A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma.
BACKGROUND
E1694 tested GM2-KLH-QS21 vaccine versus high-dose interferon-α2b (HDI) as adjuvant therapy for operable stage IIB-III melanoma. We tested banked serum specimens from patients in the vaccine arm of E1694 for prognostic biomarkers.


METHODS
Aushon Multiplex Platform was used to quantitate baseline serum levels of 115 analytes from 40 patients. Least absolute shrinkage and selection operator proportional hazard regression (Lasso PH) was used to select markers that are most informative for relapse-free survival (RFS) and overall survival (OS). Regular Cox PH models were then fit with the markers selected by the Lasso PH. Survival receiver operating characteristic (ROC) analysis was used to evaluate the ability of the models to predict 1-year RFS and 5-year OS.


RESULTS
Four markers that include Tumor Necrosis Factor alpha Receptor II (TNF-RII), Transforming Growth Factor alpha (TGF-α), Tissue Inhibitor of Metalloproteinases 1 (TIMP-1), and C-reactive protein (CRP) were found to be most informative for the prediction of OS (high levels correlate with worse prognosis). The dichotomized risk score based on the four markers could significantly separate the OS curves (p = 0.0005). When using the four-marker PH model to predict 5-year OS, we achieved an area under the curve (AUC) of 89% (cross validated AUC = 72%). High baseline TNF-RII was also significantly associated with worse RFS. The RFS with high (above median) TNF-RII was significantly lower than low TNF-RII (p = 0.01).


CONCLUSIONS
The biomarker signature consisting of TNFR-II, TGF-α, TIMP-1 and CRP is significantly prognostic of survival in patients with high-risk melanoma and warrants further investigation.
University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue, 5th Floor, Suite 555, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu.
Ahmad A
AA
Tarhini
Yan
Y
Lin
Oladapo
O
Yeku
William A
WA
LaFramboise
Madeeha
M
Ashraf
Cindy
C
Sander
Sandra
S
Lee
John M
JM
Kirkwood
D014408:Biomarkers, Tumor / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism*; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000097:blood* / Q000473:pathology / Q000601:surgery*; D011379:Prognosis; D016016:Proportional Hazards Models; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000097:blood / Q000473:pathology / Q000601:surgery; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D016211:Transforming Growth Factor alpha / Q000097:blood*
D014408:Biomarkers, Tumor; D047889:Receptors, Tumor Necrosis Factor, Type II; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016211:Transforming Growth Factor alpha; D002097:C-Reactive Protein