ABSTRACT
BACKGROUND: Due to the low specificity of the prostate-specific antigen (PSA) assay and a high false positive rate, a large number of prostate cancer (PCA) biopsies are performed unnecessarily. Consequently, there is a need for new biomarkers that can identify PCA at any stage of progression while limiting the number of false positives. The use of autoantibody signature-developed biomarkers has proven to be an effective method to solve this problem. RESULTS: Using T7 phage-peptide detection, we identified a panel of eight biomarkers for PCA on a training set. The estimated receiver-operating characteristic (ROC) curve had an area under the ROC curve of 0.69 when applied to the validation set. Spearman correlations were high, within 0.7 to 0.9, indicating that the biomarkers have a degree of inter-relatedness. The identified biomarkers play a role in processes such as androgen response regulation and cellular structural integrity and are proteins that are thought to play a role in prostate tumorigenesis. CONCLUSIONS: Autoantibodies against PCA can be developed as biomarkers for detecting PCA. The scores from the algorithm developed here can be used to indicate a relative high or low risk of PCA, particularly for patients with intermediate (4.0 to 10 ng/ml) PSA levels. Since most commercially available assays test for PSA or have a PSA component, this novel approach has the potential to improve diagnosis of PCA using a biologic measure independent of PSA.
ABSTRACT
BACKGROUND: One in 4 patients with lymph node-negative, invasive colorectal carcinoma (CRC) develops recurrent disease after undergoing curative surgery, and most die of advanced disease. Predicting which patients will develop a recurrence is a significantly growing, unmet medical need. METHODS: Archival formalin-fixed, paraffin-embedded (FFPE) primary adenocarcinoma tissues obtained at surgery were retrieved from 74 patients with CRC (15 with stage I disease and 59 with stage II disease) for Training/Test Sets. In addition, FFPE tissues were retrieved from 49 patients with stage I CRC and 215 patients with stage II colon cancer for an External Validation (EV) Set (n = 264) from 18 hospitals in 4 countries. No patients had received neoadjuvant/adjuvant therapy. Proprietary genetic programming analysis of expression profiles for 225 prespecified tumor genes was used to create a 36-month recurrence risk signature. RESULTS: Using reverse transcriptase-polymerase chain reaction, a 5-gene rule correctly classified 62 of 92 recurrent patients and 87 of 172 nonrecurrent patients in the EV Set (sensitivity, 0.67; specificity, 0.51). "High-risk" patients had a greater probability of 36-month recurrence (42%) than "low-risk" patients (26%; hazard ratio, 1.80; 95% confidence interval, 1.19-2.71; P = .007; Cox regression) independent of T-classification, the number of lymph nodes examined, histologic grade/subtype, anatomic location, age, sex, or race. The rule outperformed (P = .021) current National Comprehensive Cancer Network Guidelines (hazard ratio, 0.897). The same rule also differentiated the risk of recurrence (hazard ratio, 1.63; P = .031) in a subset of patients from the EV Set who had stage I/II colon cancer only (n = 251). CONCLUSIONS: To the authors' knowledge, the 5-gene rule (OncoDefender-CRC) is the first molecular prognostic that has been validated in both stage I CRC and stage II colon cancer. It outperforms standard clinicopathologic prognostic criteria and obviates the need to retrieve ≥12 lymph nodes for accurate prognostication. It identifies those patients most likely to develop recurrent disease within 3 years after curative surgery and, thus, those most likely to benefit from adjuvant treatment.
