Poly (ADP-ribose) Polymerase (PARP)-1 Expression in BRCA1-Associated Breast Cancers: Relationship to Estrogen Receptor (ER) Status.
Jennifer S Kaplan, Stuart Schnitt, Laura Collins, Katharina Fetten, Vivian Villegas-Bergazzi, Kam M Sprott, Nadine Tung. Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA; On-Q-ity, Waltham, MA
Background: BRCA1 is integral to the repair of double strand DNA breaks through homologous recombination. Cells deficient in BRCA1 are sensitized to the inhibition of the enzyme poly (ADP-ribose) polymerase (PARP) which is critical in single strand DNA repair through base excision repair. PARP inhibitors have demonstrated significant clinical activity in BRCA1-associated invasive breast cancers (IBC). However, whether or not PARP inhibitors are as effective in treating the less common ER-positive (ER+) BRCA1-associated IBC as the more frequent ER-negative (ER-) BRCA1-associated IBC has not previously been evaluated.
Design: To address this issue, we compared the levels of PARP-1 expression by immunohistochemistry in 60 ER+ and 85 ER- IBC arising in women with BRCA1 germline mutations. In addition, ER+ BRCA1-associated IBC were matched on age and year of diagnosis with 174 ER+ sporadic breast cancers. Tissue microarrays (TMAs) containing these tumors were constructed and TMA sections were immunostained with an antibody to PARP-1 (Serotec, 1:80,000). PARP-1 nuclear expression was scored for intensity and distribution using the Allred scoring system blinded to carcinoma category. Differences between groups were compared using the Kruskal-Wallis test.
Results: ER+ BRCA1-associated IBC were not significantly different from ER- BRCA1-associated IBC with respect to their PARP-1 staining intensity and distribution (p=0.45; see Table). In contrast, ER+ BRCA1-associated IBC had a significantly higher percentage of tumors showing strong and diffuse PARP-1 staining and a significantly lower percentage of tumors that were negative for PARP-1 expression when compared to the matched ER+ sporadic cancers (p=0.002; see Table).
|Allred Score||ER- BRCA1||ER+ BRCA1||ER+ Sporadic|