Association between the founder brazilian TP53 p.R337H mutation and HER2-positive status.

Abstract

e22154 Background: Recent studies in North American and British series have suggested an association between germline TP53 mutations and early onset HER2-positive breast cancer (BC). Mutations in the TP53 gene are estimated to occur in 1:2,000-1:5,000 individuals of the general population. Among women with BC who are unselected for family history they occur in up to 0.25%. In women with early-onset BC (<30 years) they occur in up to 7%. A specific germline TP53 mutation (c.1010G>A; p.R337H) has been encountered in 0.3% of the general population, in 13.3% of Li-Fraumeni-like families and in 0.5-2.4% of BC-affected women in Brazil. In an exploratory approach, the aim of this study was to investigate, in our series, if there is an association between human epidermal growth factor receptor 2 (HER2) amplification and the germline TP53 p.R337H mutation in a series of BC-affected women. Methods: A series of 718 Brazilian BC-affected women was genotyped in our previous study and 64 (8.9%) were mutation carriers. These cases were recruited from 3 centers and HER2 analysis was performed by immunohistochemistry (IHC) in each center according to validated protocols. Statistical analysis was done using SPSS software. Results: In 47 of 64 mutation carriers (73.5%), BC showed HER expression (either 1+, 2+ or 3+) while among 654 non-carriers, this immunophenotype was observed in 320 (48.9%) (p<0.001). This pattern was still observed after stratification of groups according to age at diagnosis (≤45 and ≥55 years) (p<0.001 and 0.03, respectively) and was independent of recruiting center. Conclusions: These results indicate that BC developing on a background of the founder Brazilian TP53 p.R337H mutation shows more frequently some amplification of HER2, consistent with recent studies showing an association between germline TP53 mutations and BC with HER2 hyperexpression. These findings should be confirmed in larger series to understand the significance of the association. If confirmed, this finding may justify germline TP53 p.R337H mutation testing in all HER2-positive Brazilian BC patients and would have a significant impact on patient and family counseling as well as on treatment.