Abstract
BackgroundE1694 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.MethodsAushon 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.ResultsFour 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).ConclusionsThe 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.
Highlights
The immune system plays a critical role in surveillance, suppression, and the host inflammatory response to cancer
In this study nested within the E1694 GMK trial arm, we identify four markers: C-reactive protein (CRP), Tissue inhibitor of Metalloproteinases 1 (TIMP-1), Tumor Necrosis Factor alpha Receptor II (TNF-RII) and Transforming Growth Factor alpha (TGF-α) where the linear combination in the analysis of our model generates a risk score that has a significant prognostic value for high risk melanoma patients
A panel of 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), at baseline was found to be most informative for overall survival (OS)
Summary
Study design and patients Banked baseline serum samples from 40 patients participating in the Eastern Cooperative Oncology Group–led intergroup E1694 trial and treated with the GMK vaccine were utilized for this analysis [18]. RFS analysis TNF-RII was selected as the only main contributor for RFS among the markers tested. We used the Cox PH model with TNF-RII as a predictor for 1 year RFS using survival ROC analysis [22]. High baseline levels of TNF-RII, dichotomized at the median, were significantly associated with worse RFS (log rank test p–value = 0.01). The three markers that were most reliable were TNF-RII, TIMP-1 and CRP (being selected by the model most of the time during the cross validation). The survival ROC analysis demonstrated that the Cox PH model using these four markers predicts the 5 year OS well with an AUC for the full dataset of 88% and a cross-validated AUC of 72%. Dichotomizing the linear score by the Cox PH model, at the median, was significantly predictive of OS (log rank test pvalue = 0.0005).
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