Postmenopausal Hormone Therapy

And

The Risk of Breast Cancer

A Contrary Thought Leon Speroff, M.D.

The Cover of The LancetThe Cover of The LancetJuly 9-15, 2005July 9-15, 2005

““If everything has to beIf everything has to bedouble-blinded, randomised,double-blinded, randomised,and evidence-based, whereand evidence-based, wheredoes that leave new ideas?”does that leave new ideas?”

Speroff

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

Speroff

WHI: E/P Updated Breast Cancer ReportWHI: E/P Updated Breast Cancer Report

E/P Placebo RatioInvasive 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

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, 1997Speroff

Reanalysis of World’s Breast Cancer Data

Lancet 350:1047, 1997

Current and recent users had no metastaticdisease.

Decreased risk of fatal breast cancer in users.

Speroff

AN APPARENT PARADOX

The observational studies that find:

At the same time, indicate:

Increased risk

Decreased mortality

Speroff

BETTER PROGNOSISFOR ESTROGEN USERS

BETTER PROGNOSISFOR 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

Detection/surveillance bias = Earlier diagnosis

Hormonal effects on a pre-existing tumor = Less aggressive stage

PLUS

Speroff

Review of Oregon ExperienceReview 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

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 EffectOn Pre-Existing Tumors

Differentiation of tumor cells (or inhibition ofde-differentiation) allowing time for the stromalreaction that leads to earlier detection.

Speroff

Causation or Early DetectionSimilar 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

Ontogeny of Breast Cancer

CancerStartsHere

StemCells

TransitionDuctal CellsLobular Cells

HormoneEffects

Speroff

WHI: Updated Breast Cancer ReportWHI: Updated Breast Cancer Report

E/P Placebo RatioInvasive 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

WHI: Updated Breast Cancer ReportWHI: 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 wereclassified as localized disease!!

Maturitas 2006;55:103

0 1 2 3 4 5 6

0.8

0.6

0.4

0.2

0

DE

TE

CT

ION

(%

) E+P

PLACEBO

SEER Data, 1983-1987

OHSU HRT WHI HRT

SEER Data, 1983-1987

OHSU No HRTWHI No HRT

Speroff

WHI: Updated Breast Cancer ReportWHI: Updated Breast Cancer Report

E/P Placebo RatioInvasive 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

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

WHI: Updated E-Only Breast Cancer ReportWHI: 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

WHI: Differences Between E-P and E Arms WHI: Differences Between E-P and E Arms

1. Cardiovascular E-only: more obese,more hypertension & diabetes, less activity.

2. 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

Int J Cancer 2005;114:448Breast Cancer Res Treat 2008;107:103

Int J Cancer 2011;128:144

French E3N Cohort Study

133,744 women; 8.6 years follow-up55% 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)

SPEROFF

Int J Cancer 2005;114:448Breast Cancer Res Treat

2008:107:103

French E3N Cohort Study

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

SPEROFF

Cancer 101:1490, 2004

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.

Speroff

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

Speroff

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

All Causes MortalityStage I:E only 1.04 (0.77-1.42) 1.23 (0.72-2.10)E-P 0.69 (0.48-0.99) 0.52 (0.26-1.04)Stage II:E only 0.86 (0.65-1.14) 1.01 (0.72-1.41)E-P 0.53 (0.39-0.73) 0.69 (0.48-0.98)

Br J Cancer 93:392, 2005

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 Dx Adj. Rate RatioFormer 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)

1.56

Speroff

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 SAMEDECREASE 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

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

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

Progestins & PR-A, PR-B Molec Endocr 19:574, 2005 Br Ca Res Treat 79:233, 2003

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

2. 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

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

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.

The Message for Clinicians

Effect greater with E/P, more rapid, andlower 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 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 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 Risk of Breast Cancer:

The evidence does not support a major increase in risk.

Positive family history not a contraindication.

Speroff

The Message for Patients

The Risk of Breast Cancer:

1. A contrasting example.

2. An alternative explanation.

Speroff