Iliana C. Lega

Association Between Metformin Therapy and Mortality After Breast Cancer A population-based study

OBJECTIVE Metformin has been associated with a reduction in breast cancer risk and may improve survival after cancer through direct and indirect tumor-suppressing mechanisms. The purpose of this study was to evaluate the effect of metformin therapy on survival in women with breast cancer using methods that accounted for the duration of treatment with glucose-lowering therapies. RESEARCH DESIGN AND METHODS This population-based study, using Ontario health care databases, recruited women aged 66 years or older diagnosed with diabetes and breast cancer between 1 April 1997 and 31 March 2008. Using Cox regression analyses, we explored the association between cumulative duration of past metformin use and all-cause and breast cancer–specific mortality. We modeled cumulative duration of past metformin use as a time-varying exposure. RESULTS Of 2,361 breast cancer patients identified, mean (± SD) age at cancer diagnosis was 77.4 ± 6.3 years, and mean follow-up was 4.5 ± 3.0 years. There were 1,101 deaths(46.6%), among which 386 (16.3%) were breast cancer–specific deaths. No significant association was found between cumulative duration of past metformin use and all-cause mortality (adjusted hazard ratio 0.97 [95% CI 0.92–1.02]) or breast cancer–specific mortality (0.91 [0.81–1.03]) per additional year of cumulative use. CONCLUSIONS Our findings failed to show an association between improved survival and increased cumulative metformin duration in older breast cancer patients who had recent-onset diabetes. Further research is needed to clarify this association, accounting for effects of cancer stage and BMI in younger populations or those with differing stages of diabetes as well as in nondiabetic populations.

A physician reminder to improve postpartum diabetes screening in women with gestational diabetes mellitus.

AIMS Women with gestational diabetes (GDM) have a 20% risk of developing diabetes in the 10 years following pregnancy, but the risk may be as high as 70% in higher risk populations. Guidelines recommend screening for diabetes postpartum, but screening rates are low. We evaluated the effect of a physician reminder on postpartum screening and in women with GDM. METHODS We conducted a retrospective chart review among women with GDM seen at our urban, academic endocrine clinic in Toronto, Canada between 2006 and 2010. Our primary outcome was to evaluate the effect of a reminder checklist on postpartum diabetes screening rates. RESULTS We included 314 women in our study, 173 had a checklist on their chart. Women had a mean age of 34.9 years, 45% were Caucasian and 23% had a previous GDM. The checklist was associated with a 3 fold increase in odds of being screened postpartum, and nearly 4 fold increase in postpartum follow up visits (OR 2.99, 95% CI 1.84-4.85 and OR 3.71, 95% CI 2.26-6.11). CONCLUSION A physician based reminder system is an effective way to improve postpartum screening rates. To further increase screening rates, a multilevel approach targeting both patients and physicians is required.

The Effect of Metformin on Mortality Following Cancer among Patients with Diabetes

Diabetes may be a risk factor for cancer and is associated with worse cancer outcomes. Metformin may reduce cancer risk; however, its effect on mortality following cancer remains less clear. EMBASE and Medline were searched through February 10, 2014, for studies reporting an adjusted risk estimate for the effect of metformin therapy on mortality following cancer among diabetic patients. Random-effects models were used to obtain summary HR for the association between metformin and all-cause and cancer-specific mortality. Twenty-one observational studies were meta-analyzed in the primary analysis. Metformin was associated with a reduction in all-cause mortality [HR, 0.73; 95% confidence intervals (CI), 0.64–0.83] and cancer-specific mortality (HR, 0.74; 95% CI, 0.62–0.88). Subgroup analyses by cancer site showed a significant reduction in mortality for colon cancer (four studies, HR, 0.65; 95% CI, 0.56–0.76) but not for breast and prostate cancers. Observational studies indicate that metformin exposure at cancer diagnosis may be associated with a reduction in mortality. However, these findings need to be interpreted with caution as methodologic limitations of individual studies may have introduced biases in these findings. Our results emphasize the need for well-designed studies to further understand the relationship between metformin and survival following cancer. Cancer Epidemiol Biomarkers Prev; 23(10); 1974–84. ©2014 AACR.

Association between Metformin Use and Mortality after Cervical Cancer in Older Women with Diabetes

Background: To examine the association between metformin use and mortality in patients with diabetes and cervical cancer. Methods: Using Ontario health databases, a retrospective, population-based cohort study was conducted in women with diabetes ≥ age 66 years diagnosed with cervical cancer between 1997 and 2010. The association between metformin exposure and cervical cancer–specific mortality was examined using Fine–Gray regression models, with noncancer death as a competing risk and cumulative metformin use as a time-varying exposure. The association with overall mortality was examined using Cox regression models. Results: Among the 181 women with diabetes and cervical cancer, there were 129 deaths, including 61 cervical cancer–specific deaths. The median follow-up was 5.8 years (interquartile range 4.2–9.6 years) for surviving patients. Cumulative dose of metformin after cervical cancer diagnosis was independently associated with a decreased risk of cervical cancer–specific mortality and overall mortality in a dose-dependent fashion [HR 0.79; 95% confidence interval (CI), 0.63–0.98; and HR 0.95; 95% CI, 0.90–0.996 per each additional 365 g of metformin use, respectively]. There was no significant association between cumulative use of other antidiabetic drugs and cervical cancer–specific mortality. Conclusion: This study suggests an association between cumulative metformin use after cervical cancer diagnosis and lower cervical cancer–specific and overall mortality among older women with diabetes. Impact: Cumulative dose of metformin use after cervical cancer diagnosis among older women with diabetes may be associated with a significant decrease in mortality. This finding has important implications if validated prospectively, as metformin is inexpensive and can be easily combined with standard treatment for cervical cancer. Cancer Epidemiol Biomarkers Prev; 25(3); 507–12. ©2015 AACR.

Metformin and breast cancer stage at diagnosis: a population-based study

PURPOSE The objective of the present study was to use a large, population-based cohort to examine the association between metformin and breast cancer stage at diagnosis while accounting for mammography differences. METHODS We used data from Ontario administrative health databases to identify women 68 years of age or older with diabetes and invasive breast cancer diagnosed from 1 January 2007 to 31 December 2012. Adjusted logistic regression models were used to compare breast cancer stage at diagnosis (stages i and ii vs. iii and iv) between the women exposed and not exposed to metformin. We also examined the association between metformin use and estrogen receptor status, tumour size, and lymph node status in the subset of women for whom those data were available. RESULTS We identified 3125 women with diabetes and breast cancer; 1519 (48.6%) had been exposed to metformin before their cancer diagnosis. Median age at breast cancer diagnosis was 76 years (interquartile range: 72-82 years), and mean duration of diabetes was 8.8 ± 5.9 years. In multivariable analyses, metformin exposure was not associated with an earlier stage of breast cancer (odds ratio: 0.98; 95% confidence interval: 0.81 to 1.19). In secondary analyses, metformin exposure was not associated with estrogen receptor-positive breast cancer, tumours larger than 2 cm, or positive lymph nodes. CONCLUSIONS This population-based study did not show an association between metformin use and breast cancer stage or tumour characteristics at diagnosis. Our study considered older women with long-standing diabetes, and therefore further studies in younger patients could be warranted.

Response to “Letter to the Editor Concerning the Paper by Fung et al titled ‘Differential Effects of Cyproterone Acetate vs Spironolactone on Serum High-Density Lipoprotein and Prolactin Concentrations in the Hormonal Treatment of Transgender Women”

We thank Drs T’Sjoen and Justine Defreijne for their comments. We agree there is currently little evidence supporting routine measurement and follow-up of prolactin levels in this population. However, we believe it is premature to conclude that monitoring of prolactin is of no benefit especially in the absence of data from long-term prospective studies. We also agree there are other potential confounders that can affect prolactin levels in this population; such factors will be important to study in the future. There have been instances in which we believed that monitoring benefitted the patient. Case reports such as that by García-Malpartida et al have suggested the potential for benefit. We also recently had a patient with a normal baseline prolactin level (within the cisgender male reference) who had a rapid increase of prolactin to three times above the upper limit of normal of the cisgender female reference range while on estrogen and cyproterone therapy. In this case, we switched her from cyproterone to spironolactone, and subsequently her prolactin decreased to within the cisgender female range while staying on the same estrogen therapy. Because her prolactin level decreased with switching her medication, no magnetic resonance imaging was performed. She had no overt symptoms of prolactinoma. It is quite possible that she would have

The Relation between Type 2 Diabetes and Breast Cancer Incidence in Different Ethnic Groups - A Review

In addition to rising type 2 diabetes and breast cancer incidence rates worldwide, diabetes may also increase breast cancer risk, and the association may vary by ethnicity. This review summarizes published data evaluating the association between diabetes and breast cancer in women of Asian, Hispanic and African American ancestry while considering a measure of obesity, body mass index (BMI). Published reports were identified through a search of PubMed and previous publications. Of 15 age-adjusted studies, 11 reported on Asian women from various countries, 3 on Hispanics and 1 on African Americans. The studies of Asian women described significant associations in 8 reports, with risk estimates of 1.5 to 8.4, but 3 were case-control studies and 6 did not adjust for BMI. The 3 case-control studies of Hispanic people included BMI, but only 1 detected a weak association between diabetes and breast cancer risk and was limited to postmenopausal women. The only study of African American women was a prospective cohort, and it showed no significant association between diabetes and breast cancer. In contrast to a 10% to 20% higher risk for breast cancer associated with diabetes reported for Caucasian women, there is little evidence for an association in Hispanics and African Americans. Although several studies of Asian women included in our review reported a higher risk for breast cancer with diabetes, methodologic shortcomings, such as lack of adjustment for obesity, use of a general population as controls, case-control design and small sample sizes, raise questions about the validity of the findings.