IntroductionGiven that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors.MethodsGermline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and included in a modified Manchester scoring method.ResultsOur study in an Asian series of TNBC patients demonstrated that 27 (24.5%) of 110 patients have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110). We found that among women diagnosed with breast cancer aged 36 to 50 years but with no family history of breast or ovarian cancer, the prevalence of BRCA1 and BRCA2 mutations was similar in TNBC (8.5%) and non-TNBC patients (6.7%). By contrast, in women diagnosed with breast cancer, younger than 35 years, with no family history of these cancers, and in women with a family history of breast cancer, the prevalence of mutations was higher in TNBC compared with non-TNBC (28.0% and 9.9%; P = 0.045; and 42.1% and 14.2%; P < 0.0001, respectively]. Finally, we found that incorporation of estrogen-receptor and TNBC status improves the sensitivity of the Manchester Scoring method (42.9% to 64.3%), and furthermore, incorporation of PTEN status further improves sensitivity (42.9% to 85.7%).ConclusionsWe found that TNBC is an important criterion for highlighting women who may benefit from genetic testing, but that this may be most useful for women with early-onset breast cancer (35 years or younger) or with a family history of cancers. Furthermore, addition of TNBC and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context, where risk-assessment models underestimate the number of mutation carriers.

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Background: Given that BRCA1 carriers are more likely to develop triple negative breast cancers (TNBC) and that current risk assessment models underestimate BRCA carriers in Asian populations, we have sought to determine the prevalence of BRCA mutations amongst TNBC patients and whether addition of pathological features improves the sensitivity of the Manchester scoring method of BRCA risk assessment. Methods: A total of 399 patients from the Malaysian Breast Cancer Genetic Study were fully analysed for BRCA1 and BRCA2 mutations, including 101 patients with TNBC. Pathological features, including estrogen receptor (ER) and PTEN status were assessed and included in a modified Manchester scoring method. Results: Our study in an Asian series of triple negative breast cancer patients has demonstrated that 22% [22/101] of patients have germline mutations in BRCA1 [18/101] and BRCA2 [4/101]. We find that amongst patients who were diagnosed with breast cancer aged 36-50 but with no family history of breast or ovarian cancer, the prevalence of BRCA mutations was similar amongst those who developed triple negative breast cancer (7%) and non-TNBC (7%). By contrast, in two other groups of patients (a) those who were diagnosed with breast cancer β35 years old with no family history of these cancers, and (b) those with family history of breast cancer, the prevalence of mutations was higher in those with TNBC compared to those with non-TNBC [29% and 11%; p=0.07; and 40% and 14%; p=0.001 respectively]. Furthermore, we find that incorporation of estrogen-receptor status improves the sensitivity of the Manchester Scoring method [38% to 62%] and in particular, incorporation of the status of PTEN, further improves sensitivity [43% to 100%]. Conclusion: We find that TNBC is an important criteria for highlighting patients who may benefit from genetic testing, but that this may be most useful for individuals with early onset breast cancer (≥35 years old) or with family history of cancers. Furthermore, addition of ER and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context when family history is often inaccurately reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2609. doi:1538-7445.AM2012-2609