Expression of XPG mRNA and protein as potential biomarker of response to trabectedin in sarcoma patients (2007)

C127 Introduction: Trabectedin has recently received positive opinion from EMEA as treatment for advanced soft tissue sarcoma (STS) after failure to anthracyclines and ifosfamide. Objective responses and tumour control have been noted in patients resistant to conventional therapy. Moreover, the emergence of acquired resistance to trabectedin in sensitive patients is generally a late event. In experimental models trabectedin sensitivity correlates with a functional nucleotide excision repair (NER) pathway. Recently it has been described that XPG endonuclease binds to trabectedin adducts in the DNA leading to cell death. The present work characterized the impact of of XPG mRNA and protein expression levels in the tumor samples on the clinical outcome of STS patients treated with trabectedin.  Methods: Retrospective analysis of paraffin embedded tumor tissue of STS patients obtained before treatment with trabectedin. A tissue microarray was constructed for analysing XPG protein expression by immunohistochemistry (IHC) using the monoclonal antibody XPG/ERCC5 Ab-1 (Clone 8H7)(LabVision, CA). XPG mRNA expression levels was determined by qRT-PCR after laser microdissection of the tumor cells from the paraffin embedded tumor sections.  Results: XPG protein was determined in 98 patients with tumor tissue block available and mRNA expression was successfully determined 118 samples from a cohort of 159 unselected STS patients. Clinical response to trabectedin in the study population is superimposable to phase II and comparative studies in pretreated STS.  XPG protein expression was high (IHC 2+ and 3+) in 28% of patients studied. Weak (1+) or no expression (0) of XPG protein was associated with a significant worst outcome in terms of median Progression Free Survival (PFS) (3.7 vs 7.1 moths (mo), p= 0.0411) and a clear but statistically non-significant trend in terms of PFS>6 mo (39.9 vs 55.6%) median survival (OS) (11.7 vs 27.7 mo), Response rate (RR) (13 vs 24%), tumor control rate (TCR = CR+PR+SD>6) (42 vs 60%).  The median value of XPG mRNA expression was 1.54 and was used as cut off value to determine high and low expressing patients. High expression of XPG mRNA was associated to a significant better outcome in terms of median PFS (2.5 vs 7.1 mo, p=0.0019), PFS>6 rate (28.3 vs 53.8%, p=0.0038) and TCR (34 vs 56%, p=0.0249) and shows a clear trend in terms of median OS (9.3 vs 19.1) and RR (10 vs 19%).  A strong correlation was found between XPG mRNA expression above the median and high (2+, 3+) expression of XPG protein measured by IHC (p=0.0173).  Conclusions: Previous studies has demonstrated a lack of negative impact of functional TC-NER expression in the outcome of trabectedin treatment. However, this study shows for the first time that an increased expression of XPG protein or mRNA is correlated to a better outcome after trabectedin treatment. This profile is the opposite to the previously reported for platinum salts and anthracyclines. In addition, the use of IHC for the analysis of XPG protein expression highly facilitate the routine use of this technique for selection of responding STS patient population. The potential transtumoral nature of the XPG biomarkers will allow its use in other tumor types as lung, prostate, breast and ovarian cancer, known to be sensitive to trabectedin. Prospective studies are warranted.