Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma.
In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.
Augustine
Christina K
CK
Medical Center Duke University Medical Center, Durham, NC 27710, USA. Christi.augustine@duke.edu
Jung
Sin-Ho
SH
Sohn
Insuk
I
Yoo
Jin Soo
JS
Yoshimoto
Yasunori
Y
Olson
John A
JA
Friedman
Henry S
HS
Ali-Osman
Francis
F
Tyler
Douglas S
DS
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008558:Melphalan / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D012044:Regression Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077204:Temozolomide; D014158:Transcription, Genetic / Q000187:drug effects
D003606:Dacarbazine; D008558:Melphalan; D000077204:Temozolomide