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
All rapid responses
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