Although CDDP is highly active in NSCLC, rapid development of resistance limits its usefulness. One mechanism mediating CDDP resistance involves the protein kinase C (PKC) signal transduction pathways. The oncogene c-fos is amplified in patients failing CDDP-based therapy and is involved in estrogen-estrogen receptor interaction and PKC pathways. Early studies report variable expression of ER in NSCLC, ranging from 23-97%. The triphenylethylenes tamoxifen and toremifene have been shown to modulate PKC and enhance CDDP chemosensitivity in preclinical models. We hypothesized that ER and/or PKC expression would predict response to treatment with toremifene as a CDDP modulator in NSCLC. As part of an ongoing Phase II trial, we obtained pre-treatment tumor tissue to determine ER and basal levels of PKC isoforms. Toremifene was orally administered at 600 mg/d on days 1-7 while CDDP was given intravenously at 50 mg/m2 on days 4 and 11. Cycles were repeated every 28 days. ER, PKC-α, and PKC-ε were determined by immunohistochemistry on tumor tissue. To-date, 15 of 38 patients enrolled in the trial have tissue available for analysis. Patient response was determined using standard cooperative group criteria. Two patients had insufficient tissue for ER and PKC staining respectively. There were 6 females and 9 males. ER was positive in only 1/5 females and 0/9 males. Both PKC-α and PKC-ε were positive in 3 patients. One patient was PKC-α (+)/PKC-ε (-) while another was PKC-α (-)/PKC-ε (+). In this cohort, one patient had a confirmed partial response (7%), five with stable disease (33%), seven with progression (47%), and two with inevaluable disease. The sole responder was a male who had previous CDDP-based therapy and was ER/PKC negative The low proportion of ER expression in this cohort (7%) confirms more recent data showing infrequent ER expression (DiNunno, Proc ASCO 1998, 1769). In this interim analysis, no correlation between ER and/or PKC status with response could as yet be determined because of the small sample size and the availability of tumor tissue from only one of the four known responders. As this trial is nearing its accrual goals, more patient tissue samples will be available for analysis, including c-fos expression.
|Original language||English (US)|
|Journal||Journal of Investigative Medicine|
|State||Published - Feb 1999|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)