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.

Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I² = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I² = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I² = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I² = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.

Purpose: Tamoxifen, which is actually the gold standard adjuvant treatment in estrogen receptor–positive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy because of the development of resistance. Therefore new approaches are required. Patients and Methods: We conducted a prospective randomized trial to test the efficacy of switching postmenopausal patients who were already receiving tamoxifen to the aromatase inhibitor anastrozole. After 2 to 3 years of tamoxifen treatment, patients were randomly assigned either to receive anastrozole 1 mg/d or to continue receiving tamoxifen 20 mg/d, for a total duration of treatment of 5 years. Disease-free survival was the primary end point. Event-free survival, overall survival, and safety were secondary end points. Results: Four hundred forty-eight patients were enrolled. All women had node-positive, estrogen receptor–positive tumors. At a median follow-up time of 36 months, 45 events had been reported in the tamoxifen group compared with 17 events in the anastrozole group (P = .0002). Disease-free and local recurrence-free survival were also significantly longer in the anastrozole group (hazard ratio [HR] = 0.35; 95% CI, 0.18 to 0.68; P = .001 and HR = 0.15; 95% CI, 0.03 to 0.65; P = .003, respectively). Overall, more adverse events were recorded in the anastrozole group compared with the tamoxifen group (203 v 150, respectively; P = .04). However, more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group (33 of 150 events v 28 of 203 events, P = .04). Conclusion: Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer.

Adjuvant chemotherapy with anthracyclines improves disease-free and overall survival compared with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. The role of HER2 status as a marker of anthracycline responsiveness has been explored by subset analyses within randomized clinical trials, with inconsistent results. We performed a pooled analysis of the interaction between HER2 status and the efficacy of adjuvant anthracyclines based on the published subset data. We searched literature databases to identify randomized trials that compared anthracycline-based with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer and reported efficacy data according to HER2 status. Log hazard ratios (HRs) for disease-free and overall survival were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided. Eight studies (with 6564 randomly assigned patients, of whom 5354 had HER2 status information available) were eligible for this analysis. In HER2 -positive disease (n = 1536 patients), anthracyclines were superior to non–anthracycline-based regimens in terms of disease-free (pooled HR of relapse = 0.71; 95% confidence interval [CI] = 0.61 to 0.83; P < .001) and overall (pooled HR of death from any cause = 0.73; 95% CI = 0.62 to 0.85; P < .001) survival. In HER2 -negative disease (n = 3818 patients), anthracyclines did not improve disease-free (HR = 1.00; 95% CI = 0.90 to 1.11; P = .75) or overall (HR = 1.03; 95% CI = 0.92 to 1.16; P = .60) survival. The test for treatment by HER2 status interaction yielded statistically significant results: for disease-free survival, the chi-square statistic for interaction was 13.7 ( P < .001), and for overall survival, it was 12.6 ( P < .001). The added benefits of adjuvant chemotherapy with anthracyclines appear to be confined to women who have HER2 overexpressed or amplified breast tumors.

Purpose: Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer. Patients and Methods: After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values. Results: Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, −5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] × insulin [mU/L]/22.5; P_interaction = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, −26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, −0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P_interaction = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080). Conclusion: 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.

Evidence shows that a substantial proportion of patients with COVID-19 experiences long-term consequences of the disease, but the predisposing factors are poorly understood. We conducted a systematic review and meta-analysis to identify factors present during COVID-19 hospitalization associated with an increased risk of exhibiting new or persisting symptoms (Post-COVID-19 Syndrome, PCS). MedLine and WebOfScience were last searched on 30 September 2021. We included English language clinical trials and observational studies investigating prognostic factors for PCS in adults previously hospitalized for COVID-19, reporting at least one individual prospective follow-up of minimum 12 weeks. Two authors independently assessed risk of bias, which was judged generally moderate. Risk factors were included in the analysis if their association with PCS was investigated by at least two studies. To summarize the prognostic effect of each factor (or group of factors), odds ratios were estimated using raw data. Overall, 20 articles met the inclusion criteria, involving 13,340 patients. Associations were statistically significant for two factors: female sex with any symptoms (OR 1.52; 95% CI 1.27–1.82), with mental health symptoms (OR 1.67, 95% CI 1.21–2.29) and with fatigue (OR 1.54, 95% CI 1.32–1.79); acute disease severity with respiratory symptoms (OR 1.66, 95% CI 1.03–2.68). The I² statistics tests were calculated to quantify the degree of study heterogeneity. This is the first meta-analysis measuring the association between factors present during COVID-19 hospitalization and long-term sequelae. The role of female sex and acute disease severity as independent prognostic factors must be confirmed in robust longitudinal studies with longer follow-up. Identifying populations at greatest risk for PCS can enable the development of targeted prevention and management strategies. Systematic review registration: PROSPERO CRD42021253467.