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Postmenopausal Hormone Therapy And The Risk of Breast Cancer A Contrary Thought. Leon Speroff, M.D. The Cover of The Lancet July 9-15, 2005. “If everything has to be double-blinded, randomised, and evidence-based, where does that leave new ideas?”. Speroff.

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Postmenopausal Hormone Therapy And The Risk of Breast Cancer A Contrary Thought

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Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Postmenopausal Hormone Therapy

And

The Risk of Breast Cancer

A Contrary Thought

Leon Speroff, M.D.


The cover of the lancet july 9 15 2005

The Cover of The LancetJuly 9-15, 2005

“If everything has to be

double-blinded, randomised,

and evidence-based, where

does that leave new ideas?”

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

              

Most Important Unanswered Question

Postmenopausal Hormone Therapy and

the Risk of Breast Cancer:

Do hormones initiate new tumor growth or

promote the growth of pre-existing tumors?

Speroff

              


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI: E/P Updated Breast Cancer Report

E/P Placebo Ratio

Invasive breast ca

Year 1 12 19 cases 0.62 (0.29-1.23)

Year 2 26 32 0.77 (0.46-1.30)

Year 3 29 22 1.26 (0.73-2.20)

Year 4 44 27 1.54 (0.95-2.49)

Year 5 43 21 1.99 (1.18-3.35)

Year 6 + 45 29 1.35 (0.85-2.16)

Noninvasive 47 37 (NS)

Deaths 4 4

JAMA 2003;289:3243

Speroff


Reanalysis of world s breast cancer data

Reanalysis of World’s Breast Cancer Data

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

Findings:

Current users 5+ years: RR = 1.35 (1.21-1.49)

No effect of family history

Lancet 350:1047, 1997

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Reanalysis of World’s Breast Cancer Data

Lancet 350:1047, 1997

Current and recent users had no metastatic

disease.

Decreased risk of fatal breast cancer in users.

Speroff


An apparent paradox

AN APPARENT PARADOX

The observational studies that find:

Increased risk

At the same time, indicate:

Decreased mortality

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

BETTER PROGNOSIS

FOR ESTROGEN USERS

Detection/surveillance Bias:

Hormone users have more mammograms.

Different biology, corrected for mammography:

Fewer large tumors,

More grade 1 tumors.

Bonnier, et al, Obstet Gynecol 85:11, 1995

Manjer, et al, Int J Cancer 92:919, 2001

Gertig, et al, Br Ca Res Treat 80:267, 2003

Pappo, et al, Ann Surg Oncol 11:52, 2004

Speroff


An answer to the apparent paradox

An Answer to the Apparent Paradox

Detection/surveillance bias = Earlier diagnosis

PLUS

Hormonal effects on a pre-existing tumor

= Less aggressive stage

Speroff


Review of oregon experience

Review of Oregon Experience

Long-term hormone users had:

More tumors detected by mammography

More ductal ca-in-situ

More stage I, node negative tumors

Better survival rates (100% after 12 yrs)

in tumors detected by mammography)

No differences in histology or ER status

Am J Surg 2008;196:505


The hormonal effect on pre existing tumors

The Hormonal EffectOn Pre-Existing Tumors

Differentiation of tumor cells (or inhibition of

de-differentiation) allowing time for the stromal

reaction that leads to earlier detection.

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Causation or Early Detection

  • Similar results with: hormone therapy, oral contraceptives, and pregnancy.

  • Observations that favor early detection:

  • Increase observed very fast.

  • ER+ lower grade and stage disease.

  • Return to baseline after therapy.

  • Better survival rates.

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Ontogeny of Breast Cancer

Cancer

Starts

Here

Stem

Cells

Hormone

Effects

Ductal Cells

Lobular Cells

Transition


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI: Updated Breast Cancer Report

E/P Placebo Ratio

Invasive breast ca

Year 1 12 19 cases 0.62 (0.29-1.23)

Year 2 26 32 0.77 (0.46-1.30)

Year 3 29 22 1.26 (0.73-2.20)

Year 4 44 27 1.54 (0.95-2.49)

Year 5 43 21 1.99 (1.18-3.35)

Year 6 + 45 29 1.35 (0.85-2.16)

Noninvasive 47 37 (NS)

After adjustments 1.20 (0.94-1.53) !!

JAMA 2003;289:3243

2010;304:1684

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI: Updated Breast Cancer Report

Problem with tumor size and localized disease:

Tumor size of 1.5-1.8 25-28% positive nodes in

literature and SEER

15.8% in WHI placebo group

WHI: No nodes examined-9.9/9.1%; missing info-4.0/4.7%

Tumors less than 1 cm with no node information were

classified as localized disease!!

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

0.8

0.6

0.4

0.2

0

E+P

PLACEBO

DETECTION (%)

0 1 2 3 4 5 6

Maturitas 2006;55:103


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

OHSU HRT

WHI HRT

SEER Data, 1983-1987


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

OHSU No HRT

WHI No HRT

SEER Data, 1983-1987


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI: Updated Breast Cancer Report

E/P Placebo Ratio

Invasive breast ca

Year 1 12 19 cases 0.62 (0.29-1.23)

Year 2 26 32 0.77 (0.46-1.30)

Year 3 29 22 1.26 (0.73-2.20)

Year 4 44 27 1.54 (0.95-2.49)

Year 5 43 21 1.99 (1.18-3.35)

Year 6 + 45 29 1.35 (0.85-2.16)

After adjustments 1.20 (0.94-1.53) !!

Risk decreased with time!!

JAMA 2003;289:3243 2010:304:1684

Maturitas 55:103, 2006

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI Comparison: Trial & Observ. Data

“Both yield same conclusions when adjusted

for time from menopause to treatment.”

Problem: Trial- more BSO, parity differences,

less mammography, less prior use,

fewer risk factors, older, heavier.

THE TWO POPULATIONS DIFFER IN RISK PROFILE!!

Am J Epidemiol 2008;167:1207 JNCI 2013;105:526

\

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI: Updated E-Only Breast Cancer Report

Overall: HR=0.80; CI=0.62-1.04

Adherent Pts: HR=0.67 CI=0.47-0.97

No effect on in-situ disease.

Only ductal cancers and in women with no prior

hormone therapy.

More follow-up mammograms/biopsies/aspirations.

JAMA 2006;295:1647

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

WHI: Differences Between E-P and E Arms

  • Cardiovascular E-only: more obese,

  • more hypertension & diabetes, less activity.

  • Breast Cancer E-only:

  • – more early and less late births.

  • – 21% more previous and

  • 17% more with longer duration

  • of hormone use.

  • TWO DIFFERENT POPULATIONS!

  • Ann Epidemiol 2003;13:S78

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

French E3N Cohort Study

SPEROFF

133,744 women; 8.6 years follow-up

55% gels; 45% patches

E alone RR = 1.29 (1.02-1.65)

E/Progesterone RR = 1.00 (0.83-1.22)

E/Progestins RR = 1.77 (1.40-2.24)

Int J Cancer 2005;114:448

Breast Cancer Res Treat 2008;107:103

Int J Cancer 2011;128:144


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

French E3N Cohort Study

SPEROFF

Nonoral E/Progestins <2yrs: 1.37 (1.07-1.72)

<1yr: 1.7 (1.3-2.3)

Problems: Users & nonusers not comparable

Very fast detection!

? Bioequivalent doses

? E/Progestins: More potent differentiation

Int J Cancer 2005;114:448

Breast Cancer Res Treat

2008:107:103


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Nurses Health Study:

Risk of Invasive Breast Cancer

ER+/PR+ <5 yrs 5+ yrs

E alone 46 1.02 (0.77-1.38 73 1.37 (1.06-1.78)

E/P 112 1.74 (1.40-2.17) 99 2.05 (1.64-2.57)

E/P users: younger, lower stage & grade,

increase only in ER+/PR+ & greater in lean women.

Cancer 101:1490, 2004

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Is E/P Better?

Very large prospective study, 374,465 screened women in 6 U.S. mammography registries:

<5 yrs 5+ yrs

E alone 0.86 (0.71-1.03) 0.92 (0.84-1.00)

E/P 0.85 (0.73-0.98) 1.49 (1.36-1.63)

After E/P for 5+ yrs: lower grade & stage, more ER+

J Clin Oncol 21:431, 2003

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Kaiser Cohort Study

1,081 E only; 1,399 E-P; 4,956 nonusers:

Breast Ca Case

All Causes Mortality

Stage I:

E only1.04 (0.77-1.42)1.23 (0.72-2.10)

E-P0.69 (0.48-0.99)0.52 (0.26-1.04)

Stage II:

E only0.86 (0.65-1.14)1.01 (0.72-1.41)

E-P0.53 (0.39-0.73)0.69 (0.48-0.98)

Br J Cancer 93:392, 2005

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Breast Cancer Mortality Cancer Epidem Biomark Prev 17:864, 2008

Collaborative Breast Cancer Study Cohort: 12,269 women

in Wisc., Mass., NH; followed 1980 to 2006

Tx at DxAdj. Rate Ratio

Former E 0.86 (0.71-1.05)

Current E 0.91 (0.77-1.09)

Former E-P 0.96 (0.62-1.50)

Currrent E-P 0.69 (0.55-0.88)

E-P for 5 or more years 0.60 (0.43-0.84)


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

U.S. Breast Cancer Prevalence

NEJM 356:1670, 2007

Rate decreased 2.5% in 2002, 7% in 2003, level in 2004.

Mostly ER+ tumors in women ages 50-69, BUT SAME

DECREASE IN WOMEN 70+ (low use of hormones).

Two possible reasons:

1. Use of mammography declined 2000 through 2005.

2. This decrease occurred within two years of initial WHI

reports: WILL PRE-EXISTING TUMORS REGRESS

OR SHOW UP LATER?

1.56

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Geneva Prevalence Statistics

BMC Cancer 2006;6:78

Beginning in 1997, peak of breast cancer in Geneva:

Increased in younger women, peak at age 60-64.

Increase only in Stage I & II disease, ER+ tumors.

Increase only in hormone users.

1.56

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

E-P Favorably Influences Gene

Expression

BMC Medicine 2006;4:16

In ER positive tumors, E-P therapy was associated

with better survival, altering the regulation of

276 genes involved in DNA repair and cell-cycle

regulation.

1.56

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Progestins & PR-A, PR-B

Molec Endocr 19:574, 2005

Br Ca Res Treat 79:233, 2003

  • Genes up-reg. by E are down-reg. by progestins.

  • PR-A excess: aggressive, poorly diff. tumors.

  • 4. PR-A dominant in absence of progestins.

  • 4. Progestins decrease breast tissue levels of PR-A,

  • producing benefical change in PR-A:PR-B ratio.

1.56

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Benefits of Progesterone Receptor

Molec Endocrinol 2008;22:1812

1. PR functions with and without ligand.

2. Antagonizes inflammatory response.

3. Blocks expression of oncogenic growth factors.

4. Inhibits induction of aromatase enzyme activity.

5. Decreases expression of COX-2, mediator of

aromatase and HER-2/neu.

1.56

Speroff


Postmenopausal hormone therapy and the risk of breast cancer a contrary thought

Evidence for Beneficial Effect

of Progestins

1. E/P increases receptor-postiive tumors quickly.

2. E/P down regulates estrogen-regulated genes.

3. E/P actives repair and normal function genes.

4. E/P alters the PR-A:PR-B ratio.

5. E/P associated with lower grade/stage tumors and reduces breast cancer mortality.

1.56

Speroff


The message for clinicians

The Message for Clinicians

Effect greater with E/P, more rapid, and

lower grade/stage, better survival rates:

JAMA 289:3243, 2003

JAMA 289:3254, 2003

Cancer 97:1387, 2003

Cancer 100:2328, 2004

Cancer Causes Control 17:695, 2006

Speroff


The message for clinicians1

The Message for Clinicians

Effect in ER+/PR+, lobular cancers,

only in current users:

JAMA 289:3254, 2003

Br J Cancer 91:644, 2004

Cancer 100:2328, 2004

Cancer 101:1490, 2004

Cancer Causes Control 17:695, 2006

Arch Intern Med 166:1027, 2006

Speroff


The message for clinicians2

The Message for Clinicians

There is either a small increase in the risk of

breast cancer with E/P or the data reflect

an impact on pre-existing tumors.

It’s possible that E/P causes greater

differentiation and earlier detection of pre-

existing tumors resulting in better outcomes.

Speroff


The message for patients

The Message for Patients

The Risk of Breast Cancer:

The evidence does not support a major

increase in risk.

Positive family history not a contraindication.

Speroff


The message for patients1

The Message for Patients

The Risk of Breast Cancer:

1. A contrasting example.

2. An alternative explanation.

Speroff


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