Richard J. Santen, MD Disclosures NAMS 2016 Translational Science - - PDF document

10/11/2016 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 21:1038-48,2012 Santen RJ, Yue W, Heitjan D

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ADH DCIS HELU

Start of mutation cascade through Initiation events

IBC IBC

Life History of a Breast Tumor

ADH DCIS HELU

Start of mutation cascade through Initiation events

IBC IBC Average of 11 driver mutations in breast cancers

ADH

DCIS

HELU

Detection threshold

IBC

To be diagnosed, the tumor must exceed the detection threshold

What determines the detection threshold?

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• <40 1.63 cm
• 40-49

1.44 cm

• 50-59

1.25 cm

• 60-69

1.07 cm

• >70

0.88 cm

Average for the WHI age 50-69 1.16 cm

Influence of Age

• n Detection Threshold

30 40 50 60 70 80

Change in mammographic density with age

30 40 50 60 70 80

Change in mammographic density with age

30 40 50 60 70 80

Change in mammographic density with age

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ADH

DCIS

HELU

IBC

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

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50 100 150 200 250 50-69 year old

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 ?

Only tumors with a doubling time of 50 days or less

50 100 150 200 250 50-69 year old

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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

Percentage of tumors in the WHI arising de novo

ADH

DCIS

HELU

IBC

What was prevalence of undiagnosed tumors at start of WHI Study?

Total 7% Invasive 1% In Situ 6%

Occult breast cancers diagnosed at autopsy Ages 40-80

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ADH

DCIS

HELU

IBC

Prevalence of undiagnosed tumors at start of WHI Study

• 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

Iterative Modeling

De Novo Tumor

ADH

DCIS

HELU

IBC

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Observed incidence is taken from the SEER 1998 to 2007 population data

Compare observed with expected

200 day doubling time

• 200 day average doubling time
• 1.16 cm detection threshold
• 7 % prevalence in women ages 50-80

Model parameters based

• n best fit with observed data

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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

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• 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 +

WHI E+P Study

Effective doubling times of: 190 days 170 days 150 days 130 days 110 days

Iterations

150 day doubling time 200 day doubling time ADH

DCIS

HELU

IBC

E+P HR 1.26

Life history of a breast tumor

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41

1 2 3 4 5 6 7 1 5 10 15 20 25 30 Percent in each doubling category Doublings Hormone naïve Hormone therapy

43

How does the predicted risk of breast cancer Influence excess risk attributable to E + P ?

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Relative Risk Absolute Risk Per 5 years Excess Risk per 1000 women per 5 years

1.25 1.0% 3 1.25 2.5% 6 1.25 5.0% 13 1.25 7.5% 19 1.25 10% 25

CEE alone arm

• f the WHI

23% reduction In breast cancer incidence

Ages 50-79

placebo CEE HR 0.77 (CI 0.62-0.95)

• 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

Hypothesis

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MCF-7 >6 months LTED

Estrogen deprived media

In Vitro Model of Long Term Estrogen Deprivation

0.5 1 1.5 control

• 14
• 12
• 10
• 8

Apoptosis (fold of induction) E2 concentration (M)

Wild Type Cells

2 4 6 8 10 control

• 14
• 12
• 10
• 8

Apoptosis (fold of induction) E2 concentration (M)

LTED Cells

0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8

Weeks

Average tumor volume (cm2) Control 0.3 cm E2 Treatment Begins P<.0001

Data of VC Jordan

Long term anti-estrogen treated xenografts

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10 20 30 40 50 60 P<.00014

*

control E2 (5 days)

Percent apoptosis

Jordan et al

Model based on apoptosis used to predict effect

• f estrogen alone on breast cancer risk

Women treated with estrogen, washed out, and then randomized to CEE experienced no decrease in breast cancer HR 1.02 (0.70-1.50)

Data in support of need for long term estradiol deprivation to experience breast cancer reduction

10/11/2016 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

• 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

Implications Summary

• 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 Thank you for your attention