[The importance of p53 and ras mutation as predictive markers for adjuvant chemotherapy in non-small-cell lung cancer].

OBJECTIVE: A previous large, randomized, control trial(JBR.10)revealed that adjuvant chemotherapy with cisplatin(CDDP) and vinorelbine(VNR)was effective for non-small-cell lung cancer(NSCLC). It was also reported that adjuvant chemotherapy was not effective for p53-negative or K-ras mutation-positive patients. To clarify whether p53 and ras statuses are true predictive markers for chemotherapy with cisplatin, chemosensitivity was examined using an in vitro drug sensitivity assay. MATERIALS AND METHODS: Surgically resected fresh tumor specimens obtained from 27 patients at our institute with NSCLC were used for this study. Histoculture Drug Response Assay(HDRA)was applied to evaluate the chemosensitivity of CDDP and VNR in these specimens. p53 expression was evaluated by immunohistochemistry, and K-ras mutation by direct sequencing. RESULT: Four of the 27 patients were positive for K-ras mutation. The inhibition rate of CDDP was 54±5% for K-ras mutation positive-patients, and 50±13% for negative-patients. There was no significant difference between these two groups. p53 overexpression was observed in 14 patients, but not in 13 patients. The inhibition rate of CDDP was 50±12% for p53- overexpressed patients, and 50±12% for patients not overexpressed. The inhibition rate of VNR was 36±17% for p53- overexpressed patients, and 33±14%for patients not overexpressed. As for 8 adenocarcinoma patients, the inhibition rate of CDDP of p53-overexpressed patients(59±8%)was significantly(p=0. 018)higher than that of patients not overexpressed (45±9%). p53 overexpression may be a predictive marker for chemotherapy using CDDP in lung adenocarcinoma. CONCLUSION: p53 overexpression may be a possible predictive marker for adjuvant chemotherapy using CDDP in NSCLC.

Epidermal growth factor receptor mutations are associated with docetaxel sensitivity in lung cancer.

INTRODUCTION: A recent large randomized controlled trial revealed that patients with lung cancer with epidermal growth factor receptor (EGFR) mutations had better prognoses when treated with the EGFR-tyrosine kinase inhibitor, gefitinib, than with cytotoxic chemotherapeutic agents. Lung cancer with EGFR mutations is highly sensitive to EGFR-tyrosine kinase inhibitors. The previous trial implied that EGFR mutations might be predictive of the response to cytotoxic chemotherapy. METHODS: Forty-six tumor tissue specimens (32 adenocarcinomas and 14 nonadenocarcinomas) were obtained from patients with lung cancer who underwent surgical resection. EGFR mutations were detected using polymerase chain reaction-invader assay. A histoculture drug response assay was used as an in vitro drug sensitivity test. The inhibition rates of cisplatin, docetaxel (DOC), vinorelbine, and gemcitabine were measured. RESULTS: Sensitizing EGFR mutations were detected in samples from 14 patients, all with adenocarcinomas. The inhibition rate of cisplatin in tumors with EGFR mutations (group M) was 34.8 ± 15.5%, which was significantly lower (p = 0.0153) than in wild-type tumors (group W; 46.6 ± 14.0%). The inhibition rate of DOC in group M (18.8 ± 13.4%) was also significantly lower (p = 0.0051) than in group W (35.4 ± 19.1%). There were no significant differences in inhibition rates of gemcitabine and vinorelbine between groups M and W. Inhibition rates of DOC were significantly lower in group M (p = 0.0256) than in group W (32.6 ± 18.4) in samples from patients with adenocarcinoma. CONCLUSION: The histoculture drug response assay indicated that lung cancers with EGFR mutations were less sensitive to DOC than EGFR wild-type tumors.

Is class III beta-tubulin a true predictive marker of sensitivity to vinorelbine in non-small cell lung cancer? Chemosensitivity data evidence.

AIM: To clarify whether class III ß-tubulin (TUBB3) is a true predictive marker for chemotherapy with vinorelbine, chemosensitivity was examined using an in vitro drug sensitivity assay. PATIENTS AND METHODS: Initially, 9 specimens were obtained to analyze the dose-response curve and to measure the median effective dose 50 (ED(50)) in the histoculture drug response assay (HDRA). Subsequently, 68 surgically resected non-small cell lung cancer (NSCLC) specimens were applied to the HDRA and H-scores were calculated by immunohistochemical staining. RESULTS: The mean (±SD) slope factor, ED(50) and maximal response was 8.7±5.4, 39.0±17.9 µg/ml and 85.5±5.1% respectively. The mean inhibition rate was 26.4±16.2% and the mean H-score was 1.09±1.07. The inhibition rate was significantly correlated with TUBB3 expression (r=0.27, p=0.03), and was significantly higher in TUBB3-positive specimens than in TUBB3-negative specimens (p=0.003). CONCLUSION: Tumors with high TUBB3 levels exhibited greater chemosensitivity to vinorelbine than tumors with low TUBB3 levels. This finding provides support for the results of the JBR.10 trial.