Abstract
Background
Study undertaken to find any association of metformin intake to that of survival in ovarian cancer.
Methods
In this retrospective case control study, ovarian cancer patients who took metformin (cases) were compared with patients having ovarian cancer but no metformin (controls). Two-layered analysis was conducted. In preliminary analysis, all cases (OC cohort) were compared with controls in 1:2 ratio. Subsequently in definitive analysis, only Epithelial Ovarian Cancer cases (EOC cohort) were compared with controls in 1:3 ratio. In EOC cohort, cases were matched with controls for age (+/−5 years), FIGO stage and residual disease. Prognostic variables and Disease Specific Survival (DSS) were compared with Chi square, Kaplan-Meier (log rank) and Cox proportional hazards.
Results
In the preliminary analysis on the OC cohort (72 cases, 143 controls), cases had a better survival (5 year DSS for cases 73% vs. controls 44%; p=0.0002). In the definitive analysis on the EOC cohort (61 cases, 178 controls) distribution of age, stage, optimal cytoreduction, serous histology and platinum chemotherapy remained similar amongst the cases and controls (p>0.05). Despite these similarities, cases had a significantly better survival (5 year DSS for cases 67% vs. controls 47%; p=0.007). On a multivariate analysis, metformin remained an independent predictor of survival (hazards ratio 3.7; 95% CI 1.6–9.0; p=0.002) after controlling for stage, grade, histology, chemotherapy, body mass index and surgical cytoreduction.
Conclusion
This study reports association rather than causation. Metformin intake was associated with better survival in ovarian cancer. Metformin is worthy of clinical trials in ovarian cancer.
Keywords: Metformin, ovarian cancer, survival, drug repositioning
Introduction
The case fatality ratio of ovarian cancer is extremely high. [1] This is because 75% of patients have extensive (>stage III) disease at diagnosis, and the currently available therapies in upfront and recurrent ovarian cancer have limited efficacy [2]. Consequently, there is great need to develop improved up-front and salvage therapies for ovarian cancer [2].
Novel therapies for ovarian cancer can originate by designing and discovering new drugs de novo. Although promising, this approach carries the limitation of being tremendously expensive and very time consuming. In fact, it is estimated that de novo drug discovery may take up to 10–17 years and 800 million US dollars per agent [3]. Therefore, alternative means of finding novel therapies need to be explored. One such avenue is “drug repositioning”, which is an approach whereby already existing drugs are used to treat a different and new disease. This approach carries the promise of accelerating the translation of laboratory research to the clinical practice in a shorter time frame.[4] Numerous examples of successful drug positioning exist; one of which is the FDA approval of a morning sickness drug Lenalidomide, for multiple myeloma. [5]
Originating from the French Lilac plant (Galega officinalis), metformin is one of the most commonly used medications for diabetes worldwide. We have previously shown metformin to have anticancer effect in ovarian cancer in-vitro [6] as well as in-vivo [7]. Similar observations from others have suggested the anticancer effects of metformin in prostate, [8] colon, [9] pancreas, [10] and brain [11] neoplasms. In breast cancer, a large phase III randomized clinical trial is already underway to test metformin in more than 200 oncology centers [NCT01101438]. However, only a small study has assessed the association of metformin to prognosis in actual ovarian cancer patients thus far [12].
The objective of this study is to investigate if there is an association between metformin and prognosis in ovarian cancer.
Methods
This study was approved by the Institutional Review Board (IRB) of the Mayo Clinic, Rochester, MN, USA. Consecutive patients with a diagnosis of ovarian cancer who were prescribed metformin were identified by inpatient hospital records (metformin given) as well as outpatient pharmacy prescription records (prescription filled) of the Mayo Clinic, Rochester, MN, USA between 1995 to 2010. ICD-03 diagnosis codes were used for patient identification. Mean duration of metformin intake was 2.3 years (range 1–11 years). Minimum amount of metformin use included in the study was 1 year. Metformin use, as captured by our hospital records, was at or after the cancer diagnosis. Metformin was used at a dose of 500 mg twice a day to 1 gram twice a day. The duration of metformin use prior to cancer diagnosis was unknown due to non-availability of patient records before the cancer diagnosis. The reason of metformin use was the presence of diabetes in the cases.
In this manuscript, patients which had ovarian cancer and consumed metformin, are labeled as “cases”. Patients with ovarian cancer without diabetes and without metformin are labeled as “controls” (non diabetic controls). Patients with ovarian cancer with diabetes who took insulin or other anti-diabetic medications (but not metformin) are labeled as “diabetic controls”.
Body mass index (BMI) was calculated by weight (kilograms)/height (meter) squared. Stage of disease was assigned in accordance to the FIGO (International Federation of Gynecology and Obstetrics) surgical staging criteria. For the purpose of comparison, early or low stage disease was classified as FIGO stage I & II whereas the late or advanced stage disease was classified as FIGO stage III & IV. For statistical brevity without losing biologic significance; the histologic grade was categorized as high grade and low grade. Surgical cytoreduction was classified as optimal if the residual disease diameter was ≤1cm or suboptimal if the residual disease diameter was more than 1cm. Patients where no evidence of gross residual disease remained, were classified as completely cytoreduced. Comparison of histology was completed using each distinct histologic group as well as non-serous vs. serous histologies. Type of chemotherapy, number of cycles and number of agents was recorded for each patient. In addition, platinum chemotherapy was compared to non-platinum chemotherapy. Disease specific survival (DSS) is reported. None of the patients had BRCA mutation or neoadjuvant chemotherapy. Patients with a platinum free interval of ≥12 months were deemed to have platinum sensitive disease.
The OC cohort
A total of 72 cases were identified (ovarian cancer with metformin). Two-layered analysis was conducted. In the initial preliminary analysis, all 72 cases were compared to 143 randomly selected controls. Because this analysis involved all ovarian cancer patients irrespective of tumor histology, we labeled this cohort “OC” (all ovarian cancer cohort). In OC cohort cases, all but one had two controls each. Consequently, the OC cohort consisted of 215 patients in total. The purpose of this preliminary analysis was to describe the full spectrum of ovarian cancer seen in association with metformin intake denovo and to compare them with controls.
The EOC cohort
In the subsequent definitive analysis, epithelial ovarian cancer cases (n=61) were identified from the parent cohort of 72 cases after excluding non-epithelial ovarian cancer (n=5), tumors of low malignant potential (n=2) and atypical rare histology types (transitional & small cell cancers of ovary, n=4). These 61 cases were matched with controls in a 1:3 ratio based on three variables-age at diagnosis (+/−5 years), FIGO stage and surgical cytoreduction (optimal vs. suboptimal). Of those matched cases, 57 had all three controls, 3 had two controls and 1 had only one control. Hence, the definitive analysis cohort of cases matched with controls consisted of 239 patients (61 cases, 178 controls). As the definitive cohort had patients with epithelial ovarian cancer only; we labeled this as EOC (epithelial ovarian cancer cohort). The purpose of the definitive analysis was to find the association of metformin to that of survival in epithelial ovarian cancer as the later accounts for the vast majority of the mortality ascribed to the disease in adult population and the distribution of histology & FIGO stage was disparate in our initial analysis on the OC cohort (table 1) amongst the cases and controls.
Table 1.
Distribution of key variables in cases and controls in overall sample of ovarian cancer (OC cohort).
| Variable | Cases n (%) |
Controls n (%) |
p | |
|---|---|---|---|---|
| Age (years) | Mean€ | 60.6(SD=11) | 60.3(SD=11) | 0.8 |
| Body Mass Index (BMI) | Mean€ | 33(SD=7) | 29(SD=7) | <0.001 |
| Year of Diagnosis | Median | 2005 | 2004 | |
| Optimal Cytoreduction* | Yes | 57(89.1) | 114(89.1) | |
| No | 7(10.9) | 14(10.9) | ||
| FIGO Stage | I | 22(30.6) | 20(14) | 0.01 |
| II | 5(6.9) | 4(2.8) | ||
| III | 38(52.8) | 97(67.8) | ||
| IV | 7(9.7) | 22(15.4) | ||
| Stage Comparison | Early stage (I&II) | 27(37.5) | 24(16.8) | 0.0008 |
| Late Stage (III&IV) | 45(62.5) | 119(83.2) | ||
| Grade** | High | 48(70.6) | 126(88.1) | 0.002 |
| Low | 20(29.4) | 17(11.9) | ||
| Histology*** | Serous | 39(54.2) | 106(74.1) | 0.03 |
| Clear Cell | 5(6.9) | 9(6.3) | ||
| Endometrioid | 14(19.4) | 18(12.6) | ||
| Mucinous | 3(4.2) | 4(2.8) | ||
| LMP | 2(2.8) | 0(0) | ||
| Sarcoma | 1(1.4) | 5(3.5) | ||
| Granulosa cell tumor | 4(5.6) | 0(0) | ||
| Others | 4(5.6) | 1(0.7) | ||
| Histology Comparison | Serous | 39(54.2) | 106(74.1) | 0.003 |
| Non-Serous | 33(45.8) | 37(25.9) | ||
| Chemotherapy**** | Platinum | 52(77.6) | 116(83.5) | 0.2 |
| Non-Platinum | 1(1.5) | 9(6.7) | ||
| None | 14(20.9) | 14(10.1) |
23 Unknown
4 Unknown
LMP= Low malignant potential tumors, Others= transitional cell cancer, small cell cancer
9 Unknown
SD=Standard deviation
The diabetic control group
Data was collected on the 103 patients who had diabetes and epithelial ovarian cancer, and used insulin or other anti-diabetic medications rather than metformin. This cohort was labeled as the “diabetic control” group. Because of small sample size (n=103), matching was not feasible between the cases of EOC cohort and the diabetic control group.
Student’s t test and Chi-square /Fisher’s exact test were used to compare groups as appropriate for parametric and non-parametric comparisons. Kaplan-Meier estimates were used to compare survival using log-rank test. Univariate and multivariate Cox proportional hazards model were used to access the effect of risk factors on survival outcomes. In the later analysis biologically as well as clinically important variables, well known to be associated with prognosis (stage, histology, grade and chemotherapy etc.) in ovarian cancer were included. This model was constructed to assess if metformin exhibits independent association with survival in ovarian cancer. All tests were two-sided, with a p value ≤ 0.05 considered significant. Statistical analyses were done using the SAS version 9.1.3 software package (SAS Institute, Cary, North Carolina).
Results
The OC cohort
Initial analyses (OC cohort) were based on 72 cases and 143 randomly selected controls. One case had only one control (hence a total of 143 controls rather than 144). Table 1 shows the key variables for the cases and controls. The distribution of age, year of diagnosis, optimal surgical cytoreduction and platinum based chemotherapy remained similar in cases and controls (table 1). The BMI of cases was expectedly higher than those of controls. As depicted in table 1, early stage, lower grade and non-serous histology tumors were significantly more prevalent in cases when compared to controls. The entire cohort had a median DSS of 5.5 (95% CI 4.1–7.5) years. While the median survival for the controls was 4.1 years, the median survival for the cases was not reached (log rank p=0.0002). The five-year survival for the controls was 44% vs. 73% for the cases (log rank p=0.0002, figure 1). The results of the multivariable analysis for the OC cohort are presented in table 2. In this analysis, after adjusting for age, year of diagnosis, BMI, stage, histology and chemotherapy, only tumor grade (hazards ratio 9.6; 95% CI 2.1–170.4; P=0.001) and metformin (hazards ratio 2.0; 95% CI 1.1–4; P=0.02) remained independent predictors of survival.
Figure 1.
Survival comparison in Ovarian Cancer (OC cohort) between cases (metformin) and controls (no metformin).
Table 2.
Multivariable analysis of prognostic variables in ovarian cancer (OC cohort)
| Variable | Category | Hazard Ratio |
Lower 95% CI |
Upper 95% CI |
p |
|---|---|---|---|---|---|
| Metformin | No | 2.7 | 1.4 | 5.4 | 0.004 |
| Yes | 1 | ||||
| FIGO Stage | Late (III&IV) | 2.4 | 0.8 | 7.0 | 0.10 |
| Early (I&II) | 1 | ||||
| Grade | High (III&IV) | 8.6 | 1.2 | 63 | 0.03 |
| Low (I&II) | 1 | ||||
| Histology | Serous | 1.3 | 0.7 | 2.4 | 0.4 |
| Non-serous | 1 | ||||
| Chemotherapy | Non-platinum | 0.99 | 0.4 | 2.4 | 0.8 |
| Platinum | 1 |
The EOC cohort
In the definitive analysis on the EOC cohort, 61 cases of epithelial ovarian cancer were matched with 178 controls. The distribution of the key variables amongst the cases and controls in definitive analysis on the EOC cohort is depicted in table 3. The mean duration of follow up for the cases was 3.7 (median 3.4) vs 4.3 (median 3.3) years for the controls. The distribution of matching variables (age, FIGO stage and surgical cytoreductive effort measured by postoperative residual disease) remained similar amongst cases and controls (table 3). Furthermore, the distribution of grade, histology (serous vs. non serous), and chemotherapy remained similar between the cases and controls (p>0.05, table 3). Recurrence after chemotherapy was known for 194 patients (47 cases, 147 controls). Platinum sensitive disease was present in 62% (29/47) cases versus 56% (82/147) controls, p=0.5. The median recurrence free survival for cases and controls was 32 vs 22 months respectively, p=0.04.
Table 3.
Distribution of key variables in cases and controls (non diabetic) in epithelial ovarian cancer (EOC cohort). Comparison is also made with the diabetic control group.
| Variable | Cases n(%) |
Controls n(%) |
Diabetic controls€ € n(%) |
p | |
|---|---|---|---|---|---|
| Total | 61(100) | 178(100) | 103 (100) | ||
| Age (years)* | Mean€ | 62(SD=11)* | 61(SD=11)* | 65(SD=13) | 0.06 |
| Body Mass Index (BMI) | Mean€ | 34 (SD=7) | 28 (SD=6) | 30 (8) | <0.001 |
| FIGO Stage* | I | 15(25)* | 43(24)* | 16 (17) | 0.7 |
| II | 5(8)* | 13(7)* | 5 (5) | ||
| III | 35(57)* | 105(59)* | 59 (63) | ||
| IV | 6(10)* | 17(10)* | 13 (14) | ||
| Grade | High | 45(74) | 141(79) | 81 (80) | 0.6 |
| Low | 16(26) | 37(21) | 20 (20) | ||
| Histology | Serous | 39(64) | 126(71) | 78 (76) | 0.2 |
| Non-Serous | 22(36) | 52(29) | 25 (24) | ||
| Optimal Cytoreduction* | Yes | 49(80)* | 146(82)* | 80 (78) | 0.2 |
| No | 11(18)* | 30(17)* | 21 (20) | ||
| Unknown | 1(2) | 2(1) | 2 (2) | ||
| Chemotherapy** | Platinum based | 49(86) | 152(88) | 74 (83) | 0.3 |
| Non-Platinum | 0(0) | 5(3) | 2 (2) | ||
| None | 8(14) | 15(9) | 13 (15) |
Matching variable
Unknown for 10 patients
SD=Standard deviation
Matching with cases not possible due to small sample size in the diabetic control group. In the diabetic control group, FIGO stage was unknown for 10, grade unknown for 2 and chemotherapy was unknown for 14 patients.
The 5 year DSS of the entire cohort was 52%. The 5 year DSS for the cases (67%) was significantly better when compared to controls (47%, log rank p=0.007; figure 2). The results of the multivariable analysis are presented in table 4. After adjusting for BMI, grade, histology and chemotherapy; metformin remained independent predictor of survival in ovarian cancer.
Figure 2.
Survival comparison in Epithelial Ovarian Cancer (EOC) between cases (metformin) and controls (no metformin).
Table 4.
Multivariable analysis of the prognostic variables in epithelial ovarian cancer (EOC cohort)
| Variable | Category | Hazard Ratio | Lower 95% |
Upper 95% |
p |
|---|---|---|---|---|---|
| Metformin | No | 2.2 | 1.2 | 3.8 | 0.007 |
| Yes | 1 | ||||
| Grade | High (III&IV) | 1.3 | 0.6 | 2.8 | 0.5 |
| Low (I&II) | 1 | ||||
| Histology | Serous | 2.6 | 1.4 | 4.9 | 0.003 |
| Non-serous | 1 | ||||
| Chemotherapy | Non-platinum | 1.4 | 0.33 | 5.6 | 0.7 |
| Platinum | 1 |
The definitive study cohort of 239 EOC patients was further divided into two subgroups based on absence (residual disease 0cm) or presence (residual disease >0cm) of gross residual disease to assess the association of metformin with prognosis in these two subgroups. Of 239 EOC patients, 130 (55%) had complete cytoreduction (residual disease 0cm), 106(45%) had incomplete cytoreduction (residual disease >0cm) whereas in 3 patients, the status of residual disease remained unknown. In EOC patients with complete cytoreduction, 5 year survival of the cases was 90% vs. 69% in controls (figure 3a, p=0.04). On the other hand, in EOC patients with incomplete cytoreduction, the 5 year survival for cases was 41% vs. 21% for controls (figure 3b, p=0.047). Finally, restricting the survival analysis in the EOC cohort to advanced stage (FIGO III&IV) disease (5 year DSS for cases vs. controls-55% vs. 33%; HR 2.0, 95% CI 1.2–3.5; p=0.008, figure 3c) or to serous histology only (5 year DSS for cases vs. controls-60% vs. 38%; HR 2.2, 95%CI 1.3–4; p=0.007, figure 3d); cases still had a better survival when compared to controls.
Figure 3.
a. Survival comparison in Epithelial Ovarian Cancer (EOC cohort), gross residual disease 0cm
b. Survival comparison in Epithelial Ovarian Cancer (EOC cohort), gross residual disease >0cm
c. Survival comparison in Epithelial Ovarian Cancer (EOC cohort), only advanced stage disease (FIGO III & IV).
d. Survival comparison in Epithelial Ovarian Cancer (EOC cohort), serous histology only.
Comparison of the EOC cohort to the diabetic control group
The comparative data on the diabetic control group to that of the EOC cohort is presented in the table 3. As compared to the EOC cohort cases, the controls in the diabetic control group were slightly older and had marginally lower BMI. Notwithstanding the above, the distribution of stage, histology, grade, extent of surgical cytoreduction and platinum based chemotherapy remained similar in the EOC cohort cases and the diabetic controls. Despite these similarities, the 5 year DSS of the diabetic controls was the lowest (40%) when compared to the EOC cases (67%) or non diabetic controls (47%, p=0.003; figure 4). Survival was also assessed based on metformin intake vs insulin or other anti-diabetic medication intake in ovarian cancer patients. As presented in figure 5, metformin intake was associated with best 5 year DSS (67%) vs insulin (43%) vs other antidiabetic medications (34%, p=0.004).
Figure 4.
Survival comparison of Epithelial Ovarian Cancer (EOC cohort) cases (1) with non diabetic controls (2) or diabetic controls (3).
Figure 5.
Survival comparison of Epithelial Ovarian Cancer (EOC cohort) cases (took metformin) with diabetic controls (took insulin) or diabetic controls (took other anti-diabetic medications).
Discussion
This is the largest case control study evaluating the association of metformin with survival in ovarian cancer. Although causation could not be assessed; we found that metformin intake was associated with significantly better survival in ovarian cancer. The interest in metformin as an anticancer compound was initially ignited by two key epidemiologic reports. Evans et al. reported a reduced risk of cancer in diabetic patients taking metformin [13] whereas Bowker et al. showed reduced cancer related mortality in association with metformin. [14] These epidemiologic observations were complimented by in-vitro and in-vivo data of anticancer activity of metformin in several human cancers. [8] [11] [10] [9].
The current study placed heavy emphasis on the survival comparisons between the cases to that of non-diabetic controls (labeled as “controls” in the manuscript) rather than the “diabetic control group”. There are two reasons for this approach-i) diabetes has been shown to have negative impact on ovarian cancer survival [15] and therefore survival comparison of cases to that of diabetic control group is likely to overestimate the magnitude of survival benefit associated with metformin. And ii) vast majority of ovarian cancer patients are non-diabetic and will be candidates of enrolment into future clinical trials employing metformin in ovarian cancer. Therefore, in terms of clinical applicability, the study results employing non-diabetic controls are more relevant. However, one could argue that in an ideal study, the cases and controls should only differ in terms of exposure (metformin) and not in terms of other confounders (e.g. diabetes). To overcome this limitation, clinical and survival data are also provided for the diabetic control group (table 3, figure 4).
Before metformin can be used in patients for its anticancer effect, prospective trials employing metformin in ovarian cancer are warranted. Our data provide support for such trials. To that end, the most important question is to decipher if the observations made by our study are merely by chance or a true clinical effect. It is noteworthy that in our initial analysis on the OC cohort incorporating all metformin associated ovarian cancers, metformin associated tumors were more likely to be lower grade, earlier stage and had a more favorable histology profile. One could attribute the association of better prognosis in OC cohort with that of metformin on the constellation of these lower risk attributes. Part of our data in the OC cohort lends some support to this hypothesis. For example, 4 cases (5.6%) in the OC cohort had granulosa cell tumors (table 1). The granulosa cell tumors have a much better prognosis (when compared to epithelial ovarian cancer) and diabetes and obesity are commonly a result of the hormonal effects of the tumor itself [16], leading to prescription of metformin. Along similar lines, tumors of low malignant potential were observed more frequently in the cases rather than controls (table 1) and have a better prognosis when compared to frankly invasive epithelial ovarian cancers. In spite of these limitations, the primary value of the preliminary analysis of the OC cohort was to describe the full spectrum of ovarian tumors associated with metformin intake. Further, the emergence of metformin as an independent predictor of survival in the OC cohort multivariable analysis (table 2) where stage, grade and histology were controlled; would tend to favor a true association of metformin with clinically beneficial impact in ovarian cancer.
We next conducted our definitive analysis on the EOC cohort to overcome the above mentioned limitations posed by the non-uniform distribution of FIGO stage and tumor types in the OC cohort. The EOC cohort only had epithelial ovarian cancers and the controls were matched for age, FIGO stage and residual disease after cytoreductive surgery (table 3). All these three matching criteria are the primary determinants affecting survival in ovarian cancer[17] [18]. The distribution of all the variables analyzed was statistically similar amongst cases and controls in the EOC cohort except BMI (table 3). Cases had a higher BMI because metformin is usually prescribed to obese diabetic individuals [19]. This unequal distribution of BMI is unlikely to affect our survival analysis because:- a) BMI is not considered to be of prognostic value in ovarian cancer [20] and b) BMI was controlled in the multivariable analysis. In the analysis of the EOC cohort, the association of metformin with better survival persisted in the overall analysis as well as in the subgroup analysis of complete & incomplete cytoreduction subgroups. Secondly, When the analysis was restricted to serous histology only or advanced stage tumors only, the survival advantage associated with metformin persisted. Finally the multivariable analysis after controlling for BMI, histology, tumor grade and type of chemotherapy suggested metformin to be an independent predictor of survival for ovarian cancer. These observations suggest that confounding is unlikely to be the sole factor accounting for a remarkable difference in prognosis between cases and controls. Moreover, the previous data from our lab show a potent inhibition of cell division, cell survival and antitumor activity of metformin in the mice model of ovarian cancer [6] [7]. Taken together, these data imply a possible causative role of metformin in exhibiting antitumor activity in ovarian cancer.
The limitations of this study are its retrospective nature, small sample size and lack of information on metformin use prior to cancer diagnosis due to lack of medical records prior to establishment of the patient care. However, this is the largest clinical study which evaluates the association of metformin to prognosis in ovarian cancer. One prior study evaluated the association of metformin to survival in ovarian cancer[12] and demonstrated better recurrence free survival, similar to our report. However, the present report overcomes several limitations posed by the previous study. These include- a much larger sample size of 72 cases (vs 16 cases), ability to match the EOC cases with non diabetic controls for important clinical variables (vs non matched controls) and ability to show overall survival difference (vs only recurrence free survival advantage in cases) in the present (vs the previous study) respectively. Moreover, a sample size of 72 cases, though may perceived to be relatively small, but metformin intake because of diabetes in cancer patients is rather uncommon. This notion is supported by the study of metformin in breast cancer patients from MD Anderson cancer center by Jiralerspong et al., where only 68 such patients could be identified. [21] On the other hand, our ability to match cases and controls for three variables including age, FIGO stage and surgical cytoreduction is a noteworthy strength of the present study. The later is especially so because surgical effort is largely surgeon dependent (rather than tumor biology) and diabetic patients have higher operative morbidity [22] which may limit the fraction of patients having comprehensive surgical staging at a given institution. [15] This factor was hence eliminated by matching for surgical effort.
In conclusion, in the present case control study we show that metformin intake independently predicted better survival in ovarian cancer patients. Although causation could not be assessed by our retrospective study; metformin nevertheless is a strong contender for further clinical studies in ovarian cancer. These may be retrospective confirmatory studies by other institutions and/or prospective phase II/III studies in ovarian cancer patients.
Research highlights.
Metformin intake in ovarian cancer patients is uncommon.
Metformin intake is associated with better survival in ovarian cancer.
Metformin should be tested in prospective clinical trials in ovarian cancer.
Acknowledgments
This work was supported, in whole or in part, by Fred C. and Katherine B. Andersen Foundation CA123249 and P50 CA13639 National Institutes of Health Grants.
Footnotes
Conflicts of interest statement/ Financial disclosures
All the authors declare that there are no conflicts of interest in association with this work.
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