REGULAR ARTICLE

Breast cancer risk among patients with Klinefelter syndromeLouise A Brinton (brinton@nih.gov)Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Executive Boulevard, Rockville, MD, USA

KeywordsGenetics, Gynaecomastia, Hormones, Klinefeltersyndrome, Male breast cancer, Risk

CorrespondenceLouise A Brinton, Ph.D., Hormonal and ReproductiveEpidemiology Branch, Division of Cancer Epidemiol-ogy and Genetics, National Cancer Institute, 6120Executive Boulevard, Room 5018, Rockville, MD20852-7234, USA.Tel: +301-496-1693 |Fax: 301-402-0916 |Email: brinton@nih.gov

Received30 August 2010; revised 29 November 2010;accepted 16 December 2010.

DOI:10.1111/j.1651-2227.2010.02131.x

Presented in part at the International Workshop onKlinefelter Syndrome Copenhagen, 6–8 May 2010

ABSTRACTAim: To evaluate male breast cancer (MBC) risk among patients with Klinefelter syn-

drome (KS) and relate this to possible biological explanations.Methods: A literature review was conducted to identify case series and epidemiologic

studies that have evaluated MBC risk among patients with KS.Results: Case reports without expected values have often led to false impressions of

risk. Problems include that a diagnosis of cancer can prompt a karyotypic evaluation and

that many cases of KS are unrecognized, resulting in incomplete denominators. Few care-

fully conducted epidemiologic studies have been undertaken given that both KS and MBC

are rare events. The largest study found 19.2- and 57.8-fold increases in incidence and

mortality, respectively, with particularly high risks among 47,XXY mosaics. These risks were

still approximately 70% lower than among females, contradicting case reports that patients

with KS have breast cancer rates similar to females. Altered hormone levels (especially the

ratio of oestrogens to androgens), administration of exogenous androgens, gynaecomastia

and genetic factors have been offered as possible explanations for the high risks.Conclusions: Additional well-designed epidemiologic studies are needed to clarify

which patients with KS are at a high risk of developing MBC and to distinguish between

possible predisposing factors, including altered endogenous hormones.

INTRODUCTIONIn 1942, Harry F. Klinefelter described a syndrome charac-terized by gynaecomastia, small testes, complete spermato-genic failure, Leydig cell insufficiency and increasedexcretion of follicle-stimulating hormones (FSH). Suchpatients were subsequently discovered to have the sex chro-mosome genotype of 47,XXY, and the condition becameknown as Klinefelter syndrome (KS). In addition to hypo-gonadism, KS has been found to be characterized by variousphysical, developmental and hormonal alterations, includ-ing increased oestrogen to androgen ratios. There have beena number of reports of male breast cancer (MBC) occurringamong patients with KS, prompting an interest in furthercharacterizing and understanding underlying biologicalmechanisms.

Although it is now recognized that patients with KS haveelevated rates of MBC, the magnitude of the relationshipremains uncertain. Few epidemiologic studies have beenconducted, and most have been plagued by small numbersor surveillance and selection biases. We reviewed the

relevant literature, assessing strengths and limitations of theinvestigations. Findings were related to biological correlatesto add insights into possible mechanistic pathways.

METHODOLOGIC DIFFICULTIES INVOLVED IN ASSESSING CANCERRISKS AMONG PATIENTS WITH KSClinical reports of MBCs developing among patients withKS are difficult to interpret given the absence of a compari-son group and inability to derive expected values. In somestudies, the strength of the association appears enhancedbecause a cancer diagnosis leads to a karyotypic evaluationand the diagnosis of KS. Further problems arise as a resultof under-recognition of KS on a population basis.

Epidemiologic studies are required to derive conclusionsregarding the true extent of risk, but these are difficult toundertake, and can have inherent methodologic limitations.For instance, case–control studies, which compare expo-sures between individuals with and without a condition(e.g. MBC), usually depend on patient reports of exposures(e.g. the prior diagnosis of KS) and involve small numbersof pertinent events.

Another approach is to undertake a cohort investigation,which assesses cancer risk subsequent to a diagnosis of KS.To enable the assessment of cancers that generally occur atolder ages (such as is the case for MBC), the most feasible

Abbreviations

CI, confidence interval; FSH, follicle-stimulating hormone; KS,Klinefelter syndrome; MBC, male breast cancer; SIR, standard-ized incidence ratio; SMR, standardized mortality ratio.

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approach is a retrospective cohort study, whereby a cohortof patients with KS is assembled from historical records,allowing subsequent assessment of development of cancers.

A difficulty faced by retrospective cohort studies, how-ever, is the fact that a sizeable proportion of patients withKS are never diagnosed with the condition. A presumptiveclinical diagnosis will prompt cytogenetic studies. There-fore, subjects who are assessed for cancer risk are usuallybiased towards having greater degrees of clinical abnormali-ties. In the largest study conducted (1), phenotypic abnor-malities were admittedly over-represented. Further, thisstudy did not include patients with mosaicism associatedwith Down syndrome trisomies because of a recognized linkwith cancer, further limiting the generalizability of theresults.

The final difficulty in assessing the relationship of KS toMBC risk is in assembling sufficient numbers of each condi-tion for investigation. KS is grossly under-diagnosed, withapproximately 7 of every 10 cases being unrecognized, for aprevalence at birth of only 1 in every 660 males (2). Thus, itis difficult to assemble sufficiently sized cohorts to evaluatesubsequent cancer risk, particularly for MBC, which has anestimated lifetime occurrence of one in every 1000 individu-als (3). MBC is also a condition that is usually not diagnoseduntil the mid-sixties or seventies, requiring long-term fol-low-up of patients.

CASE SERIESThe association of MBC with KS was first suggested by Bau-er and Erickson in 1955 (4). Subsequent reports of 21 (5)and 150 (6) patients with MBC composed of unusually highproportions of patients with KS provided further supportfor an association. These studies have been widely quoted,particularly as one of them postulated that the incidence ofbreast cancer in patients with KS may approximate thatfound among women (5).

A number of additional case reports described concomi-tant occurrences of MBC and KS. Scheike and others (7)assembled results of five studies that showed nine sex chro-matin-positive males among 242 patients with MBC, or a 3%prevalence rate. Evans and Crichlow (8) comprehensivelyreviewed 27 reported cases of MBC among patients with KSand noted an average age of 58 years, with a high proportionof the cases (13 of 27) diagnosed with gynaecomastia. Basedon expected incidence rates in the general population, Sche-ike and others (7) estimated that patients with KS have a20-fold higher risk of developing MBC than karyotypicallynormal men and a risk one-fifth lower than that of womenin the general population. However, even with the higherrates than the general population, KS is generally rare,accounting for only a small proportion of all breast cancersin men. Thus, in the United Kingdom, it has been estimatedthat the population attributable risk (or the amount ofdisease attributable to the syndrome) is only 3.6% (6).

Differing accounts of the relative occurrence of MBCamong patients with KS may reflect that reported caseshave not been obtained by systematic screening of a defined

population with and without the syndrome. One Swedishstudy attempted to overcome this by systematically karyo-typing 93 unselected patients with MBC. This found a 7.5%prevalence rate of KS (9), a rate considerably higher thanthe 3% previously reported rate. These authors estimatedthat patients with KS have a 50-fold increased risk of devel-oping MBC.

A final complication that affects case reports (as well asepidemiologic studies) is that patients with KS may receivegreater scrutiny for cancer, i.e. results may be affected bysurveillance bias. This could have particular implicationsfor the detection of MBC, a cancer that is often not sus-pected or given serious diagnostic attention.

REVIEW OF EPIDEMIOLOGIC STUDIESCase–control investigationsAn early case–control study found that two of 72 MBCcases tested positive for sex chromatin versus none of 69controls (10). Another study found two patients with KSamong their 181 patients with MBC (11); this lower preva-lence rate of KS most likely reflected that this study focusedon men who were eligible for care within the VeteransAdministration systems of hospitals.

The largest case–control study focused on prior inpatientmedical diagnoses among over 4.5 million U.S. veterans(12). Among 642 men diagnosed with primary MBC duringthe period 1969–1996, KS was noted as a primary diagnosisamong only five subjects, resulting in a rate ratio of 29.6[95% confidence interval (CI), a measure of certainty of theassociation of 12.3–71.7]. The risk was somewhat higher forblack (93.3) than white subjects (20.2), but this differencewas based on very small numbers (3 and 2 MBCs, respec-tively). The prevalence of KS in this investigation was con-siderably lower than the figure of 7.5% previously noted (9),which was attributed to the fact that individuals eligible forVeterans Administration benefits must be medically quali-fied to enter military service. Although gynaecomastia, acondition often associated with KS (3), was also found to bea significant risk predictor in this study, no patients hadboth diagnoses, obviating concerns that this was the factorresponsible for the high rates of MBC observed among thepatients with KS.

Cohort investigationsTwo cohort studies of patients with KS have been reportedfrom Denmark and Scotland. The Danish study included 832men with KS established from the Danish Cytogenetic Regis-ter (2). Among patients with KS, three cases of breast cancerwere observed vs. 0 among 4022 age-matched controls fromthe general population. The Scottish study (13) focused on466 X chromatin-positive male patients identified through aregister of patients with chromosome abnormalities. Follow-up for mortality identified two cases of MBC among patients55 years of age and older, a rate twice as high as thatexpected among women in the general population.

The largest investigations have been conducted by Swerd-low et al. (1,14,15). In the first investigation (14), involving

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646 patients with KS diagnosed at three cytogenetic centresin the United Kingdom between 1959 and 1990, two deathsfrom breast cancer were observed. In fact, these two caseswere the same as those previously observed in the Scottishstudy (13). In Swerdlow’s analysis, cancer mortality wascompared to expected rates based on national populationfigures, leading to derivation of standardized mortalityratios (SMRs). A SMR of >1.0 indicates a higher thanexpected occurrence, and these two cases resulted in a SMRof 61.7, with 95% CI 7.5–222.7.

In a subsequent study, Swerdlow et al. (1) expanded hiscohort to include 3518 men diagnosed with KS at 27 cyto-genetic laboratories in the United Kingdom between 1959and 2002. In follow-up of the cohort members, five subjectswere found to have died with breast cancer (SMR 57.8, 95%CI 18.8–135.0) and four to have incident breast cancers.Compared to the general population, this translated into astandardized incidence ratio (SIR) of 19.2 (95% CI 5.2–49.2). Although substantially elevated compared to the gen-eral population of men, the SMR was significantly lowerthan expectation when general population rates for womenwere employed (SMR = 0.3, 95% CI 0.1–0.8).

The majority of the cohort members in this investigationhad a 47,XXY (n = 3002) or 47,XXY mosaic (n = 320)chromosomal constitution. Of note was that the highestrisks of either breast cancer mortality or incidence werefound among the relatively small group of men with47,XXY mosaic karyotypes (SMR = 222.8, 45.9–651.0,SIR = 33.7, 0.9–187.7), the majority of whom (n = 226) hada 47,XXY ⁄ 46,XY karyotype (SMR = 235.4, 28.5–850.4).

BIOLOGICAL PLAUSIBILITY OF ASSOCIATIONIn deciphering why patients with KS experience high rates ofMBC, attention has focused on various biological and clini-cal correlates of the condition, including altered hormonelevels, administration of exogenous androgens, frequentlong-standing gynaecomastia and genetic constitution.

Altered endogenous hormones have been the primaryfocus for explaining the observed increases in MBC amongpatients with KS. During puberty, patients with KS begin toexhibit elevated levels of gonadotrophins and decreasedlevels of testosterone, resulting in their characteristic bodyproportions and gynaecomastia (16). In adults, low testo-sterone in relation to estradiol levels are cardinal features ofKS, resulting in increased oestrogen to testosterone ratios(17).

Several well-established risk factors for female breast can-cer appear to operate through hormonal mechanisms,namely obesity and physical inactivity, and both factors pre-sumably affect MBC risk (18). Obesity has also been fre-quently associated with KS (19), although in at least onestudy the increased risk of MBC associated with KS per-sisted after adjustment for diagnoses of obesity (12). Inwomen, it is generally thought that these factors reflectincreased oestrogen levels, but in men the underlying mech-anisms relate not only to increased oestrogens but also todecreased testosterone and sex hormone–binding globulin

levels (20). This has led to speculation that alterations in theratio of estradiol ⁄ testosterone might be more relevant formale than female breast cancers, consistent with the hor-monal alterations found among patients with KS. An alteredoestrogen ⁄ androgen ratio has also been offered as an expla-nation for a recently observed relationship between bonefractures and an increased risk of MBC (18), given that bothhormones appear to be involved with bone maintenanceand osteoporosis among men and that androgens tend todecrease preferentially with age. This hypothesis would alsobe consistent with the fact that patients with KS have a pre-dilection for bone loss and fractures (21).

In addition to a focus on altered endogenous hormones,there has been interest regarding possible iatrogenic effectsof exogenous hormones. Many KS patients with hypogona-dism are treated with androgens, and there are case reportsof breast cancer developing after such therapy. One study of45 patients with KS treated with testosterone noted thedevelopment of two cases of MBC, both occurring 10 ormore years after initiation of therapy (22). Among patientswith KS, androgen supplementation could still be consistentwith an effect of a high oestrogen to androgen ratio giventhat patients with KS presumably experience more periph-eral conversion of testosterone to estradiol than karyotypi-cally normal men (23).

Another explanation for the increased risk of MBCamong patients with KS is that many, although far from all,patients with KS have gynaecomastia, a recognized risk fac-tor for MBC. Despite gynaecomastia providing increasedtissue at risk, its aetiologic relevance to MBC has been ques-tioned. It is possible that surveillance issues or uncontrolledconfounding by more direct predictors, such as obesity andcorrelated hormonal alterations, may be involved. How-ever, it is of note that many patients with KS begin to experi-ence gynaecomastia early in life and therefore have long-standing conditions. Histologic evidence of a transitionfrom atypical proliferative ductal epithelium in gynaeco-mastia to carcinoma in patients with KS has been reported,supporting the notion of abnormal hormonal stimulation ofcell proliferation in the mammary ductal epithelium (24).Further, elevated levels of oestrogen and progesterone tis-sue receptors have been found among patients with KS withgynaecomastia when compared to other gynaecomastiapatients (25).

Finally, in addition to the role of endogenous hormonesand gynaecomastia as predictors of MBC among patientswith KS, consideration must be given to the possibility thatpatients with KS have a genetic predisposition to MBC.Some studies suggest that the additional X chromosomepresent in KS is responsible (26,27). Lynch et al. (26) havesuggested that XXY males may inherit the same predisposi-tion to breast cancer as XX females. This could affect notonly breast cancer risk, but also risks of other cancers thathave been suggested to be elevated among patients with KS,including non-Hodgkin lymphomas as well as germ cellmediastinal, lung and intracranial tumours (1). The geneticmechanisms involved with this predisposition are currentlyunknown, but it is of interest that fibroblasts from 47,XXY

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patients have been shown to have an abnormally high trans-formation frequency by simian virus 40 (28), raising the pos-sibility that patients with KS share phenomena observed intumour-susceptible individuals.

CONCLUSIONSBased on the rather scant data available, it can be con-cluded that patients with KS are at an increased risk ofdeveloping breast cancer. The most convincing data seem tosupport that this risk may be around 20- to 30-fold higherthan expected. This risk, although elevated, is still consider-ably lower than that of women in the general population.

The level of absolute risk of MBC among patients withKS does not justify prophylactic mastectomy, but does sup-port the need for patient education, monthly breast self-examinations and periodic physical examination. Althoughmammography has been shown to be useful in the diagnosisof MBC (29), it is difficult at the moment to determinewhether this should be employed among patients with KS.There is clearly a need for additional studies to furtherunderstand the magnitude of risk of breast cancer amongpatients with KS and to determine whether there are certainfactors that might most strongly predict risk. Further studiesshould allow a better understanding of the biological mech-anisms involved in the genesis of breast cancer amongpatients with KS, enabling future targeted interventions andimproved treatment approaches.

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5. Jackson AW, Muldal S, Ockey CH, O’Connor PJ. Carcinoma ofmale breast in association with the Klinefelter syndrome. BrMed J 1965; 1: 223–5.

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APPENDIX: DISCUSSION FOLLOWING LOUISE BRINTON’SPRESENTATIONBreast cancer in Klinefelter syndromeNiels E Skakkebæk (Copenhagen, Denmark):I am interested in racial differences in the incidence ofKlinefelter syndrome (KS) and its associated morbidities,

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particularly breast cancer, but could find very little data inthe literature. You will be seeing mainly Caucasians andAfro-Americans. Have you seen any differences in the blackand white populations in USA?

Louise Brinton:There is a greater incidence of male breast cancer in Afri-can-Americans than in Caucasians, but I have no informa-tion of racial differences in KS.

Ewa Rajpert-De Meyts (Copenhagen, Denmark):There are large differences in the incidence of female breastcancer in different countries and that is related to affluenceand lifestyle. Have you seen any environmental influenceson the prevalence of male breast cancer in KS?

Louise Brinton:No epidemiological studies have yet been conducted assess-ing the role of environmental factors in KS-associated malebreast cancers. It is difficult to assess the environmentaleffect on male breast cancer because numbers are so small.A trend may be detected by combining data from interna-tional registries or investgations. For male breast cancer ingeneral, studies have identified potential associations withobesity, lack of physical activity, and certain occupationalfactors including those involving intensive heat and electro-magnetic exposures. There are anecdotal reports that someAfrican countries have increased incidences of male breastcancer but these data are difficult to assess because of thepoor quality of these registries.

Ronald Swerdloff (Los Angeles, USA):Difficulties exist in the interpretation of your data becauseof the design of the study. The diagnosis of gynaecomastia isvery clinician dependent and is not obvious unless it ismarked and looks like the pictures illustrating the feature.Most cases of gynaecomastia have small breast glands andrequire skilled examiners to make a diagnosis. In your

analysis of sex steroids, you should control for the degree ofobesity in individuals. Very sensitive assays for testosterone(T) and oestradiol (E2) are required because these are usu-ally present at low levels. E2 levels in particular may be closeto the level of sensitivity and measurements are affected bybackground noise. The reference ranges for these steroidsare poorly defined.

Louise Brinton:We have preliminary data on E2 levels in males using aLCMS assay which is very sensitive and provides accurateresults. These levels are similar to postmenopausal levels inwomen.

Claus Gravholt (Aarhus, Denmark):Rather than looking for breast cancer in KS patients, hasany tried to look for KS in male patients developing breastcancer.

Louise Brinton:This has been examined in a number of small studies, butfor the most part these have been selected samples limitingthe generalisability of results. There are ongoing large stud-ies in Denmark and in Florence, Italy, where tissue samplesare being tested for genetic alterations. These studies are notspecifically looking for KS, but karyotyping should detect ifany of the samples are characteristic of KS.

Fred Wu (Manchester, UK):There are a significant number of KS patients having breastsurgery, either reduction mammoplasty or mastectomy.Have you included that in your risk calculations? Are thereany plans to make use of the breast tissue to study potentialprecancerous changes?

Louise Brinton:We have not corrected our results for breast surgery. Itwould be very useful to study the tissue samples.

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