1. Romero IL, McCormick A, McEwen et al. 2012. Obstetrics & Gynecology, vol. 119:61-67

3. What does the descriptive epidemiology teach us?

5. Changes in Cancer Mortality Rates, 2006-2010. U.S.

6. Trend in Ovarian Cancer Incidence and Mortality Rates, California, 1988-2011

7. Age Adjusted Incidence and Mortality Rates of Ovarian Cancer in California, 2007-2011, by Race/Ethnicity

8. Age Specific incidence Rates of Ovarian cancer In California, 2007-2011

9. Age Specific incidence rate of Ovarian Cancer in California, 1988-2011, by Race/Ethnicity

10. Age Adjusted Ovarian Cancer Incidence Rates in California, 2007-2011, by County of Residence

11. Age Adjusted Ovarian Cancer Mortality Rates, 2007-2011, in California, By County of residence

12. What does the analytic epidemiology teach us? What “risk factors” alter risk of ovarian cancer?

13. Risk Factors for Ovarian Cancer by Strength of Evidence

14. What is the distribution of stage at diagnosis for ovarian cancer and why is this important for survival?

15. Ovarian Cancer Stage Distribution, SEER Data, 2004-2010 (N=33,841)

16. Five Year Relative Survival, Ovarian Cancer, U.S., SEER Data, 2004-2010, by Stage at Diagnosis

18. Five Year Relative Survival, Ovarian Cancer, U.S. SEER Data, 2006-2010

19. Type II Diabetes It is estimated that two in five women born in the United States in the year 2000 will have type II diabetes diagnosed during their lifetime. Available data suggest that ovarian cancer patients with type II diabetes have decreased survival. It is biologically plausible that hyperinsulinemia and hyperglycemia induced by type II diabetes promotes tumorigenesis. Hypergylcemia 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.

20. Proportions of the California Female Population, Age > 45 years, Ever Diagnosed with Diabetes (2011-2012 CHIS data)

21. Metformin Metformin is the most commonly prescribed drug for the treatment of type II diabetes. Metformin reduces both insulin and glucose levels. In ovarian cancer preclinical studies, metformin inhibits proliferation of cancer cell lines in a dose-dependent fashion (Gotlieb, 2008) and in a time dependent manner (Rattan, 2009).

24. Frequency of Metformin prescription, U.S., 2012 (Lindsley, ACS. Chem Neuroscience, 2013, 4, 1133-1135).

25. Epidemiology of Ovarian Cancer With Reference to the Role of Metformin CCRA Meeting, November 7, 2014 Paul K Mills, Ph.D., Kristine McLane, B.S., Cynthia Cortez, B.S., Soe Naing, MD, Maria Arambula, MD and Theresa Gipps, MD

26. Institutional Review Board and Funding Approval for the study was received from CMC IRB: Approval #2012026, March, 2012 Funding generously provided from: Central California Faculty Medical Group, Maria Arambula, MD, P.I.

27. Ovarian Cancer-Metformin Study: Methodology Retrospective Cohort Study Design Inclusion Criteria: Epithelial Ovarian cancer patients (ICD-O-3 =56.9) diagnosed 2001-2010 at CRMC, Fresno, California Exclusion criteria: Non-invasive pathology, non-epithelial malignancies, non ovarian primary cancer that metastasized to ovary.

28. Ovarian Cancer-Metformin Study: Predictors, Outcomes and Analysis. Primary Predictor Variable: Metformin Exposure Primary Outcome Variable: Time to recurrence and time to death. Analyses: Simple descriptive analysis of means, standard deviations and proportions with use of Student’s t test and chi-square to compare groups. Survival analysis using Kaplan –Meier and Cox Proportional hazards regression. Statistical significance set at p<=0.05, two- sided tests.

29. Data Sources, Data Collection, Coding and Quality Control Four primary data sources: Epic (post-2009), Last Word, EMR and paper medical records. Data dictionary developed, standardized data abstracting and coding techniques were developed by two trained research coordinators (Kristine M and Cynthia C.). Results recorded on excel spreadsheets, analysis performed using IBM/SPSS, version 21.

30. Results

31. Characteristics of the Study Cohort, Histology HistologyNumber (N=220)Percent Serous9844.5 Mucinous2310.5 Endometrioid2410.9 Clear Cell73.2 Adenocarcinoma, NOS5324.1 Carcinoma, NOS156.8 Total220100

32. Characteristics of the Cohort, Demographics, Labs and Follow-up (means, medians and SD) VariableMeanSD Age at Dx (N=220)59.114.6 BMI (N=199)29.76.8 Blood Glucose at Dx (N=186)120.337.7 CA-125 at Dx (N=142)1,361.3 (mean) 288.5 (median) 3394 Follow-up, Dx to Last f.u.845 days (median) Follow-up, Dx to death (N=122)497.5 days (median)

33. Characteristics of the Study Cohort, Race/Ethnicity Race/EthnicityNumber (N=220)Percent Non-Hispanic White14565.9 Non-Hispanic Black73.2 Hispanic5625.5 Asian/Pacific Islander125.5 Total220100

34. Characteristics of the Cohort, Stage at Diagnosis Stage at DiagnosisNumber (N=220)Percent Localized4922.3 Regional177.7 Remote8840 Distant Metastasis6228.2 Unknown41.8 Total220100

35. Characteristics of the Cohort, Smoking Smoking StatusNumber (N=220)Percent Never Smoker14967.7 Current Smoker2210 Past Smoker3817.3 Unknown115 Total220100

36. Characteristics of the Cohort, Treatment Related Variables VariableNumber (N=220)Percent ASA Class No Surgery4721.3 Class I-II5223.6 Class II-IV4118.6 Unknown8036.4 Platinum Chemo. Rx None6127.7 Rec’d7735.0 Unknown8237.3 Taxane Chemo Rx None6027.3 Rec’d.7735.0 Unknown8337.7

37. Characteristics of the Cohort, Diabetes StatusNumber (N=220) Percent Non-Diabetic15972.3 Diabetic4821.8 Unknown Diabetes Status135.9 Total220100

38. Characteristics of the Cohort, Metformin Use/Exposure Metformin UseNumber (N=220) Percent No Metformin Exposure17981.4 Metformin taken at or after Ca Dx188.2 Metformin taken only prior to Ca Dx41.8 Unknown Status198.6 Total220100

39. Characteristics of the Cohort, Vital Status at End of Follow-up Vital Status at End of Follow-up Number (N=220) Percent Alive9040.9 Known Dead12255.4 Dead, Ovarian Ca2913.2 Dead, Other Cause104.5 Dead, Unknown Cause8337.7 Unknown Vital Status83.6 Total220100

40. Comparisons of the Study Groups VariableNon-Diabetic (n=159) Diabetic, no Metformin Use (N=18) Diabetic, Metformin Use (N=18) p-value Age at Dx (mean, SD) 57.3 (14.3)65.8(14.5)64.1( 15)0.02 Race/Ethnicity NHW111 (.69)8 (.44).005 NHB4 (.02)1 (.06) Hispanic37 (.23)9 (.50)5 (.28) Asian/PI7 (.04)04 (.22) BMI (Kg/M2)28.8 (5.9)30.6 (7.1)28.9 (6.1)0.64 Gravidity (mean) 2.6 (2.2)3.4 (3.1)5.3 (4.2)0.02 Parity (mean)2.2 (1.9)2.9 (2.5)4.9 (3.7)0.004

41. Comparisons of Study Groups VariableNo Diabetes (N=159) Diabetic, no Metformin (N=18) Diabetic with Metformin (N=18) P-value FIGO Stage I38 (23.9)3 (16.7) 0.16 II10 (6.3)4 (22.2)3 (16.7) II67(42.109 (50.0)6 (33.3) IV43 (27.0)2 (11.1)6 (33.3) Histology0.64 Serous74 (46.5)6 (33.3)7 (38.9) Mucinous18 (11.3)2 (11.1)1(5.6) Endometriod18 (11.3)3 (16.7)1 (5.6) Clear cell6 (3.8)1 (5.6)0 (0.0) Carcinoma, NOS43 27.0)6 (33.3)9 (50.0)

42. Treatment Related Variables in Study Groups VariableNon-Diabetics (N=159) Diabetics, no Metformin (N=18) Diabetes, with Metformin (N=18) P-Value ASA Class I-II38 (23.9)5 (27.8)7 (38.9)0.28 II-IV34 (21.4)3 (16.7)2 (11.1) No Surgery25 (15.7)7 (38.9)5 (27.8) Not recorded62 (39.0)3 (16.7)4 (22.2) Platinum Received63 (39.6)3 (16.7)6 (33.3)0.11 None44 (27.7)8 (44.4)3 (16.7) Not recorded52 (32.7)9 (50.0)11 (61.1) Taxane Received62 (39.0)4 (22.2)6 (33.3)0.31 None44 (27.7)7 (38.9)3 (16.7) Not recorded53 (33.3)9 (50.0)11 (61.1)

43. All Cause Mortality Proportions Among Three Exposure Groups (N=122 deaths)

44. Median Survival Time, Date of Diagnosis until date of Recurrence or Death, CRMC, Epithelial Ovarian Cancer Patients, 2001-2010

45. Life table estimates of progression–free survival among three groups of epithelial ovarian cancer patients, CRMC, Fresno, 2001-2010. (log rank test p=0.549)

46. P=0.05

47. Cox Regression estimates of survival without recurrence outcomes among epithelial ovarian cancer patients, adjusted for age at diagnosis. The two groups are ovarian cancer patients with type II diabetes using Metformin (n=16) and ovarian cancer patients with or without type II diabetes not using Metformin (n=149). (p = 0.393)

48. Cox Regression Model Hazard Ratios for Progression-Free and Overall Survival VariableProgression Free Survival Overall Survival DM/Metformin StatusHazard ratioHazard Ratio Non-Diabetic1.00 Diabetic, no metformin1.18 (.63-2.20)O.83(.40-1.67) Diabetic, metformin0.85 (.45-1.58)0.92(.46-1.79)

49. Limitations/Conclusions This is not a randomized clinical trial and sample size is limited. Data quality issues are important, and it is important to recognize the limitations of medical records as a source for research data. Among 220 epithelial ovarian cancer patients at CRMC, Fresno, approximately 72% had never been diagnosed with diabetes, 8 % had diabetes but no metformin exposure and, 8% had exposure to the drug metformin. Metformin users were older, more likely to be Hispanic and to be of higher parity and gravity than non metformin users. Survival among ovarian cancer patients exposed to metformin was not statistically different from those not exposed, although there was a suggestive improvement in survival in metformin users in younger aged women.

50. The French Lilac plant, Galega officinalis