The aim of the present study was to evaluate the risk of breast cancer in MtF and FtM transsexual people in a large consecutive series with long‐term follow‐up.

Even those who have undergone mastectomy may still retain some vulnerability and two cases of cancer have been reported in residual breast tissue 10 years after bilateral mastectomy 17 , 19 . A recent study has also found an association between testosterone administration to FtM transsexual persons and breast cancer–related gene expression signatures 20 . It is not yet clear what the role of testosterone is in the pathogenesis of breast cancer. It may have a role, especially in postmenopausal women 21 , though there is no consensus as yet on this topic 22 .

In testosterone‐treated FtM persons there is usually a marked reduction of glandular tissue and an increase of fibrous connective tissue 15 , 16 . Usually, breasts are surgically removed in the course of sex reassignment treatment, but due to financial constraints this does not always occur. Administered testosterone is partially aromatized to estradiol, and serum estradiol levels do not decrease substantially as a result of testosterone treatment of FtM persons. This can be a risk factor for those who have not undergone mastectomy. The reported cases of breast cancer in FtM individuals are summarized in Table 2 . Two cases of breast cancers have been diagnosed in subjects who have been treated with supraphysiological doses of testosterone, suggesting a possible role of testosterone in the development of breast cancer 18 , although estradiol derived from aromatization of testosterone may have been relevant as well.

Focal apocrine metaplasia was observed in one patient after approximately 54 months of estrogen treatment. In addition, two cases of a fibroadenoma in the breasts of MtF persons have been reported 13 , 14 .

One of the concerns of long‐term estrogen treatment is the induction of carcinomas of estrogen‐sensitive tissues such as the breast 5 . Indeed, eight individual cases of malignancies of the breast in MtF persons have been reported in the literature 6 - 12 as detailed in Table 1 .

The induction of female breasts in MtF individuals is of pivotal significance. This requires reduction of androgen impact (since androgens inhibit the formation of female type breast development 1 ) and the establishment of an estrogen environment. A target could be to achieve female androgen levels. There are two studies that have examined the histological features of breast induction in MtF persons, and it has been reported that only in those in whom a progestational anti‐androgen (like cyproterone acetate) is combined with feminizing dosages of estrogen therapy will full acinar and lobular formation occur with hormonally stimulated nuclei and pseudolactational changes 2 , 3 . While androgen‐blocking treatment is usually stopped or reduced following surgical procedures including orchidectomy, estrogen treatment has to be continued to prevent the sequels of hormone deprivation such as osteoporosis 4 .

This study analyzes the occurrence of breast cancer in transsexual people undergoing cross‐sex hormone administration. Transsexual people are those with apparently normal somatic sexual differentiation who strongly feel they actually belong to the opposite sex. This conviction is accompanied by an intense desire to live in every way as an ordinary member of the sex that is identified with. Treatment to enable the transition to the opposite sex includes cross‐sex hormone administration, usually followed by surgery.

The expected incidence of breast cancer was calculated based on Dutch incidence numbers for men and women (2009: Borstkanker: incidentie, prevalentie en sterfte naar leeftijd en geslacht, http://www.nationaalkompas.nl/ , accessed March 15, 2013). These were standardized for the age distribution of the 2,307 MtF and 795 FtM subjects included in our cohort.

The incidence rate of breast cancer was calculated per 100,000 patient years of follow‐up. The 95% confidence interval for FtM subjects was calculated using the model proposed by Byar because of the small number of cases 23 .

When initiating sex reassignment treatment, all subjects had agreed by informed consent that their data could be used in future scientific analysis with the provision that data could not be related to an individual. This policy was approved by the institute's review board on scientific investigations in humans.

This brought the total of MtF transsexual persons to 2,307. The mean age was 29.3 ± 12.7 years at the start of cross‐sex hormone administration (range 16–83 years). The mean follow‐up period of subjects receiving anti‐androgens and estrogens or only estrogens was 21.4 ± 8.7 years (median 17.6, range 6.0–43.5 years). Of the FtM subjects, 795 could be followed up. The mean age at the start of testosterone treatment was 23.2 ± 6.5 years. The mean follow‐up period was 20.1 ± 7.3 years (median 16.8, range 6.0–36 years). Subjects were followed until December 31 , 2012.

Baseline and follow‐up data of all MtF transsexual subjects referred to the transgender outpatient clinic of the VU University Medical Center in Amsterdam have been entered into a cumulative database since 1975. The MtF : FtM sex ratio of transsexualism is about 3:1. In the present analysis, which aims to measure long‐term effects, included subjects were restricted to those who had started cross‐sex hormone treatment from 1975 to December 31, 2006, ensuring that follow‐up was available for at least 6 years (Table 3 ).

Fewer person‐years of follow‐up exist for FtM subjects. Our estimate of the incidence rate of breast cancer in these individuals was 5.9 per 100,000 person‐years (one case in 17,025 person years of follow‐up), with a 95% confidence interval of 0.5 to 27.4 per 100,000 person years. For comparison, the expected incidence of breast cancer would be 154.7 per 100,000 person‐years for biologic women and 1.1 per 100,000 person‐years for biologic men (2009: Borstkanker: incidentie, prevalentie en sterfte naar leeftijd en geslacht, http://www.nationaalkompas.nl/ , accessed March 15, 2013).

The incidence rate of breast cancer in our MtF cohort was thereby 4.1 per 100,000 person‐years (i.e., two cases divided by the total amount of 49,370 person‐years of follow‐up). The 95% confidence interval of the incidence ranged from 0.8 to 13.0 per 100,000 patient‐years. For comparison, the calculated expected incidence of breast cancer in biologic women would be 170.0 per 100,000 person‐years of follow‐up. In our sample, the one or possibly two incident cases of breast cancer in MtF subjects more closely approximate the expected incidence of breast cancer of 1.2 per 100,000 patient‐years that would occur in biologic men.

Discussion

The administration of cross‐sex hormones to transsexual people in doses that are at least as high but often higher than those used for the treatment of hypogonadal subjects carries, at least in theory, the risk of inducing hormone‐sensitive cancers. This article addresses that risk. There is no indication that any biological difference exists between MtF persons and biologic men, nor between FtM individuals and biologic women. It is not known whether long‐term exposure to sex hormones of the other sex produces fundamental changes in the sex‐typical biology of men and women and would thereby increase breast cancer risk. The question, therefore, arises as to whether breast carcinomas in transsexual subjects must be conceptualized as cancers of the acquired sex or the natal one. This question is fundamental since recent research has highlighted the existence of distinctive differences between male and female breast cancers 24, 25. The vast majority of male breast cancer is of the luminal type and basal‐like, and HER2‐driven cancers are very rare 25. Also on the protein 24 and genetic level there are important differences between male and female breast cancer 26, 27. Expression of individual growth factor receptors (IGF1‐R, FGFR2, and MET) and CD44v6, CAXII in male breast cancer also differ from female breast cancer 28.

Male‐to‐Female Transsexual Subjects In the MtF population we encountered one, possibly two cases of breast cancer. This is not an elevated rate if seen in terms of male breast cancer, and it is certainly lower than observed breast cancer incidence rates in women. In several studies with systematic long‐term follow‐up of a series of MtF subjects, no cases of breast malignancies have been encountered. Benjamin, in a report of 1964, did not note breast cancer in the follow‐up of 40 castrated MtF subjects over a range of 3 months–12 years 29. Other, more recent long‐term follow‐ups of transsexual subjects have also indicated no occurrence of breast cancers 30-32. There are eight case reports of breast cancer in MtF persons in the literature (Table 1). Three cases are not likely to be related to estrogen use. These include a secretory carcinoma (that is often ER negative known to have a driver translocation) 10, a malignant (fibroepithelial) phylloides tumor 7 and a triple negative breast carcinoma 12. The other cases occurred at a relatively young age after estrogen exposure of 5–10 years. In women the incidence normally increases with age until menopause, when a decline sets in. The incidence of male breast cancer is approximately 1 in 100,000, and its peak occurs between the ages of 68–71 years 33. Our results more closely resemble this incidence, though not the high age of occurrence. Since somatic treatment of transsexualism is of rather recent date, most transsexual people now being surveyed tend to be younger than 68–71 years (Table 3). Risk factors for male breast cancer are BRCA1 and BRCA2 gene mutations, obesity, androgen insufficiency as in Klinefelter syndrome and estrogen exposure. The latter two, androgen insufficiency and estrogen exposure, are inherent in the cross‐sex hormonal treatment of MtF subjects. Thus it remains to be seen whether the incidence of breast carcinomas in MtF individuals will increase in the future. Ductal carcinoma is by far the most common histologic subtype, with special histological types (especially invasive lobular cancer) only very rarely occurring. Most of the cases of breast cancer in MtF persons were, indeed, ductal carcinomas (Table 1).