THYMIDYLATE SYNTHASE EXPRESSION AND RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH ADVANCED HEAD AND NECK-CANCER

Background: Thymidylate synthase (TS), an essential enzyme in DNA synt hesis, is a target for the fluoropyrimidines, an important group of an tineoplastic agents used widely in the treatment of head and neck canc er, Purpose: We evaluated relationships between the level and/or patte rn of tumor TS expression and response to fluorouracil (5-FU)-based ne oadjuvant chemotherapy in patients with advanced head and neck cancer, Methods: Tumor specimens from 86 patients were available for this ret rospective analysis, The patients were enrolled in four consecutive ph ase II studies that tested combinations of 5-FU, leucovorin, and cispl atin with or without added methotrexate plus piritrexim or interferon alfa-2b (IFN alpha-2b), TS protein expression in the tumors was assess ed by use of the TS 106 monoclonal antibody and standard immunohistoch emical staining techniques, TS immunostaining was classified according to its level of intensity (TS 0-1 = low, TS 2 = intermediate, and TS 3 = high) and according to its extent (focal pattern = less than 25% o f tumor cells positive; diffuse pattern = greater than or equal to 25% of tumor cells positive), Data from 79 patients were available for an analysis of tumor TS expression and patient/tumor characteristics; 70 patients were assessable for their response to neoadjuvant chemothera py. Results: There was a statistically significant association between the level of tumor TS expression and the degree of tumor differentiat ion; a higher proportion of patients whose tumors exhibited TS 0-1 imm unostaining had undifferentiated or poorly differentiated tumors than patients whose tumors exhibited TS 2 or TS 3 immunostaining (P = .03, Jonckheere-Terpstra trend test), Among the 70 patients who were assess able for response to neoadjuvant chemotherapy, TS 3 tumor immunostaini ng was associated with a lower rate of complete response (i.e., comple te disappearance of clinically detectable disease for a minimum of 4 w eeks from time of initial determination) than was TS 2 or TS 0-1 immun ostaining, but this association was not statistically significant (P = .09, exact trend test); among the 39 patients who were treated with r egimens that included 5-FU, leucovorin, cisplatin, and IFN alpha-2b, t his inverse association between TS immunostaining intensity and respon se was statistically significant (P = .02, exact trend test), Tumor TS immunostaining intensity and overall survival were not found to be as sociated, Patients with tumors exhibiting a focal pattern of TS immuno staining have experienced significantly longer survival than patients with tumors exhibiting a diffuse pattern; for the 53 patients with dif fuse tumor TS immunostaining, the median survival was 24.7 months, whe reas the median survival has not yet been reached for the 22 patients with focal tumor TS immunostaining (P = .04, two-tailed logrank test), However, the survival advantage for the focal versus diffuse TS immun ostaining pattern was limited to patients whose tumors also exhibited a TS 3 level of immunostaining intensity. Conclusions and Implications : Characterization of tumor TS expression may he of value in identifyi ng patients with advanced head and neck cancer who would benefit from fluoropyrimidine-based neoadjuvant chemotherapy.