Download Contraception after treatment

Contraception after treatment
Dr Ann Pastijn
Breast Clinic
UMC St Pieters,Brussels
SBS/BVS
Introduction
• Literature search is very poor on this
subject
• Women who develop breast cancer when
young and survive,will need advice on
contraception
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Introduction
• The use of female sex hormones as
contraceptives began in 1960
• Since than, more than 200 million women
used “the pill” which became the most
popular reversible contraception
• Extensive research has been done on the
safety of oral contraceptives
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Collaborative group on hormonal factors in
breast cancer (Lancet,1996)
– Re-analysed 90% epidemiological information
on the relationship between BC risk and
hormonal contraception
– 53.297 women with BC and 100.239 without
BC from 54 studies in 25 countries
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Collaborative group on hormonal factors in breast
cancer (Lancet,1996)
– While women are taking combined oral
contraceptives and in the 10 years after stopping,
there is a small increase in the RR of BC
•
•
•
•
Current use:
1-4 years since last use:
5-9 years since last use:
10-15years since last use:
RR:1.24
RR: 1.15
RR: 1.07
RR: 0.98
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Collaborative group on hormonal factors in
breast cancer (Lancet,1996)
– Since BC incidence rises with age, the
estimated excess number of cancers
diagnosed in the period between starting and
10years after stopping, increases with age at
last use:
•
•
•
•
16-19years:
20-24years:
25-29years:
40 years:
0.5/10000
1.5/10000
4.7/10000
19/10000
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Collaborative group on hormonal factors in
breast cancer (Lancet,1996)
– No influence by duration of use,dose and type
of hormones or family history
– Tumours clinically localised
– Women starting before age 20 had higher
RR(1.22) of having BC diagnosed while they
were using combined oral contraception and
in the 5 years after stopping
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Collaborative group on hormonal factors in
breast cancer (Lancet,1996)
– Relation between cancer risk and exposure
are unusual
• Increased risk soon after first exposure
• No increase with duration of use
• Returns to normal 10 years after stopping
Incompatible with a genotoxic effect
Promotion of tumours already initiated??
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Collaborative group on hormonal factors in
breast cancer (Lancet,1996)
– 50% were diagnosed before 1984
• Higher dosage of estrogen
• Since then
– newer progestins (desogestrel,norgestimate)
– New delivery systems
– breast cancer screening raised…
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• More recent evidence
– Marchbanks (NEJM,2002)
• Women between 35 to 64 years
– 4575 with BC diagnosed between 1994-1998
– 4682 without BC
• No higher risk
– RR:1.0 for current users
– RR: 0.9 for previous users
• No influence by duration of using,age of initiation or
family history
• No difference in the risk according to the type of
progestin
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• More recent evidence
– Kahlenborn (Mayo Clin Proc 2006)
• Meta-analysis of 39 case-control studies that had most cases
diagnosed since 1980
• Only premenopausal women
• Ever user compared to never user is associated with a
small (stat sign.) increased risk of breast cancer (RR:
1.09-1.29)
• Ever user before first full term pregnancy was more
strongly associated with breast cancer risk than ever
user after first full term pregnancy (RR: 1.28-1.62 vs 1.061.26)
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
• Estrogen is known as mitogen to breast cancer
cells
– Higher levels of endogeneous estradiol levels are associated with increased
risk for breast cancer. Levels of progesterone are not associated with breast
cancer (J Natl Cancer Inst 2006)
• Progestogens may be mitogenic in breast
tissue
– Proliferation (Ki67)is positively correlated with progesterone levels (Breast
Cancer Res Treat 2001)
– Progestins regulate VEGF (Vascular endothelial growth factor) expression in
human breast cancer cells :
Increased angiogenesis in response to endogeneous progesterone or its
therapeutically used analogues may play a role in cell growth or
metastasis in a subset of human breast tumours.(Cancer Res 1998)
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and breast cancer
in women with a family history
• Grabrick (JAMA 2000)
– Historical cohort study of 426 families of breast
cancer probands
– Women with a first degree relative with breast
cancer will have a 3x higher risk of breast cancer if
they used OC before 1976(thus higher doses of
estrogen and progestin) than women who never
used OC
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and BRCA1/2
carriers
• Grabrick (JAMA 2000)
– Rise in risk with increasing numbers of affected
first degree family members
Strong support for an amplified effect of estrogen in
the presence of genetic risk for breast cancers
• Ursin (Cancer Res 1997)
– OC may increase the risk of breast cancer more in
mut BRCA carriers than in non carriers
• Small sample size(50pts with 9BRCA1 and 5BRCA2)
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and BRCA1/2
carriers
• Fan (Science 1999)
– In vitro experiments on breast cancer cell lines,
show that BRCA1 inhibits the transcription activity
of the ER-α. Mutations in BRCA1 may remove this
inhibitory effect
• Increasing estrogen dependant epithelial proliferation
increased risk associated with OC use
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill and BRCA1/2
carriers
• Modan(NEJM 2001)
– The use of OC reduces the risk of ovarian cancer
in non carriers but not in carriers
– breast cancer is more frequent in this group
– OC increases the risk of BC
It’s not advised to use OC in this group
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
The combined pill?
All those arguments concerning women
who don’t have breast cancer, combined
with the knowledge of effect on breast
epithelial proliferation, can lead us to the
conclusion that the oral combined
contraception is not a good option for
breast cancer survivors
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Progestogen-only contraception?
• Progesterone will probably act different on breast
tissue, when combined with estrogen (Breast Cancer
Res Treat 1998)
– ECE increases Ki67
– ECE +MPA increases more Ki67
– MPA alone decreases Ki67
• MPA “retard” (Depoprovera IM)
– Contradictory results
• No increased risk? (Strom-Contraception 2004)
• Increased risk for women under 35years till 5years after stopping((Skegg-Jama
1995)
– Interesting decrease of estrogenic pool
– Decrease in mastodynia/mammographic density?(Pons 1966)
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Progestogen-only contraception?
• The Collaborative group found a non significant
17%increase in the risk of breast cancer in women
taking the progestogen-only pill
– Small number of cases
– Even if the risk is real, it’s probably lower
than that for the combined pill
• IARC (1999) : no evidence of increased
risk of breast cancer
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Progestogen-only contraception?
• A large study on the incidence of breast cancer in
users of the subdermal 6-rod levonorgestrel
implant
– Norplant postmarketing surveillance study
– 5-year cohort with 78000 womenyears of
observation
– No statistically difference in the occurence of
cancer
(Sivin,Drug Saf 2003)
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Progestogen-only contraception?
• Minipill(Levonorgestrel) and LNG-IUD(Mirena) can
both give ovarian dystrophy with suprafysiological
estradiol levels, but is more important with the
minipill(Ann Med 1990)
• Minipill(Desogestrel or Cerazette) gives less
ovarian dystrophy than Levonorgestrel minipill
• Implanon(Etonogestrel) will sometimes give an
important hyperestrogenia(Contraception 1998)
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Plasma LNG concentrations on Mirena and other
contraceptive methods
Pg/ml
6000
5000
4000
pilule combinée
Minipilule
3000
Norplant
Mirena®
2000
1000
0
time
Diaz S et al, Contraception 1987;35:551-557
Kuhnz W et al, Contraception 1992;46:455-469
Nilsson CG et al, Fertility and Sterility 1986;45:805-807
Weiner E et al, Contraception 1976;14:563-570
Progestogen-only contraception?
• Probably will Mirena be the most preferred
method, if hormonal contraception is the only
option because of
– Low frequence of hyperestrogenemia
– Low and stable levels of levonorgestrel
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Mirena?
• Backman: Obs Gyn 2005
– Post-marketing study on 17360 users compared to average
Finnish female population(Finnish Cancer Registry)
– Mean age 35.4years (30-54years)
the use of the LNG-IUD is not associated with an
increased risk of breast cancer
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Mirena?
• Is the LNG IUD the ideal contraception?
– Faculty of family planning and reproductive health care
clinical effectiveness unit (FFPRHC) guidance (Fam Plann
Reprod Health Care 2004)
Non hormonal contraception is most appropiate for a
woman with a history of BC, however, the LNG-IUD
may be considered individually
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Conclusion
• The general view is that hormonal methods will be
contraindicated after treatment of breast cancer
• Barrier methods and IU copperdevice could be an option
• Although, the WHO advices that combined pill as also
other hormonal contraceptives could be an option as a
last resort for women over 5 years post-diagnosis
• The concern about progression of the disease may be
less for the LNG IUD than with combined oral
contraceptives or higher dose progestin-only
contraceptives
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS
Thank You
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS