Download breast cancer survivors - CHU Saint

THS et Risque de cancer du sein
Club de Sénologie 29.01.04
Serge Rozenberg
CHU St Pierre, Free Universities of
Brussels
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HRT & Risk
HRT & prognosis
HRT after breast cancer
Epidemiological data
• Cumulative Risk of Breast Cancer to Age 70 Years According to Risk
Factor Status: Data from the Nurses' Health Study Colditz and Rosner
Am J Epidemiol 2000
Thomas Br J Cancer 1997
Relation between osteoporosis & Breast
cancer risk
BMD and breast cancer risk
Lowest quartile
Quartile 2
Quartile 3
Highest quartile
0
2
4
6
8
10
12
97 cancers in cohort of 6854 women >65 yrs Cauley et al 1996
Relation between osteoporosis & Breast
cancer risk
adapted from Zhang et al 1997
Bone mineral density and the risk of
breast cancer: the Rotterdam Study
• Cumulative breast cancer
incidence in quartiles of
absolute bone mineral
density (BMD). LS,
lumbar spine BMD; TR,
intertrochanteric BMD;
FN, femoral neck BMD;
WD, Ward's triangle
BMD.
van der Klift et al Bone 2003
Relation between osteoporosis & Breast
cancer risk
Screening Mammography in Elderly Women
(Rozenberg, Ham, Liebens JAMA. 2000;283:3202-3204)
Low risk of hip fracture among
elderly breast cancer survivors
• Medicare program hip fracture
• elderly women survivors of stage 0, I, or II breast
cancer (N = 5980) diagnosed between the ages of
55 and 64 years; using the Medicare 5% file,
• elderly women without histories of cancer
(N = 23,165) from National Cancer Institute's
Surveillance Epidemiology and End Results
(SEER)- regions.
• Medicare claims from 1993 through 1998,
followed women for hospitalization for hip
fracture or death until December 31, 1998.
Lamont and Lauderdale Annals of Epidemiology
Low risk of hip fracture among
elderly breast cancer survivors
• the rate ratio of hospitalization for hip
fracture for breast cancer survivors
relative to comparison patients was 0.63
(95% CI: 0.43–0.94) after adjusting for age,
race, socioeconomic status, geographic
location, cohort entry year, and medical
comorbidity.
Lamont and Lauderdale Annals of Epidemiology
November 2003,
Randomized controlled trial of
exercise training in postmenopausal
breast cancer survivors:
cardiopulmonary and quality of life
outcomes.
Courneya et al J Clin Oncol. May
2003.
To treat or not to treat ?
Breast cancer & HRT: collaborative
reanalysis of 51 epidemiological studies
Never users
< 1 yr
1-4 yr
5-9 yr
10-14
>=15 yr
0
Lancet 1997
0,5
1
1,5
2
Breast cancer & HRT: collaborative reanalysis
of 51 epidemiological studies
• among never-users of HRT the relative risk of
breast cancer increases by a factor of 1·028 (95%
CI 1·021-1·034) for each year older at menopause.
• increased by a factor of 1·023 (95% CI 1·0111·036; 2p=0·0002) for each year of use
• Lancet 1997
Obstet Gynecol 2001
Breast cancer and hormonereplacement therapy in the Million
Women Study
Lancet 2003; 362: 419-27
Relative risk of incident invasive breast cancer in relation
to recency of use of HRT
Breast cancer risk and HRT
regimens
1. Estrogens alone
• RR 1,34 (CI 95% 1,25-1,43) after 5 years
of use.
•
Risk disapears when last use exceeds 5
years.
Lancet 1997 oct 11;350(9084):1047-59
Relative risk of incident invasive breast cancer in relation to
recency, total duration of use, and type of HRT used at
baseline
Lancet 2003 Aug 9;362:419-27
Introduction
• Double blind randomized trial: WHI
RR 1,26 (CI 95% 1,00-1,59) after 5 years
of CHRT use.
JAMA 2002 Jul 17;288(3):321-33
Breast cancer risk and HRT
regimens
2. Estrogen and progestin
• Recent studies.
•
Limited number of cases (n ~ 100 à 400)
except in MWS (n = 1934).
•
One randomized trial: WHI (n = 166).
Relative risk of incident invasive breast cancer in relation to
recency, total duration of use, and type of HRT used at
baseline
Lancet 2003 Aug 9;362:419-27
Estimated cumulative incidence of breast and endometrial cancer per 1000
women in developed countries who never used HRT and who used HRT for 10 years,
beginning at age 50 years
Progesterone ?
• progestogens are reported to stimulate,
reduce, or have no effect on the mitotic
activity and proliferation of breast epithelial
cells
• stimulate, reduce, or have no effect on
hyperplastic lesions
Relative risk of incident invasive breast cancer by constituent
and regimen of oestrogen-progestagen combination HRT used at
baseline*
Lancet 2003 Aug 9;362:419-27
Relative risk of incident invasive breast cancer by constituent
and regimen of oestrogen-progestagen combination HRT used at
baseline*
Lancet 2003 Aug 9;362:419-27
Breast cancer risk and HRT
regimens
5. Estrogen used and dose:
Lancet 2003 Aug 9;362:419-27
Breast cancer risk and HRT
regimens
6. Type of administration:
Lancet 2003 Aug 9;362:419-27
Breast cancer risk and HRT
regimens
7. Tibolone
• Only one study: MWS (n = 184).
• Increased RR: 1,45 (CI 95% 1,25-1,68).
Prognostic factors and HRT
1. Observational studies
• Tumors are less agressive using HRT
(smaller, more often negative nodes and
lower grade…).
Prognostic factors and HRT
• 4 studies show an increased RR for ILC
with HRT.
• 3 studies show that RR especially increase
with CHRT: 2,01 (CI 95% 1,25-3,22) to
3,91 (CI 95% 2,05-7,44).
Prognostic factors and HRT
• Many biases:
-few cases,
-heterogenous studies,
-surveillance bias,
-confounding factors…
Prognostic factors and HRT
2. Randomized trial: WHI
• Increased risk of more advanced stages with
CHRT:
-Increased size (1,7 cm vs 1,5 cm) p = 0,04.
-Increased number of invaded nodes (45/199
vs 21/150) p = 0,03.
JAMA 2003 June 25;289(24):3243-3253
Prognostic factors and HRT
• Diminished accuracy of mammography
with HRT.
• But worsening of prognosis cannot be ruled
out.
Breast cancer mortality and HRT
• Recent meta-analysis shows a diminution of
mortality using HRT.
Am J Obstet Gynecol 2002 Feb;186:325-334
• WHI: few number of deaths (3 vs 2)
JAMA 2002 Jul 17;288(3):321-333
Breast cancer mortality and HRT
• Million Women Study (n = 191): Increased
mortality using HRT: RR 1,22 (CI 95%
1,05-1,41).
• Insufficient data to analyse the role of
different HRT regimens.
Lancet 2003 Aug 9;362:419-27
Conclusions
1. RR of breast cancer using HRT
• Breast cancer risk increases using HRT.
• Especially with CHRT in current users for
more than 5 years.
• No influence of dose, component used and
type of administration.
Conclusions
• RR also increases with estrogens alone and
tibolone.
• Increased RR disapears after 5 years since
last use.
Relative risk of incident invasive breast cancer in relation to
recency and type of HRT used.
Lancet 2003 Aug 9;362:419-27
Conclusions
• One randomized trial (WHI): CHRT.
• Many observational studies with insufficient
power.
• Not always comparable.
Conclusions
• Criticizable points about Million Women
Study :
-Recall bias,
-Selection bias,
-Surveillance bias.
Conclusions
• But this is the first observational study with
so many cases.
Conclusions
2. Prognostic factors and HRT
• Observational data are insufficient.
• WHI: worsening of prognosis.
Conclusions
3. Breast cancer mortality and HRT
• Insufficient data.
• An increased mortality cannot be excluded.
Questions
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Prevalence of postmenopausal symptoms ?
HRT data ?
Physicians willing to prescribe HRT ?
Patients willing to take HRT ?
Efficacy/ safety of other treatments?
(vaginal dryness)
(Osteoporosis prevention)
Prevalence and Treatment of Menopausal
Symptoms Among Breast Cancer Survivors
Harris et al 2002
Estrogen replacement therapy in
breast cancer survivors. A time for
change.
Breast Cancer Committees of the
Eastern Cooperative Oncology Group
Cobleigh, et al JAMA 1994 272: 540545. M. A.
HRT After Breast Cancer: A
Systematic Review and Quantitative
Assessment of Risk
• 11 eligible studies through May 1999, (4 had
control groups) and included 214 BRCA survivors
using HRT , DFI =52 months.
• mean follow-up: 30 months, 17 /214 HRT users
recurrences (4.2% per year), versus 66/623
controls (5.4% per year).
• RR = 0.64, 95% CI, 0.36 -1.15
• Including all 11 studies (669 HRT users), using
estimated control groups for the seven
uncontrolled trials, the combined RR was 0.82
(95% CI, 0.58 to 1.15).
Col et al Journal of Clinical Oncology, 2001
Cancer recurrence and mortality in
women using hormone replacement
therapy after breast cancer:
Meta-analysis
• Meurer, Milwaukee, The Journal of Family
Practice • December 2002 • Vol. 51, No. 12
References
Controled studies
Eden, et al; Menopause 1995
DiSaia, et al; Am J Obst Gynecol 1996
Marttunen, et al; Maturitas 2001
Ursic-Vrscaj, et al; Eur J Surg Oncol 1999
DiSaia, et al; Am J Clin Oncol 2000
Espie, et al; Proc ASCO 1999
Beckmann, et al; Gerburtsh u Frauenheilk 1998
Jo Marsden et al Fertility and Sterility, February 2000
Uncontroled studies
Wile, et al; Am J Surg 1993
Vassilopoulou-Sellin, et al; Gynecol Oncol 1997
Peters, et al; Ann Surg Oncol 2001
Guidozzi, et al; Int J Gynecol Obstet 1999
Natrajan, et al; Am J Obstet Gynecol 1999
Brewster, et al; Int J Fertil Womens Med 1999
Bluming, et al; Proc Ann Meet Am Soc Clin Oncol 1999
Powles, et al; Lancet 1993
Decker, et al; Breast J 1997
Natrajan & Don Gambrell Am J Obstet Gynecol 2002
HRT in BRCA patients: A qualitative systematic
review. S Neusy, et al 2001
• None of the studies show an increased recurrence
rate.
• They suggest that it is unlikely that the ERT/HRT
risk is very high.
• But a great heterogeneity characterises these
studies.
– Many essential data were missing in some
studies: the Disease-free interval (DFI), number
of lost of follow up, the stage of disease.
– The proportion of women treated with
tamoxifen varied from 3.8%-100%.
– It is currently not possible to draw conclusions
about the use of HRT after breast cancer.
Are randomized trials of hormone
replacement therapy in symptomatic
women with breast cancer feasible?
• 100 postmenopausal women with early-stage breast cancer,
experiencing vasomotor symptoms and/or vaginal dryness.
• Randomization (1:1) to HRT or no HRT for 6 months.
• Acceptance (38.8%) and continuance rates (>80%) were
encouraging. The efficacy of HRT did not appear to be
antagonized with concomitant tamoxifen. 65 % continued
HRT after the study ended. Three women developed
metastatic disease. Two used HRT.
• Jo Marsden et al Fertility and Sterility, February 2000
Estrogen replacement therapy in
patients with early breast cancer
• Estrogen replacement therapy apparently does
not increase either the risk of recurrence or of
death in patients with early breast cancer.
These patients may be offered estrogen
replacement therapy after a full explanation of
the benefits, risks, and controversies.
• Natrajan, Don Gambrell Am J Obstet Gynecol
2002;187:289-95.
Estrogen replacement therapy in
patients with early breast cancer
• Retrospective study of clinical practice
• n=123 women (mean age, 65.4 ± 8.85 years)
– 69 patients ERT for 32 years after diagnosis.
– 22 women who used nonestrogenic hormones (androgens with or
without progestogens) for 18 years
– 32 women who used no hormones for 12 years.
– Of the 63 living hormone users, 56 women are still being treated in
our clinic, as are 15 of the 22 subjects who receive nonestrogenic
hormone replacement therapy. Follow-up was done through the
tumor registry at University Hospital; those patients whose tumor
records were not current were contacted by telephone.
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Natrajan, Don Gambrell Am J Obstet Gynecol 2002;187:289-95.
Estrogen replacement therapy in
breast cancer survivors: a
matched-controlled series.
• No significant difference between the ERT and
control groups in
– ipsilateral primary/recurrence (5/155 v 5/143; P =
0.85)
– contralateral breast cancers (10/258 v 9/260; P =
0.99)
– systemic metastasis (8/277 v 15/277; P = 0.13).
– Noncause-specific deaths in the control group
numbered 15 (of 277), and in the ERT group, 7 (of
277) (P = 0.03).
– Overall survival favored the ERT group (P = 0.02).
Decker et al Menopause. 2003 Jul-Aug;10(4):277-85
Estrogen replacement therapy in
breast cancer survivors: a
matched-controlled series.
• prospectively ERT as part of clinical practice
(n=277) compared with a historical matchedcontrol group (stage, a recurrence-free period
similar to the period to ERT initiation in the
ERT group, approximate age, and duration of
follow-up).
• The mean time from breast cancer diagnosis to
initiation of ERT was 3.61 (+/- 0.25) years, with
a median of 1.88 years. The mean duration of
ERT was 3.7 (+/- 3.01) years, with a median of
3.05 years.
•Decker et al Menopause. 2003 Jul-Aug;10(4):277-85.
ERT for menopausal women with
BRCA : 5 yr Prospective study
• Patient and disease characteristics, comparable for
women who were on ERT and women who were
not on ERT.
• These same parameters also were comparable for
women who joined the trial and women who did
not.
• The introduction of ERT did not compromise
disease free survival. 2/56 women on ERT (3.6%)
developed a contralateral, new breast carcinoma vs
33/ 243 women (ERT-)(13.5%)
Vassilopoulou-Sellin et al Cancer 2002;95:1817-26
ERT for menopausal women with
BRCA : 5 yr Prospective study
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Stage I, II
DFI =2 yr (ER-)/ DFI=10 yr (ER ?)
Menopausal
ER+ : excluded
N1=100 but only 77 analysed (5 yr and complete data)
– 34 ERT/43 non users
• N2 (another cohort) 222
– 22 ERT/ 200 non users
• Vassilopoulou-Sellin et al Cancer 2002;95:1817-26
Attitude in relation to symptoms
(523 analysable responses (33%) one mail)
Symptoms
HRT
Yes
mild
Severe
P
No
33%
67%
49%
51%
P=0.001
Menopause after breast cancer: a
survey on breast cancer survivors
• 78% against the use of HRT after breast cancer.
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concern cancer relapse (33%)
fear of HRT side effects (24%)
the negative opinion of their physician (15%)
the mild discomfort caused by their menopausal symptoms (10%)
• 22% be willing to take HRT under medical supervision
when asked.
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vasomotor symptoms relief (50%)
osteoporosis prevention (45%)
vaginal dryness reduction (19%)
cardiovascular disease prevention (13%)
Biglia et al Maturitas 2003
Oral clonidine in postmenopausal patients with
breast cancer experiencing tamoxifen-induced hot
flashes:
Pandya et al Ann Intern Med. May 2000
• Double-blind, placebo-controlled :194 using
tamoxifen
• Oral clonidine hydrochloride, 0.1 mg/d/ placebo for
8 weeks.
• Hot flash : -37% clonidine group -20% placebo
group
• Clonidine more difficulty sleeping (41% vs 21%; P
= 0.02).
• quality-of-life scores (+0.3 points: clonidine vs -0.2
points placebo; P = 0.02) at 8 weeks, although the
median difference was 0 in both groups.
Venlafaxine in management of hot
flashes in survivors of breast cancer:
a randomised controlled trial.
Mean decreases in hot-flash scores.
placebo vs 75 mg and 150 mg, p<0·0001; placebo vs 37·5 mg, P=0·008;
Note that doses increased gradually in the 75 mg and 150 mg groups.
Loprinzi CL, et al. Lancet 2000;356:2059–63
Phase III evaluation of fluoxetine for
treatment of hot flashes.
Mean hot flash score changes from baseline for the two study arms
Loprinzi CL, et al. J Clin Oncol 2002;20:1578–83.
Paroxetine controlled release in the treatment of
menopausal hot flashes: randomized controlled trial.
Stearns V, et al JAMA 2003;289:2827–34
Active tamoxifen metabolite plasma
concentrations after coadministration of
tamoxifen and the selective serotonin reuptake
inhibitor paroxetine.
paroxetine statistically significantly reduced the
concentrations of 4-hydroxy-N-desmethyltamoxifen (endoxifen), a metabolite resulting from
CYP2D6-mediated hydroxylation of N-desmethyltamoxifen.
Endoxifen suppressed estradiol-stimulated MCF7
proliferation, with potency comparable to that of
4-hydroxy-tamoxifen
Hot Flash Drug May Hinder Effectiveness of
Tamoxifen
Stearns V, et al. J Natl Cancer Inst 2003;95
Phytoestrogens