Obstetrics & Gynecology:
Relationship of Type II Diabetes and Metformin Use to Ovarian Cancer Progression, Survival, and Chemosensitivity
Romero, Iris L. MD, MS; McCormick, Anna MD, DO; McEwen, Kelsey A. BS; Park, SeoYoung PhD; Karrison, Theodore PhD; Yamada, S. Diane MD; Pannain, Silvana MD; Lengyel, Ernst MD, PhD
From the Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology–Center for Integrative Science, Health Studies, and Medicine/Section of Endocrinology, University of Chicago, Chicago, Illinois.
Supported by grants from the Reproductive Scientist Development Program (National Institutes of Health 2K12HD00849-22) and the Gynecologic Cancer Foundation/St. Louis Ovarian Cancer Awareness (to Dr. Romero). Dr. Lengyel holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund and is supported by grants from the National Cancer Institute (RO1 CA111882).
Corresponding author: Iris Romero, MD, University of Chicago, Department of Obstetrics and Gynecology, 5841 South Maryland Avenue, MC 2050, Chicago, IL 60637; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate whether metformin use by ovarian cancer patients with type II diabetes was associated with improved survival.
METHODS: We reviewed the effect of diabetes and diabetes medications on ovarian cancer treatment and outcomes in a single-institution retrospective cohort. Inclusion criteria were International Federation of Gynecology and Obstetrics stage I–IV epithelial ovarian, fallopian, or peritoneal cancer. Exclusion criteria were noninvasive pathology or nonepithelial malignancies. The primary exposures analyzed were history of type II diabetes and diabetes medications. The primary outcomes were progression-free and overall ovarian cancer survival.
RESULTS: Of the 341 ovarian cancer patients included in the study, 297 did not have diabetes, 28 were type II diabetic patients who did not use metformin, and 16 were type II diabetic patients who used metformin. The progression-free survival at 5 years was 51% for diabetic patients who used metformin compared with 23% for the nondiabetic patients and 8% for the diabetic patients who did not use metformin (P=.03). The overall survival at 5 years was 63%, 37%, and 23% for the diabetic patients who used metformin, the nondiabetic patients, and the diabetic patients who did not use metformin, respectively (P=.03). The patients with diabetes received the same treatment for ovarian cancer as the patients without diabetes. The association of metformin use and increased progression-free survival, but not overall survival, remained significant after controlling for standard clinicopathologic parameters.
CONCLUSION: In this ovarian cancer cohort, the patients with type II diabetes who used metformin had longer progression-free survival, despite receiving similar treatment for ovarian cancer.
LEVEL OF EVIDENCE: II
It is estimated that two in five women born in the United States in 2000 will have type II diabetes diagnosed during their lifetime.1 Diabetes is associated with an increased incidence of most cancers and decreased cancer survival.2 Understanding how diabetes influences cancer treatment and prognosis is of particular importance in cancers that have high mortality rates, such as ovarian cancer, which is the most lethal gynecologic cancer.3 Although limited, the available data suggest that ovarian cancer patients with type II diabetes have decreased survival.4,5
It is biologically plausible that the hyperinsulinemia and hyperglycemia induced by type II diabetes promotes tumorigenesis. Insulin stimulates the growth of cancer cells by activating insulin-like growth factor I and decreasing insulin-like growth factor binding protein.6 Hyperglycemia provides a nutrient-rich microenvironment for rapidly dividing cancer cells, which have elevated metabolic demands and consume glucose at a higher rate than normal cells.7 Consistent with this concept, elevated plasma glucose levels at the time of ovarian cancer cytoreductive surgery are predictive of decreased survival.8
Interestingly, metformin, a diabetic treatment that reduces both insulin and glucose levels, may have anticancer effects.9 Epidemiologic studies indicate that patients who use metformin have decreased cancer incidence10,11 and increased cancer survival.11–14 Preclinical studies also corroborate the antitumorigenic effect of the drug in breast, prostate, and colon cancer.15–17 In ovarian cancer, two preclinical studies have shown that metformin inhibits the proliferation of cancer cell lines in a dose-dependent and time-dependent manner.18,19
Based on preclinical evidence of a strong anticancer effect, we hypothesized that the use of metformin may be associated with improved ovarian cancer outcomes. To test this hypothesis, we evaluated whether ovarian cancer patients with type II diabetes who used metformin had increased progression-free and overall survival.
MATERIALS AND METHODS
This is a retrospective, single-institution, cohort study utilizing an established dataset of women treated for ovarian cancer at the University of Chicago from 1992 to 2010. All women with International Federation of Gynecology and Obstetrics stage I–IV epithelial ovarian, fallopian, or peritoneal cancer were included in the study. We identify, and refer to, these three cancers as ovarian cancer because of their common origin in the Müllerian epithelium. Patients were excluded from the study if they had noninvasive pathology, nonepithelial malignancies, or nonovarian primary cancer that had metastasized to the ovary. They were also excluded if they did not receive their primary cancer treatment at the University of Chicago but were only treated for recurrences. The study was approved by the institutional review board at the University of Chicago.
As previously reported, the ovarian cancer dataset contains information on clinicopathologic parameters, treatment, and outcomes.20,21 All pathologic diagnoses had been confirmed by a subspecialty-trained gynecologic pathologist. Follow-up data were obtained from medical records at the University of Chicago, the Illinois Cancer Registry, the United States Social Security Index, and by communicating with physicians involved in the patient's care. For this study, an additional chart abstraction was performed to extract data pertaining to diagnoses of diabetes, diabetic medications, body mass index, glycosylated hemoglobin A1C, fasting glucose, and renal function. Fasting blood glucose and glycosylated hemoglobin A1C values were missing for a large portion of the cohort, prohibiting analysis of these variables. The person abstracting the data regarding diabetes was unaware of the individual's cancer survival status. All records of diabetic patients were reviewed again by a second blinded investigator (I.R.). For secondary review of records for nondiabetic patients, the entries in the dataset were consecutively numbered and every tenth medical record was reviewed again.
The primary exposures of interest for the study were a history of type II diabetes and the type of diabetic medications used. The primary outcome measures included progression-free and overall survival. Recurrence was defined using previously published clinical criteria22 and included evidence of reappearance of the cancer by clinical examination (eg, tumor, ascites), new tumor findings on computed tomography or ultrasound scan, or an increase in CA 125 two times or more the upper limit of normal (70 units/mL). Progression-free survival was calculated from the date of diagnosis until the date of ovarian cancer recurrence or death. Patients without recurrence or death were censored at last follow-up. Overall survival was calculated from the date of diagnosis until death from ovarian cancer or the observation was censored as of the date of last follow-up. The six patients out of 341 who died from causes other than ovarian cancer were censored at the time of death.
All statistical analyses were performed using R 2.11.0 (The R Project for Statistical Computing, http://www.r-project.org/). For comparison, the cohort was stratified into three groups: patients without diabetes, patients with diabetes who did not use metformin, and patients with diabetes who used metformin. F tests were used for comparing continuous variables and the Fisher exact tests were used for categorical variables. Kaplan-Meier survival curves were plotted for the three groups and compared with log-rank tests. Of note, in the metformin group, the event rates and the duration of follow-up were not sufficient to estimate the upper limit of the confidence interval (CI) of progression-free and overall survival. These CIs are reported as not estimable. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for progression-free and overall survival while adjusting for confounders. For model selection, a univariable Cox regression was performed with each of the potential confounders, and those found to be significant in predicting recurrence or survival were included in the final model. The resulting Cox regression calculated the HRs for diabetic patients who used metformin and diabetic patients who did not use metformin, with patients without diabetes as the reference group. The HR of diabetic patients who used metformin relative to diabetic patients not using metformin was also calculated.
The study included 341 women. The cancer types included epithelial ovarian (n=273), fallopian (n=34), and peritoneal (n=34) cancer. The median duration of follow-up was 63 months (range 1–245 months). For comparison, the cohort was stratified into three groups as follows: nondiabetic patients (n=297), diabetic patients who did not use metformin (n=28), and diabetic patients who used metformin (n=16). Among the metformin users, five used only metformin, four used metformin and insulin, and seven used metformin plus another oral antidiabetic agent. The baseline characteristics of the three groups are reported in Table 1. The patients with diabetes were more likely to have higher body mass indexes, and to be African American than were the patients without diabetes.
The patients with diabetes received the same treatment for ovarian cancer as the patients without diabetes. The rate of primary cytoreductive surgery with residual disease smaller than 1 cm after surgery, the type of chemotherapy agent used, and the mean number of chemotherapy cycles were comparable among the groups. Despite the long study interval (18 years), 95% of patients received both platinum-based and taxane-based chemotherapy; the most common agents were carboplatin (72%) and taxol (94%). The response to chemotherapy was assessed using the clinical parameter of platinum sensitivity, defined as 6 months or more without recurrence of disease after the end of chemotherapy. The group using metformin had the highest percentage of patients sensitive to platinum chemotherapy, although the difference did not reach statistical significance (P=.18) (Table 1).
Despite similar ovarian cancer treatment, the type II diabetic patients who used metformin had longer progression-free and overall survival. The progression-free survival at 5 years for diabetic patients who used metformin was 51% (median 72 months, 95% CI 13.3–not estimable) compared with 23% (median 16 months, 95% CI 13.9–19.5 months) for patients without diabetes and 8% (median 10 months, 95% CI 13.3–37.2 months) for the diabetic patients who did not use metformin (log rank test P=.03; Fig. 1A). The overall survival at 5 years for diabetic patients who used metformin was 63% (median 138 months, 95% CI 31.1–not estimable) compared with 37% (median 42 months, 95% CI 35.1–49.6 months) for patients without diabetes and 23% (median 35 months, 95% CI 24.6–54.3 months) for the diabetic patients who did not use metformin (log rank test P=.03; Fig. 1B). The difference in survival could not be explained by stage, grade, or histologic subtype, because the tumor characteristics of the three groups were similar (Table 2).
In a survival analysis adjusted for confounders, when comparing diabetic patients who used metformin to diabetic patients who did not use metformin, the metformin group had a significantly decreased hazard for disease recurrence (HR 0.38, 95% CI 0.16–0.90). The metformin group also had a decreased hazard of dying (HR 0.43, 95% CI 0.16–1.19), but this difference was not statistically significant. Variables significantly predictive of progression-free or overall survival (or both) and included in the models were age, body mass index, creatinine, International Federation of Gynecology and Obstetrics stage, tumor grade, residual implants larger than 1cm after surgery, and histologic subtype. The variables that were not significant predictors of survival and excluded from the models were American Society of Anesthesiologists class, ethnicity, and history of cardiovascular disease. The hazards for both disease recurrence and dying were also lower in patients with diabetes who used metformin when compared with the group without diabetes, but this reduction was not statistically significant. In contrast, patients with diabetes who did not use metformin had an increased hazard of ovarian cancer recurrence (HR 1.42, 95% CI 0.87–2.33) and an increased hazard of dying from ovarian cancer (HR 1.33, 95% CI 0.77–2.28) when compared with patients without diabetes (Table 3).
In a single-institution retrospective cohort, we found that ovarian cancer patients with type II diabetes who used metformin had increased progression-free survival, but not overall survival, when compared with type II diabetic patients who did not use metformin. These findings are consistent with those of Landman et al13 who analyzed a prospective diabetic cohort and found that diabetic patients who used metformin had an adjusted overall cancer mortality hazards ratio of 0.43 (95% CI 0.23–0.80) when compared with diabetic patients not using metformin. In fact, we report a similar magnitude of risk reduction in ovarian cancer patients.
The suggestion that metformin use is associated with improved ovarian cancer outcomes may not be intuitive to most gynecologists because patients with type II diabetes have more comorbidities. However, our findings are congruent with the translational research that has demonstrated a distinct anticancer effect of the drug in several cancers (eg, breast, prostate, colon), including ovarian cancer.15–19 Three possible mechanisms have been proposed. First, the anticancer effect of metformin may be a result of the activation of a critical energy sensor in cancer cells, adenosine monophosphate-activated protein kinase. On activation, adenosine monophosphate-activated protein kinase contributes to energy conservation by decreasing cancer cell proliferation.23 Second, insulin and glucose promote tumorigenesis6,8 and, through inhibiting hepatic gluconeogenesis and increasing insulin sensitivity, metformin decreases both insulin and glucose levels.24 Finally, clinical and laboratory studies indicate that metformin may improve response to chemotherapy.25 In a study of neoadjuvant chemotherapy for breast cancer, Jiralerspong et al26 reported that diabetic patients who used metformin had a pathologic complete response rate of 24% compared with an 8% pathologic complete response rate among diabetic patients who did not use metformin. In our ovarian cancer cohort, we also noted that the type II diabetic patients who used metformin had the best response to chemotherapy.
The findings reported here are provocative, but given the retrospective study design, they can only be considered hypothesis-generating and should not be generalized to clinical practice at this time. That being said, the study has some notable strengths. We include an analysis of the association of metformin use and ovarian cancer survival, whereas previous studies have only examined the association of diabetes and ovarian cancer survival without consideration of diabetic medications.5 Also, by using a large ovarian cancer dataset that contained detailed chemotherapy and platinum sensitivity data, we were able to estimate the relationship between metformin use and response to chemotherapy. Finally, the homogeneity of ovarian cancer treatment among diabetic patients and nondiabetic patients in the cohort allowed us to make relatively strong inferences about the effects of metformin.
An important limitation of the study was the small sample size. The sample size limited our ability to detect a difference in survival between diabetic patients using metformin and patients without diabetes. Based on retrospective power calculations, assuming a true HR of the magnitude reported here and assuming that 5% of ovarian cancer patients have type II diabetes and use metformin, for progression-free survival a total sample size of 870 patients would be required to have 80% statistical power. For overall survival, 1,570 patients would be required. The sample size also prohibited an analysis of the effects of diabetic medications other than metformin. A final limitation was that because of lack of available data, we could not control for diabetes severity, which may represent an independent risk factors for death.
In summary, the findings in this ovarian cancer cohort of improved progression-free survival among type II diabetic patients who used metformin add to a growing body of evidence from epidemiologic and preclinical studies indicating that metformin may have antitumorigenic effects. The idea that specific diabetic treatments affect cancer survival is clinically relevant given the increasing prevalence of diabetes. According to the World Health Organization, 171 million people worldwide have type II diabetes, and this number is expected to double by 2030.27 If future studies continue to support the protective effect of metformin in cancer, then this will be an important consideration when managing diabetic patients with cancer.
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