Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2871
Published Online First on March 9, 2010 as 10.1158/1078-0432.CCR-09-2871
Clinical
Cancer
Research
Imaging, Diagnosis, Prognosis
Germline BRCA Mutations Denote a Clinicopathologic Subset
of Prostate Cancer
David J. Gallagher1, Mia M. Gaudet2, Prodipto Pal1, Tomas Kirchhoff1, Lisa Balistreri1, Kinjal Vora3, Jasmine Bhatia1,
Zsofia Stadler1, Samson W. Fine4, Victor Reuter4, Michael Zelefsky5, Michael J. Morris6, Howard I. Scher6,
Robert J. Klein7, Larry Norton8, James A. Eastham3, Peter T. Scardino3, Mark E. Robson1, and Kenneth Offit1
Abstract
Purpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined.
Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and
compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. KruskalWallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were
used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard
ratios (HR) for clinical end points were estimated using Cox proportional hazards models.
Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95%
confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason
score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer.
BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for
clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers
had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and
prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than
noncarriers.
Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic
grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer.
Clin Cancer Res; 16(7); OF1–7. ©2010 AACR.
Genome-wide association studies have identified common susceptibility loci in more than a dozen independent
chromosomal regions associated with an increased risk for
prostate cancer (1), but candidate genes at these loci have
yet to be functionally implicated. Although present in only
a small proportion of prostate cancer cases overall, mutations of the BRCA2 and BRCA1 genes are commonly observed in families with multiple cases of breast cancer.
Authors' Affiliations: 1 Clinical Genetics Service, Departments of
Medicine, 2 Departments of Biostatistics and Epidemiology, 3 Urology
Service, Department of Surgery, Departments of 4Pathology, 5Radiation
Oncology, 6 Genitourinary Oncology Service, Division of Solid Tumor
Oncology, Department of Medicine, 7 Cancer Biology and Genetics
Program, Sloan-Kettering Institute, and 8 Breast Oncology Service,
Division of Solid Tumor Oncology, Department of Medicine, Memorial
Sloan-Kettering Cancer Center, New York, New York
Note: K. Offit 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.
Corresponding Authors: Kenneth Offit or Mark E. Robson, Memorial
Sloan-Kettering Cancer Center, Box 192, 1275 York Avenue, New
York, NY 10021. Phone: 646-888-4050; Fax: 646-888-4081; E-mail:
[email protected] or [email protected].
doi: 10.1158/1078-0432.CCR-09-2871
©2010 American Association for Cancer Research.
Whether detected in affected families or in the general
population, BRCA mutations cause an increased risk for
breast and ovarian cancer in women, and breast and prostate cancer in men (2–8).
Histologic differentiation is an established surrogate for
survival in prostate cancer, and Gleason scoring is the
most widely used grading system (9, 10). Clinical management of this malignancy depends on assessment of clinical
features, age of the patient, as well as histopathology of
the tumor. There remains a critical need for prognostic
markers to tailor therapeutic strategies, which may range
from “watch and wait” to surgery or radiation therapy
(11). BRCA mutations may constitute one such prognostic
marker; however, few studies have investigated the tumor
characteristics of BRCA-associated prostate cancer. A more
aggressive phenotype has been suggested by four analyses
of BRCA-associated prostate cancer (12–15), but the largest study found no difference in histopathology between
carriers and noncarriers of BRCA mutations (16). Furthermore, loss of heterozygosity has been identified in prostate tumors of BRCA2 carriers and has been associated
with higher Gleason score (17). Prostate cancer–specific
mortality is a more robust end point, and an association
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Gallagher et al.
Translational Relevance
Prostate cancer is a heterogeneous disease with a variable natural history that is not accurately predicted by
currently used prognostic tools. We report that BRCAassociated localized prostate cancer represents an aggressive subset of the disease that may require active
management with radiation therapy or surgery, and
that expectant observation may not be appropriate.
There has been little progress in the systemic management of prostate cancer beyond androgen deprivation
therapy, and a novel therapeutic approach is urgently
needed. Platinum-based therapies and, more recently,
poly(ADP-ribose) polymerase inhibitors seem particularly active in BRCA-associated breast and ovarian cancer, and a clinical trial investigating these agents in
BRCA-associated prostate cancer is warranted.
between BRCA2 mutation and earlier death due to prostate cancer has been reported for patients with advanced
disease (12). Here, we confirm a more aggressive histology
associated with BRCA2-associated prostate cancer and, for
the first time, show the independent prognostic significance of this genetic marker in early-stage prostate cancer,
taking into account known prognostic factors for the disease, including prostate-specific antigen (PSA) and clinical
features.
Materials and Methods
DNA was extracted from blood samples of 894 prostate
cancer cases treated at the Memorial Sloan-Kettering Cancer Center between June 1988 and December 2007. DNA
samples were also acquired from 454 noncancer controls
who provided informed consent as part of a prospective
study of healthy people conducted from 2000 to 2002
in New York City (18). Both cases and controls identified
themselves as being of Ashkenazi Jewish background. The
inclusion of only Ashkenazi Jewish men enabled targeted
genotyping for founder mutations, and all blood samples
were genotyped for the two major Ashkenazi BRCA founder mutations BRCA1*185delAG and BRCA2*6174delT. The
third founder mutation BRCA1*5382insC was not genotyped. The Taqman (fluorogenic 5′ nuclease) assay was
used for single-nucleotide polymorphism genotyping.
The primers and probes were obtained from Applied Biosystems. PCR was conducted with both primers and
probes added in ABI 9700 thermocycler, and the endpoint results were scored using the ABI 7900HT Sequence
Detection System (version 2.3). In each 384-well plate,
one reference sample and one negative control were included for quality control. Cases' medical records and pathology reports were collected as part of an institutional
prostate cancer research database using standardized questionnaires and chart abstraction forms, created and main-
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Clin Cancer Res; 16(7) April 1, 2010
tained by the prostate cancer disease management team at
the Memorial Sloan-Kettering Cancer Center. Analysis for
this study was based on data on clinical stage, Gleason
score (from needle biopsy), PSA levels, and age at diagnosis of the primary prostate tumor as well as dates of biochemical recurrences, development of castrate metastasis,
death due to prostate cancer, and overall survival. Biochemical recurrence refers to the detection of rising PSA
after local therapy, and castrate metastasis refers to time
to progression of disease following initiation of antiandrogen therapy. Biochemical recurrence was defined as PSA
of ≥0.2 ng/mL after radical prostatectomy and a value of
“nadir + 2” after other therapy (19, 20). Castrate metastasis was defined as progression of disease despite castrate
levels of testosterone. Data were collected on 894 genotyped cases, but only patients with localized disease at
presentation were included in the analysis of clinical outcome; 62 cases presented with metastatic prostate cancer
and were excluded for the survival analysis. In accordance
with an Institutional Research Board–approved protocol,
patient identifiers were removed at time of genetic analysis. Therefore, 832 prostate cancer cases and 454 controls
were included in subsequent analyses.
Gleason scores of the prostate tumors were categorized
into <7 and ≥7 subgroups. This cutoff was chosen based
on clinical experience and prior literature suggesting that
clinical outcome for Gleason score 7 prostate cancer is
more similar to that for Gleason score 8 to 10 than for
Gleason score <7 disease (21). Among cases, KruskalWallis tests were used to compare distribution of age at
diagnosis and Gleason score by carrier status. Logistic regression models, adjusted for age and clinical stage, were
used to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for the association between carrier status
and prostate cancer risk, and between carrier status and
Gleason score (case only model). Unconditional logistic
regression was used as controls and cases were not
matched. Time at risk was calculated from the date of diagnosis of prostate cancer to the date of death or date of
last contact. As a secondary analysis, time at risk intervals
were calculated from date of blood draw for genetic testing
(left truncation). The Kaplan-Meier method stratified by
genotype was used to generate survival curves (22). Hazard ratios (HR) and 95% CI for mortality, biochemical recurrence, and castrate metastases associated with mutation
status were estimated using Cox proportional hazard models (23), adjusting for age, clinical stage, Gleason score,
PSA levels of primary tumor, and treatment type. We
checked for violations of the proportional hazards assumption for all variables by visual inspection of the log
(−log) plots and analytically using Schoenfeld residuals
(24). All statistical analyses were conducted using Stata
10.0 (StataCorp LP).
Results
The median age for controls was 42 years (interquartile
range, 42-57), whereas the median age for cases was 68
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Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2871
BRCA in Prostate Cancer
Table 1. Frequency of BRCA1/2 mutation carrier status in prostate cases and controls
Noncarrier
BRCA1 carrier
BRCA2 carrier
Case, n (%)
Control, n (%)
Age-adjusted
OR (95% CI)
806 (96.9)
6 (0.7)
20 (2.4)
447 (98.5)
4 (0.9)
3 (0.7)
1.00
0.38 (0.05-2.75)
3.18 (1.52-6.66)
years (interquartile range, 62-73). Prostate cancer cases
were more likely to carry a BRCA2 mutation than controls
(2.4% versus 0.7%; P = 0.002). Men who carried a BRCA2
mutation had a 3.18 times higher risk of prostate cancer
than noncarriers (OR, 3.18; 95% CI, 1.52-6.66; Table 1).
The frequency of BRCA1 mutation was similar for cases
and controls (P = 0.34); 3.1% of prostate cancer cases in
this series carried either a BRCA1 or a BRCA2 mutation.
Among the total of 832 cases eligible for analysis of clinical outcome with a median follow-up in excess of 8 years,
the age of diagnosis was slightly greater (median age, 68.2
years) for 806 patients with no BRCA mutations compared
with 20 cases with BRCA2 mutations (median age, 62.0
years), although this difference was not statistically significant (P = 0.1). After adjusting for Gleason score and
stage, there was no difference in age at presentation between BRCA2 mutation carriers and noncarriers (HR,
1.23; 95% CI, 0.76-2.00; P = 0.41) nor between BRCA1 mutation carriers and noncarriers (HR, 0.67; 95% CI, 0.281.61; P = 0.37). Mutation carriers' dates of diagnoses were
spread across the duration of the study, and carriers do not
represent a more contemporary cohort that could have received higher Gleason scoring. Poorly differentiated prostate cancers (Gleason score 7-10; Fig. 1) were found in
57% of noncarrier cases and in 85% of BRCA2 mutationassociated cases (P = 0.0002), but there were no differences between BRCA1 mutation carriers and noncarriers
(P = 0.71). Adjusting for age and stage, BRCA2 mutation
carriers were more than twice as likely to have a Gleason
score 7 to 10 (HR, 2.63; 95% CI, 1.23-5.6; P = 0.01) than
noncarriers, but the distribution of Gleason scores did not
differ for BRCA1 mutation carriers and noncarriers (HR,
0.53; 95% CI, 0.09-3.29; P = 0.50; Table 2). Younger patients were more likely to have a Gleason score 7 to 10
compared with lower scores (HR, 0.76; 95% CI, 0.650.89; P = 0.001). Distribution by type of treatment received is shown in Table 2; half of BRCA2 mutation carriers
were treated by radical prostatectomy compared with
30% of BRCA wild-type cases.
After 7,254 person-years of follow-up for the entire cohort, the following outcomes occurred: 369 biochemical recurrences, 158 castrate metastases, and 184 deaths, of
which 98 were due specifically to prostate cancer (Table 3;
Fig. 2). Compared with noncarriers, prostate cancer patients, who carried mutations in BRCA1/2, were at higher
risk of recurrence and death (Fig. 2). Results of a Cox proportional hazards model (Table 3) analysis taking into
www.aacrjournals.org
P
0.34
0.002
account age, clinical stage, Gleason score, PSA, and treatment showed that both BRCA1 and BRCA2 mutation carriers had an increased risk of developing biochemical
recurrence (HR, 4.32; 95% CI, 1.31-13.62; P = 0.016 and
HR, 2.41; 95% CI, 1.23-4.75; P = 0.011, respectively).
BRCA2 mutation carriers had a greater risk of castrate metastases (HR, 3.01; 95% CI, 1.26-7.14; P = 0.013) compared
with noncarriers. This translated into a greater risk of death
due to prostate cancer (HR, 5.16; 95% CI, 1.09-24.53; P =
0.039 and HR, 5.48; 95% CI, 2.03-14.79; P = 0.001) for
BRCA1 and BRCA2 carriers, respectively.
The median time from diagnosis to blood collection for
genotyping in this cohort was 4.6 years. When we left truncated time at risk, HR estimates were in a similar direction
and magnitude, and the HR for risk of death due to prostate cancer in BRCA2 mutation carriers was 11.21 (95% CI,
3.6-34.53; other data not shown).
A separate analysis was made comparing time from biochemical recurrence to castrate metastasis. There were 369
men with biochemical recurrence, and 158 of those had
castrate metastasis. There was a trend toward a higher frequency of biochemical recurrence progressing to castrate
metastasis in BRCA2 carriers than noncarriers (HR, 2.01;
95% CI, 0.85-4.79). There was no difference in the frequency of castrate metastasis after biochemical recurrence
in BRCA1 carriers compared with controls (HR, 1.08; 95%
CI, 0.15-7.85).
Fig. 1. Example of a poorly differentiated (Gleason 4 + 5 = 9) prostate
adenocarcinoma in a 76-yr-old carrier of a BRCA2 mutation.
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Table 2. Features of prostate cancer cases
Total n (%)
Median age (range)
Gleason score <7 (%)
Gleason score ≥7 (%)
Gleason score NA
Median PSA (range)
Treatment
RP
XRT
XRT with hormones
Hormone therapy alone
Chemotherapy alone
Watchful waiting
BRCA wild-type
BRCA1 mutant
BRCA2 mutant
806 (96.9)
68.2
(42.7-94.4)
324 (40.2)
437 (54.2)
45 (5.6)
7 (2-10)
6 (0.7)
67.1
(44.7-81.5)
3 (50)
3 (50)
0
6.5 (5-8)
20 (2.4)
62.0
(40.8-83.0)
2 (10)
17 (85)
1 (5)
7 (6-9)
0
1
3
2
0
0
10
4
6
0
0
0
244
276
217
34
(30.3)
(34.2)
(26.9)
(4.2)
1
34 (4.2)
P
0.057
0.009
0.99
Abbreviations: RP, radical prostatectomy; XRT, radiation therapy; NA, not available.
Discussion
Although early studies of smaller subsets of patients were
inconclusive (7, 25–28), recent studies have associated
BRCA1 and BRCA2 mutations with a hereditary predisposi-
tion to prostate cancer, noting up to a 33% cumulative risk
by age 80 (3, 4, 16). It has previously been suggested that
BRCA mutation confers a greater risk of early-onset prostate
cancer (<65 years; ref. 29), although Giusti et al. (16) reported no difference in mean age of presentation between
Table 3. HRs and 95% CIs for the associations between BRCA1/2 mutation status and recurrence or
mortality among 832 prostate cancer cases
Outcomes
No. events
Biochemical recurrence
No mutation
354
BRCA 1 mutation
4
BRCA2 mutation
11
Castrate metastasis
No mutation
149
BRCA 1 mutation
2*
BRCA2 mutation
7
Death due to prostate cancer
No mutation
90
BRCA 1 mutation
3
BRCA2 mutation
5
Death due to any cancer
No mutation
132
BRCA 1 mutation
3
BRCA2 mutation
8†
P
Start of follow-up at date of diagnosis
Median survival time (y)
Total person-years
HR (95% CI)
8.7
2.3
2.6
4,560.3
19.6
72.4
1.00
4.32 (1.31-13.62)
2.41 (1.23-4.75)
0.016
0.011
17.2
10.5
10.5
6,669.0
49.9
139.9
1.00
2.15 (0.28-16.31)
3.01 (1.26-7.14)
0.46
0.013
22.0
13.0
13.8
7,036.2
54.0
161.1
1.00
5.16 (1.09-24.53)
5.48 (2.03-14.79)
0.039
0.001
19.1
13.0
12.5
7,036.2
54.0
161.1
1.00
2.35 (0.53-10.37)
5.26 (2.29-12.08)
0.26
<0.0001
NOTE: HRs were adjusted for age, clinical stage, PSA levels, Gleason score at biopsy, and treatment (radical prostatectomy,
radiation therapy alone, radiation therapy with hormone therapy, hormone therapy, chemotherapy, and watchful waiting).
*Date of biochemical recurrence could not be confirmed in one additional BRCA mutation carrier.
†
The three additional cancer-related deaths in BRCA2 carriers were due to papillary thyroid cancer, angioimmunoblastic
lymphoma, and non–small cell lung cancer.
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Clinical Cancer Research
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BRCA in Prostate Cancer
Fig. 2. Kaplan-Meier plot of death due to
cancer for 806 BRCA wild-type compared
with 6 BRCA1 and 20 BRCA2 mutation
carriers. Tick marks indicate last follow-up.
men with and without BRCA mutations; such mutations
were found in only 0.78% of 290 men diagnosed with prostate cancer at <55 years of age (30). Our study, one of
the largest to date, again shows no significant difference
in age of presentation between BRCA mutation carriers
and noncarriers.
The proportion of high-grade prostate cancer in our
population was significantly higher in the subset with inherited BRCA2 mutations compared with other subsets analyzed. The findings were striking, with 17 of 20 (85%) of
BRCA2 mutation carriers showing Gleason ≥7 disease, representing a group with an aggressive phenotype and confirming this recently reported association (15). However,
the proportion of cases with high-grade prostate cancer
was higher than expected for both cases and controls. Although the Prostate Cancer Prevention Trial included only
patients with a PSA of ≤4 ng/mL, only 14.9% of cases had
Gleason ≥7 disease (31) compared with 53% in controls in
a large study in Iceland (12) and 57% of our population. It
is probable that differences in these populations could be
due to differences in PSA or stage. Cases referred for care
at a specialty center, for example, may be weighted toward
more aggressive disease. The 57% of cases in this series with
Gleason score >7 is comparable with the annual proportion
(in 2007) of 59% of all cases biopsied at our institution and
the 50% of cases biopsied outside the institution whose pathology showed Gleason score >7. It is also possible that the
higher baseline Gleason scores in some series are population (e.g., Ashkenazi and Icelandic) specific. Racial variation in both Gleason score at presentation and clinical
outcome has been reported (32, 33). However, in two prospective studies of >800,000 men, prostate cancer death
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rates were significantly lower among Jewish men than
non-Jewish men (34), suggesting that the clinicopathologic
associations observed here may result from genetic factors
in a subset of cases.
When results were stratified by gene, BRCA2 mutations
were associated with more poorly differentiated disease,
but BRCA1 mutations were not. We found no differences
in Gleason scores between BRCA1 mutation carriers and
noncarriers, although we genotyped for only one of two
BRCA1 founder mutations and may have been underpowered to observe such differences. The “threshold” Gleason
score ≥7 was chosen based a priori on previous literature
and on clinical experience. Reanalysis of the data using an
alternative definition of Gleason score ≥8 revealed essentially the same correlation, with a HR of >3 (95% CI, 1.387.53) for BRCA2 mutation carriers. The association between
BRCA mutation and aggressive histology has now been repeatedly reported but remains unexplained. Recent data
suggest that double-strand DNA breaks, acting through
the androgen receptor, produce the TMPRSS2-ERG gene
fusion that is found in 50% of prostate cancer (35, 36).
The TMPRSS2-ERG gene fusion has been associated with
aggressive disease, and it is possible that, in the absence
of BRCA, accumulating double-stranded breaks facilitate
this translocation.
BRCA mutations were not only associated with a more
aggressive histology but also independently predicted increased risk of disease progression through the prostate
cancer clinical states model (37). A Cox proportional hazards model incorporating the clinical predictors included
in commonly used prostate cancer nomograms (Gleason
score, PSA at diagnosis, and stage; ref. 38) and treatment
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type showed a significance of BRCA mutation status that
was independent of these known prognostic factors; there
was an increased risk of biochemical recurrence and the
development of castrate metastases for BRCA carriers compared with noncarriers. As expected, the more advanced
disease in BRCA mutation carriers was associated with
worse overall and disease-specific survival. In a previous
report suggesting an inferior survival for BRCA-associated
prostate cancer (12), 16 of 29 (55%) cases with the Icelandic founder mutation (BRCA2 999del5) had metastatic
prostate cancer at presentation, whereas all men in our
study had localized disease. In the prior study, the 13 cases
with localized disease had a greater risk of dying from
prostate cancer compared with noncarriers, a finding that
is supported by our larger study. A recent consortium of
prostate cancer patients in BRCA1- and BRCA2-linked families noted an inferior survival of BRCA2 compared with
BRCA1-associated prostate cancer cases; however, direct
genotyping of all cases was not done, there was no available BRCA wild-type comparison group, and no information was available on pathology or clinical features of the
disease (14). In contrast to that series, we observed an association with aggressive disease in both BRCA1 and
BRCA2 mutation carriers (14). Although the size of our
BRCA1 cohort was small, carriers had more aggressive disease with earlier biochemical recurrence and more prostate-specific deaths compared with noncarriers despite
similar Gleason scores, suggesting that the effect of BRCA1
mutation on clinical outcome may be independent of
aggressive histology.
The current series of BRCA-genotyped prostate cancer
cases is among the largest to date, but there is the general
concern that combining incident and prevalent cases
could have introduced a survival bias in our results. Recent
studies of genetic risk factors have noted that inclusion of
prevalent cases did not result in a bias of the HR estimates
with or without left truncation of the data, as was observed in our study (39, 40). In addition, a survival bias
due to a higher HR in the years following diagnosis would
tend to obscure adverse prognostic markers (a bias toward
the null) and would lead to an underestimation of the adverse prognostic effect of BRCA mutations in the current
study. Another limitation of this study is the use of a nonconcurrent, albeit more recent, cohort of controls, which
may not have had the same opportunity for being diagnosed with prostate cancer due to secular trends. However,
the prevalence of subclinical prostate cancer in a younger
control group would have resulted in a bias toward the
null in the OR analysis and would not have affected the
prognostic findings that are based on a case-case analysis.
If it is confirmed that BRCA mutations confer a more aggressive clinical course for men with localized prostate cancer, tailored interventions may be warranted. However, due
to the small number of mutation carriers in this study, the
strong effect reported must be viewed as hypothesis generating and requires confirmation in a larger cohort. The additional finding that the interval to castrate metastases after
biochemical relapse seems shorter in BRCA2 mutation car-
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Clin Cancer Res; 16(7) April 1, 2010
riers may be an appropriate factor to include in the consideration of antiandrogens in this genetically defined subset.
Recent therapeutic strategies, such as small molecules inhibiting poly(ADP-ribose) polymerase (PARP), may biologically target a spectrum of BRCA-deficient tumors, with
evidence of response in hereditary breast, ovarian, and
prostate cancers (41). Given the estimated 0.0069 BRCA2
mutation frequency in the population and the relative risk
for prostate cancer of 3.18 observed here, this translates to
∼1.5% of the 180,000 prostate cancer cases in the United
States attributable to BRCA2 mutations or 2,790 cases each
year that could benefit from treatments tailored to BRCA2
status. PARP inhibitors may improve outcome for patients
with advanced BRCA-associated prostate cancer, but due
to the aggressive nature of this disease, investigation of
PARP inhibitors in the neoadjuvant setting may also be
warranted.
Further large-scale studies will be needed to determine if
the findings shown here, in a genetic isolate (Ashkenazi
Jews), can be generalized to the population at large. The
types of protein-truncating mutations of BRCA studied here
are representative of BRCA mutations in the general population, and the clinical findings about risk and outcome of
BRCA-associated malignancies in Ashkenazim have been
applied to other populations (3, 42). This is further supported by concordant findings in an Icelandic population
with advanced BRCA2-associated prostate cancer (12).
Nonetheless, due to the small number of BRCA carriers in
this study, large consortia will be needed to confirm the associations with histology and clinical outcome reported
here. Pending such studies, recommendations for screening
for and treatment of BRCA-associated prostate cancer
should be individualized based on established clinical factors and prognostic markers.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Dr. Hans Lilja (Department of Clinical Laboratories) for
helpful conversations. H.I. Scher thanks the Memorial Sloan-Kettering
Cancer Center Prostate Cancer Specialized Program of Research
Excellence program supported by the National Cancer Institute and the
Prostate Cancer Foundation. DNA from control subjects was provided as
part of the New York Cancer Study of the Academic Medicine
Development Company (AMDec) of New York City.
Grant Support
Breast Cancer Research Foundation (K. Offit), W. James and Jane K.
Truettner Foundation, Carmel Cancer Research Fund, Lymphoma Foundation, and Robert and Kate Niehaus Research Foundation. D.J. Gallagher has
been funded by a scholarship from the Irish Society of Medical Oncology.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received 10/27/2009; revised 12/23/2009; accepted 01/23/2010;
published OnlineFirst 03/09/2010.
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BRCA in Prostate Cancer
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Clin Cancer Res; 16(7) April 1, 2010
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OF7
Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2871
Germline BRCA Mutations Denote a Clinicopathologic Subset
of Prostate Cancer
David J. Gallagher, Mia M. Gaudet, Prodipto Pal, et al.
Clin Cancer Res Published OnlineFirst March 9, 2010.
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