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


Our study in an Asian series of triple-negative breast cancer patients demonstrated that up to 24.5% (27 of 110) women have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110), and that the addition of negative estrogen-receptor status and PTEN loss improves the sensitivity of the Manchester Scoring method in our Asian cohort.

The results in this study are consistent with that in other cohorts of triple-negative breast cancer patients, in whom 11% to 39% have germline mutations in BRCA1 and BRCA2,[3,6,20–23] and cohorts of estrogen-receptor-negative breast cancer patients, of whom 24% to 29% have germline mutations in BRCA1 and BRCA2.[4,6,24,25] A recent single-institution study showed that 50% of high-risk patients with TNBC had mutations in BRCA1/2, but notably, 76% of this cohort had a family history of breast cancer.[10] For all of these series and for our study, BRCA1 mutations are more common than BRCA2 mutations.

Cost-effectiveness analyses have suggested that mutation testing for all TNBC patients younger than 50 years old may be a cost-effective approach, assuming that 10% to 25% of these patients have BRCA1 or BRCA2 mutations.[5] However, we find that although TNBC is associated with an increased prevalence of BRCA1 and BRCA2 mutations among those younger than 35 years old (28.0% in TNBC versus 9.9% in non-TNBC; P = 0.045], TNBC is not associated with an increased prevalence of mutations among those aged 36 to 50 years without a family history of breast or ovarian cancer (BRCA prevalence of 8.5% and 6.7%, respectively). This may be because BRCA1 is a high-penetrance gene and is associated with both early-onset disease and multiple affected family members, and therefore, in the absence of these features, a low prevalence of BRCA1 mutations is found, even in TNBC. Further studies with larger population-based datasets are needed to determine the prevalence of BRCA1 and BRCA2 mutations and the cost-effectiveness of testing women diagnosed with isolated breast cancer, aged 40 to 49 years old.

We find that the prevalence of BRCA1 mutations is higher in TNBC compared with non-TNBC in women in whom early-onset breast cancer develops and in women with a family history of breast and ovarian cancer. This effect is largely due to a difference in prevalence of BRCA1 mutations and is consistent with the observation that the majority of BRCA1 carriers develop early-onset triple-negative basal-like breast tumors that have distinctive morphologic and immunohistochemical characteristics.[6–8] Intriguingly, the significant proportion of TNBC patients who have BRCA1 germline mutations in these two subgroups of patients (28.0% and 34.2%) suggests that mutation in BRCA1 is a key driver of the development of TNBC. This could be due to the roles of BRCA1 in determining cell fate of luminal progenitor cells,[26] its effect on transcriptional regulation of ER-gene expression,[27] its effect on regulation of mi155,[27] or a combination of these.

Taken together, we suggest that TNBC status may be helpful in stratifying women with a moderate risk of having BRCA1 mutations (for example, a weak family history or isolated case of early-onset breast cancer), but may have limited utility in the absence of such features (for example, women with a single case of TNBC aged 40 to 50 years old).

Finally, we find that addition of negative estrogen receptor and TNBC status improves the sensitivity and specificity of the Manchester Scoring method in our cohort and that addition of PTEN loss further improves the sensitivity of the method. PTEN loss is highly associated with BRCA1 breast cancers (28 (82.4%) of 34 of tumor samples from BRCA1 carriers showed the loss of PTEN by immunohistochemistry) and can result from gene rearrangements involving DNA double-strand breaks, intragenic inversions on insertions, homozygous deletions, and focalized CNIs.[8] However, given that the data on PTEN loss were available on only a small subset of patients, this result requires further validation in a larger cohort of patients. We believe that methods for stratifying the likelihood of carrying a BRCA1 and BRCA2 mutation that is independent of family history are important, particularly in the Asian context, because the familial and social stigma associated with cancer makes accurate family-history reporting challenging.[28]