Niki Karachaliou1, Jillian Wilhelmina Paulina Bracht2, Manuel Fernandez Bruno3, Ana Drozdowskyj4, Ana Gimenez Capitan2, Teresa Moran5, Enric Carcereny5, Manuel Cobo6, Manuel Domine7, Imane Chaib8, Jose Luis Ramirez9, Carlos Camps10, Mariano Provencio11, Alain Vergnenegre12, Guillermo Lopez-Vivanco13, Margarita Majem14, Bartomeu Massuti15, Rafael Rosell16. 1. Institute of Oncology Rosell, University Hospital Sagrat Cor, QuironSalud Group, Barcelona, Spain; Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain. 2. Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain. 3. Institute of Oncology Rosell, University Hospital Sagrat Cor, QuironSalud Group, Barcelona, Spain. 4. PIVOTAL SL, Madrid, Spain. 5. Catalan Institute of Oncology, Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Spain. 6. Medical Oncology Service, Hospital Carlos Haya, Malaga, Spain. 7. Medical Oncology Service, Fundacion Jimenez Diaz, Madrid, Spain. 8. Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain. 9. Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain; Medical Oncology Service, Hospital General de Valencia, Valencia, Spain. 10. Medical Oncology Service, Hospital Puerta de Hierro, Madrid, Spain. 11. Chest Department, CHU Limoges, Limoges, France. 12. Chest Department, Chu de Limoges, Limoges, France. 13. Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain. 14. Medical Oncology Service, Hospital General de Alicante, Alicante, Spain. 15. Institute of Oncology Rosell, Quirón-Dexeus University Institute, Barcelona, Spain. 16. Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain; Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain; Medical Oncology Service, Hospital General de Valencia, Valencia, Spain. Electronic address: rrosell@iconcologia.net.
Abstract
INTRODUCTION: Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656). METHODS: The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatin-docetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response. RESULTS: In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio = 0.63, 95% confidence interval: 0.42-0.83, p = 0.0080). PALB2 was also predictive of overall survival (hazard ratio = 0.68, 95% confidence interval: 0.42-0.90, p = 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive of response to cisplatin-docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared with a rate of only 23 % for those with low PALB2 mRNA expression (p = 0.0448). CONCLUSIONS: High PALB2 mRNA expression identified patients with NSCLC who significantly benefited from cisplatin-docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy will become the standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making.
INTRODUCTION: Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656). METHODS: The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatin-docetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response. RESULTS: In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio = 0.63, 95% confidence interval: 0.42-0.83, p = 0.0080). PALB2 was also predictive of overall survival (hazard ratio = 0.68, 95% confidence interval: 0.42-0.90, p = 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive of response to cisplatin-docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared with a rate of only 23 % for those with low PALB2 mRNA expression (p = 0.0448). CONCLUSIONS: High PALB2 mRNA expression identified patients with NSCLC who significantly benefited from cisplatin-docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy will become the standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making.
Authors: Niki Karachaliou; Oscar Arrieta; Ana Giménez-Capitán; Erika Aldeguer; Ana Drozdowskyj; Imane Chaib; Noemí Reguart; Rosario Garcia-Campelo; Jing-Hua Chen; Miguel Angel Molina-Vila; Rafael Rosell Journal: JTO Clin Res Rep Date: 2020-10-23