Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the NetherlandsBMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1652 (Published 14 May 2019) Cite this as: BMJ 2019;365:l1652
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Preventing breast cancer Re: Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands
Preventing breast cancer
The Dutch study by Christel J M de Blok and colleagues found that trans women (men who had been given antiandrogens and oestrogens) had a 46-fold higher risk of breast cancer by a median age of 52 years than normal men.1 Most tumours were of ductal origin and oestrogen and progesterone receptor positive. Median duration of hormone treatment was 18 years and the number of breast cancers had increased in recent years.
Evans and colleagues previously found that women with BRCA1 and BRCA2 had a cumulative risk of 8%of breast cancer by age 40 if they were born before 1930. However, the risk increased to 22% for women born after 1940 (p =.0005).2 Interestingly, the average duration of OC use by breast cancer cases was only three years in a Collaborative re-analysis of 54 studies and two years of HRT.3,4
It is wrong to claim that oestrogens do not cause breast cancer. Beral and colleagues found “remarkably similar” increased risks in the Women’s Health Initiative studies (WHI), the Million Women Study (MWS) and the worldwide Collaborative Group’s study (in which 80% of HT users had used estrogen-only preparations).5 The estimated excess incidence of breast cancer with estrogens increased from 2 to 6 per 1000 users in the Collaborative study and from 1.5 to 5 per 1000 users in the MWS for 5 and 10 years of use. The excess incidence for progestin/estrogen HT increased from 6 to 18 per 1000 users in for 5 and 7 years of use in the WHI trial and from 6 to 19 per 1000 for 5 to 10 years of use in the MWS. Progestin containing HT caused 4 times more breast cancer than estrogen HT in both the WHI trial and the MWS. Longer use of either estrogen HT or combination HT for up to 10 years trebled breast cancer risks compared with use for up to five years.
After the premature termination of the WHI randomized trial of CHT in 2002 and the EHT study in 2004, a fall in HT use in hormone taking countries matched declines in breast cancer incidences and mortality in older women. 6,7 Estrogen positive breast cancers particularly decreased. 8
1 Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1652 (Published 14 May 2019) Cite this as: BMJ 2019;365:l1652
2 Evans DG. Shenton A, Woodward E, Lalloo F, Howell A, Mather ER. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer 2008, 8:155
3 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996 22;347(9017):1713-27.
4 Collaborative Group on Hormonal factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet. 1997;350 (9084):1047-1058.
5 Beral V. Banks E, Reeves G, Bull D, on behalf of the Million Women Study collaborators. Breast cancer and hormone replacement therapy: the Million Women Study. Lancet 2003;362:1330-1331.
6 Grant ECG. Reduction in mortality from breast cancer: fall in use of hormones could have reduced breast cancer mortality. BMJ. 2005 Apr 30;330(7498):1024.
7 Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res. 2007;9:108.
8 Ravdin M, Cronin KA, Howlander N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The Decrease in Breast Cancer Incidence in 2003 in the United States.NEJM. Vol. 356, No.16. April 19, 2007
Competing interests: No competing interests
As we discussed in our previous response to the excellent work of Professor den Heijer on the safety of hormone replacement therapy for transgendered women in the long-term outcome of the cardiovascular and oncology risks, it is difficult to interpret the absolute risk with this population using the extant literature due mainly to the variety of different hormonal regimens that are used internationally and even within the same country. We therefore have to apply what is known from other relevant populations to hormone replacement therapy use for transgendered women.
Despite the use of synthetic oestrogen treatment, the oestrogen only arm of the WHI and HERS trials demonstrated no excess breast cancer risk; with the excess breast cancer risk being present in the oestrogen and progesterone combined arm. While the formulation of oestrogen used was not ideal, we can say that oestrogen on its own appeared to be safe in this population. The mechanism by which this result may have occurred is discussed eloquently by Joshi et al (2015) who point out that “Estrogen is instrumental for breast development during puberty, but its primary role during adult mammary growth cycles is to induce progesterone receptor expression to facilitate progesterone’s proliferative effects in this tissue”. What is interesting from the Dutch data is that the breast cancer risk is again increased in the transgender population where the progestin cyproterone acetate is used in combination with oestrogen. On balance therefore the current evidence points towards oestrogen and progesterone in combination increasing breast cancer risk in transgendered women.
We appreciate that the risks may be different with micronised progesterone, but at the moment the quality of the data in the cisgendered female population is suggestive, but not definitive, in its outcome with regards to safety. There is no data at all in the transgendered female population on the use of this product.
There is also no published work in the transgendered female population that suggests breast outcome is improved. By combining oestrogen and progesterone/oestrogen only HRT. We should also look to the standard practice both in disorders of sexual differentiation, where, for example, females with oestrogen insensitivity syndrome achieve adult female breast development without the benefit of oestrogen just using oestradiol which has been aromatised from testosterone, to achieve adult breast development. This is also standard gynaecological practice in oophorectomised females.
Professor Prior’s paper is an interesting opinion paper summarising the current literature on micronised progesterone therapy compared to synthetic progestin therapy in the cisgendered female population and how that might apply to the transgendered female population. However, there is no outcome data quoted in this work.
In the absence of good quality data of either breast development, or improved cardiovascular outcomes for transgendered women, we urge caution before recommending progesterone as part of standard hormone replacement therapy for transgendered women as this is not standard practice currently in the main centres practising in this field.
Purna A. Joshi, ; Pamela J. Goodwin, ; Rama Khokha, 2015 JAMA Oncol. 2015;1(3):283-285
Competing interests: No competing interests
Re: Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands
Dear Professor den Heijer and colleagues,
Thank you for your excellent work to report a nation-wide Netherlands study of breast cancer observed related to expected in trans gender people. The comparison of breast cancer risk by sex at birth shows that those trans women who have been on “gender affirming hormone therapy” of estrogen and anti-androgens have a 46-fold higher risk than born and continued male people. In discussing this you state “the most important difference between transgender people and cisgender men and women is the use of hormone treatment.”
That statement is true but incomplete—the years of feeling like they are living in a body of the wrong sex and trying to be gender that “feels wrong” are very stressful. It is likely that their endogenous glucocorticoid (cortisol) and sympathetic (epinephrine and norepinephrine) hormones have been higher than usual for years. There is evidence that the breast glucocorticoid receptor causes cell proliferation which is a breast cancer risk factor (Courtin-2012).
The other important reason that transgender women have an increased breast cancer risk is that they have traditionally been treated with estrogen/estradiol as their only with gonadal steroid. In contrast to biological men who do have a single testicular hormone (testosterone), biological women have estradiol and progesterone that are essential for women’s reproductive system. Estradiol is proliferative for the breast while progesterone inhibits breast proliferation. Numerous studies confirm this physiology which is why I have recently advocated that progesterone be added to the gender affirming therapy of transgender women (Prior JC, “Perspectives” J. Clinical Endocrinology and Metabolism, 2019).
Jerilynn C Prior MD FRCPC
Professor of Endocrinology / Department of Medicine
Centre for Menstrual Cycle and Ovulation Research
University of British Columbia
Competing interests: No competing interests
Interpretation of Results of 'Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands' in the UK
We applaud the recent article by de Blok and colleagues, which adds some much needed evidence in an under-researched area. It is a well-designed study and the authors have gone to great lengths to robustly link data.
We, do, however, recommend some caution in its interpretation.
Firstly, in the case of trans women, it may be that this study misses a number of cancers developed in older age. In this cohort, the upper quartile of the age range was 60 years and the median age of development of cancers was 50 years. Given that hormones were commenced at a median age of 31 years (approximately 15 years later than the oestrogen rise seen in pubertal cisgender women), and that for both cisgender men and cisgender women the highest number of breast cancer cases is in the 64-69 years age group (CRUK, 2019), it is feasible that this peak would be pushed to a higher age bracket and missed in this study due to a shorter follow-up. It would therefore be interesting to look again at this cohort in 10-15 years.
Secondly, trans female patients were treated with the antiandrogen cyproterone acetate prior to gonadectomy. Cyproterone is a known progestin (Raudrant & Rabe, 2003) and therefore could be linked to increased breast cancer development (Carroll et al., 2017). This may explain the increased rate of cancers seen compared to previous studies (Gooren et al., 2013, Brown & Jones, 2014) and may also explain the development of cancers at a younger median age than is typical for cisgender women. In the UK, cyproterone is no longer routinely used due to increased risk of low mood, thromboembolic events, liver dysfunction and meningiomas. Instead, GnRH analogues such as triptorelin or goserelin are given if oestrogen alone does not result in sufficient testosterone suppression. Thus, the results may not be directly translatable to the UK population.
Thirdly, the oestrogen preparations that were used in transwomen, such as premarin and ethinyl oestradiol, are not measurable in the blood and, therefore, there is no indication of exposure levels of the breast to oestrogenic compounds. In modern practise oestradiol itself is used for therapy and the aim is to keep the plasma oestradiol levels in the physiological range.
Finally, in the Dutch cohort studies the prevalence of smoking in this population is extremely high, 43-46% in a similar long term review paper by this group looking at cardiovascular risk (Nota et al, 2019). However, in the UK, smoking cessation is mandated prior to endorsement of hormones and referral for chest or genital reconstruction surgery. In the Netherlands, there is no such recommendation, and, therefore tobacco use may contribute to a higher breast cancer risk in younger transwomen and transmen, as it does in pre-menopausal cisgender women.
Cross-sex hormonal regimens, surgeries, and lifestyle advice vary between countries and change over-time, and - as gender identity clinics begin to see greater numbers of referrals from children and adolescents - are being commenced at younger ages. This means that studies like this must be conducted worldwide and repeated over-time in different cancer types in order to give patients the most up-to-date risk information and better inform screening practices.
Brown GR, Jones KT. Incidence of breast cancer in a cohort of 5,135 transgender veterans. Breast Cancer Res Treat. 2015;149(1):191-8. doi: 10.1007/s10549-014-3213-2.
Cancer Research UK. Breast cancer incidence (invasive) statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/s... (accessed: 17 May 2019)
Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer. 2017;17(1):54-64. doi: 10.1038/nrc.2016.116.
Gooren LJ, van Trotsenburg MA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med. 2013;10(12):3129-34. doi: 10.1111/jsm.12319.
Nota NM, Wiepjes CM, de Blok CJM, Gooren LJG, Kreukels BPC, den Heijer M. Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy. Circulation. 2019;139(11):1461-1462.
Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs. 2003;63(5):463-92.
Competing interests: No competing interests