686P - Overall survival (OS) to first- and second-line chemotherapy associated with mRNA expression of multiple myeloma SET (MMSET) domain, p53-binding pro...

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Gastric Cancer
Translational Research
Presenter Jia Wei
Authors J. Wei1, B. Liu1, L. Yu1, Z. Zou1, X. Qiang1, J.J. Sánchez2, C. Costa3, A. Gimenez-Capitan3, N. Karachaliou4, R. Rosell5
  • 1Oncology, Drum Tower Hospital, 210008 - Nanjing/CN
  • 2Statistics, Autonomous University of Madrid, 28029 - Madrid/ES
  • 3Laboratoy Of Biology Department, Pangaea Biotech, USP Dexeus University Institute, 08028 - Barcelona/ES
  • 4Oncology, Instituto Oncologico Dr Rosell, USP Dexeus University Institute, 08028 - Barcelona/ES
  • 5Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona/ES

Abstract

Background

Low BRCA1 expression enhances sensitivity to platinum, while high levels increase sensitivity to taxanes (Quinn et al. Cancer Res 2003). In response to cisplatin-induced DNA double strand breaks (DSBs), MDC1 binds to γH2AX, promoting DSB repair by 53BP1 and BRCA1. MMSET is required for the accretion of 53BP1, PIAS4 and Ubc9 to DSB sites. We hypothesized that the mRNA expression of these components of the MDC1-MMSET-53BP1 pathway could impact the predictive model based on BRCA1 mRNA expression (Wei et al. JNCI 2011).

Methods

Tumor samples were obtained from 132 advanced gastric cancer p treated with first-line FOLFOX, 58 of whom also received second-line docetaxel. mRNA expression of MDC1, MMSET, 53BP1, PIAS4, Ubc9 and BRCA1 was analyzed by real-time PCR.

Results

A close correlation was found between MMSET and BRCA1 (&rgr; = 0.28; P = 0.002), 53BP1 (&rgr; = 0.54; p < 0.001), PIAS4 (&rgr; = 0.27; P < 0.001) and Ubc9 (&rgr; = 0.50; P < 0.001). Median OS for all 132 p was 12.5 months (m). Among p receiving only first-line treatment, OS was 12.3 m in p with low MMSET and 8.8 m in p with high MMSET (P = 0.004). In the subset of p with low levels of 53BP1 receiving only first-line treatment, OS was 19.9 m for p with low levels of MMSET (2- and 5-year OS = 56.6% and 14.5%, respectively) vs 5.9 m for p with high MMSET (2-year OS = 16.7%) (P = 0.02). Among p receiving second-line docetaxel, OS was 13.9 m in p with low MMSET and 19.1 m in p with high MMSET (P = 0.003). Among p receiving second-line docetaxel, OS was 28.6 m for p with high BRCA1 vs 9.8 m for p with low BRCA1 (P < 0.001). In the subset of p with high BRCA1 levels receiving second-line docetaxel, OS was 36.6 m in p with high MMSET (2- and 5-year OS = 82.4% and 33%, respectively) and 13.9 m in p with low MMSET (2-year OS = 25%) (P = 0.003).

Conclusions

Longer OS to FOLFOX was associated with low levels of both MMSET and 53BP1, while longer OS to second-line docetaxel was associated with high levels of both MMSET and BRCA1. MMSET, together with 53BP1 or BRCA1 can be useful for customizing chemotherapy in advanced gastric cancer p.

Disclosure

All authors have declared no conflicts of interest.