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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


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

WHI: E/P Updated Breast Cancer Report
E/P
Invasive breast ca
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6 +
12
26
29
44
43
45
19 cases
32
22
27
21
29
Noninvasive
47
37
4
4
Deaths
Speroff
Placebo
JAMA 2003;289:3243
Ratio
0.62 (0.29-1.23)
0.77 (0.46-1.30)
1.26 (0.73-2.20)
1.54 (0.95-2.49)
1.99 (1.18-3.35)
1.35 (0.85-2.16)
(NS)
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
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
The observational studies that find:
Increased risk
At the same time, indicate:
Decreased mortality
Speroff
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
Detection/surveillance bias = Earlier diagnosis
PLUS
Hormonal effects on a pre-existing tumor
= Less aggressive stage
Speroff
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
Differentiation of tumor cells (or inhibition of
de-differentiation) allowing time for the stromal
reaction that leads to earlier detection.
Speroff
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
Ontogeny of Breast Cancer
Cancer
Starts
Here
Stem
Cells
Hormone
Effects
Transition
Ductal Cells
Lobular Cells
WHI: Updated Breast Cancer Report
E/P
Placebo
Invasive breast ca
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6 +
12
26
29
44
43
45
19 cases
32
22
27
21
29
Noninvasive
47
37
Ratio
0.62 (0.29-1.23)
0.77 (0.46-1.30)
1.26 (0.73-2.20)
1.54 (0.95-2.49)
1.99 (1.18-3.35)
1.35 (0.85-2.16)
(NS)
After adjustments 1.20 (0.94-1.53) !!
Speroff
JAMA 2003;289:3243
2010;304:1684
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
E+P
PLACEBO
DETECTION (%)
0.8
0.6
0.4
0.2
0
0
1
2
3
4
Maturitas 2006;55:103
5
6
OHSU HRT
SEER Data, 1983-1987
WHI HRT
OHSU No HRT
WHI No HRT
SEER Data, 1983-1987
WHI: Updated Breast Cancer Report
E/P
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6 +
Placebo
Invasive breast ca
12
19 cases
26
32
29
22
44
27
43
21
45
29
Ratio
0.62 (0.29-1.23)
0.77 (0.46-1.30)
1.26 (0.73-2.20)
1.54 (0.95-2.49)
1.99 (1.18-3.35)
1.35 (0.85-2.16)
After adjustments 1.20 (0.94-1.53) !!
Risk decreased with time!!
Speroff
JAMA 2003;289:3243 2010:304:1684
Maturitas 55:103, 2006
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 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.
Speroff
JAMA 2006;295:1647
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!
Speroff
French E3N Cohort Study
SPEROFF
133,744 women; 8.6 years follow-up
55% gels; 45% patches
E alone
RR =
E/Progesterone RR =
E/Progestins
RR =
1.29 (1.02-1.65)
1.00 (0.83-1.22)
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
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
Nurses Health Study:
Risk of Invasive Breast Cancer
ER+/PR+
<5 yrs
E alone 46 1.02 (0.77-1.38
E/P
5+ yrs
73 1.37 (1.06-1.78)
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
Cancer 101:1490, 2004
Is E/P Better?
Very large prospective study, 374,465 screened women
in 6 U.S. mammography registries:
<5 yrs
E alone
E/P
0.86 (0.71-1.03)
0.85 (0.73-0.98)
5+ yrs
0.92 (0.84-1.00)
1.49 (1.36-1.63)
After E/P for 5+ yrs: lower grade & stage, more ER+
J Clin Oncol 21:431, 2003
Speroff
1,081 E only; 1,399 E-P; 4,956 nonusers:
Breast Ca Case
All Causes
Mortality
Stage 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
Speroff
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 Ratio
Former E
Current E
0.86 (0.71-1.05)
0.91 (0.77-1.09)
Former E-P
Currrent E-P
0.96 (0.62-1.50)
0.69 (0.55-0.88)
E-P for 5 or more years
0.60 (0.43-0.84)
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.
1.56
2. This decrease occurred
within two years of initial WHI
reports: WILL PRE-EXISTING TUMORS REGRESS
OR SHOW UP LATER?
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,
1.56
producing benefical change in PR-A:PR-B ratio.
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. Decreases1.56
expression of COX-2, mediator of
aromatase and HER-2/neu.
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.
1.56 with lower grade/stage tumors and
5. E/P associated
reduces breast cancer mortality.
Speroff
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 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 preexisting 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