BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years

Robertson, Lindsay; Hanson, Helen; Seal, Sheila; Warren-Perry, Margaret; Hughes, Deborah; Howell, I; Turnbull, Clare; Houlston, Richard S.; Shanley, Susan; Butler, Steven M.; Evans, D. Gareth; Ross, Gill; Eccles, Diana; Tutt, Andrew; Rahman, Nazneen

doi:10.1038/bjc.2012.31

Cited by 88 publications

(63 citation statements)

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“…This is a much higher percentage than the 10-20% seen in other studies of patients with TNBC unselected for family history. 7,8,15 Considering the results from both our diagnostic and research cohorts, we wondered whether the high prevalence of mutation c.4183C4T in the Zillertal and LIV region is associated with an increased incidence of cancer. Detailed regional data from the Tyrolean Cancer Registry confirmed an increased risk for breast and ovarian cancer especially in the region of Zillertal with SIRs of 1.23 for breast cancer below the age of 50 and 2.13 years for ovarian cancer below the age of 65 years.…”

Section: Discussionmentioning

confidence: 99%

“…Tumour characteristics (triple-negative breast cancer; TNBC) are also used for the identification of patients with a high probability of carrying a BRCA mutation. 7,8 Reduced costs of novel sequencing methods and better knowledge of the clinical relevance of alterations in BRCA1 and BRCA2 will increase the number of individuals eligible for sequence analysis, although some selection process will still remain necessary in the foreseeable future. Identification of common founder mutations in certain ethnicities allows integration of genetic testing strategies in the routine care of all cancer patients.…”

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High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

et al. 2015

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Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c. 4183C4T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C4T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region. European Journal of Human Genetics (2016) 24, 258-262; doi:10.1038/ejhg.2015.108; published online 27 May 2015 INTRODUCTIONA central aim of preventive oncology is the identification of patients with a heritable predisposition to cancer. An estimated 1-7% of unselected breast cancer patients 1-4 and 6-17% of women with ovarian cancer 5,6 have hereditary breast and ovarian cancer (HBOC) disposition caused by variants in either BRCA1 or BRCA2 that confer a high risk of developing cancer. In agreement with a widely used terminology, such variants will be called mutations throughout this paper. Because of high costs, comprehensive molecular analyses for HBOC are usually restricted to individuals with a suggestive family history, young age, or several independent tumours. Tumour characteristics (triple-negative breast cancer; TNBC) are also used for the identification of patients with a high probability of carrying a BRCA mutation. 7,8 Reduced costs of novel sequencing methods and better knowledge of the clinical relevance of alterations in BRCA1 and BRCA2 will increase the number of individuals eligible for sequence analysis, although some selection process will still remain necessary in the foreseeable future. Identification of common founder mutations in certain ethnicities allows integration of genetic testing strategies in the routine care of all cancer patients. Here we report the identification of a highly prevalent BRCA1 founder mutation in a particular region of the Tyrol and consider the implications for a screening programme offered to all breast and ovarian cancer patients in this region.

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High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

et al. 2015

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“…Compared to other subtypes of breast cancers, the population of women with estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (HER2) negative (Triple-negative) breast cancer is enriched for germline BRCA mutations [14–20]. However, the published literature shows a wide variation in the prevalence of germline BRCA mutations in triple-negative breast cancer (TNBC) patients with reported rates varying from 10–42 % [14–23]. The majority of these prior studies evaluated BRCA mutations in either high-risk cohorts (selected by family history, age, or ethnicity) or were based on subsets of patients from tissue banks/clinical practices explaining this variability in the reported prevalence rates.…”

Section: Introductionmentioning

confidence: 99%

Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing

Sharma

Klemp

Kimler

et al. 2014

Breast Cancer Res Treat

157

111

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NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I–IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African–American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51–60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC.

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“…4,5 Additionally, germline BRCA mutations are also overrepresented in TNBC patients, predominantly those with early-onset breast cancer. [6][7][8][9] This suggests a link between the BRCA-associated DNA repair pathway and TNBC.…”

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Low prevalence of germline PALB2 mutations in Australian triple‐negative breast cancer

Wong‐Brown

Avery‐Kiejda

Scott

2013

Intl Journal of Cancer

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Triple-negative breast cancer (TNBC) is a tumour classification that is defined by oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor negativity. TNBCs share a similar gene expression profile to BRCAmutated tumours, have been shown to carry a high proportion of BRCA mutations and have a more adverse prognosis compared to other types of breast tumours. PALB2 has been shown to be a moderate-penetrance breast cancer susceptibility gene and is involved in the same DNA damage repair pathway as BRCA1 and BRCA2; this raises the possibility that germline PALB2 mutations may be involved in the pathogenesis of TNBCs. In our study, we sequenced the coding regions of PALB2 (including intron=exon boundaries) in genomic DNA from 347 patients diagnosed with TNBC to determine the prevalence of deleterious mutations in this population. Two novel truncating mutations (c.758dup and c.2390del) and one previously detected truncating mutation (c.311315G>C) were found. In addition, five variants predicted to be protein-affecting were also identified. Our study shows that the prevalence of PALB2 germline mutations in individuals with TNBC is~1%, similar to the prevalence of PALB2 germline mutation of 1% in familial non-BRCA1=2 breast cancer cohorts.Triple-negative breast cancer (TNBC) is a histological classification of breast cancer that is negative for the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. TNBCs represent an important subtype of breast cancer as they have a lower recurrence-free and overall survival compared to receptor-positive disease, regardless of disease stage at time of diagnosis.

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BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years

Cited by 88 publications

References 23 publications

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing

Low prevalence of germline PALB2 mutations in Australian triple‐negative breast cancer

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