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Romero IL, McCormick A, McEwen et al. 2012. Obstetrics & Gynecology, vol. 119:61-67 What does the descriptive epidemiology teach us? Changes in Cancer Mortality Rates, 2006-2010. U.S. Trend in Ovarian Cancer Incidence and Mortality Rates, California, 1988-2011 18 16 14 12 AGE ADJUSTED RATE/100,000 10 8 6 4 2 0 YEAR DX OR DEATH Incidence Rate Mortality rate Age Adjusted Incidence and Mortality Rates of Ovarian Cancer in California, 2007-2011, by Race/Ethnicity Incidence Rate 16 Mortality Rate 14 12 10 8 6 4 2 0 NH White NH Black Hispanic Asian/PI Age Specific incidence Rates of Ovarian cancer In California, 2007-2011 Age Specific Rate 60 50 40 RATE/100,000 30 20 10 0 AGE DX Age Specific incidence rate of Ovarian Cancer in California, 1988-2011, by Race/Ethnicity 70 60 50 40 RATE/100,000 30 20 10 0 AGE DX NH White NH Black Hispanic Asian/PI Age Adjusted Ovarian Cancer Incidence Rates in California, 2007-2011, by County of Residence Age Adjusted Ovarian Cancer Mortality Rates, 2007-2011, in California, By County of residence What does the analytic epidemiology teach us? What “risk factors” alter risk of ovarian cancer? Risk Factors for Ovarian Cancer by Strength of Evidence What is the distribution of stage at diagnosis for ovarian cancer and why is this important for survival? Ovarian Cancer Stage Distribution, SEER Data, 2004-2010 (N=33,841) Percent 70 61 60 50 40 PERCENT DX 30 20 15 18 10 6 0 Localised Regional Distant Unstaged Five Year Relative Survival, Ovarian Cancer, U.S., SEER Data, 2004-2010, by Stage at Diagnosis 100 90 80 70 PERCENT SURVIVING 5 YEARS 60 50 40 30 20 10 0 Localized Regional Distant STAGE AT DX Unstaged Five Year Relative Survival, Ovarian Cancer, U.S. SEER Data, 2006-2010 100 100 90 80 75.4 70 63.9 60 55.5 49.5 PERCENT SURVIVING 50 45.2 40 30 20 10 0 Diagnosis 1-Year 2-Year 3-Year YEARS SINCE DIAGNOSIS 4-Year 5-Year 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. Proportions of the California Female Population, Age > 45 years, Ever Diagnosed with Diabetes (2011-2012 CHIS data) 25 20 15 PERCENT OF THE POPULATION 10 5 0 SJV California AREA OF RESIDENCE All Race/Ethnic Groups Hispanics Only 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). Frequency of Metformin prescription, U.S., 2012 (Lindsley, ACS. Chem Neuroscience, 2013, 4, 1133-1135). 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 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. 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. 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, twosided tests. 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. Results Characteristics of the Study Cohort, Histology Histology Number (N=220) Percent Serous 98 44.5 Mucinous 23 10.5 Endometrioid 24 10.9 Clear Cell 7 3.2 Adenocarcinoma, NOS 53 24.1 Carcinoma, NOS 15 6.8 Total 220 100 Characteristics of the Cohort, Demographics, Labs and Follow-up (means, medians and SD) Variable Mean SD Age at Dx (N=220) 59.1 14.6 BMI (N=199) 29.7 6.8 Blood Glucose at Dx (N=186) 120.3 37.7 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) Characteristics of the Study Cohort, Race/Ethnicity Race/Ethnicity Number (N=220) Percent Non-Hispanic White 145 65.9 Non-Hispanic Black 7 3.2 Hispanic 56 25.5 Asian/Pacific Islander 12 5.5 Total 220 100 Characteristics of the Cohort, Stage at Diagnosis Stage at Diagnosis Number (N=220) Percent Localized 49 22.3 Regional 17 7.7 Remote 88 40 Distant Metastasis 62 28.2 Unknown 4 1.8 Total 220 100 Characteristics of the Cohort, Smoking Smoking Status Number (N=220) Percent Never Smoker 149 67.7 Current Smoker 22 10 Past Smoker 38 17.3 Unknown 11 5 Total 220 100 Characteristics of the Cohort, Treatment Related Variables Variable Number (N=220) Percent No Surgery 47 21.3 Class I-II 52 23.6 Class II-IV 41 18.6 Unknown 80 36.4 None 61 27.7 Rec’d 77 35.0 Unknown 82 37.3 None 60 27.3 Rec’d. 77 35.0 Unknown 83 37.7 ASA Class Platinum Chemo. Rx Taxane Chemo Rx Characteristics of the Cohort, Diabetes Status Number (N=220) Percent Non-Diabetic 159 72.3 Diabetic 48 21.8 Unknown Diabetes Status 13 5.9 Total 220 100 Characteristics of the Cohort, Metformin Use/Exposure Metformin Use Number (N=220) Percent No Metformin Exposure 179 81.4 Metformin taken at or after Ca Dx 18 8.2 Metformin taken only prior to Ca Dx 4 1.8 Unknown Status 19 8.6 Total 220 100 Characteristics of the Cohort, Vital Status at End of Follow-up Vital Status at End of Follow-up Number (N=220) Percent Alive 90 40.9 Known Dead 122 55.4 Dead, Ovarian Ca 29 13.2 Dead, Other Cause 10 4.5 Dead, Unknown Cause 83 37.7 Unknown Vital Status 8 3.6 Total 220 100 Comparisons of the Study Groups Variable Non-Diabetic (n=159) Diabetic, no Diabetic, Metformin Use Metformin Use (N=18) (N=18) p-value Age at Dx (mean, SD) 57.3 (14.3) 65.8(14.5) 64.1( 15) 0.02 NHW 111 (.69) 8 (.44) 8 (.44) .005 NHB 4 (.02) 1 (.06) 1 (.06) Hispanic 37 (.23) 9 (.50) 5 (.28) Asian/PI 7 (.04) 0 4 (.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 Race/Ethnicity Comparisons of Study Groups Variable No Diabetes (N=159) Diabetic, no Metformin (N=18) Diabetic with Metformin (N=18) P-value I 38 (23.9) 3 (16.7) 3 (16.7) 0.16 II 10 (6.3) 4 (22.2) 3 (16.7) II 67(42.10 9 (50.0) 6 (33.3) IV 43 (27.0) 2 (11.1) 6 (33.3) FIGO Stage Histology 0.64 Serous 74 (46.5) 6 (33.3) 7 (38.9) Mucinous 18 (11.3) 2 (11.1) 1(5.6) Endometriod 18 (11.3) 3 (16.7) 1 (5.6) Clear cell 6 (3.8) 1 (5.6) 0 (0.0) Carcinoma, NOS 43 27.0) 6 (33.3) 9 (50.0) Treatment Related Variables in Study Groups Variable Non-Diabetics (N=159) Diabetics, no Metformin (N=18) Diabetes, with Metformin (N=18) P-Value I-II 38 (23.9) 5 (27.8) 7 (38.9) 0.28 II-IV 34 (21.4) 3 (16.7) 2 (11.1) No Surgery 25 (15.7) 7 (38.9) 5 (27.8) Not recorded 62 (39.0) 3 (16.7) 4 (22.2) Received 63 (39.6) 3 (16.7) 6 (33.3) None 44 (27.7) 8 (44.4) 3 (16.7) Not recorded 52 (32.7) 9 (50.0) 11 (61.1) Received 62 (39.0) 4 (22.2) 6 (33.3) None 44 (27.7) 7 (38.9) 3 (16.7) Not recorded 53 (33.3) 9 (50.0) 11 (61.1) ASA Class Platinum 0.11 Taxane 0.31 All Cause Mortality Proportions Among Three Exposure Groups (N=122 deaths) 0.8 0.7 0.6 0.5 % Dead at End 0.4 of F.U. 0.3 0.2 0.1 0 No Diabetes DM/No Metformin Diabetes/Metformin Median Survival Time, Date of Diagnosis until date of Recurrence or Death, CRMC, Epithelial Ovarian Cancer Patients, 2001-2010 Comparison Groups 1000 900 P=0.549 893 800 765 700 600 NO. OF 500 DAYS 579 400 300 200 100 0 Non Diabetic (N=134) Diabetes, no Metformin (N=15) Diabetes, Metformin (N=15) 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) P=0.05 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) Cox Regression Model Hazard Ratios for Progression-Free and Overall Survival Variable Progression Free Survival Overall Survival DM/Metformin Status Hazard ratio Hazard Ratio Non-Diabetic 1.00 1.00 Diabetic, no metformin 1.18 (.63-2.20) O.83(.40-1.67) Diabetic, metformin 0.85 (.45-1.58) 0.92(.46-1.79) 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. 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