Prostate Cancer

Age-Specific Risk of Incident Prostate Cancer and Risk of Death

from Prostate Cancer Defined by the Number of Affected Family

Members

Andreas Brandt a,*, Justo Lorenzo Bermejo a,b, Jan Sundquist c,d, Kari Hemminki a,c

a Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germanyb Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germanyc Centre for Primary Care Research, Lund University, Malmo, Swedend Stanford Prevention Research Centre, Stanford University School of Medicine, Stanford, CA, USA

E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 2 7 5 – 2 8 0

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Article history:

Accepted February 3, 2010Published online ahead ofprint on February 13, 2010

Keywords:

Prostate cancer

Familial prostate cancer

Familial risk

Prostate cancer mortality

Population-based studies

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Abstract

Background: The thorough assessment of familial prostate cancer (PCa) risk is as

important as ever to provide a basis for clinical counselling and screening recom-

mendations.

Objective: Our aim was to determine the age-specific risks of PCa and the risk of

death from PCa according to the number and the age of affected first-degree

relatives.

Design, setting, and participants: The nationwide Swedish Family-Cancer Data-

base includes a record of >11.8 million individuals and their cancers from 1958 to

2006. All men from the database with identified parents (>3.9 million individuals)

were followed between 1961 and 2006. The study included 26 651 PCa patients, of

whom 5623 were familial.

Measurements: The age-specific hazard ratios (HRs) of PCa and the HRs of death

from PCa were calculated according to the number and age of affected fathers and

brothers.

Results and limitations: The HRs of PCa diagnosis increased with the number of

affected relatives and decreased with increasing age. The highest HRs were

observed for men <65 yr of age with three affected brothers (HR: approximately

23) and the lowest for men between 65 and 74 yr of age with an affected father (HR:

approximately 1.8). The HRs increased with decreasing paternal or fraternal

diagnostic age. The pattern of the risk of death from familial PCa was similar to

the incidence data.

Conclusions: The present results should guide clinical counselling and demon-

strate the vast increases in risk when multiple first-degree relatives are affected.

soc

. Division of Molecular Genetic Epidemiology, German Cancer Researchnheimer Feld 580, D-69120 Heidelberg, Germany. Tel. +49 6221 421805;

.brandt@dkfz.de (A. Brandt).

# 2010 European As

* Corresponding authorCentre (DKFZ), Im NeueFax: +49 6221 421810.E-mail address: andreas

0302-2838/$ – see back matter # 2010 European Association of Urology. Publis

iation of Urology. Published by Elsevier B.V. All rights reserved.

hed by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2010.02.002

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E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 2 7 5 – 2 8 0276

1. Introduction

A family history of prostate cancer (PCa) is a well-

established risk factor for the disease [1]. Family studies

consistently found a 2- to 4-fold increased risk in sons and

brothers of PCa patients [2,3]. Yet no high-risk susceptibility

genes have been identified, and the currently identified

common low-risk variants associated with cancer suscepti-

bility are not thought to have an impact on clinical practice

[4]. The European Randomised Study of Screening for

Prostate Cancer (ERSPC) showed a PCa–specific mortality

reduction of 20% by prostate-specific antigen (PSA)–based

screening but also a high degree of overdiagnosis [5].

Therefore, the thorough assessment of the risk according to

the number and the age of affected first-degree relatives is

as important as ever to provide a basis for clinical

counselling and screening recommendations [6]. The risk

of death from PCa in individuals at familial risk is a measure

for familial aggregation that has been rarely used. However,

the relative risk of death in men with a family history is

likely to be less biased than the risk of being diagnosed with

PCa, which may be overestimated because men at familial

risk may preferentially take part in screening for PCa [7–9].

In this study, we used the nationwide Swedish Family-

Cancer Database to estimate age-specific familial risks of

being diagnosed with PCa according to the number and type

of affected first-degree relatives and, respectively, accord-

ing to the parental and fraternal diagnostic ages. We also

calculate the risks of dying from PCa according to family

history. With a total number of 26 651 PCa patients, of

whom 5623 were familial, this is the largest family study

yet published.

2. Patients and methods

The Swedish Family-Cancer Database was created in the 1990s by

linking information from the Multigeneration Register, national

censuses, Swedish Cancer Registry, and death notifications [10]. Data

on family relationships were obtained from the Multigeneration

Register, in which children born in 1932 and later are registered with

their biological parents as families. Thus the individuals in the database

can be divided into the offspring generation (individuals born in 1932

and later) and the parental generation. The Swedish Cancer Registry is

based on compulsory reports of diagnosed cases, with coverage of the

cancer registration close to 100% [11]. Cases are reported separately by

clinicians and pathologists/cytologists; information on cancers based on

death certificates is not used. The underlying cause of death was

available from the Swedish Causes of Death Register. The 2008 update of

the database includes >11.8 million individuals and their cancers from

1958 to 2006 [12]. Our study population comprised 3.9 million men from

the offspring generation of the database with linkage to both parents.

Most men without identified parents (approximately 850 000) were

immigrants. The age structure of the database (offspring born after 1932)

implies that the maximum age of diagnosis in the offspring generation

was 74 yr. The age at diagnosis in the parental generation was not

limited. Tumour characteristics have been available since 2002

according to the TNM system introduced by the American Joint

Committee on Cancer [13]. However, only T was useful for the present

study because of the abundance of missing information for N and M.

Men in the offspring generation of the database were classified

according to number, type, and diagnostic age of affected first-degree

E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 2 7 5 – 2 8 0 277

relatives (father or brother). Hazard ratios (HRs) of diagnosis with PCa

and PCa-specific mortality were estimated using Cox regression; the HR

can be interpreted as an estimate of the relative risk [14] (‘‘PROC

PHREG’’; SAS v.9.1; SAS Institute, Cary, NC, USA). Age-specific HRs were

calculated using time-dependent variables. Individuals entered the risk

period at birth, immigration date, or first year of the study (1961). The

first year of the study was set as 1961 because of lower data quality

between 1958 and 1960. For the analysis of incident PCa, censoring

events were death; emigration; December 31, 2006; absence at census;

and diagnosis of malignancy at sites other than prostate. Men were also

censored at diagnosis of malignancy at sites other than prostate because

their subsequent risk might be different from the risk of the general

population. Men absent at census were censored because they were

probably not living in Sweden anymore. For the analysis of death from

PCa, censoring events were emigration; December 31, 2006; absence at

census; and death from a cause other than PCa. Socioeconomic status,

calendar period, and region were taken into account as covariates.

The Swedish Family-Cancer Database was approved by the Lund

regional ethical committee on August 12, 2008 (No. 409/2008), with

complementary approvals dated September 1, 2009, and January 22, 2010.

3. Results

Table 1 shows the age-specific HRs of diagnosis with PCa

according to number and type of affected first-degree

Table 2 – Age-specific hazard ratios of diagnosis with prostate cancer

0–54 yr 55–64 yr

n HRa 95% CI n HRa 95% C

Father affected

0–59 yr 27 6.14 4.21–8.98 69 3.13 2.47–3

60–64 yr 34 3.41 2.43–4.79 148 2.77 2.36–3

65–74 yr 216 3.83 3.33–4.42 740 2.42 2.25–2

75–82 yr 128 2.25 1.88–2.69 780 2.15 2.00–2

�83 33 1.52b 1.07–2.14 338 1.79 1.61–2

Brother affected

0–59 yr 48 6.62 4.97–8.83 229 4.16 3.65–4

60–64 yr 29 3.72 2.57–5.37 277 3.28 2.91–3

65–74 yr 19 2.76 1.75–4.43 247 2.47 2.18–2

CI = confidence interval; HR = hazard ratio.a p values are <0.0001 unless otherwise stated.b p = 0.02.

Table 3 – Hazard ratio of diagnosis with prostate cancer for men withdiagnosis of youngest affected relative

Affected relatives Age of diagnosis of relative diagnosed at y

Father and brother 0–59

60–64

65–74

Two brothers 0–59

60–64

65–74

Father and two brothers 0–59

60–64

65–74

Three brothers 0–59

60–64

65–74

CI = confidence interval; HR = hazard ratio.a p values are <0.0001 unless otherwise stated.b p = 0.1.

relatives. The HRs increased with the number of affected

relatives and decreased with increasing age. The highest

HRs were observed for men <65 yr of age with three

affected brothers (HR: approximately 23) and the lowest for

men between 65 yr and 74 yr with an affected father (HR:

approximately 1.8). An affected brother conferred a higher

risk than an affected father even in families with more than

one patient.

Table 2 shows the age-specific HRs according to paternal

and fraternal diagnosis age. In general, the HRs increased

with decreasing diagnosis age of the relative and decreased

with increasing age. The HRs ranged from 1.5 for men with a

father affected after 83 yr of age to 6.6 for men before 55 yr

of age with a brother affected before 60 yr of age.

Table 3 lists the HRs for PCa for men with multiple

affected first-degree relatives according to the age of

diagnosis of the affected relative diagnosed at the youngest

age. The HRs were highest for those men whose youngest

diseased relative was diagnosed at an early age (<60 yr).

Table 4 lists the HRs of death from PCa considering the

number and type of affected first-degree relatives. The

results were in line with the results reported earlier on

incident PCa, showing an increase in the risk of death from

according to paternal and fraternal diagnostic age

65–74 yr Any age

I n HRa 95% CI n HRa 95% CI

.97 32 3.06 2.16–4.33 128 3.45 2.90–4.10

.26 59 1.86 1.44–2.40 241 2.52 2.22–2.87

.61 386 2.08 1.88–2.30 1342 2.44 2.31–2.58

.31 420 1.66 1.50–1.83 1328 1.97 1.87–2.08

.00 226 1.52 1.34–1.74 597 1.67 1.54–1.81

.74 102 3.02 2.49–3.67 379 3.94 3.56–4.36

.69 177 2.57 2.22–2.98 483 3.01 2.75–3.29

.80 249 2.40 2.12–2.72 515 2.46 2.25–2.69

multiple affected first-degree relatives according to the age of

oungest age, yr n HRa 95% CI

160 7.63 6.53–8.92

138 5.16 4.36–6.10

104 4.12 3.40–5.00

67 8.79 6.92–11.18

54 6.60 5.06–8.63

23 7.90 5.25–11.90

21 10.86 7.08–16.66

13 7.79 4.52–13.42

2 3.16b 0.79–12.64

23 24.35 16.18–36.64

4 6.89 2.59–18.37

1 – –

Table 4 – Hazard ratio of death from prostate cancer for menwith first-degree relatives diagnosed with prostate cancerconsidering the number and type of affected relatives

Family history n HRa 95% CI

No affected relatives 2113 – –

Father affected 306 1.81 1.61–2.04

One brother affected 139 2.75 2.32–3.26

Father and one brother affected 24 2.96 1.98–4.43

Two brothers affected 15 6.29 3.79–10.46

Father and two brothers affected 5 9.74 4.05–23.43

Three brothers affected 2 8.12b 2.03–32.50

CI = confidence interval; HR = hazard ratio.a p values are <0.0001 unless otherwise stated.b p = 0.003.

Table 6 – Hazard ratio of death from prostate cancer in relativesof men who died from prostate cancer

Relatives died fromprostate cancer

n HRa 95% CI

Father 202 2.08 1.80–2.41

Brother 15 2.30b 1.38–3.81

Father and brother 4 6.86 2.57–18.28

CI = confidence interval; HR = hazard ratio.a p values are <0.0001 unless otherwise stated.b p = 0.002.

E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 2 7 5 – 2 8 0278

PCa with the number of affected relatives. However, the

number of deaths among individuals with multiple affected

relatives was small.

Table 5 lists the HRs of death from PCa for men with a

paternal or fraternal history according to the relative’s

diagnosis age. Interestingly, risks were similar when the

father was diagnosed between 75 and 82 yr and when the

diagnosis occurred after 82 yr (HR: approximately 1.6). The

risks were also similar for men with a brother diagnosed

between 60 and 64 yr or between 65 and 74 yr (HR:

approximately 2.6).

Table 6 lists the HRs of death from PCa for men with a

father or brother who died from PCa. Interestingly, the risks

were similar when the father or the brother died from PCa.

Fatal events among individuals with multiple first-degree

relatives who died from PCa occurred only for men whose

father and a single brother died from PCa (four deaths; HR:

approximately 7).

Table 7 shows the distribution of T classes for PCa

diagnosed after 2002 according to family history. Generally,

the distributions of the T classes were similar for men

without family history and for the different types of family

histories.

4. Discussion

The present study shows age-specific familial risks of PCa

according to the number and type of affected first-degree

Table 5 – Hazard ratio of death from prostate cancer for men with anconsidering the relative’s diagnosis age

Relative’s diagnosis age, yrPaternal history

n HRa

0–59 7 2.06b

60–64 23 2.55

65–74 105 1.97

75–82 112 1.67

�83 59 1.63c

CI = confidence interval; HR = hazard ratio.a p values are <0.0001 unless otherwise stated.b p = 0.06.c p = 0.0002.

relatives and according to the relative’s diagnosis age based

on the whole Swedish population up to 74 yr of age and

their parents. A family history is an established risk factor

for PCa, and familial risks have been reported in numerous

studies [3]. However, with a total number of 26 651 PCas, of

which 5623 were familial, this is by far the largest family

study yet published. Most studies report the risks for the

categories ‘‘with an affected brother,’’ ‘‘with an affected

father,’’ and ‘‘with multiple affected relatives’’ [3]. In the

present study, it was also possible to estimate familial risks

for men with multiple affected first-degree relatives

according to number, age at diagnosis, and type (father

or brother) of affected first-degree relatives. Furthermore,

we described the risk of death from familial PCa. The

information on cancer, diagnostic age, cause of death, and

family relationships were obtained from register sources of

high reliability [12]. Thus an important advantage was the

accuracy and completeness of the analysed data, with

minimal biases related to over- and underreporting of

family history, selection, and recall. It has been shown that

missing PCa diagnosed in fathers before the start of cancer

registration in Sweden in the Swedish Family-Cancer

Database does not cause bias to the estimates [15].

The higher HRs for incident PCa in men with a fraternal

history compared with men with a paternal history are in

line with findings from earlier studies [3]. The same pattern

was found for men with multiple affected relatives: If the

same number of first-degree relatives was affected, the risk

was higher when only brothers were diagnosed compared

with the risk when father and brothers were diagnosed. The

fraternal diagnosis age was restricted to 74 yr because this

affected first-degree relative diagnosed with prostate cancer

Fraternal history

95% CI n HRa 95% CI

0.98–4.32 32 3.27 2.31–4.64

1.69–3.85 44 2.55 1.89–3.44

1.62–2.40 63 2.67 2.08–3.43

1.38–2.10 – – –

1.26–2.12 – – –

Table 7 – Distribution of T classes for prostate cancers diagnosed after 2002 according to family history*

T

Affected relatives

None Father Brother Father and onebrother

Two brothers Father and twobrothers

Threebrothers

n % n % n % n % n % n % n %

T0 194 1.5 38 1.7 12 1.4 4 1.7 0 0 0 0 0 0

T1 1795 13.6 319 13.9 115 14.0 39 16.5 9 11.0 1 5.3 1 7.7

T1a 264 2.0 45 2.0 15 1.8 0 0 1 1.2 0 0 0 0

T1b 105 0.8 15 0.7 6 0.7 2 0.8 1 1.2 0 0 0 0

T1c 4736 35.8 873 38.2 324 38.0 88 37.1 28 33.0 6 31.6 7 54.0

T2 3779 28.6 624 27.3 232 27.0 70 29.5 28 33.0 10 52.6 1 7.7

T3 1780 13.4 276 12.1 105 12.0 24 10.1 14 17.0 2 10.5 3 23.0

T4 270 2.0 47 2.1 16 1.9 2 0.8 2 2.4 0 0 1 7.7

Tx 313 2.4 51 2.2 23 2.7 8 3.4 1 1.2 0 0 0 0

13 236 – 2288 – 848 – 237 – 84 – 19 – 13 –

T0 = no evidence of tumour; T1 = tumour present but not detectable clinically or with imaging; T1a = tumour was incidentally found in <5% of prostate tissue

resected; T1b = tumour was incidentally found in >5% of prostate tissue resected; T1c = tumour was found in a needle biopsy performed due to an elevated

serum prostate-specific antigen; T2 = the tumour can be felt but has not spread outside the prostate; T3 = the tumour has spread through the prostatic capsule;

T4 = the tumour has invaded other nearby structures; Tx = primary tumour cannot be assessed.* x2 test for independence of T1c (yes/no) and type of family history: x2 = 6.81; p = 0.33.

E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 2 7 5 – 2 8 0 279

is highest age of the second generation in the Swedish

Family-Cancer Database. The differences in the HRs for the

same fraternal and paternal diagnostic ages were smaller.

Although familial clustering of PCa is well established, no

high-risk susceptibility gene has been found [4]. Genome-

wide scans recently identified common variants associated

with an increased risk; the genotype relative risks of these

variants were typically small [4]. Although these variants

might explain a large proportion of the overall PCa

susceptibility, they explain only a small proportion of the

observed familial excess risks [4,16].

The incidence of PCa in Sweden increased about 3-fold

between 1960 and 2006. Between 1996 and 2006, an

average annual increase of 3.7% was noted [11]. The main

increase in the recent period was reported for men in their

60 s [17]. The increase after 1995 was probably associated

with the introduction of nonsystematic (opportunistic)

screening for PCa based on PSA testing, although the

Swedish Council on Technology Assessment in Healthcare

recommended against PSA screening in the general

population in 1995 [17,18]. Familial risks of diagnosis

might be influenced by increased surveillance of familial

cases: Men with a close relative affected by PCa may

participate in screening more often or earlier [7]. This is

particularly relevant for PCa because of the long lead time

for PSA screening [8]. Earlier studies have shown that the

risk of sons and brothers of PCa patients depends on the

time after the diagnosis of the relative, with the risk higher

shortly after the diagnosis of the relative [17]. In the present

study, screening might also have had an influence on the

differences in the age-specific risks according to diagnosis

age of the relative. Unfortunately, we had no information on

which PCa was detected by opportunistic screening.

Therefore, we compared the distribution of the tumour

spread (T classes) in familial and sporadic cases. The

distributions were similar in familial and nonfamilial cases;

the proportions of tumours that were probably found

because of elevated PSA (T1c) were particularly similar.

PCa screening has been shown to cause substantial

overdiagnosis and overtreatment [9,19]. The risk of dying

from PCa rather than the risk of being diagnosed with PCa

might be relevant for clinical counselling and screening

recommendations for men at familial risk. Because no

differences in the prognosis of familial and sporadic PCa

have been found in the latest studies and the distribution

of the tumour spread was similar in familial and sporadic

cases, the increased risk of death in men with a family

history was probably due to the increased incidence

[20,21]; a more detailed analysis of the familial nature of

prognosis can be found elsewhere [22]. Generally, the

pattern of the risk of death from familial PCa was similar

to the incidence data. These risks are probably less biased

upwards through overdiagnosis than those for incident

PCa. Indeed, we found that the increase in the risks for

death from PCa was generally slightly smaller than those

for incident cancer. However, the risk of death in familial

PCa might be biased downwards if men at familial risk

undergo screening more frequently or earlier because

screening decreases the mortality [5]. The numbers of

deaths were small, especially for men with multiple

affected first-degree relatives. The median age of death in

PCa in Sweden is well above 74 yr, which was the

maximum age at follow-up in this study [23]. Therefore,

only a small proportion of the expected deaths in PCa in

the study population had occurred by the end of the

study.

The results of this study should be helpful for the

decision for or against screening or an earlier start of

screening in men at increased risk. Guidelines on PCa

screening recommend average-risk men to be informed

about the risks and benefits of screening at the age of 50 yr

[6,24]. This information may be offered earlier to men with

a first-degree relative diagnosed at a young age (<65 yr) or

to those with multiple affected relatives. The present results

showed that the risk was substantially increased irrespec-

tive of the diagnostic age of the relative. Further research is

E U R O P E A N U R O L O G Y 5 8 ( 2 0 1 0 ) 2 7 5 – 2 8 0280

needed to clarify the benefits and limitations of PCa

screening in men at increased risk.

5. Conclusions

In summary, the risks of diagnosis with PCa and of death

from PCa are increased in men with affected fathers or

brothers. The present results should guide clinical counsel-

ling and demonstrate the vast increases in risk when

multiple first-degree relatives are affected.

Author contributions: Andreas Brandt had full access to all the data in the

study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Hemminki, Lorenzo, Brandt.

Acquisition of data: Sundquist.

Analysis and interpretation of data: Brandt, Hemminki.

Drafting of the manuscript: Brandt, Hemminki.

Critical revision of the manuscript for important intellectual content:

Lorenzo, Sundquist.

Statistical analysis: Brandt.

Obtaining funding: Hemminki.

Administrative, technical, or material support: Sundquist.

Supervision: Hemminki, Lorenzo.

Other (specify): None.

Financial disclosures: I certify that all conflicts of interest, including

specific financial interests and relationships and affiliations relevant to

the subject matter or materials discussed in the manuscript (eg,

employment/affiliation, grants or funding, consultancies, honoraria,

stock ownership or options, expert testimony, royalties, or patents filed,

received, or pending), are the following: None.

Funding/Support and role of the sponsor: This work was supported by

Deutsche Krebshilfe, the Swedish Cancer Society, and the Swedish

Council for Working Life and Social Research.

Acknowledgment statement: The authors acknowledge the Family-

Cancer Database, which was created by linking registers maintained at

Statistics Sweden and the Swedish Cancer Registry.

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