Nuclear Poly (Adenosine Diphosphate-Ribose) Polymerase (PARP) Expression Is Most Prevalent in BRCA Mutated and Basal-Like Breast Cancers
Paul J DiMaggio, Timothy M D'Alfonso, Yi-Fang Liu, Zhengming Chen, Rachel E Kaplan, Sandra J Shin. Weill Cornell Medical College, New York, NY
Background: Poly(adenosine diphosphate-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage repair. When activated, PARP forms polymers which bind and modify functions of numerous cellular proteins. The role of PARP inhibitors as a new anticancer agent is particularly promising in BRCA mutated tumors failing to perform homologous recombination. PARP inhibition lacks homologous recombination capacity and causes apoptosis. No studies have been performed evaluating PARP expression by immunohistochemistry (IHC) in BRCA mutated breast cancers or molecular subtypes including the basal-like subtype comprised of ER/PR/HER2 (triple) negative breast cancers. This knowledge is of future value if IHC could select patients whose tumors would be susceptible to PARP inhibitors.
Design: Primary breast carcinomas of 637 patients were evaluated using tissue microarrays (TMA). Four molecular subtypes of invasive breast carcinoma were represented: Luminal A-145; Luminal B/HER2 positive-104; Luminal B/HER2 negative and Ki-67>14%-98; Basal-like-132; HER2 enriched-94. Sixty-four cases of BRCA mutated breast cancer were also studied. TMAs were stained with anti-PARP (Abcam) using the Bond Max Autostainer (Leica) and appropriate controls. Nuclear immunoreactivity for PARP was scored via a modified H-system and intensity was scored on a 0 to 3 scale (0-negative, 1-weak, 2-moderate, 3-strong). Percentages of positive cells were categorized into 5 groups (0%, 1%-10%, 11%-50%, 51%-80%, >80%). Statistical analysis used the Chi-square test.
Results: Nuclear immunoreactivity for PARP was significantly higher in the basal-like molecular subtype than Luminal A, Luminal B/HER2 positive, and Luminal B/HER2 negative and Ki-67>14% (p=0.004, 0.006, and 0.037). Nuclear immunoreactivity for PARP was significantly higher in BRCA mutated carcinomas than in the Luminal A, Luminal B/HER2 positive, and Luminal B/HER2 negative and Ki-67>14% subtypes(p=0.004, 0.004, and 0.029). No difference existed between basal-like molecular subtypes and BRCA mutated carcinomas (p=0.356). No significant differences were found between HER2 enriched subtypes and any other group.
Conclusions: Our results confirm clinical observations that PARP expression is most prevalent in basal-like (triple negative) and BRCA mutated breast carcinomas. PARP expression by IHC may be of clinical utility for selecting breast cancer patients likely to benefit from therapy using PARP inhibitors.
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 18, Tuesday Morning