1. Contraception after treatment
Dr Ann Pastijn
Breast Clinic
UMC St Pieters,Brussels
SBS/BVS

2. 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

4. 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

5. 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
women with BC and without BC from 54 studies in 25 countries
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS

6. 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: RR:1.24
1-4 years since last use: RR: 1.15
5-9 years since last use: RR: 1.07
10-15years since last use: RR: 0.98
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS

7. 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: 0.5/10000
20-24years: 1.5/10000
25-29years: 4.7/10000
40 years: 19/10000
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS

8. 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

9. 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

10. 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

11. The combined pill and breast cancer
More recent evidence
Marchbanks (NEJM,2002)
Women between 35 to 64 years
4575 with BC diagnosed between
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

12. 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: )
Ever user before first full term pregnancy was more strongly associated with breast cancer risk than ever user after first full term pregnancy (RR: vs )
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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 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

22. 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

23. Plasma LNG concentrations on Mirena and other contraceptive methods
Pg/ml
Classiquement les auteurs (Schering) décrivent des taux circulant de Levonorgestrel bien inférieur chez les patientes porteuses d’un IUS lorsqu’on les compare aux patientes dont la contraception est assurée par le Norplant ou par la minipilule
Nilsson en 1986 (Fertil steril) démontre que le taux circulant de LNG chez des femmes porteuses de Mirena depuis moins de 16 mois est de 166 pg/ ml +/ Il est vraisemblable avec de tels chiffres qu’une proportion non négligeable des patientes (je n’ai pas pu calculer la proportion ) présente un taux supérieur à 200 pg/ml au-delà duquel une anovulation est notée
NB analyse de l’abstract: je n’ai pas vu l’article complet
time
Diaz S et al, Contraception 1987;35: Nilsson CG et al, Fertility and Sterility 1986;45:
Kuhnz W et al, Contraception 1992;46: Weiner E et al, Contraception 1976;14:

24. 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

25. Mirena? Backman: Obs Gyn 2005
Post-marketing study on 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

26. 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

27. 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

28. Thank You
Dr Ann Pastijn Breast Clinic UMC St Pieters,Brussels SBS/BVS