Breast Cancer as a Second Primaryin Patients With Prostate Cancer—EstrogenTreatment or Association With Family History of Cancer?Camilla Thellenberg Karlsson, Beatrice Malmer, Fredrik Wiklund and Henrik Grönberg*From the Department of Radiation Sciences, Oncology, University of Umeå, Umeå and Department of Medical Epidemiology andBiostatistics, Karolinska Institutet (FW, HG), Stockholm, Sweden

Purpose: In a large population based study we reported an increased risk of male breast cancer after prostate cancer. In thecurrent study we performed a comprehensive investigation of whether treatment for prostate cancer and/or family history isresponsible for the excess risk.Materials and Methods: This study had 2 parts. 1) We performed a nested case-control study in 41 men who had previouslybeen identified with first prostate cancer, followed by male breast cancer and in 81 matched controls with prostate canceronly. The medical records of these men were retrieved and clinical data such as stage, grade and treatment were extracted.2) We also performed a family study including relatives of men with a diagnosis of prostate as well as breast cancer,irrespective of which was first. The 878 relatives were identified through parish offices and linked to the Swedish CancerRegistry to evaluate the occurrence of breast, prostate and other cancers and calculate if there were any excess risks fordifferent cancers.Results: Cases with prostate plus breast cancer received estrogen treatment more often than controls with prostate canceronly (p � 0.03). The period of estrogen treatment was longer in the cases, although it was not statistically significant. Meantime from prostate cancer diagnosis to breast cancer diagnosis was 47.6 months. Cases and controls did not differ in gradeor stage. In the family study an increased risk of prostate cancer was found in relatives (SIR 2.14, 95% CI 1.09 to 3.18). Forother cancers no significantly increased risks were found. In 2 families pedigree analysis using the BRCAPRO program(http://www3.utsouthwestern.edu/cancergene/) revealed an estimated 100% and 49% probability in families 1 and 2, respec-tively, that the proband was a BRCA2 carrier.Conclusions: Our data suggest that most of the increased risk of breast cancer following prostate cancer can be explainedby estrogen treatment. However, in a small number of men with prostate as well as breast cancer pedigree analysis suggeststhat BRCA2 mutation might be the underlying cause.

Key Words: prostate, prostatic neoplasms, breast neoplasms, genetics, estrogens

As in large parts of the Western world, prostate canceris common in Sweden with approximately 8,000 newcases yearly. The incidence is increasing, partly due

to PSA testing. Among the few risk factors identified forprostate cancer are family history, ethnicity and dietaryfactors,1,2 However, most of the etiology of prostate cancer isstill unknown.

A way to find new risk factors and generate hypotheses isto study second primary tumors to find common geneticfactors and also environmental or treatment factors. In ourprevious cohort study comprising all 135,713 men diagnosedwith prostate cancer in Sweden between 1958 and 1996 anincreased risk of second primary male breast cancer (SIR2.01, 95% CI 1.44 to 2.74) following prostate cancer was the

Submitted for publication November 1, 2005.Study received approval from the ethics committee of Umeå Uni-

versity.Supported by a grant from the Lion’s Cancer Research Founda-

tion, Umeå and Swedish Cancer Foundation (Cancerfonden).* Correspondence: Department of Medical Epidemiology and Bio-

statistics, Karolinska Institutet, Box 281, SE-171 77 Stockholm,

Sweden (telephone: �46 (0) 8 524 823 47; FAX: �46 (0) 8 31 49 75;e-mail: henrik.gronberg@ki.se).

0022-5347/06/1762-0538/0THE JOURNAL OF UROLOGY®

Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION

538

most interesting finding.3 In that report no treatment datawere available, although a hypothesis is that estrogen treat-ment might explain the increased risk of breast cancer.However efficient and widely used in the 1970s and 1980s,treatment with oral estrogen has been abandoned for a longtime because of serious cardiovascular adverse effects. Morerecent studies showed that using parenteral estrogen (poly-estradiol phosphate) the cardiovascular negative side effectscould be decreased, and the same treatment efficacy as or-chiectomy or luteinizing hormone-releasing hormone ana-logues could be achieved.4 The genetic predisposition towardprostate cancer is mainly unknown but several reports in-dicate that male BRCA2 carriers are at increased risk forprostate cancer.5–7

Compared to prostate cancer male breast cancer is rarewith an age standardized incidence of 1/100,000 casesyearly. The incidence varies around the world and it ishighest in black Americans and Ashkenazi Jews. Some riskfactors have been identified for male breast cancer, such asKlinefelter’s syndrome, a familial history of female breastcancer and BRCA2 mutations. In Sweden there are somefounder mutations in the BRCA1 and 2 genes but at low

frequency.8 Previous thoracic irradiation for various condi-

Vol. 176, 538-543, August 2006Printed in U.S.A.

DOI:10.1016/j.juro.2006.03.036

BREAST CANCER AS SECOND PRIMARY IN PATIENTS WITH PROSTATE CANCER 539

tions has also been shown to increase the risk as well asdiseases that cause excess estrogen, eg liver cirrhosis.9 Infemale breast cancer it is well known and accepted thatestrogen treatment in postmenopausal women increases therisk of breast cancer.10

We hypothesized that estrogen treatment for prostatecancer and/or a common genetic predisposition explains theincreased risk of breast cancer in patients with prostatecancer. To study this we used a nested case-control study ofmen with prostate cancer with (41) or without (81) subse-quent breast cancer. In addition, we mapped in detail can-cers in close relatives of 83 men with breast as well asprostate cancer.

MATERIALS AND METHODS

Nested Case-Control StudyWe used a nested case-control design in all 153,340 menreported with a prostate cancer diagnosis in Sweden be-tween 1958 and 1998 as the founding cohort.3 The 41 caseswere defined as first having prostate cancer, followed bymale breast cancer. For each case 2 controls with prostatecancer but without breast cancer, matched by age at pros-tate cancer diagnosis, year of diagnosis and region in Swe-den, were identified in the cohort. Only 81 controls fit ourmatching criteria and, therefore, 1 case had only 1 matchedcontrol. The medical records of cases and controls were re-trieved from the treating hospital. It was possible to find therecords of 38 cases (93%) and 69 controls (85%). Medicalrecord availability was not a criterion for selecting cases orcontrols to avoid selection bias. Data on treatment, his-topathological grade and stage at diagnosis were extractedfrom the medical records.

To compare continuous variables between the 2 groupswe calculated the mean and used the Mann-Whitney non-parametric test. For dichotomous variables Fisher’s exacttest was used. All p values were 2-sided and p � 0.05 wasconsidered statistically significant. OR calculation was alsoperformed with the 95% CI for the risk of breast cancerfollowing estrogen treatment.

Family StudyFrom the same cohort of men with prostate cancer in Swe-den in 1958 to 1998 we identified all 83 men with breastcancer and prostate cancer regardless of which tumor wasdiagnosed first. For these 83 men (probands) with prostateas well as breast cancer all first-degree relatives and grand-children were identified from parish offices in Sweden. Untilrecently parish offices were responsible for population sta-tistics and they are reliable since all records are based on theunique Swedish personal identification number with a 10-digit code. The personal identification numbers of relativeswere subsequently linked to the Swedish Cancer Registry toidentify all cancer diagnoses in these individuals.

Person-years at risk were calculated using S-PLUS®.Person-years were calculated from January 1, 1958, whichwas the Swedish Cancer Registry starting date, the date ofbirth or date of migration to Sweden and December 31, 2002,the date of death or the date of emigration. Migration datesare of interest since no data on cancer were recorded in theserelatives before immigration or after emigration. Relativeswho died before January 1, 1958 were not included in the

study. The expected number of cancer cases was calculated

by multiplying person-years by the calendar and age specificcancer incidence rate in Sweden. Cancer incidence rates inSweden in 1958 to 2002 were obtained from the SwedishCancer Registry and used in all calculations.

SIR was defined as the ratio between the observed andexpected number of cases. The SIR 2-tailed 95% CI wasestimated under the assumption of normal distribution. Toestimate the probability that the proband in the familiescarried a BRCA2 mutation the program BRCAPRO wasused. The ethics committee of Umeå University providedstudy approval. All except 2 cases were dead and only 1control was alive. In these patients informed consent wasobtained by contacting the treating physician.

RESULTS

Treatment data were available on 36 cases (88%) and 69controls (85%). Primary active treatment were administeredin 24 (67%) cases and 41 (62%) controls. Of the remainingpatients 12 cases and 25 controls underwent no treatment orwatchful waiting (p � 0.40). Cases and controls did not differin tumor grade or stage, or in what treatment was givendepending on grade or stage. The most prevalent treatmentwas estrogen (table 1). Of 23 cases 20 (83%) and 23 of 40controls (56%) were treated with estrogens (p � 0.03). Mentreated with estrogens had an OR of 3.91 (95% CI 1.14 to13.50) for breast cancer.

The most commonly used estrogen was polyestradiolphosphate, which was given as intramuscular injection in85% of cases and 78% of controls. Oral preparations such asethinyl estradiol and estramustine phosphate in a few in-stances were the other commonly used estrogens. The dura-tion of estrogen treatment was not significantly differentbetween cases and controls with a median time on treatmentof 22.4 and 17.2 months, respectively (p � 0.10, table 2).

Mean time from prostate cancer diagnosis to breast can-cer diagnosis was 47.6 months (median 32). Of the cases 35

TABLE 1. Characteristics in cases and controls

No. Cases (%) No. Controls (%) p Value

Totals 41 81Records available 38 (92.7) 69 (85.2)Mean age:

Available 72.5 76.0 0.06Missing 72.3 71.6

Tumor grade:Low 8 (21.1) 22 (31.9) 0.57Medium 12 (31.6) 21 (30.4)High 8 (21.1) 14 (20.3)Missing data 10 (26.3) 12 (17.4)

TNM status:M0 35 (85.4) 64 (79.0) 0.40M1 6 (14.6) 17 (21.0)

Treatment:Expectant/none 12 (33.3) 25 (37.9) 0.40Any active 24 (66.7) 41 (62.1)

Active treatment:Orchiectomy 3 (12.5) 17 (41.4) 0.03Estrogen* 20 (83.3) 23 (56.1)Antiandrogen 1 (4.2) 0Luteinizinghormone-releasinghormoneanalogue

0 1 (2.4)

Breast radiation 4 (11.1) 3 (4.5) 0.25

* OR vs any other treatment 3.91 (95% CI 1.14 to 13.50).

BREAST CANCER AS SECOND PRIMARY IN PATIENTS WITH PROSTATE CANCER540

(85%) with prostate cancer and 29 (71%) with breast cancerwere diagnosed before the end of 1985. Radiation to themammary gland showed no significant difference betweenthe 2 groups, that is 4 cases and 3 controls received radiation(p � 0.43).

Family data from parish offices were available on 77 of 83families (93%). Overall 878 relatives were identified. The10-digit personal identification number was missing in 90relatives, which made it impossible to link individuals to thecancer registry. Of the relatives 196 died before 1958, whichis the starting date of the cancer registry. A total of 592relatives with a total of 19,333.6 person-years were linked tothe cancer registry and in these relatives 91 cancer diag-noses were observed. The SIR for all cancers was 1.23 (95%CI 0.92 to 1.55, table 3). A total of 18 prostate cancers werefound in relatives, including 1 before age 50 years (SIR 2.14,95% CI 1.09 to 3.18). There were 17 female breast cancersand 1 male breast cancer with a SIR in the women of 1.57(95% CI 0.72 to 2.41). Six female breast cancers were diag-nosed before age 50 years (SIR 3.17, 95% CI 0.62 to 5.71).There were also ovarian cancer in 3 relatives, colorectalcancer in 8 women and 5 men, and gastric cancer in 1 womanand 4 men. However, no other individual cancer site differedsignificantly from what was expected.

Analyzing the individual families identified some infor-mative families. In family 1 the proband had bilateral breastand prostate cancer (fig. 1). His mother was diagnosed withbreast cancer at age 76 years and a sister was diagnosedwith breast cancer at age 39 years. In addition, a brotherhad breast cancer at age 70 years. The initial treatment thatthe proband received for prostate cancer was orchiectomy. Infamily 2 the proband had a daughter with breast cancer atage 43 years and 3 brothers with pancreatic cancer at age 51years, prostate cancer at 75 years, and colon and rectalcancer at 71 and 78 years, respectively (fig. 1). BRCAPROestimated a 100% probability in family 1 and a 49% proba-

TABLE 2. Actively treated patients with subseque

Prostate CaDiagnosis

Age Yr

Prostate–BreastCa DiagnosisTime (mos)

Primary ProstateCa Treatment

Pre-BreastEstrogen

Durat

68 1962 27 Estrogen62 1963 0 Estrogen81 1964 0 Estrogen77 1965 142 Estrogen52 1966 22 Estrogen80 1967 18 Estrogen67 1967 34 Estrogen

70 1968 53 Estrogen57 1968 13 Estrogen57 1969 262 Estrogen64 1969 14 Estrogen72 1970 0 Estrogen64 1970 60 Estrogen64 1972 55 Estrogen77 1974 78 Estrogen83 1975 129 Estrogen69 1978 16 Estrogen79 1979 20 Estrogen80 1980 24 Antiandrogen71 1980 32 Estrogen/estramustine77 1981 92 Orchiectomy73 1982 19 Estrogen72 1983 32 Orchiectomy/estrogen82 1990 13 Orchiectomy

bility in family 2 that the proband was a BRCA2 carrier.

There were also families with familial clustering of prostatecancer and other tumors (fig. 2).

DISCUSSION

This study shows that estrogen treatment in patients withprostate cancer carries a 4-fold increased risk of subsequentbreast cancer. This suggests that estrogens are involved inthe pathogenesis of breast cancer in these men. To ourknowledge this is the first population based study to com-prehensively evaluate estrogen treatment as a possiblecause of male breast cancer. In the literature there aresporadic case reports about male breast cancer after pro-longed estrogen treatment.11,12 In addition, in a case reportstudy of 10 men with reported breast cancer before and afterprostate cancer 7 had a family history of breast cancer.13

None of the men with prostate cancer diagnosis beforebreast cancer had received any hormones. Interestinglythere are also case reports of male breast cancer after anti-androgen treatment for prostate cancer.14,15 The reason forthis might be the hyperestrogenemia caused by antiandro-gens. This supports the results in the current study.

Estrogens and hormone replacement therapy are a well-known risk factor for female breast cancer.10 It is also

TABLE 3. Observed and expected cancers in 592 close relatives ofmen with breast and prostate cancer

ICD-7 No. Observed No. Expected SIR (95% CI)

All cases 91 73.70 1.23 (0.92–1.55)Stomach 5 4.36 1.15 (0.21–2.09)Colon 5 6.25 0.80 (0.12–1.48)Rectum 8 3.51 2.28 (0.78–3.77)Breast 18 10.93 1.65 (0.77–2.52)Prostate 18 8.43 2.14 (1.09–3.18)Bladder 7 3.42 2.05 (0.36–3.74)

east cancer by year of prostate cancer diagnosis

iagnosis-tmentos)

Primary MetastaticDisease atDiagnosis

Survival(mos)

Family Member WithBreast/Prostate Ca (age)

No 29No 26 Sister, breast (73)No 5No 146No 24Yes 32No 42 Sister, breast (70), sister,

breast 70 (72)Yes 58 Brother, prostate (83)No 15No 281Yes 17No 54No 82No 81 Brother, prostate (53)No 240 Daughter, breast (57)No 139Yes 17No 38No 28Yes 32No 94 Son, prostate (61)No 21Yes 38

20

nt br

Ca DTrea

ion (m

2700

142221811

531196110

595577

1291519

26

1910

Only cancers with 5 or more observed cases are presented.

prog

BREAST CANCER AS SECOND PRIMARY IN PATIENTS WITH PROSTATE CANCER 541

known that conditions that cause hormone imbalance withexcess estrogens in men are a risk factor for male breastcancer, such as Klinefelter’s syndrome and liver cirrhosis.9

Obesity and surplus alcohol intake are also associated withmale breast cancer and this is explained by estrogen imbal-ance.16,17 In a recent study of the cancer incidence in menwith Klinefelter’s syndrome a high incidence of breast can-cer were present but there was a low risk of prostatecancer.18 The fact that patients in this current study hadprostate cancer first minimizes the likelihood thatKlinefelter’s syndrome explains our results. The hypothesisthat estrogen treatment for prostate cancer has causality formale breast cancer is further supported by the fact that themajority of breast cancers were diagnosed before 1985, whenestrogen was more intensively used.

A limitation of this study is the difficulty of collecting oldmedical records and there are some data missing on tumorcharacteristics and treatment. However, the missing datawere equally distributed among cases and controls, so that itwould not be expected to have affected the results or inter-

FIG. 1. Two families were identified in study in which BRCA2 mutaNo probands were treated with estrogen. As estimated by BRCAPROgene was 100% and for proband in family 2 probability was 49%.

pretation. In the control group some extreme outliers af-

fected the mean duration of estrogen treatment and conse-quently the results. This may be because cases werecensored after breast cancer developed and no further treat-ment was administered thereafter but controls could havereceived ongoing treatment for a longer period. This differ-ence in duration might be of clinical importance, althoughthe difference did not achieve statistical significance. Therewas also a problem when analyzing intent to treat since afew cases were given estrogen, although breast cancer wasdiagnosed simultaneously with prostate cancer. The possi-bility of controlling for other known risk factors for breastcancer was low since there was no way of collecting data onobesity or alcohol consumption, which is a limitation.

In the family study a significant increased risk of prostatecancer was observed among relatives. This was expectedsince numerous studies have demonstrated increased risk inrelatives.1 The size of this study provided enough power todetect a 2-fold increase in risk. SIR less than 2, such as forbreast cancer (SIR 1.65), could also be true but it remainedinsignificant due to the size of the study. The increased risk

as highly suspected but no data on mutation status was available.ram, probability of proband in family 1 to carry mutation in BRCA2

tion w

of breast cancer was more pronounced in relatives

tate

BREAST CANCER AS SECOND PRIMARY IN PATIENTS WITH PROSTATE CANCER542

younger than 50 years, as also shown in the study ofEdwards et al.7 In this study it was suggested that anindicator of BRCA2 mutations in cases with early onsetprostate cancer was not a relative with prostate cancer,but rather young relatives with breast and/or ovariancancer. In addition, approximately 2% of those with earlyonset prostate cancer (at ages less than 55 years) hadtruncating mutations in BRCA2.

A number of family studies have shown a relationshipbetween breast and prostate cancer.19,20 It has been sug-gested that this might be due to mutation in the BRCA2gene.21 The Breast Cancer Linkage Consortium showed anRR for prostate cancer of 4.65 (95% CI 3.48 to 6.22) in acohort study of BRCA2 families.5 There is also a report ofa family with several cases of prostate cancer and breastcancer carrying a BRCA2 mutation.6 In a Swedish studyof 34 male patients with breast cancer 7 (21%) were foundto have germline truncating mutations in BRCA2.22 Only1 mutation carrier had a positive family history. The

FIG. 2. Two families with familial/hereditary pros

families in this study were not extended to second-degree

relatives and, therefore, some cancers that would havebeen indicative of the heritability of BRCA2 or other genesmight have been missed. In the current study there are nodata regarding mutation status but the BRCAPRO pro-gram estimated a high probability of BRCA2 mutations infamilies 1 and 2.

CONCLUSIONS

Our data suggest that some of the increased risk of breastcancer following prostate cancer can be explained by estro-gen treatment. A large number of men have been treatedwith estrogen, so that the absolute risk of breast cancerfollowing estrogen treatment is actually low. However, itmust be considered when a man with prostate cancer pre-sents with breast swelling. In a small fraction of men withmale breast cancer together with prostate cancer it seemspossible that BRCA2 mutations or perhaps other, as yet

cancer. No probands were treated with estrogen.

unknown genes are the underlying cause.

BREAST CANCER AS SECOND PRIMARY IN PATIENTS WITH PROSTATE CANCER 543

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