10/11/2016. Richard J. Santen, MD. Disclosures. Key Question Regarding MHT and Breast Cancer Development. NAMS 2016 Translational Science Symposium

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1 Richard J. Santen, MD NAMS 2016 Translational Science Symposium Risks and Benefits Related to the Breast Disclosures Current Grant Funding: Pfizer Previous Advisory Boards: Pfizer, Teva, Novo-Nordisk, Shionogi Pharmaceuticals Key Question Regarding MHT and Breast Cancer Development Do the published effects represent de novo tumor formation or a hormonal effect on small, occult, undiagnosed tumors? One effect is initiation of tumors through induction of mutations and the other is receptor mediated stimulation of growth of pre-existing tumors We developed two models: one biologically based and the other computer based to answer this question Modeling of the Growth Kinetics of Occult Breast Tumors: Role in Interpretation of Studies of Prevention and Menopausal Hormone Therapy, Cancer Epidemiology Biomarkers and Prevention 21: ,2012 Santen RJ, Yue W, Heitjan D 1

2 Life History of a Breast Tumor Average of 11 driver mutations in breast cancers Start of mutation cascade through Initiation events Start of mutation cascade through Initiation events To be diagnosed, the tumor must exceed the detection threshold Detection threshold What determines the detection threshold? 2

3 Influence of Age on Detection Threshold Change in mammographic density with age < > cm 1.44 cm 1.25 cm 1.07 cm 0.88 cm Average for the WHI age cm Change in mammographic density with age Change in mammographic density with age

4 Limit of clinical detection How long does it take for a de novo tumor to reach the detection threshold? It takes 30 doublings for a tumor to go from one cancer cell to a tumor of a billion cells, the number needed to reach a size of 1 cm in diameter Depends on the doubling time Median approximates 200 days 4

5 Average 16 years How many de novo tumors would have reached the diagnostic threshold within the 5.6 year duration of the WHI E+P study? year old Only tumors with a doubling time of 50 days or less year old 5

6 Percentage of tumors in the WHI arising de novo 15% have doubling times Of 50 days or less 15% of tumors have doubling time of 50 days or less Only tumors arising de novo during years one and two of the study would have 4.1 years to reach threshold of detection Years 1-2 detectable; years 3-5 not detectable; 2/5 x 15% = 6% Therefore only 6% of tumors arose de novo The other 94% arose from tumors in the occult, small undiagnosed pool What was prevalence of undiagnosed tumors at start of WHI Study? Occult breast cancers diagnosed at autopsy Ages In Situ 6% Invasive 1% Total 7% 6

7 Prevalence of undiagnosed tumors at start of WHI Study Iterative Modeling Parameters Doubling time of occult tumors Percentage of tumors in the reservoir Detection threshold Assumptions Log linear growth kinetics (confirmed in xenografts; Hormones and Cancer 2013) Gaussian distribution of sizes of occult tumors in the reservoir De Novo Tumor 7

8 Compare observed with expected 200 day doubling time Observed incidence is taken from the SEER 1998 to 2007 population data Model parameters based on best fit with observed data 200 day average doubling time 1.16 cm detection threshold 7 % prevalence in women ages

9 Population incidence Contralateral cancer incidence Computer based model Calculate yearly incidence of de novo tumors based on age related population incidence data Vary doubling times based on Gaussian distributions Correct for deaths from competing causes in the population Calibrate based on SEER population incidence data Model Developed to interpret risk of breast cancer from MHT 9

10 WHI E+P Study Used biologically based model 200 day doubling time 7% prevalence 1.16 cm detection threshold 80% of tumors diagnosed in E+P trial were ER + Iterations Effective doubling times of: 190 days 170 days 150 days 130 days 110 days Life history of a breast tumor 150 day doubling time E+P HR day doubling time 10

11 Percent in each doubling category Hormone naïve Hormone therapy Doublings 41 How does the predicted risk of breast cancer Influence excess risk attributable to E + P? 43 11

12 Relative Risk Absolute Risk Per 5 years % 3 Excess Risk per 1000 women per 5 years % % 13 CEE alone arm of the WHI % % 25 HR 0.77 (CI ) 23% reduction In breast cancer incidence Ages placebo CEE Hypothesis Conjugated equine estrogens caused apoptosis of occult tumors Long term deprivation of estrogen causes breast cancer cells to undergo apoptosis in response to estrogen The average age of women in the WHI was 63, 12 years after the average age of menopause 12

13 In Vitro Model of Long Term Estrogen Deprivation MCF-7 >6 months LTED Apoptosis (fold of induction) Wild Type Cells control E2 concentration (M) Estrogen deprived media LTED Cells Long term anti-estrogen treated xenografts Apoptosis (fold of induction) control E2 concentration (M) Average tumor volume (cm 2 ) Control 0.3 cm E 2 Treatment Begins P< Data of VC Jordan Weeks 13

14 Percent apoptosis P< * Model based on apoptosis used to predict effect of estrogen alone on breast cancer risk 0 control E 2 (5 days) Jordan et al Data in support of need for long term estradiol deprivation to experience breast cancer reduction Women treated with estrogen, washed out, and then randomized to CEE experienced no decrease in breast cancer HR 1.02 ( ) 14

15 Historical Footnote High dose estrogen was used to treat metastatic breast cancer Only effective in women at least 5 years postmenopausal Recent studies indicate that physiologic doses of estradiol also cause tumor regression in 30% of postmenopausal women with metastatic breast cancer Implications Need to treat these occult lesions before they become clinically detectable A form of hormone therapy for menopausal women which prevents these occult lesions from growing but relieves menopausal symptoms would be ideal Proof of principle Tamoxifen prevented breast cancer in a large British trial even when estrogen was given at the same time to treat menopausal symptoms Need to exploit this concept but develop more effective methods Summary Thank you for your attention Menopausal hormone therapy does not cause breast cancer but instead, exerts effects on undiagnosed, occult tumors E+P enhances tumor growth ( doubling time 200 days to 150 days on average) E alone given years after menopause causes apoptosis and results in decreased tumor incidence Breast cancer prevention with tamoxifen or raloxifene represents early treatment not true prevention University of Virginia Richard J. Santen MD 15