186P - PALB2 mRNA expression as a predictive and prognostic marker in advanced non-small-cell lung cancer (NSCLC) patients (p) treated with cisplatin- doc...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Niki Karachaliou
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors N. Karachaliou1, A. Drozdowskyj2, A. Gimenez-Capitan3, D. Morales-Espinosa1, T. Moran4, E. Carcereny Costa4, M. Cobo5, M. Domine6, I. Bover7, C. Camps8, M. Provencio Pulla9, A. Vergnenegre10, G. Lopez-Vivanco11, M. Majem Tarruella12, S. Viteri13, B. Massuti Sureda14, R. Rosell15
  • 1Oncology. Translational Research Unit, Instituto Oncologico Dr Rosell, Quiron-Dexeus University Institute, 08028 - Barcelona/ES
  • 2Statistics, Pivotal, 28023 - Madrid/ES
  • 3Translational Research Unit, Pangaea Biotech, Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 4Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona, Barcelona/ES
  • 5Medical Oncology, Hospital Regional Universitario Carlos Haya, 29010 - Malaga/ES
  • 6Oncology, Fundacion Jimenez Diaz. Clin Nstra Señora de la Concepcion, ES-28040 - Madrid/ES
  • 7Medical Oncology, Hospital Son Llatzer, 07198 - Mallorca/ES
  • 8Oncology, Hospital General de Valencia, 46014 - Valencia/ES
  • 9Oncology Service, Hospital Universitario Puerta de Hierro de Majadahonda, 28222 - Madrid/ES
  • 10Service De Pneumologie, Hopital du CluzeauCHU Dupuytren, FR-87042 - Limoges CEDEX/FR
  • 11Oncology, Hospital de Cruces, 48903 - BARAKALDO , Vizcaya/ES
  • 12Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08026 - Barcelona/ES
  • 13Medical Oncology, Instituto Oncologico Dr Rosell, Quiron-Dexeus University Institute, 08028 - Barcelona/ES
  • 14Medical Oncology, Hospital General Universitario de Alicante, ES-03010 - Alicante/ES
  • 15Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona, Barcelona/ES

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.