postmenopausal hormone therapy and the risk of breast cancer a contrary thought leon speroff, m.d
TRANSCRIPT
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