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BRIEF COMMUNICATION

Triple negative breast cancer in a male-to-female transsexualS. T. Pattison1,2 and B. R. McLaren3

1Peter MacCallum Cancer Centre, 2Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia, and3Southern Blood and Cancer Service, Southern District Health Board, Dunedin, New Zealand

Key wordsbreast cancer, transgender,

hyperprolactinaemia, oestrogen, antipsychotic.

CorrespondenceBlair McLaren, Southern Blood and Cancer

Service, Southern District Health Board, Private

Bag 1921, Dunedin 9054, New Zealand.

Email: blair.mclaren@southerndhb.govt.nz

Received 29 March 2012; accepted 7 May

2012.

doi:10.1111/imj.12047

Abstract

There is limited published literature on the risk of breast cancer in transgender patients.

We report a case of an aggressive triple negative inflammatory breast cancer in a

male-to-female transsexual. This patient had a complicated psychiatric history with

significant antipsychotic use, and the case raises several questions about the pathogen-

esis of this breast cancer. The literature on breast cancer in transgender patients and in

relation to hyperprolactinaemia is reviewed.

A 43-year-old, male-to-female transsexual was found tohave a painful, erythematous left breast with a palpablemass on examination in July 2010 when she presentedafter an overdose of amisulpride. Prior to this, she hadbeen on antibiotics for 1 week prescribed by her generalpractitioner. She described no systemic symptoms at thistime. She was referred to a breast clinic, and at this reviewit was also thought that infection was present. There was,however, no improvement with antibiotics. Her case wasreviewed in a multidisciplinary meeting approximately 4weeks after her first presentation, when she was describedas having a 10 ¥ 10 ¥ 8 cm central thickening of her left

breast. A clinically enlarged left axillary node was nowpresent. Histology from core biopsy was consistent with aninvasive ductal carcinoma, at least grade 2, with lymphaticinvolvement. Immunohistochemical studies revealed nostaining for oestrogen receptor, progesterone receptor orHER2. Staging computed tomography (CT) and bonescans were both normal.

She was first seen in oncology outpatients in Septem-ber of 2010. At her first assessment, a prolactin level waschecked and was greater than five times the upper limitof normal. Review of her records showed that this hadbeen elevated to similar levels in the past, dating backto 2005. She commenced dose-dense doxorubicin,cyclophosphamide neoadjuvant chemotherapy, whichwas followed by dose-dense paclitaxel chemotherapy.

Funding: None.Conflict of interest: None.

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© 2013 The AuthorsInternal Medicine Journal © 2013 Royal Australasian College of Physicians 203

The patient’s history of gender identity disorderspanned several years. She had initially started takingcross-sex hormones in 1995, with conjugated oestrogenand cyproterone acetate, and she continued this consist-ently until 2002. Her use of cross-sex hormones wasthen erratic for 3 years, becoming consistent againfrom 2005 when she recommenced cyproterone (50 mg)and oestradiol valerate (2 mg BD). Spironolactone(200 mg OD) was substituted for cyproterone in 2006because of concerns that this may have been worseningher depression. She underwent gender reassignmentsurgery in Thailand in March 2010, and never had breastaugmentation.

This patient had significant psychiatric comorbidities,with multiple episodes of self-harm from the age of 25,and was considered to have a chronic high risk of com-pleted suicide. She had several psychiatric diagnosesassigned to her, including borderline personality disorderand major depressive disorder, with her depressive symp-toms controlled by use of multiple medications, includingantipsychotics. Risperidone, olanzapine, quetiapine,clonazepam, methotrimeprazine and fluoxetine had beenused at various times in the 10 years prior to this pres-entation. She was commenced on amisulpride in May of2010. At commencement of chemotherapy, her othermedications included quetiapine, doxepin, zopiclone andspironolactone. Her oestradiol had been stopped 2 weeksprior to her first oncology appointment. She had nofamily history of breast or ovarian cancer.

She completed her chemotherapy in January of 2011,with clinical improvement in the breast. Unfortunately,she presented to the emergency department with chestpain later during the same month. A CT pulmonary angi-ogram was undertaken, and showed bony metastases inthe spine and sternum. A bone scan confirmed thesefindings. A planned mastectomy was, therefore, notundertaken, and she proceeded to breast radiotherapy forlocal control.

She was found dead at her own home in March of2011. Autopsy confirmed cause of death as an overdoseof doxepin, but also noted extensive metastatic tumourdeposits in the liver secondary to her primary breastcarcinoma.

Breast cancer in transgender patients appears to berare. A review of the literature revealed seven cases ofbreast cancer in male-to-female transsexual patients,described to varying degrees.1–6 Of the four cases thatdescribe oestrogen receptor status, three cases are nega-tive and one positive on immunohistochemistry. Thereported cases include one case of breast cancer in acohort of 2236 Dutch male-to-female transsexuals,cumulative over 30 years.1 However, as discussed byGooren et al.,1 it is likely that there is underreporting of

long-term complications of cross-sex hormone use, andthere will be strong variation in oestrogen exposure ofthe patients in this cohort, making risk assessment diffi-cult. The lack of reported cases is likely contributed to byseveral reasons, in addition to underreporting, includingthat transsexualism is rare, and that the prevalence ofhormone-dependent tumours, such as breast and pros-tate cancer, is low.7 The historical use of cross-sex hor-mones may have been too short for any malignanciescaused by these to be apparent, with the first docu-mented hormone treatments of transsexuals beginning inthe 1970s.1

Prolonged exposure to oestrogen is known to be a riskfactor for developing breast cancer, with early menarcheand late menopause both associated with increased riskof breast cancer in genetic females.8 Hormone replace-ment therapy (HRT) has also been implicated as increas-ing risk of breast cancer in genetic females, with resultsfrom the Woman’s Health Initiative reporting increasedrisk for combined oestrogen and progestin HRT.9 A morerecent prospective study has also shown greater risk forcombined HRT than oestrogen-only formulations, andthat the risk of breast cancer development was greater ifHRT was initiated around menopause compared withlater.10 Transgender patients often use cross-sex hor-mones for longer periods of time than genetic femalesand often at significantly higher doses. It is unknownwhether this is safe, or as safe as, administration of long-term sex-appropriate steroids.

The origin of oestrogen receptor-negative breast canceris under debate, with the possibilities including evolutionfrom oestrogen receptor-negative stem cells and develop-ment from oestrogen receptor-positive precursors.11

Whether our patient’s cross-sex hormone use contrib-uted to the development of her cancer is unknown. Theimmunohistochemistry of her core biopsy indicates thather tumour was not sensitive to the use of oestrogen, asit was hormone receptor-negative, but in the absence ofa family history of breast cancer, it is possible that her useof cross-sex hormones may have had an impact on thedevelopment of her cancer. Her medical history suggestsother possible contributing factors to the development ofher cancer, in particular her hyperprolactinaemia.

Increased prolactin levels have been demonstrated inmale-to-female transsexuals using oestrogen and cypro-terone.12 The long-term consequences of hyperprolacti-naemia are not well understood, but there is nowlaboratory-based evidence that prolactin may be atumour promoter in humans for breast and prostate tis-sue.13 In clinical studies, plasma prolactin levels have alsobeen correlated with subsequent risk of breast cancer inpostmenopausal and premenopausal women,14–16 and aretrospective cohort study of more than 52 000 women

Brief Communication

© 2013 The AuthorsInternal Medicine Journal © 2013 Royal Australasian College of Physicians204

exposed to prolactin elevating dopamine antagonistsfound a 16% increase in the risk of breast cancer forthose exposed to dopamine antagonists compared withthose not exposed, with a dose–response relationshipbetween cumulative doses and greater risk.17 This riskwas seen both in antipsychotic dopamine antagonists, forexample risperidone, and prolactin elevating antiemeticdopamine antagonists, such as metoclopramide. Anyantipsychotic can elevate prolactin, although the fre-quency and severity differ between the various antipsy-chotics, with the highest rates of hyperprolactinaemiareported in association with risperidone and amisul-pride.18 The patient described in this case had been onantipsychotics for several years and had documentedhyperprolactinaemia. This may also have contributed toher development of breast cancer.

This case highlights several issues for transgenderpatients. This includes the lack of knowledge about therisks of long-term cross-sex hormones use and also the

risks of hyperprolactinaemia in the development ofbreast cancer. Cessation of cross-sex hormones wouldresult in loss of female characteristics, which is likely tobe unacceptable to most transgender patients. Untilfurther research into the risks of developing breastcancer is undertaken, decreasing the dose of oestrogento the lowest possible for maintenance should beconsidered. For patients on antipsychotics, furtherresearch is needed as to whether routine screening ofprolactin levels would be helpful. Physicians caring fortransgender patients need to encourage them to partici-pate in the relevant cancer screening protocols, whichfor breast cancer screening for male-to-female trans-sexuals is the same as the guidelines for biologicalwomen.19 Further reporting of cases such as the onediscussed earlier should be encouraged as the currentliterature pertaining to the risks of breast cancer fromcross-sex hormone use and hyperprolactinaemia issparse.

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