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In Vitro Drug Resistance in Non-Diploid and p53-Positive Non-Small Cell Lung Cancer: an EDR Study on 578 Freshly Resected Adenocarcinomas
I. Yu*1, W. Huang1, R. Parker1, E. Mechetner1, T. D'Amato2, R. Landreneau2. 1Oncotech, Inc., Tustin, CA, 2University of Pittsburgh Medical Center, Pittsburgh, PA,
BACKGROUND: The Extreme Drug Resistance (EDR) assay was shown to predict clinical resistance to chemotherapy in non-small cell lung cancer (NSCLC). This study examined whether the EDR assay correlates with biomarker expression, resulting in increased prognostic power to predict chemotherapy failure in NSCLC.
METHODS: 578 NSCLC adenocarcinomas were analyzed by flow cytometry for DNA ploidy and immunohistochemistry for p53 expression. In the EDR assay, tumor cells were exposed in vitro to suprapharmacological concentrations of cisplatin, carboplatin, etoposide, doxorubicin, and taxol. The data were defined as EDR (one standard deviation more resistant than the median), intermediate drug resistance (IDR - between the median and EDR), and low drug resistance (LDR - lower than the median).
RESULTS: Compared to diploid, non-diploid tumors exhibited significantly higher levels of resistance to etoposide (336 cases, p=0.0001 by chi-square statistics), doxorubicin (71 cases, p<0.0001), and taxol (346 cases, p=0.0175), with a statistical trend (339 cases, p=0.0716) for carboplatin. In the p53+ group (vs p53-), significantly higher resistance was observed for carboplatin (315 cases, p=0.0185), etoposide (370 cases, p=0.0050), and doxorubicin (145 cases, p<0.0001), with a strong statistical trend (348 cases, p= 0.0529) for cisplatin.
CONCLUSIONS: Drug resistance was significantly higher in non-diploid and p53+ NSCLS subgroups (4 out of 5 drugs tested). These results provide the first indication that combined EDR and biomarker testing may be beneficial for assay-guided chemotherapy.
EDR Patterns of Drug Resistance in Non-Diploid and p53-Positive NSCLC| EDR Patterns of Drug Resistance | | Drugs Tested | Diploid vs Non-Diploid | p53-Negative vs p53-Positive | | Resistance | p Value | Resistance | p Value | | LDR | IDR | EDR | LDR vs IDR+EDR | LDR | IDR | EDR | LDR vs IDR+EDR | | Cisplatin | 55 | 99 | 154 | NS | 63 | 108 | 177 | 0.0529 | | Carboplatin | 82 | 110 | 147 | 0.0716 | 84 | 106 | 125 | 0.0185 | | Etoposide | 57 | 112 | 167 | 0.0001 | 67 | 139 | 164 | 0.050 | | Doxorubicin | 18 | 20 | 33 | <0.0001 | 44 | 49 | 52 | <0.0001 | | Taxol | 54 | 92 | 200 | 0.0175 | 52 | 110 | 197 | NS |
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