Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling.
OBJECTIVE
Neoadjuvant chemotherapy for invasive bladder cancer, involving a regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), can improve the resectability of larger neoplasms for some patients and offer a better prognosis. However, some suffer severe adverse drug reactions without any effect, and no method yet exists for predicting the response of an individual patient to chemotherapy. Our purpose in this study is to establish a method for predicting response to the M-VAC therapy.


METHODS
We analyzed gene expression profiles of biopsy materials from 27 invasive bladder cancers using a cDNA microarray consisting of 27,648 genes, after populations of cancer cells had been purified by laser microbeam microdissection.


RESULTS
We identified dozens of genes that were expressed differently between nine "responder" and nine "nonresponder" tumors; from that list we selected the 14 "predictive" genes that showed the most significant differences and devised a numerical prediction scoring system that clearly separated the responder group from the nonresponder group. This system accurately predicted the drug responses of 8 of 9 test cases that were reserved from the original 27 cases. Because real-time reverse transcription-PCR data were highly concordant with the cDNA microarray data for those 14 genes, we developed a quantitative reverse transcription-PCR-based prediction system that could be feasible for routine clinical use.


CONCLUSIONS
Our results suggest that the sensitivity of an invasive bladder cancer to the M-VAC neoadjuvant chemotherapy can be predicted by expression patterns in this set of genes, a step toward achievement of "personalized therapy" for treatment of this disease.
Takata
Ryo
R
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Katagiri
Toyomasa
T
Kanehira
Mitsugu
M
Tsunoda
Tatsuhiko
T
Shuin
Taro
T
Miki
Tsuneharu
T
Namiki
Mikio
M
Kohri
Kenjiro
K
Matsushita
Yasushi
Y
Fujioka
Tomoaki
T
Nakamura
Yusuke
Y
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D016000:Cluster Analysis; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D014747:Vinblastine / Q000008:administration & dosage
D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate