Abstract
8015 Background: The non-classical alkylators DTIC and TMZ exert their cytotoxic effect through methylation of DNA bases. DNA damage is repaired by direct reversal of the O6-MeG lesion by the protein O6-methylguanine-DNA methyltransferase (MGMT/AGT); recognition of alkylation-damage-induced replication errors by the MMR pathway and excision repair of alkylated bases (N7-MeG and N3-MeA) conducted by the BER pathway. We report the results of a study evaluating the correlation between MGMT, MMR and BER protein expression in tumor tissue of patients (pts) with metastatic melanoma and documented clinical response to chemotherapy. Methods: Frozen tumor tissue was obtained from 17 pts with metastatic melanoma treated with DTIC/TMZ. Tumors were classified as sensitive (S) if pts showed stable disease (SD), partial response (PR) or complete response (CR) by RECIST criteria; and resistant (R) if progressive disease (PD) was observed after 2 cycles of treatment with DTIC/TMZ. Immunohistochemical staining for MGMT, MLH1 (MMR), and DNA polymerase-ß (pol-ß, BER) was performed. Levels of expression were assessed by a pathologist blinded to response data. Fisher’s Exact and Wilcoxon Rank Sum statistical tests were used to assess correlations. Results: 9 tumors were considered to be sensitive (S) and 7 resistant (R). Clinical response was found to significantly correlate with functional MMR (increased MLH1 expression): 7 of 9 S tumors had high MLH1 expression as compared to 1 of 7 R (p-value=0.015). Clinical response was also found to be inversely correlated with pol-ß expression: 6 of 9 S tumors expressed low levels of pol-ß as compared to 1 of 7 R tumors (p-value=0.08). MGMT expression did not seem to correlate with response. Conclusions: The presence of a functional MMR pathway is a requirement for the cytotoxic effect of alkylating agents and was significantly correlated with clinical response. Decreased BER potential (pol-ß expression) was correlated with increased sensitivity to alkylator-based chemotherapy. These findings lend additional support to the view that DNA repair status correlates with response to alkylator-based chemotherapy for melanoma. No significant financial relationships to disclose.
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