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

Abstract

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.

Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy

“…This observation is also consistent with a recent study in breast cancer, wherein high frequency of PTEN loss was observed in BRCA1-associated breast tumours [46]. In a separate study, PTEN loss was found to be a predictor of BRCA1 germ-line mutations in women with early onset breast cancer [47]. Taken together, this evidence suggests a possible functional link between PTEN and BRCA1 in melanomas.…”

Comprehensive spectrum ofBRCA1andBRCA2deleterious mutations in breast cancer in Asian countries

“…Several Chinese cohort studies showed that the prevalence of BRCA1 mutations among selected patients with TNBC ranged from 18.6% to 36.8%, while BRCA2 mutation only ranged from 7.3% to 10.5% 13 75 76. A similar discrepancy in BRCA1/BRCA2 mutation prevalence (24.5% vs 3.6%) has also been reported in a Malaysian study of patients with TNBC with Malay, Chinese and Indian ancestries 77. Taken together, these observations suggested that BRCA1 mutation dominancy in patients with TNBC was present in both Asian and the West.…”

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

“…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.…”