DNA repair prognostic index modelling reveals an essential role for base excision repair in influencing clinical outcomes in ER negative and triple negative breast cancers

Abdel-Fatah, Tarek M.A.; Arora, Arvind; Moseley, Paul M.; Perry, Christina; Rakha, Emad A.; Green, Andrew R.; Chan, Stephen Y.T.; Ellis, Ian O.; Madhusudan, Srinivasan

Abstract

Stratification of oestrogen receptor (ER) negative and triple negative breast cancers (TNBCs) is urgently needed. In the current study, a cohort of 880 ER- (including 635 TNBCs) was immuno-profiled for a panel of DNA repair proteins including: Pol β, FEN1, APE1, XRCC1, SMUG1, PARP1, BRCA1, ATR, ATM, DNA-PKcs, Chk1, Chk2, p53, and TOPO2. Multivariate Cox proportional hazards models (with backward stepwise exclusion of these factors, using a criterion of p < 0.05 for retention of factors in the model) were used to identify factors that were independently associated with clinical outcomes. XRCC1 (p = 0.002), pol β (p = 0.032) FEN1 (p = 0.001) and BRCA1 (p = 0.040) levels were independently associated with poor BCSS. Subsequently, DNA repair index prognostic (DRPI) scores for breast cancer specific survival (BCSS) were calculated and two prognostic groups (DRPI-PGs) were identified. Patients in prognostic group 2 (DRPI-PG2) have higher risk of death (p < 0.001). Furthermore, in DRPI-PG2 patients, exposure to anthracycline reduced the risk of death [(HR (95% CI) = 0.79 (0.64–0.98), p = 0.032) by 21–26%. In addition, DRPI-PG2 patients have adverse clinicopathological features including higher grade, lympho-vascular invasion, Her-2 positive phenotype, compared to those in DRPI-PG1 (p < 0.01). Receiver operating characteristic (ROC) curves indicated that the DRPI outperformed the currently used prognostic factors and adding DRPI to lymph node stage significantly improved their performance as a predictor for BCSS [p < 0.00001, area under curve (AUC) = 0.70]. BER strongly influences pathogenesis of ER- and TNBCs. The DRPI accurately predicts BCSS and can also serve as a valuable prognostic and predictive tool for TNBCs.

Citation

Abdel-Fatah, T. M., Arora, A., Moseley, P. M., Perry, C., Rakha, E. A., Green, A. R., Chan, S. Y., Ellis, I. O., & Madhusudan, S. (2015). DNA repair prognostic index modelling reveals an essential role for base excision repair in influencing clinical outcomes in ER negative and triple negative breast cancers. Oncotarget, 6(26), 21964-21978. https://doi.org/10.18632/oncotarget.4157

• Journal Article Type: Article
• Acceptance Date: May 19, 2015
• Online Publication Date: May 30, 2015
• Publication Date: Sep 8, 2015
• Deposit Date: Oct 16, 2018
• Publicly Available Date: Oct 17, 2018
• Journal: Oncotarget
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 26
• Pages: 21964-21978
• DOI: https://doi.org/10.18632/oncotarget.4157
• Public URL: https://nottingham-repository.worktribe.com/output/1170229
• Publisher URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=4157&path[]=17166
• Contract Date: Oct 16, 2018