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.
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.
Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
Tarek M A
TM
Abdel-Fatah
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51 PB, UK.
Arvind
A
Arora
Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
Paul M
PM
Moseley
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51 PB, UK.
Christina
C
Perry
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
Emad A
EA
Rakha
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
Andrew R
AR
Green
Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
Stephen Y T
SY
Chan
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
Ian O
IO
Ellis
Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.|Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51 PB, UK.
Srinivasan
S
Madhusudan
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076105:X-ray Repair Cross Complementing Protein 1
D018943:Anthracyclines; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D011960:Receptors, Estrogen; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D045585:Flap Endonucleases; C468317:FEN1 protein, human
DNA repair; ER-; TNBC; base excision repair; prognosis