are common therapeutic agents in the management of dyslipidemias. Epidemiologic and pharmacologic data also suggest statins have an effect on cancer biology. We sought to determine the association between use of statins and epithelial ovarian cancer survival, disease progression, and clinico-pathologic factors. Methods. After IRB approval, we performed a retrospective review of all patients with advanced stage (III/IV) epithelial ovarian or primary peritoneal cancer undergoing primary cytoreductive surgery by a gynecologist oncologist between 6/1996 and 6/2001. Abstracted data included statin use at time of initial cytoreductive surgery, as well as clinico-pathologic factors and survival. Statistical analysis included Fisher's exact test, Kaplan–Meier survival, and Cox regression analyses. Results. 126 patients met criteria for review. Seventeen (14%) patients were undergoing concurrent statin therapy at time of initial cytoreductive surgery. Statin users were statistically older (median age 67 years, versus 60 years for non-users, p = 0.002) and had a greater incidence of diabetes mellitus (18% versus 3% in non-users, p = 0.03). Of the entire cohort, 21 patients (17%) were suboptimally cytoreduced after initial surgery, with residual disease N 1 cm; statin use did not correlate with incidence of optimal resection (p = 0.3). Median progression-free survival for statin users was 24 months, compared to 16 months for statin non-users (p = 0.007). Similarly, overall survival was significantly longer for statin users (62 months) compared to statin non-users (46 months, p = 0.04). Multivariable analysis identified statin use as an independent positive prognostic factor, after controlling for age, stage, grade, and suboptimal cytoreduction (p = 0.02). Conclusions. These data indicate statin use in patients diagnosed with epithelial ovarian cancer is associated with improved survival, and suggest a potential suppressive impact of HMG-CoA reductase inhibitors on tumor biology. Studies are proposed to explore the molecular mechanisms underlying these clinical observations. © 2008 Elsevier Inc. All rights reserved. Keywords: Statins; Ovarian cancer
Introduction Cardiovascular disease continues to be the leading cause of death in the United States, and the role of dyslipidemias in its pathogenesis is well documented. In the United States, the incidence of elevated total cholesterol in women has been shown to be greater than 50% [1]. 3-hydroxy-3-methyl-glutarylCoA (HMG-CoA) reductase inhibitors, commonly referred to as statins, have gained recognition as an effective and potent interventional strategy in lowering low-density lipoprotein (LDL) cholesterol and triglycerides and raising high-density ⁎ Corresponding author. Fax: +1 310 423 0155. E-mail address: [email protected] (A.J. Li). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.06.007
lipoprotein (HDL). Early studies have shown statins to be effective in both primary and secondary prevention of coronary heart disease, myocardial infarction, stroke, and peripheral artery disease [2–6]. Furthermore, recent studies suggest aggressive statin regimens may even induce regression of severe coronary artery disease [7]. Expectedly, the rate of statin use among high-risk patients in the United States has risen from 4% in 1992 to 19% in 2002 [8]. Statins inhibit HMG-CoA reductase, an enzyme upstream in the mevalonate biosynthesis pathway. Subsequent inhibition of the coupling of farnesyl moieties to the intermediate protein pyrophosphate in the cholesterol pathway, known as isoprenylation, also affect several other proteins dependent on prenylation for their activity. These include Ras, nuclear lamins,
R.G. Elmore et al. / Gynecologic Oncology 111 (2008) 102–105 Table 1 Clinico-pathologic characteristics of statin users and non-users at time of initial cytoreductive therapy Statin user (n = 17) Median age (years) 67 Stage IV 3 (18%) Grade 3 17 (100%) Papillary serous histology 16 (94%) Suboptimal cytoreduction 1 (6%)
103
Kaplan–Meier survival, and Cox regression analyses. A p value of less than 0.05 was considered to be statistically significant.
Statin non-user (n = 109)
p
Results
60 12 (11%) 100 (92%) 98 (90%) 21 (19%)
0.002 n.s. n.s. n.s. n.s.
One hundred twenty six patients met criteria suitable for review. The mean age of the entire cohort was 61 years (range 35–89). The majority of patients had stage III (111, or 88%) and grade 3 disease (117, or 93%) with papillary serous histology (114, or 90%). One hundred four patients (83%) underwent optimal cytoreductive surgery at initial exploration to residual disease less than 1 cm. Seventeen (14%) patients were on statin therapy at time of initial cytoreductive surgery, and statins used included lovastatin, simvastatin, atorvastatin, fluvastatin, and pravastatin. For purposes of comparison, we divided the cohort into statin users and non-statin users. Incidence of stage IV and grade 3 disease as well as papillary serous histology were evenly matched. While only 6% of statin users underwent suboptimal resection at initial surgery, compared to 19% who underwent suboptimal resection in non-statin users, this difference was not statistically different (Table 1). However, age was significantly higher in patients on statin therapy (67 years) than on non-users (60 years, p = 0.002). Dyslipidemias may be associated with co-morbid medical conditions that could potentially affect survival. In this cohort, overall incidence of co-morbidities was relatively low; 32 patients (25%) reported a concurrent history of hypertension, 10 (8%) reported a history of coronary artery disease, and 6 (5%) reported a history of diabetes mellitus. There were no statistical differences between incidence of hypertension (24 versus 26%) or coronary artery disease (12 versus 14%) between statin users and non-statin users. Furthermore, incidence of obesity, as measured by mean body mass index, was similar for statin users and non-statin users (23.9 kg/m2 versus 24.3, respectively; range, 16.5–47.7). However, 18% of statin users demonstrated a concurrent diagnosis of diabetes mellitus. This compares to a 3% incidence of diabetes in non-statin users, which was statistically different (p = 0.007; Table 2). To examine the influence of preoperative statin use on disease progression and overall survival, we performed Kaplan–Meier survival analyses. Using the log-rank test, a statistical difference in time to recurrence was observed for statin users (median progression-free survival of 24 months) compared to statin non-users (16 months, p = 0.007; Fig. 1). A statistically significant difference was also identified for overall
transducin g, rhodopsin kinase, Rho, and all of the heterotrimeric and small G proteins [9]. As these proteins are also implicated in the development and progression of several human cancers, there is significant interest in exploring a potential role of statins in chemoprevention and therapeutic strategies. Pursuant to these findings, several epidemiologic studies have identified a potential protective effect of these medications on cancer risk. Specifically, case-control and meta-analysis studies indicate that the risks of breast, colorectal, prostate, and skin cancers appear modestly decreased in patients on certain statin therapies [10–14]. While other investigators have reported conflicting results, Farwell et al. recently examined a relatively large and older patient cohort of 25,594 statin users with a significantly longer median follow-up time. Compared to the referent group, the risk of cancer incidence was 24–26% less among patients using statins [15]. Emerging data also suggest a potential effect of statin use on tumor biology. Studies have reported a decreased risk of advanced stage prostate cancer with statin therapy, and initiation of statin use post breast cancer diagnosis was found to decrease rates of recurrence [16,17]. As Ras, Rho, and G proteins may also function in gynecologic malignancies, we hypothesized that statin use confers a protective effect in women with advanced stage epithelial ovarian cancers. Our objectives were to examine associations between statin use at time of initial cytoreductive surgery and clinico-pathologic prognostic factors, as well as to determine the impact of statin use on progression-free and overall survival. Materials and methods After Institutional Review Board approval, we queried our Gynecologic Oncology database at Cedars-Sinai Medical Center for consecutive patients with advanced stage (III or IV) epithelial ovarian or primary peritoneal carcinoma between 1996 and 2001. Patients must have undergone primary cytoreductive surgery by 1 of 5 gynecologic oncologists followed by at least six cycles of platinum-based chemotherapy. Type and length of chemotherapeutic or surgical interventions following disease recurrence were given at the discretion of the treating gynecologic oncologist. Patients with non-epithelial tumor histologies, borderline tumors, synchronous uterine and ovarian malignancies, and patients who underwent neoadjuvant chemotherapy were excluded from review. Medical records for all eligible patients were reviewed and abstracted data included statin use at time of initial cytoreductive surgery, clinico-pathologic factors, and time to disease recurrence and death. Medication records were taken from the patient's preoperative history and physical, and data were confirmed from routine preoperative nursing evaluations. The specific statin formulation was also recorded. For statistical considerations, the cohort was divided into statin users and statin non-users. Data were analyzed using Fisher's exact test, Chi square,
Table 2 Co-morbid medical conditions in statin users and non-users Statin user (n = 17) Hypertension 4 (24%) Coronary artery disease 2 (12%) Mean body mass index (kg/m2) 23.9 Diabetes mellitus 3 (18%)
Statin non-user (n = 109)
p
28 (26%) 15 (14%) 24.3 3 (3%)
n.s. n.s. n.s. 0.01
104
R.G. Elmore et al. / Gynecologic Oncology 111 (2008) 102–105 Table 3 Univariate analysis of potential prognostic factors of survival
Age Diabetes mellitus Grade Stage Suboptimal cytoreduction Statin use
Fig. 1. Effect of statin use on progression-free survival. Median progression-free survival was significantly longer in the statin cohort (24 months), compared to the non-statin cohort (16 months, p = 0.007).
p
Relative risk
Confidence interval
n.s. n.s. n.s. 0.06 0.009 0.004
0.99 0.62 1.64 1.68 1.90 0.43
0.97–1.01 0.23–1.70 0.76–3.55 0.97–2.91 1.17–3.07 0.28–0.82
optimal cytoreductive surgery, only statin use at preoperative surgery retained significance as an independent positive prognostic factor (relative risk 0.45, p = 0.02; Table 4). Discussion
survival, with median survival 62 months for statin users, compared to 46 months for statin non-users (p = 0.039; Fig. 2). While statin users demonstrated improved survival, they were as a group older and had a greater incidence of diabetes compared to statin non-users. To determine if these two factors, as well as other established clinical-pathologic prognosticators, affected survival, we initially performed univariate analyses on the entire cohort. Despite the initial differences observed for age and diabetes, they did not influence survival. Similarly, grade was not an important prognosticator in this cohort. However, stage did approach statistical significance as a univariate predictor of survival (p = 0.06). Suboptimal cytoreduction, as expected, was a significant predictor of poor survival (p = 0.009). Statin use remained significant as a positive univariate prognosticator (p = 0.004; Table 3). In order to determine the independent prognostic impact of statin use in this cohort, we performed multivariate Cox regression analyses on the entire cohort. Established prognostic factors as well as statin use at time of initial cytoreductive surgery were included in the analysis. Diabetes was not found to influence survival on univariate studies and therefore excluded in this analysis. After controlling for age, stage, grade, and
We have hypothesized that statin use confers a protective effect in women with epithelial ovarian cancers. To test this hypothesis, we retrospectively examined a cohort of women with advanced stage disease, and found that despite greater age and higher incidence of diabetes, statin use at the time of initial cytoreductive surgery was associated with improved progression-free and overall survival. In this study, statin use also retained significance as an independent positive prognostic factor. Our data are consistent with several studies published in breast, skin, colorectal, and prostate cancer research indicating that statin use may have a favorable effect on the natural course of neoplasias. The exact mechanisms by which statins exert anti-tumor effects are currently not well established, and the study of the interaction of these agents on intracellular processes is the focus of significant on-going research. Several in vitro studies demonstrate that statins inhibit tumor growth and induce apoptosis in a variety of malignant cell lines, including melanoma, glioma, neuroblastoma, and epithelial ovarian [18–21]. While there is a relative paucity of data examining the influence of statins specific to ovarian cancer biology, studies in other tumor types suggest that the observed antitumor effects may result from inhibition of angiogenesis. For example, pravastatin was found to induce a dose-dependent decrease in the proliferative activity of human umbilical vein endothelial cells, and inhibited tube formation on Matrigel and adhesion to extracellular matrix [22]. Similarly, simvastatin was shown to inhibit signaling by vascular endothelial growth factor (VEGF), AKT, and focal adhesion kinase, three RhoA-
Table 4 Multivariable Cox proportional hazard analysis of potential prognostic factors on survival
Fig. 2. Effect of statin use on overall survival. Overall survival was significantly longer in the statin cohort (62 months) compared to the non-statin cohort (46 months, p = 0.05).
Variable
Risk ratio
95% confidence interval
p value
Age Stage Grade Optimal cytoreduction Statin use
1.00 1.42 1.81 1.53 0.45
0.98–1.01 0.80–2.51 0.81–4.05 0.92–2.53 0.23–0.88
n.s. n.s. n.s. n.s. 0.02
R.G. Elmore et al. / Gynecologic Oncology 111 (2008) 102–105
dependent pathways known to be involved in angiogenesis [23]. Simvastatin has also been observed to inhibit TNF-alphainduced NF-kappa B activation, with correlation of downregulated gene products that mediate cell proliferation (cyclin D1, cyclooxygenase-2), survival (Bcl-2), invasion (matrix metalloproteinase-9), and angiogenesis (VEGF) [24]. Chemosensitivity assays also indicate statins may potentiate platinumand taxane-induced cell death in a synergistic manner, with enhanced cell cycle arrest, inhibition of cell migration and invasion, and increased apoptosis [25–27]. Taken together, these data suggest statins may effect tumor biology through several antiangiogenic mechanisms applicable to ovarian cancer as well. Our study is limited by its retrospective nature, relatively small study cohort, and examination of patients from only one institution. Furthermore, complete data was not available regarding length of statin use, and we did not have access to serum to determine actual levels of lipoproteins. Although these findings are exploratory, this is the first study to suggest statins may have a role in epithelial ovarian cancer biology. Confirmation studies in a separate, larger cohort of women with ovarian cancer are underway, as are examinations of potential molecular mechanisms that may be responsible for these clinical observations. Conflict of interest statement The authors have no conflicts of interest to declare.
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