Abstract
3202 Background: The expression level of the DNA excision repair gene ERCC1 has been correlated with outcome in pts receiving platinum agents for a variety of malignancies. While ribonucleotide reductase (RRM1) levels have been associated with responsiveness to gemcitabine (G), deoxycytidine kinase (DOCK), cytidine deaminase (CD), and other enzymes may also be useful to predict response to G. Therefore, pharmacogenetic correlations were carried out in pts with transitional cell bladder cancer (BC). Methods: mRNA enzyme levels (MEL) of ERCC1, RRM1, DOCK, and CD were determined using quantitative realtime PCR (Taqman) in microdissected paraffin-embedded tumor from treatment-naïve patients with locally advanced or metastatic BC who received G and a platinum agent. The result was expressed as a ratio of the PCR product of each enzyme compared to the β-actin gene. Thresholds for chemotherapy (CT) resistance were determined using the bootstrap technique. Statistical correlations between MEL and clinical endpoints were performed using the Chi square method. Results: 50 consecutive pts with locally advanced or metastatic BC (41 M, 9 F) received G and cisplatin or carboplatin. Among 18 pts with metastatic disease, there were 6 PD, 3 SD, 5 PR, and 2 CR. The median survival for pts with SD, PR, and CR was 13.4 m (range 6.5–25.0); and for pts with PD, 7.6 m (range 3.3–13.5). Among 25 pts who received adjuvant post-operative therapy, 7 died of disease an average of 10.6 m from the start of CT. An additional 4 pts relapsed and are receiving treatment, while 14 remain disease free with a median F/U of 19 m. Among 4 pts with bladder sparing CT-XRT, 3 are alive and disease free and 1 has succumbed to disease with a median F/U of 23.6 m. Among 2 pts with neoadjuvant CT, downstaging occurred in both cases, and both are alive with a median F/U of 12.3 m. Correlations with MEL will be presented at the meeting. Conclusions: MEL may permit the identification pts with a high probability of benefit before CT and avoid ineffective CT when the enzyme profile indicates resistance. Prospective validation of these results would establish MEL for treatment selection in patients with BC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Response Genetics Response Genetics Eli Lilly
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