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

Contraception after treatment

Dr Ann PastijnBreast 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


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


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


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




– 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




– 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 effectPromotion of tumours already initiated??




– 50% were diagnosed before 1984• Higher dosage of estrogen• Since then

– newer progestins (desogestrel,norgestimate)– New delivery systems– breast cancer screening raised…



• 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



• 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 1.06-1.26)



• 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)


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


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)



• 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



• 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


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


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)



• 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



• 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)



• 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)


Plasma LNG concentrations on Mirena and other contraceptive methods

Diaz S et al, Contraception 1987;35:551-557 Nilsson CG et al, Fertility and Sterility 1986;45:805-807Kuhnz W et al, Contraception 1992;46:455-469 Weiner E et al, Contraception 1976;14:563-570

0

1000

2000

3000

4000

5000

6000

pilule combinée

Minipilule

Norplant

Mirena®

Pg/ml

time


• 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


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


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


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


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

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