Background: The association between BRCA1 germ-line mutations and breast ca
ncer prognosis is controversial. A historical cohort study was designed to
determine the prognosis for women with axillary lymph node negative heredit
ary breast cancer.
Patients and methods: We tested pathology blocks from 118 Ashkenazi Jewish
women with axillary lymph node negative breast cancer for the presence of t
he two common BRCA1 founder mutations, 185delAG and 5382insC. Patients were
followed up for a median of 76 months. Somatic TP53 mutations were screene
d for by immunohistochemistry, and direct sequencing was performed in the B
RCA1-positive tumours.
Results: Sixteen breast cancer blocks (13.6%) carried a BRCA1 mutation. You
ng age of onset, high nuclear grade, negative estrogen receptor status and
over-expression of p53 were highly associated with BRCA1-positive status (P
-values all < 0.01). BRCA1 mutation carriers had a higher mortality than no
n-carriers (five-year overall survival, 50% and 89.6%, respectively, P = 0.
0001). Young age of onset, estrogen receptor negative status, nuclear grade
3, and over-expression of p53 also predicted a poor outcome. Cox multivari
ate analyses showed that only germ-line BRCA1 mutation status was an indepe
ndent prognostic factor for overall survival (P = 0.01). Among nuclear grad
e 3 tumours, the BRCA1 mutation carrier status was a significant prognostic
factor of death (risk ratio 5.8, 95% confidence interval: 1.5-22, P = 0.00
9). Sequencing of BRCA1-related breast cancers revealed one TP53 missense m
utation not previously reported in breast cancer.
Conclusions: Using a historical cohort approach, we have identified BRCA1 m
utation status as an independent prognostic factor for node negative breast
cancer among the Ashkenazi Jewish women. Those managing women carrying a B
RCA1 mutation may need take these findings into consideration. Additionally
, our preliminary results, taken together with the work of others suggest a
different carcinogenic pathway in BRCA1-related breast cancer, compared to
non-hereditary cases.