186PPALB2 MRNA EXPRESSION AS A PREDICTIVE AND PROGNOSTIC MARKER IN ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS (P) TREATED WITH CISPLATIN- DOCETAXEL CHEMOTHERAPY

Abstract Aim: The Spanish Lung Cancer Group (SLCG) undertook an industry-independent, two biomarker-directed, randomized trial in advanced NSCLC p. The study (NCT00617656/GECP-BREC) compared non-selected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 mRNA levels. The trial was closed prematurely due to a detrimental effect in the biomarker-directed arm. Further genetic analysis defined PALB2, the bridging molecule that connects BRCA1 and BRCA2, as a promising biomarker to elucidate DNA repair mechanisms. Methods: We assessed mRNA levels of PALB2, RIF1, 53BP1, RNF8 and ATM (as biomarkers with critical roles in homologous recombination [HR]) in tissue from 177 cisplatin plus docetaxel-treated NSCLC p in the BREC trial. We correlated our findings with PFS, OS and response. Results: Median age 62; 79.1% male; 51.4% adenocarcinoma. Results of PALB2 mRNA expression were intriguing. PFS was 5.6 months (m) for p with high/intermediate (H-I) PALB2 and 4.1 m for p with low (L) PALB2 (p = 0.0018). OS was 13.2 m for p with H-I PALB2 compared to 9.9 for p with L PALB2 (p = 0.0377). In the univariate analysis, H-I PALB2 was a marker of longer PFS (HR = 0.56, 95% CI, 0.38, 0.80; p = 0.002) and OS (HR = 0.64, 95% CI, 0.41, 0.98; p = 0.0394). In the multivariate analysis, only H-I PALB2 was associated with longer PFS (here HR = 0.56 and p = 0.0022) and OS (HR = 0.61 and p = 0.0343). Among 143 p with data for response and PALB2 expression, 49.5% of p with H-I PALB2 were responders, compared to only 28% with L PALB2 (p = 0.0131). No significant differences were found for PFS, OS or response according to expression status of the other 4 biomarkers. Conclusions: Our findings reveal PALB2 to be a predictive and prognostic biomarker in advanced NSCLC p treated with docetaxel plus cisplatin. The BRCA1-PALB2-BRCA2 network is a critical determinant of responsiveness to DNA interstrand cross-linking agents and antimicrotubule agents. In our study, BRCA1 had no effect on treatment outcome of this population. PALB2 was found to be a strong marker to predict sensitivity to antimicrotubule agents, without affecting sensitivity to DNA damage-based chemotherapy. Disclosure: All authors have declared no conflicts of interest.