Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non-Small Cell Lung Cancer

J Thorac Oncol. 2019 Feb;14(2):304-310. doi: 10.1016/j.jtho.2018.10.168. Epub 2018 Nov 22.

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.

Keywords: Docetaxel; Non–small cell lung cancer; PALB2; RNA expression.

Publication types

  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Biomarkers / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Cisplatin / administration & dosage
  • DNA-Binding Proteins / genetics
  • Docetaxel / administration & dosage
  • Fanconi Anemia Complementation Group N Protein / genetics*
  • Female
  • Gene Expression
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism*
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Proportional Hazards Models
  • RNA, Messenger / metabolism*
  • Survival Rate
  • Telomere-Binding Proteins / genetics
  • Treatment Outcome
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Biomarkers
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human
  • RNA, Messenger
  • RNF8 protein, human
  • Rif1 protein, human
  • TP53BP1 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • Docetaxel
  • Ubiquitin-Protein Ligases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT00617656