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RESEARCH PRODUCT

Prognostic and Predictive Significance of Pharmacogenetic Analysis in Patients with Carcinomas of Unknown Primary (CAUP)

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ABSTRACT Purpose To investigate the prognostic/predictive significance of the expression of BRCA1, ERCC1, RRM1, TOPO-I, TOPO-IIa, TOPO-IIb, TXR1 TYMS and HIF1a mRNA in patients with Carcinomas of Unknown Primary (CaUP). Material and methods Ninety-three patients with CaUP and available tumoral samples diagnosed in three institutions were included in the study. The mRNA levels of the target genes were determined by quantitative real-time PCR from microdissected cells derived from patients' tumoral specimens. β-actin and PGK1 were used as reference genes. Results Successful amplification of at least one gene was achieved in all samples. BRCA1, ERCC1, HIF1a and TXR1 were amplified in all samples, while RRM1, TOPO-I, TOPO-IIa, TOPO-IIb were amplified in 88 samples and TYMS in 86 of them. Patients' characteristics were: median age 68 (28-84) years; 53 (57%) males; ECOG-PS 0 in 23 (25%), 1 in 33 (35%) and ≥ 2 in 37 (40%) patients. The histological type was: 47 (50%) adenocarcinomas, 18 (19%) squamous cell carcinomas, 14 (15%) undifferentiated carcinomas, 8 (9%) carcinomas with neuroendocrine features and 6 (6%) clear cell carcinomas. Forty-one (47%) patients received a platinum analog as 1st line treatment, while 21 (24%) were treated with taxane-based chemotherapy. Patients with high ERCC1 mRNA levels presented increased median overall survival compared with those with low ERCC1 expression (mOS: 16.5 versus 8.3 months; p = 0.034). Also, high compared to low expression of TXR1 or TOPO-I was significantly correlated with decreased survival (4.5 months vs. 22.6 months; p = 0.015 and 5.9 months vs. 16.5 months; p = 0.042, respectively). A statistical trend for increased survival was also observed in patients with low HIF1a expression (p = 0.07), while the expression of the other genes did not show significant prognostic correlation. No predictive significance of any gene was observed in patients treated with a platinum analog. Conclusions The ERCC1, TXR1, TOPO-IA and HIF1a expression may be used as prognostic markers in patients with CaUP. The predictive significance of these genes was not confirmed in the small subgroup of patients treated with platinum analogs. Disclosure All authors have declared no conflicts of interest.