Abstract 4739: Prognostic impact of abnormal DNA damage response protein expression in breast cancer

Abstract

Abstract Purpose Defects of DNA damage repair are known to be associated with the efficacy of anthracycline or platinum-based chemotherapy as well as poly[ADP-ribose] polymerase (PARP) inhibitors (PARPi) and PD-1/PD-L1 checkpoint inhibitors. Since multiple proteins are involved in DNA-damage response (DDR) and operate collectively, our main aim was to better understand the expression of proteins in DDR machinery and their integrated prognostic value in the different subtypes of breast cancer. Methods A total of 419 consecutive breast cancer patients who underwent curative resection in 2008 were enrolled in the study. Tissue microarray has been constructed, and NBS1, BRCA1, BRCA2, ATM and p53 expression were determined by immunohistochemistry. Results All patients were female, with a median age of 47 years; 280 (67%) had luminal A, 36 (9%) had luminal B, 37 (9%) had HER2-enriched, and 56 (13%) had triple-negative breast cancer (TNBC). Loss of NBS1, BRCA1, BRCA2, and ATM expression was observed in 6.7%, 33.7%, 89.9%, and 30.8% of breast cancer patients, respectively, and abnormal p53 expression was observed in 39.3% of patients. Loss of NBS1, BRCA1, ATM and abnormal p53 expression was associated with significantly lower disease-free survival (DFS) rates, respectively. “Abnormal DDR protein expression”, defined as loss of any one of NBS1, BRCA1, ATM and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER- and/or PR-negative status. Majority of patients with luminal B (31/36, 86.1%), HER2-enriched (34/35, 94.4%), and TNBC (46/53, 86.8%) subtype showed abnormal DDR protein expression. In comparison, 136/264 patients (53.8%) with luminal A subtype had abnormal DDR protein expression. Abnormal DDR protein expression was associated with significantly lower 5-year DFS rate than those in patients with normal DDR protein expression in all patients (95.6% vs. 84.8%, p = 0.001), as well as in luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DDR protein expression remained as an independent predictor of shorter DFS for luminal A subtype tumors (hazard ratio 3.14; 95% confidence interval, 1.16 – 8.47, p = 0.024). Conclusion We demonstrated differential expression of proteins in DDR machinery according to breast cancer subtypes and its prognostic implication. Most of luminal B and HER2-enriched tumors has abnormal DDR expression as frequently as triple negative tumors. Less but significant proportion of luminal A tumors also shows abnormal DDR protein expression, which is an independent poor prognostic factor. Citation Format: Koung Jin Suh, Han Suk Ryu, Kyung-Hun Lee, Hyojin Kim, Ahrum Min, Tae-Yong Kim, Hyeong-Gon Moon, Sae-Won Han, Do-Youn Oh, Wonshik Han, In Ae Park, Dong-Young Noh, Seock-Ah Im. Prognostic impact of abnormal DNA damage response protein expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4739. doi:10.1158/1538-7445.AM2017-4739