Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer.
OBJECTIVE
Standard treatment for advanced non-small-cell lung cancer (NSCLC) includes the use of a platinum-based chemotherapy regimen. However, response rates are highly variable. Newer agents, such as pemetrexed, have shown significant activity as second-line therapy and are currently being evaluated in the front-line setting. We utilized a genomic strategy to develop signatures predictive of chemotherapeutic response to both cisplatin and pemetrexed to provide a rational approach to effective individualized medicine.


METHODS
Using in vitro drug sensitivity data, coupled with microarray data, we developed gene expression signatures predicting sensitivity to cisplatin and pemetrexed. Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 samples from patients previously treated with cisplatin.


RESULTS
Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict sensitivity in vitro and, in the case of cisplatin, to predict treatment response in patients treated with cisplatin. The accuracy of the cisplatin predictor, based on available clinical data, was 83.1% (sensitivity, 100%; specificity 57%; positive predictive value, 78%; negative predictive value, 100%). Interestingly, an inverse correlation was seen between in vitro cisplatin and pemetrexed sensitivity, and importantly, between the likelihood of cisplatin and pemetrexed response in patients.


CONCLUSIONS
The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.
Hsu
David S
DS
Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC 27710, USA.
Balakumaran
Bala S
BS
Acharya
Chaitanya R
CR
Vlahovic
Vanja
V
Walters
Kelli S
KS
Garman
Katherine
K
Anders
Carey
C
Riedel
Richard F
RF
Lancaster
Johnathan
J
Harpole
David
D
Dressman
Holly K
HK
Nevins
Joseph R
JR
Febbo
Phillip G
PG
Potti
Anil
A
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D005971:Glutamates / Q000494:pharmacology* / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D018579:Patient Selection; D000068437:Pemetrexed; D011237:Predictive Value of Tests; D012044:Regression Analysis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D002945:Cisplatin