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Identification of chemosensitivity markers for postoperative adjuvant chemotherapy using cellular, molecular, and immunohistochemical profiles of advanced carcinomas from gastrointestinal tract.

55 Background: The prediction of chemotherapeutic efficacy is a fundamental problem. We have developed an effective system to identify prediction markers based on an in vitro approach using a quantitative matrix of chemosensitivity assay (CSA) and protein expression by reverse-phase protein lysate microarrays (RPA), followed by tissue microarrays (TMA). In the present study, we attempted to identify predictive markers by extracting candidate proteins from the "chemosensitivity x protein expression matrix" of 12 cancer cell lines and 12 chemotherapeutic agents, followed by examination using TMA in post-operative adjuvant chemotherapy for advanced gastric and colorectal carcinomas.


METHODS
The "chemosensitivity x protein expression matrix" was constructed using quantitative data from CSA and RPA. TMA was constructed from parafin-embedded, formalin-fixed surgically removed tissues from 30 gastric and 49 colorectal carcinomas. All subjects had received post-operative adjuvant chemotherapy. Expression and/or localization of candidate marker proteins on TMA were evaluated for the comparison of time to relapse (TTR) between the groups based on the score of each candidate marker protein.


RESULTS
TTR was compared in each binary score for a candidate marker that showed a moderate to high correlation coefficient of the "chemosensitivity x protein expression matrix" of 144 combinations. Among these candidate combinations, it was found that the presence/absence of NFkB protein nuclear localization and the TTR of those patients who received 5-FU based adjuvant chemotherapy differed significantly. The three-year relapse rate was 28% in NFkB absent cases, whereas it was 84% in the present cases.


CONCLUSIONS
We identified NFkB nuclear localization as an effective 5-FU based chemotherapeutic prediction marker in the context of gastrointestinal post-operative adjuvant chemotherapy. The combination of CSA, RPA, and TMA technologies may allow rapid identification of chemotherapeutic prediction markers. No significant financial relationships to disclose.