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

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

0

2

4

6

8

10

12

14

16

18

Incidence Rate Mortality rate

Year Dx or Death

Age Adjusted Rate/100,000

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

NH White NH Black Hispanic Asian/PI0

2

4

6

8

10

12

14

16 Incidence Rate Mortality Rate

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

00 yea

rs

01-0

4 ye

ars

05-0

9 ye

ars

10-1

4 ye

ars

15-1

9 ye

ars

20-2

4 ye

ars

25-2

9 ye

ars

30-3

4 ye

ars

35-3

9 ye

ars

40-4

4 ye

ars

45-4

9 ye

ars

50-5

4 ye

ars

55-5

9 ye

ars

60-6

4 ye

ars

65-6

9 ye

ars

70-7

4 ye

ars

75-7

9 ye

ars

80-8

4 ye

ars

85+ y

ears

0

10

20

30

40

50

60

Age Specific Rate

Age Dx

Rate/100,000

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

00 yea

rs

01-0

4 ye

ars

05-0

9 ye

ars

10-1

4 ye

ars

15-1

9 ye

ars

20-2

4 ye

ars

25-2

9 ye

ars

30-3

4 ye

ars

35-3

9 ye

ars

40-4

4 ye

ars

45-4

9 ye

ars

50-5

4 ye

ars

55-5

9 ye

ars

60-6

4 ye

ars

65-6

9 ye

ars

70-7

4 ye

ars

75-7

9 ye

ars

80-8

4 ye

ars

85+ y

ears

0

10

20

30

40

50

60

70

NH White NH Black Hispanic Asian/PI

Age Dx

Rate/100,000

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)

Localised Regional Distant Unstaged0

10

20

30

40

50

60

70

1518

61

6

Percent

Percent Dx

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

Localized Regional Distant Unstaged0

10

20

30

40

50

60

70

80

90

100

Stage at Dx

Percent Surviving 5 Years

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

Diagnosis 1-Year 2-Year 3-Year 4-Year 5-Year0

10

20

30

40

50

60

70

80

90

100100

75.4

63.9

55.5

49.545.2

Years Since Diagnosis

Percent Surviving

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)

SJV California0

5

10

15

20

25

All Race/Ethnic Groups Hispanics Only

Area of Residence

Percent of the Population

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, two-sided 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

ASA Class

No Surgery 47 21.3

Class I-II 52 23.6

Class II-IV 41 18.6

Unknown 80 36.4

Platinum Chemo. Rx

None 61 27.7

Rec’d 77 35.0

Unknown 82 37.3

Taxane Chemo Rx

None 60 27.3

Rec’d. 77 35.0

Unknown 83 37.7

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 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

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

Comparisons of Study Groups

Variable No Diabetes (N=159)

Diabetic, no Metformin (N=18)

Diabetic with Metformin (N=18)

P-value

FIGO Stage

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)

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

ASA Class

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)

Platinum

Received 63 (39.6) 3 (16.7) 6 (33.3) 0.11

None 44 (27.7) 8 (44.4) 3 (16.7)

Not recorded 52 (32.7) 9 (50.0) 11 (61.1)

Taxane

Received 62 (39.0) 4 (22.2) 6 (33.3) 0.31

None 44 (27.7) 7 (38.9) 3 (16.7)

Not recorded 53 (33.3) 9 (50.0) 11 (61.1)

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

No

Diabe

tes

DM/N

o M

etfo

rmin

Diabe

tes/M

etfo

rmin

0

0.2

0.4

0.6

0.8

% Dead at End of F.U.

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

Non Diabetic (N=134) Diabetes, no Metformin (N=15)

Diabetes, Metformin (N=15)

0

100

200

300

400

500

600

700

800

900

1000

579

765

893

Comparison Groups

No. of Days

P=0.549

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.

The French Lilac plant, Galega officinalis