Baretta 2016
Baretta 2016
Baretta 2016
OPEN
Abstract
Background: The contribution of BRCA germline mutational status to breast cancer patients’ prognosis is unclear. We aimed to
systematically review and perform meta-analysis of the available evidence of effects of BRCA germline mutations on multiple survival
outcomes of breast cancer patients as a whole and in specific subgroups of interest, including those with triple negative breast
cancer, those with Ashkenazi Jewish ancestry, and patients with stage I–III disease.
Methods: Sixty studies met all inclusion criteria and were considered for this meta-analysis. These studies involved 105,220 breast
cancer patients, whose 3588 (3.4%) were BRCA mutations carriers. The associations between BRCA genes mutational status and
overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and distant metastasis-free survival
(DMFS) were evaluated using random-effect models.
Results: BRCA1 mutation carriers have worse OS than BRCA-negative/sporadic cases (hazard ratio, HR 1.30, 95% CI: 1.11–1.52)
and worse BCSS than sporadic/BRCA-negative cases among patients with stage I–III breast cancer (HR 1.45, 95% CI: 1.01–2.07).
BRCA2 mutation carriers have worse BCSS than sporadic/BRCA-negative cases (HR 1.29, 95% CI: 1.03–1.62), although they have
similar OS. Among triple negative breast cancer, BRCA1/2 mutations carriers had better OS than BRCA-negative counterpart (HR
0.49, 95% CI: 0.26–0.92). Among Ashkenazi Jewish women, BRCA1/2 mutations carriers presented higher risk of death from breast
cancer (HR 1.44, 95% CI: 1.05–1.97) and of distant metastases (HR 1.82, 95% CI: 1.05–3.16) than sporadic/BRCA-negative
patients.
Conclusion: Our results support the evaluation of BRCA mutational status in patients with high risk of harboring BRCA germline
mutations to better define the prognosis of breast cancer in these patients.
Abbreviations: BCSS = breast cancer specific survival, CI = confidence interval, DMFS = distant metastasis free survival, HR =
hazard ratio, OS = overall survival, PICOS = population, intervention, comparison, outcome, REMARK = reporting recommendations
for tumor MARKer prognostic studies, RFS = recurrence free survival.
Keywords: BRCA germline mutations, breast cancer, meta-analysis, prognosis, survival, systematic review
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controversy is partially due to the relatively small sample size in BRCA-negative), median age of patients in the study and
many studies because BRCA1/2 mutation carriers are rare in the reference groups, Ashkenazi Jewish ancestry (yes/no), triple
breast cancer population. For oncologists, it would be important negative subtype (yes/no), pathological stage of the breast cancer,
to know whether BRCA mutational status is a reliable prognostic HRs and their 95% confidence interval (CI), factors considered in
factor to be used for risk stratification and thus considered in the multivariate analysis (see Supplemental Contents–Master data-
therapeutic management of hereditary breast cancer cases. base, which reports the PUBMED identification number to
The aim of the present work is to systematically review and retrieve the studies involved in the meta-analysis, and data for
meta-analyze the available evidence regarding the effects of each study, http://links.lww.com/MD/B317). Extraction of data
BRCA germline mutations on multiple survival outcomes of was done by ZB and EG.
patients with breast cancer as a whole and in specific subgroups
of interest, including those with triple negative breast cancer,
2.3. Statistical analysis
those with Ashkenazi Jewish ancestry, and patients with stage
I–III disease. Hazard ratios and their 95% CIs were used as measures of the
association between BRCA mutations and patients’ survival. The
random effects model described by DerSimonia and Laird was
2. Methods
used to calculate the summary HR and 95% CI.[17] Three main
Literature search, study design, and data analysis were performed analyses were performed based on the mutational status in the
following PRISMA (Preferred Reporting Items for Systematic experimental group: (1) in BRCA1 mutated patients; (2) in
Reviews and Meta-Analyses) guidelines (see Supplemental BRCA2 mutated patients; (3) in BRCA1/2 mutated patients. In
Contents—PRISMA checklist, http://links.lww.com/MD/ the latter analysis, HRs were calculated considering data from
B316).[15] Ethical approval was not necessary for this study BRCA1-studies, BRCA2-studies, and BRCA1/2-studies. Patients
because this study does not involve patients. The PICOS with sporadic breast cancer (without being tested for BRCA
(Population, Intervention, Comparison, Outcome) worksheet mutational status) or BRCA mutation tested negative patients
was used to identify the main question of the meta-analysis and represented the reference group. An HR > 1 indicated a poorer
define the targets of the search strategy (see in Supplemental outcome for the experimental group (i.e., BRCA-positive
Contents–PICOS worksheet, which describes type of population, subjects).
intervention, type of comparison, and outcomes considered in the Between-study heterogeneity was quantified by the I-square
meta-analysis, http://links.lww.com/MD/B315). Finally, the RE- statistic (25% low heterogeneity, 25–50% medium, >50%
MARK (Reporting recommendations for tumor MARKer high).[18] In order to investigate potential sources of heterogene-
prognostic studies) checklist was used to evaluate the quality ity, we performed the following pre-specified subgroup analyses:
of studies included in the meta-analysis;[16] for each study, a first, we focused our analysis on the studies where all control
quality score was calculated based on the number of recom- patients were BRCA tested negative; second, we conducted
mendations met by the study over the total 20 items, assigning 1 separate analyses for studies including and excluding patients
point to each met recommendation. with distant metastatic disease (TNM stage IV); third, we focused
on studies including only patients with triple negative breast
cancer; fourth, we investigated the role of BRCA mutational
2.1. Literature search and study selection
status in breast cancer patients with Ashkenazi Jewish ancestry as
We used PubMed database to search articles published until this is a population with high prevalence of BRCA
August 2016, which evaluated the impact of BRCA mutational mutations.[19–21] Finally, mixed effects meta-regression was
status on breast cancer prognostic outcomes. To this aim, we used utilized to investigate whether between-study heterogeneity is
∗
the following search string “BRCA AND breast cancer correlated with study quality, which was the ranking score from
survival.” Moreover, we screened the references of all original the REMARK checklist (range: 0–20) and year of study
articles as well as those cited in reviews articles focusing on this publication; both were considered as continuous covariates in
topic, in order to maximize the likelihood of identifying all the meta-regression.
relevant articles. The 2 key inclusion criteria were as follows: (1) HRs and 95% CIs were extracted from articles, when
the study compared the survival of BRCA-positive women available; when unreported, they were extrapolated from
affected by breast cancer with that of women with sporadic/ Kaplan–Meier survival curves adopting a hierarchical series of
BRCA-negative breast cancer; (2) the article reported survival steps as per Parmar et al.[22] If both univariate and multivariate
outcomes as hazard ratios (HRs) or Kaplan–Meier survival analyses were available, HRs from the latter were considered.
curves. Screening of eligible records and selection of articles to be However, the pooled estimates and heterogeneity analysis
included in the meta-analysis were independently performed by 2 according to univariate and multivariate analyses are available
reviewers (ZB and EG). Disagreements were resolved by (see Supplemental Contents—Table S1, http://links.lww.com/
discussion and consensus. MD/B313, which reports pooled estimates and heterogeneity
analysis according to univariate and multivariate analyses). Small
study effects (which includes publication bias) was evaluated by
2.2. Endpoints and data extraction visual assessment of funnel plot symmetry and formally
Endpoints of the meta-analysis were overall survival (OS), breast investigated by using Egger’s test.[23] The test was performed
cancer-specific survival (BCSS), recurrence-free survival (RFS), only when at least 10 studies were available.
and distant metastasis-free survival (DMFS). For each included The level of significance was set at 5% with the exception of
study, we retrieved the following information: type of genetic test, Egger’s test, for which a 10% level was chosen due to the low
type of biospecimen used to perform the genetic test (blood/ power for characterizing this test. Analyses were conducted using
paraffin blocks of primary tumor), number of the BRCA-positive Review Manager 5.2 (Cochrane Collaboration) and Stata 14.1
patients, number of the reference group patients (sporadic or (StataCorp, College Station, TX).
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Table 1
Number of studies and patients involved in the meta-analysis.
All studies (N = 60) Studies with tested patients (N = 42)
∗
Outcome N° studies Control group patients BRCA+ patients N° studies BRCA– patients BRCA+ patients
BRCA1 OS 27 89,627 1636 17 9974 926
BCSS 16 6732 885 14 5901 646
RFS 6 2366 327 4 2098 262
DMFS 11 4337 745 9 3457 429
BRCA2 OS 12 83,733 457 6 4732 197
BCSS 10 8527 598 8 7554 459
RFS 3 217 61 0 – –
DMFS 3 2430 202 1 1555 71
BRCA 1/2 OS 8 2498 326 5 500 203
BCSS 2 507 99 1 277 28
RFS 8 702 338 6 444 260
DMFS 2 447 60 2 447 60
BCSS = breast cancer-specific survival, DMFS = distant metastasis-free survival, OS = overall survival, RFS = recurrence-free survival.
∗
Control group includes BRCA-negative patients or sporadic cases.
Table 2
Pooled estimates and between study-heterogeneity analysis in all studies and in the studies that considered only tested patients.
All studies (N = 60) Studies with tested patients† (N = 42)
∗ ∗
Outcome Studies HR (CI 95%) P I2
Studies HR (CI 95%) P I2
BRCA1 OS 27 1.30 (1.11–1.52) 0.001 37% 17 1.46 (1.12–1.91) 0.006 47%
BCSS 16 1.17 (0.91–1.49) 0.22 45% 14 1.22 (0.91–1.63) 0.17 48%
RFS 6 0.98 (0.68–1.41) 0.90 59% 4 1.08 (0.72–1.63) 0.70 50%
DMFS 11 1.06 (0.78–1.46) 0.70 55% 9 1.11 (0.71–1.73) 0.66 57%
BRCA2 OS 12 0.98 (0.76–1.25) 0.85 42% 6 1.10 (0.82–1.47) 0.54 0%
BCSS 10 1.29 (1.03–1.62) 0.03 24% 8 1.34 (1.04–1.73) 0.02 23%
RFS 3 1.41 (0.41–4.85) 0.59 66% 0 – – –
DMFS 3 0.78 (0.59–1.02) 0.07 0% 1 1.00 (0.62–1.61) 1.00 –
BRCA1/2 OS 8 1.11 (0.68–1.80) 0.68 49% 5 0.85 (0.44–1.65) 0.64 54%
BCSS 2 1.22 (0.42–3.49) 0.71 58% 1 2.08 (0.79–5.46) 0.14 –
RFS 8 1.04 (0.67–1.60) 0.87 41% 6 0.90 (0.52–1.57) 0.71 49%
DMFS 2 1.81 (1.03–3.17) 0.04 0% 2 1.81 (1.03–3.17) 0.04 0%
Overall OS 37 1.19 (1.04–1.35) 0.009 41% 22 1.28 (1.06–1.53) 0.009 42%
BCSS 22 1.22 (1.04–1.44) 0.02 36% 18 1.29 (1.07–1.57) 0.009 38%
RFS 17 1.04 (0.80–1.35) 0.78 48% 10 1.01 (0.74–1.38) 0.96 44%
DMFS 13 1.03 (0.82–1.31) 0.78 53% 11 1.19 (0.85–1.65) 0.31 51%
BCSS= breast cancer-specific survival, CI = confidence interval, DMFS = distant metastasis-free survival, HR = hazard ratio, I2 = between study-heterogeneity index, OS= overall survival, RFS = recurrence-free survival.
∗
When both univariate and multivariate HRs were reported, multivariate HR was chosen.
†
In this analysis, the reference group is BRCA-negative patients.
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1.12–1.91; P-value = 0.006) as well as to studies excluding stage studies, and 17.5 (range 13–19) for DMFS studies. Meta-
IV (HR 1.55, 95% CI: 1.24–1.95; P-value = 0.0001, Table 3). In regression analysis did not demonstrate any association between
all cases, between-study heterogeneity was moderate to low. REMARK score and all considered survival outcomes, as well as
Meta-analysis for BCSS, RFS, and DMFS included 16, 6, and between year of publication and BRCA1 effect on survival, with
11 studies, respectively (Table 1). No difference was found in the exception of DMFS (HR decreased by 7% per year, 95
these clinical outcomes between BRCA1 mutation carriers and percent CI: 0–13%; P = 0.049. See Supplemental Contents—
control group (Table 2, Figs. 2–4). Heterogeneity was high for Figure S1, http://links.lww.com/MD/B313, which illustrates the
RFS and DMFS in both general, and restricted to studies with all relationship between HRs of DMFS for BRCA1 mutational
tested patients analyses. Interestingly, the risk of dying from status and publication years).
breast cancer was significantly higher for BRCA1 cases than
control group when the studies including stage IV cases were
excluded from the analysis (HR 1.45, 95% CI: 1.01–2.07; P- 3.3. Prognostic role of BRCA2 gene mutations
value = 0.045, Table 3). The prognostic role of BRCA2 gene mutations in terms of OS,
The mean REMARK score was 15 (range 9–19) for OS studies, BCSS, RFS, and DMFS was evaluated in 12, 10, 3, and 3 studies,
16 (range 13–19) for BCSS studies, 14.5 (range 12–17) for RFS respectively (Table 1). In 6 OS-studies and in 8 BCSS-studies, all
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Table 3
Pooled estimates and heterogeneity analysis according to disease stage.
Studies including stage IV (N = 25) Studies excluding stage IV (N = 28)
∗ ∗
Outcome Studies HR (CI 95%) P I2 Studies HR (CI 95%) P I2
BRCA1 OS 11 1.15 (0.92–1.42) 0.21 28% 11 1.55 (1.24–1.95) 0.0001 20%
BCSS 8 0.94 (0.67–1.32) 0.74 38% 8 1.45 (1.01–2.07) 0.045 49%
RFS 3 0.80 (0.48–1.33) 0.38 64% 3 1.27 (0.69–2.33) 0.44 59%
BRCA2 OS 9 1.12 (0.93–1.36) 0.24 2% 0 – – –
BCSS 8 1.28 (0.93–1.76) 0.13 37% 1 1.90 (0.59–6.11) 0.28 –
RFS 2 0.82 (0.43–1.54) 0.54 0% 1 4.10 (1.30–13.00) 0.016 –
BRCA1/2 OS 3 1.55 (0.89–2.68) 0.12 0% 5 0.99 (0.49–2.02) 0.98 63%
BCSS 0 – – – 2 1.22 (0.42–3.49) 0.72 58%
RFS 4 1.40 (0.73–2.69) 0.32 0% 3 0.66 (0.28–1.60) 0.36 75%
Overall OS 16 1.15 (1.01–1.32) 0.04 11% 16 1.42 (1.10–1.82) 0.006 43%
BCSS 11 1.11 (0.88–1.39) 0.37 37% 10 1.42 (1.05–1.92) 0.02 39%
RFS 9 0.90 (0.69–1.17) 0.43 6% 7 1.12 (0.68–1.85) 0.65 70%
BCSS = breast cancer specific survival, CI = confidence interval, DMFS = distant metastasis-free survival, HR = hazard ratio, I2 = between study-heterogeneity index, OS = overall survival, RFS = recurrence-free
survival.
∗
When both univariate and multivariate HRs were reported, multivariate HR was chosen.
patients received the genetic test; however, all RFS studies and 2 mutation carriers and the control groups for OS, RFS, or DMFS.
DMFS studies compared the BRCA2 mutation carriers with Very few studies for BRCA2 excluded stage IV breast cancer
sporadic nontested cases. The meta-analysis of these data showed (Table 3).
a worse BCSS for BRCA2 carriers as compared to control group The mean REMARK score was 15.6 (range 12–19) for OS
in both general population (HR 1.29, 95% CI: 1.03–1.62; P = studies, 16.3 (range 14–18) for BCSS studies, 13.6 (range 13–15)
0.03. Table 2 and Fig. 2) and among tested patients (1.34, 95% for RFS studies, and 18.3 (range 17–19) for DMFS studies. Meta-
CI: 1.04–1.73; P = 0.02. Table 2), with low heterogeneity being regression analysis did not demonstrate any association between
observed. No difference was found between the BRCA2 REMARK score and all considered survival outcomes, as well as
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Baretta et al. Medicine (2016) 95:40 Medicine
between year of publication and BRCA2 effect on survival (data the analysis was restricted to studies including only tested patients
not shown). (Table 2) as well as to studies excluding stage IV (Table 3). RFS and
DMFS of BRCA carriers were not significantly different of those of
control group. Meta-regression analysis did not show any
3.4. Prognostic role of BRCA genes mutations
association between REMARK score or year of publication for
In order to reduce potential bias due to stringent inclusion criteria, the considered survival outcomes (data not shown).
we conducted meta-analysis that accounted for data of BRCA1-
studies, BRCA2-studies and studies that pooled BRCA1 and
3.5. Prognostic role of BRCA mutations in triple negative
BRCA2 carriers (BRCA1/2-studies). BRCA carriers were associ-
patients
ated with worse OS (HR 1.19, 95% CI: 1.04–1.35; P = 0.009.
Table 2 and Fig. 1) and BCSS (HR 1.22, 95% CI: 1.04–1.44; P = Six studies (n = 1748) focused on triple negative patients: 4 out of
0.02 Table 2 and Fig. 2). These results were also confirmed when these 6 studies evaluated the prognostic role of BRCA1
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Table 4
Pooled estimates and heterogeneity analysis in Ashkenazi Jewish and triple negative breast cancer patients.
Studies focusing on Ashkenazi Jewish (N = 12) Studies focusing on triple negative BC (N = 6)
∗ ∗
Outcome Studies HR (CI 95%) P I2 Studies HR (CI 95%) P I2
BRCA1 OS 4 1.46 (0.91–2.34) 0.12 32% 0 – –
BCSS 7 1.45 (0.90–2.35) 0.13 57% 3 0.84 (0.27–2.62) 0.76 64%
RFS 0 – – 1 0.92 (0.45–1.90) 0.82 –
DMFS 2 2.50 (0.47–13.31) 0.28 78% 4 0.87 (0.48–1.57) 0.65 43%
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We found that BRCA1 mutation carriers had a 30% higher Another novel and interesting results of our work came from
risk of dying than BRCA1 negative/sporadic cases, which the meta-analyses performed in women with triple negative
confirmed the results of 2 previous meta-analysis studies,[27,28] breast cancer and of Ashkenazi Jewish ancestry, 2 populations
although our meta-analysis included many more studies. Of note, with high probability of being BRCA carriers. Concerning the
we found that the association between BRCA1 and OS was analyses on women with triple negative breast cancer, we found
stronger when excluding studies with sporadic breast cancer that the presence of BRCA mutations correlates with better OS.
cases (e.g., nontested for BRCA mutations), which eliminated However, this information derives from data of only 2 studies,
misclassification bias (HR = 1.46). Furthermore, the association where BRCA1/2 carriers were compared with noncarriers
between BRCA1 and OS was stronger in studies excluding stage women, suggesting the need of more studies in this subgroup
IV disease (HR = 1.55) than in studies that included stage IV of patients. In contrast, a sufficient number of studies have
disease (HR = 1.15). As regards BCSS, we did not find a evaluated the prognostic role of BRCA mutations in Ashkenazi
statistically significant association between BRCA1 and the risk Jewish women, demonstrating a higher risk of dying from breast
of death from breast cancer, with moderate heterogeneity across cancer as well as of developing distant metastasis of BRCA
the studies. Interestingly, we found that the heterogeneity can be carriers compared with sporadic/BRCA-negative cases.
at least in part explained by study design: in fact, among the 8 Although multivariable analyses have been used in many of the
studies including patients with stage IV disease, no evidence of studies to adjust for age at diagnosis, tumor stage, estrogen
association between BRCA1 and BCSS was observed (HR = receptor status, and other clinical factors, our meta-analysis still
0.94), whereas among the 8 studies excluding patients with state found that BRCA mutation carriers had worse survival outcomes
IV disease, we found that BRCA1 was associated with 45% than noncarriers, suggesting that the aggressive nature of breast
increased risk of dying from breast cancer (HR = 1.45). Thus, our cancer in mutation carriers may not be fully characterized by
findings suggest that the future prospective studies, which aim to known clinical and pathological factors. It is also possible that
define the role of BRCA1 mutational status on breast cancer other causes of deaths, in particular ovarian cancer, account for
outcomes, should exclude patients with stage IV breast cancer, the decreased OS, especially for BRCA1 carriers because lifetime
and offer the genetic test to entire study population allowing risk of ovarian cancer is higher for BRCA1 than for BRCA2
comparison between BRCA carriers and tested BRCA-negative mutation carriers.[5–7] As regard the effect of clinical and
cases. pathological factors as modifiers of survival in BRCA carriers,
With regard to BRCA2, we did not find a significant Templeton et al evaluated the interaction between hormonal
association between the mutational status of BRCA2 and OS, receptor, age at diagnosis, and survival in patients with BRCA1
which is consistent with the results of previous meta- and/or BRCA2 mutations.[30] These authors identified only an
analyses.[27–29] However, we demonstrated a significant associa- inverse association between estrogen receptor status and OS in
tion between BRCA2 mutation and worse BCSS (HR = 1.29), a BRCA1 carriers, concluding that the estrogen receptor expres-
finding even stronger after excluding studies with sporadic breast sion is a modifier of prognosis in BRCA1 carriers. Future studies
cancer cases (HR = 1.34). Only van den Broek et al[29] evaluated are required to evaluate the role of hormone receptor status in
the association between BRCA2 and BCSS and concluded that BRCA carriers.
BRCA2 had worse BCSS compared with the control group (HR The quality of studies included in the present meta-analysis was
1.57; CI: 1.29–1.86), but this analysis included only 2 studies, moderate to high, ranging the REMARK score between 9 and 19
judged as high-quality studies according to a scoring system for BRCA1-studies, and between 14 and 19 for BRCA2-studies.
developed by the authors, without demonstrating that the quality However, we acknowledge that our meta-analysis presents some
of studies was an effect modifier. We evaluated the quality of limitations. First, all studies are retrospective, which increases the
studies using the REMARK checklist, a well-accepted tool to risk of selection bias. Second, in order to eliminate confounding
define the quality of studies evaluating a tumor marker. The factors, we used adjusted HR when both univariate and
REMARK score of the 10 studies considered in our analysis of the multivariate HR were reported; however, for studies reporting
association between BRCA2 and BCSS was high, with a mean only univariate analysis, unadjusted HRs were considered. Third,
score of 16.3 points out of 20. Moreover, we did not find any most of studies did not report important treatment information
evidence that this association depended on the REMARK score. related to BRCA mutation carriers, such as prophylactic
Therefore, we believe that our meta-analysis of 10 studies procedures (e.g., prophylactic mastectomy, bilateral mastectomy,
provided a more reliable estimate of the relationship between bilateral prophylactic oophorectomy, treatment with tamoxifen)
BRCA status and prognosis than just 2 studies considered by van and diagnosis of second cancers that could affect survival outcomes
den Broek’s meta-analysis. in these patients. Fourth, despite a thorough literature search, we
With the aim of comprehensively cover the topic of the might have overlooked 1 or more publications on this topic;
prognostic role of BRCA mutations in breast cancer patients, we however, no publication bias was found in the meta-analyses.
reported also the results derived from the analysis evaluating the The controversy on the prognostic value of BRCA1/2 mutation
combination of data from BRCA1-studies, BRCA2-studies, and in breast cancer patients is often related to the small sample size of
BRCA1/2 studies. However, considering that breast cancer has single existing studies, as demonstrated by the fact that more than
different characteristics in BRCA1 and BRCA2 carriers, and half of the 60 eligible studies included fewer than 40 carriers. Our
taking into account the different prognostic role of BRCA1 and work overcomes this limit and allows us to suggest that BRCA1
BRCA2 mutations (as demonstrated by the analysis of data of and BRCA2 mutation status has a significant prognostic value in
BRCA1-studies and BRCA2-studies taken separately), we early stage breast cancer, which supports BRCA mutation testing
suggest that the future studies should differentiate BRCA1 from in patients with high risk of harboring BRCA germline mutations
BRCA2 carriers. Moreover, an important question still unan- in order to better define the prognosis of these patients. Clearly,
swered is whether the prognosis of breast cancer in BRCA1 further perspective studies with larger sample size and unified
carriers is different from that in BRCA2 carriers, which warrants study design and analysis method are desirable, especially in
further investigation. subgroups such as triple-negative breast cancer patients.
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