Triple-negative Breast Cancer and PTEN (Phosphatase and Tensin Homologue) Loss Are Predictors of BRCA1 Germline Mutations in Women With Early-onset and Familial Breast Cancer, but Not in Women With Isolated Late-onset Breast Cancer

Sze-Yee Phuah; Lai-Meng Looi; Norhashimah Hassan; Anthony Rhodes; Sarah Dean; Nur AM Taib; Cheng-Har Yip; Soo-Hwang Teo


Breast Cancer Res. 2012;14(6):R142 

In This Article

Abstract and Introduction


Introduction: Given 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.

Methods: Germline 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.

Results: Our 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%).

Conclusions: We 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.


Discovery of the breast cancer-predisposition genes BRCA1 and BRCA2 has enabled us to identify carriers accurately, to target the reduction of risk of breast and ovarian cancers in carriers, and to develop a new generation of targeted therapies (PARP inhibitors).[1] However, given that deleterious mutations in these genes account for only 1% to 4% of all breast cancer cases across different populations[2] and that genetic testing and genetic counseling have hitherto been relatively expensive, genetic testing for BRCA1 and BRCA2 has typically been offered only in clinical genetics settings to women who have early-onset breast cancer, and/or to individuals with significant family history of breast and ovarian, or other BRCA-related cancers.

Recently, it was suggested that screening women with early-onset triple-negative breast cancer (TNBC) may be a cost-effective method with which to identify BRCA1 mutation carriers in Caucasian women.[3–5] This is because, in the majority of BRCA1 carriers, breast tumors have distinctive morphologic features and immunohistochemical phenotypes characteristic of basal-like breast cancers, including negative expression of the estrogen receptor, high expression of basal markers, such as basal cytokeratins CK5/6 and CK14, and loss of tumor-suppressor PTEN.[6–8] Moreover, molecular gene-expression profiling of BRCA1 tumors showed that the tumors have significant similarities with the basal-like subtype of breast cancer.[9] Up to 50% of women diagnosed with breast cancer, younger than 50 years, and women who have a family cancer history may have mutations in BRCA1 or BRCA2.[10] However, it is notable that although more than 10% women in whom an isolated TNBC develops at younger than 40 years old may have a mutation in BRCA1,[3–5] insufficient evidence exists for those aged 41 to 50 years, with no family history of breast or ovarian cancer.[11]

The purpose of this study was to determine whether TNBC is an independent criterion for stratifying women with an increased risk of having a BRCA1 mutation and to determine whether the addition of immunohistologic features of basal-like breast cancers helps to define a subset of women who are likely to have germline mutations in BRCA1.