Statins In Chemoprevention Research Articles

The role of statins in chemoprevention of colorectal carcinoma

Colorectal carcinoma is one of the most common cancers in the world both in terms of prevalence and mortality. Prospective epidemiological studies have clearly demonstrated that a diet rich in saturated fats and its related lipid metabolism disorders increase the risk of this disease. Chemoprevention is the use of drugs and natural compounds to prevent benign and malignant cancers. Chemopreventive effects with respect to carcinogenesis may be based on: inhibiting inflammatory processes, lowering serum levels of free radicals, suppressing cell divisions, and promoting cell differentiation. Because the prevalence of colorectal carcinoma is growing, a chance for potential chemoprevention raises oncologists’ interest and is a subject of various epidemiological and clinical studies. This paper presents the current state of knowledge regarding potential chemoprevention of this cancer using statin therapy, which is broadly implemented in the present-day pharmacotherapy for cardiovascular diseases. Various pleiotropic effects of statins may in consequence have a positive influence on currently observed negative epidemiological indices of colorectal carcinoma.

Strategy for prevention of cancers of the esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the animal reflux-inflammation models for Barrett's esophagus and esophageal adenocarcinoma; genomic/epigenomic analyses; eflornithine-based combinations; the molecular derangements that promote neoplastic transformation; the role of COX-2 inhibitors, proton pump inhibitors, and phase II trials in Barrett's adenocarcinoma; statins in chemoprevention and treatment of esophageal cancer; and biomarkers as potential targets in Barrett's adenocarcinoma.

Potential for statins in the chemoprevention and management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common, treatment-resistant malignancy with a complex molecular pathogenesis. Statins are a widely used class of cholesterol-lowering drugs with potential anticancer activity. We reviewed the evidence for a role of statins in primary and secondary chemoprevention of HCC and slowing the course of otherwise incurable primary or recurrent disease. A literature search (key words: Statins, hepatocellular carcinoma) conducted to this end, retrieved 119 references. Here we summarize the history, mechanism of action and cardiovascular use of statins and highlight that statins can affect several pathways implicated in the development of HCC. In vitro and animal studies provide strong evidence for a favorable effect of statins on HCC. However, evidence in humans is conflicting. We discuss in full detail the methodological strengths and pitfalls of published data including three cohort studies suggesting that the use of statins may protect from the development of HCC and of a single trial reporting increased survival in those with advanced HCC randomized to receive statins. A remarkably hepato-safe class of drugs acting on both hepatocyte and endothelial cells, statins also have potentially beneficial effects in lowering portal hypertension. In conclusion, there is strong experimental evidence that statins are beneficial in chemopreventing and slowing the growth of HCC. However, randomized controlled trials are necessary in order to investigate the role of statins in the chemoprevention of HCC and in slowing the course of otherwise incurable disease in humans.

Statin use and the development of bone metastasis in breast cancer patients.

40 Background: The Mevalonic Acid Pathway has been implicated in the promotion of a microenvironment suitable for establishment of bony metastasis from breast cancer. The statins, which act on this pathway, have been shown to have in vitro antineoplastic activity against breast cancer. This study was designed to evaluate the association of statin use and development of bony metastasis in breast cancer patients. Methods: Medical records of patients treated for stage II-III breast cancer from 1999 to 2010 were retrospectively reviewed. Statin use was defined as medication use for at least 3 months in patients with no evidence of disease after initial diagnosis and treatment. The primary outcome was development of metastasis to bone. Secondary outcomes were overall survival, disease free survival and other sites of distant metastasis. Results: A total of 841 patients were included in the study of which 223 used statins. Both unadjusted and multivariate analysis adjusted for age, race, grade, stage, BRCA status, showed that patients on statins had a significantly lower incidence of metastasis to bone (OR 0.49, 95% CI 0.25-0.96, p=0.04). Adjusted analysis for other sites showed a trend towards decreased incidence of metastasis for statin users, but was not statistically significant (95% CI 0.39-1.08, p=0.10). Overall survival was increased in statin users with mean survival of 66.45 +/- 2.48 months versus non-users 58.78 +/ - 1.41 months (p=0.05). Statin users had significantly longer disease free survival with a mean of 63.65 +/- 2.49 months versus 53.96 +/- 1.42 months in non statin users (p=0.00). Conclusions: The use of statin drugs in patients with breast cancer was significantly associated with decreased incidence of metastasis to bone, but not to other distant sites. The role of statins in chemoprevention of bone metastasis should be further explored.

Statin use and the development of bone metastasis in breast cancer patients.

536 Background: The Mevalonic Acid Pathway has been implicated in the promotion of a microenvironment suitable for establishment of bony metastasis from breast cancer. The statins, which act on this pathway, have been shown to have in-vitro anti-neoplastic activity against breast cancer. This study was designed to evaluate the association of statin use and development of bony metastasis in breast cancer patients. Methods: Medical records of patients treated for stage II-III breast cancer from 1999 to 2010 were retrospectively reviewed. Statin use was defined as medication use for at least 3 months in patients with no evidence of disease after initial diagnosis and treatment. The primary outcome was development of metastasis to bone. Secondary outcomes were overall survival, disease free survival and other sites of distant metastasis. Results: A total of 841 patients were included in the study of which 223 used statins. Both unadjusted and multivariate analysis adjusted for age, race, grade, stage , BRCA status, showed that patients on statins had a significantly lower incidence of metastasis to bone (OR 0.49, 95% CI 0.25-0.96, p=0.04). Adjusted analysis for other sites showed a trend towards decreased incidence of metastasis for statin users, but was not statistically significant (95% CI 0.39-1.08, p=0.10). Overall survival was increased in statin users with mean survival of 66.45 +/- 2.48 months versus non-users 58.78 +/ - 1.41 months (p=0.05). Statin users had significantly longer disease free survival with a mean of 63.65 +/- 2.49 months versus 53.96 +/- 1.42 months in non statin users (p=0.00). Conclusions: The use of statin drugs in patients with breast cancer was significantly associated with decreased incidence of metastasis to bone, but not to other distant sites. The role of statins in chemoprevention of bone metastasis should be further explored.

Prognostic factors in resections for pancreatic ductal adenocarcinoma

s / Pancreatology 12 (2012) e1–e8 e6 reviewed for information on medications prior to diagnosis. Odds ratios, plus 95% CI, for the development of pancreatic cancer, were estimated using unconditional logistic regression. Results: 276 cases (median age1⁄471 years, range 48-99 years, 53% women) and 402 controls were identified. 19.5% of the cases also had diabetes. In the general study population, the risk of pancreatic cancer with regular statins use was reduced (OR1⁄40.67, 95% CI1⁄40.44-1.03, p1⁄40.07). In diabetics, the risk was further reduced (OR1⁄40.38 95% CI 0.12-1.20. p1⁄40.10). Conclusions: This preliminary data showed statin use reduces the risk of pancreatic cancer in the general study population and in type 2 diabetics. The study will progress to more precisely define the effect size, but may support the use of statins for chemoprevention in diabetics Take-home message: Preliminary results from this two centre, casecontrol study, support the hypothesis of a protective effect for statins in the development of pancreatic cancer in type 2 diabetics. As such theremay be a role for statins in chemoprevention in this at risk group

Fluvastatin has biologic effects on stage 0 and 1 breast cancer.

Abstract Abstract #4122 Introduction: Statins are safe, reduce cardiovascular risk, and impact pathways critical to cancer progression. We and others have shown lipophilic statins cause apoptosis and growth suppression in vitro and in vivo, and though epidemiologic data are mixed, statin effect appears most evident in estrogen receptor (ER) negative or grade 3 disease. To look for a direct biologic effect of lipophilic statins, we conducted a perioperative pilot window trial in women with breast cancer (BC).
 Methods: 40 subjects with stage 0,1 BC were randomized to high dose (80mg/day) or low dose (20mg/day) fluvastatin for 3-6 weeks prior to surgery. Paired tissue (core biopsy and surgical specimen), peripheral blood and MRI were obtained. Primary endpoint was Ki-67 (proliferation) change. Secondary endpoints included cleaved caspase-3 (CC3, apoptosis), longest diameter (LD) by MRI, and C-reactive protein (CRP) change. Subgroup analyses was planned by grade (3 vs. 1,2), statin dose; and ER status. Immunohistochemistry (IHC) on paraffin tissue used standard streptavidin biotin methods. A single breast pathologist reviewed all slides; a single radiologist read all MRIs, both blinded to timepoint.
 Results: Median serum cholesterol decreased by 16% (-23% and -12% for high and low dose, respectively p=0.012), indicating drug effect and compliance. 29 patients had sufficient tumor for paired IHC, 14 and 15 were grade 3 and 1,2, and 10 and 19 were ER - and +, respectively. In grade 3 (73% of which were ER-) vs. 1,2 tumors, there was a significant decrease in Ki-67, -7.2% (interquartile range (IQR) -13.4%, 0% ) vs. -0.3% (IQR -3%, .8%), respectively, p=0.04. CC3 (apoptosis) increased, 60% vs. 13% for grade 3 vs. 1,2 tumors, respectively, p=0.015. ER- and ER+ cases had a similar reduction in Ki67 with a median drop of 2% (IQR -13.4%, 1%) and 1.2% (IQR -6.6%,0.8%), respectively, p=0.56. While CC3 was increased in ER- vs. + (55% vs. 29%), the difference was not statistically significant. There was no dose dependent effect on Ki-67or CC3.There was no evidence of Ki67 or CC3 change when all grades were analyzed together (median drop 1.2%) and no change in CRP. Of 14 subjects with paired MRIs, 4 grade 3 cases showed a significant decrease in LD, marked ductal dilatation and increased necrosis.with statin exposure.
 Conclusions: A lipophilic statin, fluvastatin, reduced cholesterol and had measurable biologic changes (reduced proliferation, size and increased apoptosis) in stage 0,1 BC after only 3-6 weeks of exposure, specifically in the grade 3 subset. Results support the study of statins for chemoprevention for women at risk for or with stage 0 grade 3 BC, where new agents are needed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4122.

Chemoprevention of breast cancer: current status and future prospects

Chemoprevention plays an important role in the prevention of cancer. Due to being an estrogen-dependent cancer, breast carcinomas are ideal candidate for chemoprevention. The two main approaches to chemoprevention of breast cancer are to attain a balance in estrogen or to eliminate all estrogens by selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). A series of clinical trials have proven tamoxifene quite useful as a preventive strategy for women at high risk of breast cancer. The third-generation, AIs, hold a great promise in chemoprevention of breast cancer. In this review, the mechanisms, side effects and main clinical trials of SERMs and AIs are discussed. The use of other drugs including CoQ10, retinoids, cyclooxygenase (COX)-2 inhibitors, vitamin E, soy isoflavones, tea polyphenols and statins in chemoprevention is introduced. Since most studies on these drugs were conducted on animal models or cell culture, further studies are needed to determine the efficacy of these drugs in chemoprevention of human cancers.