Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched. Cancer Prev Res; 3(11); 1451-61. ©2010 AACR.

Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.

The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.

A B S T R A C T PurposeTamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. Patients and MethodsA total of 235 premenopausal women with pT1mic/pT1a breast cancer (n ϭ 21), or intraepithelial neoplasia (IEN, n ϭ 160), or 5-year Gail risk Ն 1.3% (n ϭ 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. ResultsDuring the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n ϭ 48) was 3.5% Ϯ 1.0%, 2.1% Ϯ 0.8%, 4.7% Ϯ 1.3%, and 5.2% Ϯ 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen ϫ fenretinide adverse interaction P ϭ .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. ConclusionDespite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

Several studies have identified an increased risk of cancer in type 2 diabetic patients and this is in accordance with the hypothesis that increased insulin levels might promote cancer. Thus, there is a great interest in exploring the possibility that antidiabetic therapies lowering insulin levels could decrease cancer incidence or cancer-related mortality. Recent observational studies have shown that metformin, an oral safe and well-tolerated insulin-sensitizer antidiabetic drug, has been associated with reduced cancer risk. Recently, several preclinical studies have evaluated the effect of metformin in vivo on nude mice and showed a significant reduction of both breast epithelial cell proliferation and protein synthesis. Further investigations in the clinical setting are well-supported by the promising results obtained thus far. At the European Institute of Oncology, the Division of Cancer Prevention and Genetics is planning to conduct a clinical trial to evaluate the activity of metformin on tumor cell proliferation in breast cancer patients undergoing surgery. It will be a presurgical randomized, double blind, placebo-controlled phase II biomarker trial: 100 histologically confirmed breast cancer patients will be randomly assigned to metformin (850 mg twice/daily) or placebo for 28 + 7 days till surgery to assess drug activity on tumor proliferation, as measured by

Background-The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2ϫ2 retinoid-placebo trial. Methods and Results-A total of 189 postmenopausal women were randomized to 50 g/d transdermal E2 and 100 mg BID of the retinoid fenretinide (nϭ45), 50 g/d transdermal E2 and placebo (nϭ49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (nϭ46), or 0.625 mg/d oral CEE and placebo (nϭ49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI Ϫ9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI Ϫ14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE. Fenretinide did not change CRP levels at 6 and 12 months relative to placebo. Relative to oral CEE, the mean change in CRP after 12 months of transdermal E2 was Ϫ48% (95% CI Ϫ85% to Ϫ7%, Pϭ0.012), whereas fenretinide was associated with a mean change of Ϫ1% (95% CI Ϫ34% to 40%, Pϭ0.79) compared with placebo. Conclusions-In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.

A B S T R A C T PurposeAdipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrencefree survival in premenopausal women at risk for breast cancer. Patients and MethodsWe measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-toadiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n ϭ 21), intraepithelial neoplasia (n ϭ 160), or 5-year Gail risk of 1.3% or greater (n ϭ 54) who participated in a 2 ϫ 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period. ResultsAt baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P ϭ .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P ϭ .03). There was no interaction between treatment and adiponectin levels. ConclusionLow adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment. J Clin