Dong Wang

Cancer Center, Daping Hospital, Third Military MedicalUniversity

Objective:As one of the major cancers with a highmortality rate, lung cancer is still a huge health challenge worldwide.Although platinum-based doublet chemotherapy is the most common therapeuticregime for advanced non-small-cell lung cancer (NSCLC) patients, there is quitea proportion of patients are resistant to platinum-based chemotherapy. DNArepair proteins, such as ERCC1 and BRCA1 arepreviously recognized to be closelyassociated with response to platinum-based chemotherapy, but recent studyrevealed that ERCC1 is not an ideal predictive markers.DNA repair is essentialfor cell survival by maintaining genomic integrity. It has been long know thatDNA repair plays different but pivotal roles in tumorigenesis, progress andtherapeutic response of various types of cancer. DNA repair enzymes in tumortissue, as representative for DNA repair capacities, has been considered asdiagnostic, prognostic and predictive biomarkers for cancer. As most DNA repairenzyme reside in nucleus bounding with DNA, it has been difficult to monitor thealteration of DNA repair enzyme in peripheral blood samples. The currentproject was executed to evaluate the role of an important DNA repair enzyme,APE1 as a biomarker in diagnosis, prognosis and prediction of chemotherapeuticresponse of lung cancer. Method: The expression level of APE1 of 172NSCLC tissues were evaluated by immunohistochemistry (IHC) and theircorrelation with response rate to platinum-containing chemotherapy,progress-free survival (PFS) and overall survival (OS) were analyzed. In addition,ELISA kit was established and APE1 serum level were evaluated in 412 NSCLCcases and 523 healthy donors. Patients completed at least 6 monthsplatinum-containing chemotherapy and with completed follow-up information weresubsequently enrolled into prognostic analysis. Result: In tissueanalysis, the clinicopathological data demonstrate that patients withAPE1-negative tumors had a better response to chemotherapy (P=0.002),better median PFS (10.3vs.8.0 months, P=0.016), but not OS (17.1vs.10.9months, P=0.263). Moreover, patients with both APE1- and ERCC1-negativetumors had significantly higher response rate, better median PFS (12.0 vs. 6.8months; P<0.001) and OS (18.8 vs. 10.1 months; P=0.010) thanthose with both positive tumors. In serum analysis, a significantly elevationof median serum APE1 level in patients compared with controls (0.16vs.0.10, P<0.001), and the cut-off value ofAPE1 was 0.135ng/ml. Compared with patients who maintained no progression in 6months since the treatment started, patients who progressed in that periodshowed a higher serum APE1 level (50.93% vs. 35.94%, P=0.025). TheKeplan-Meire analysis revealed that an increased PFS of patients with normalserum APE1 level than those with elevated level (10.0 vs. 6.0 months, P=0.011),but not OS (29.0 vs. 29.0 months), which is in agreement of the tissue APE1expression. Conclusion: The current study identified serum APE1 as anovel biomarker for NSCLC diagnosis. Both tissue and serum APE1 proteinexpression link to poor ORR and shorter PFS of patients who receivedplatinum-containing doublet chemotherapy. The results also highlights thepossible clinical application of serum APE1as an important liquid biopsy markerfor monitoring therapeutic response for NSCLC.

Key Words: Non small Cell LungCancer  Chemoresistance  DNA damge