TATI, TAT-2, and CRP as Prognostic Factors in Colorectal Cancer.

OBJECTIVES: Colorectal cancer is the third most common cancer worldwide, with an obvious need for more accurate prognostics. Previous studies identified C-reactive protein (CRP) as a prognostic serum biomarker for colorectal cancer, whereas the biomarkers tumor-associated trypsin inhibitor (TATI) and tumor-associated trypsin-2 (TAT-2) are less well-known prognostic factors. Therefore, in this study, we aimed to compare the prognostic role of these biomarkers. MATERIALS AND METHODS: Our cohort consisted of 219 women and 274 men who underwent colorectal cancer surgery at Helsinki University Central Hospital from 1998 through 2005. Serum and plasma samples were collected before surgery, aliquoted, stored at -80°C, and then analyzed using high-sensitivity methods with commercially available time-resolved immunofluorometric assay kits. RESULTS: In univariate analysis, CRP (HR 1.67; 95% confidence interval [CI]: 1.25-2.23; p = 0.001), TATI (HR 1.87; 95% CI: 1.13-3.08; p = 0.014), and TAT-2 (HR 1.52; 95% CI: 1.13-2.06; p = 0.006) were significant prognostic biomarkers across the entire cohort. In subgroup analyses, TATI and TAT-2 represented significant negative prognostic factors among patients older than 66, while patients with left-sided disease, a high serum TAT-2, or a high plasma CRP experienced worse prognosis. None of the biomarkers emerged as important in the disease stage subgroup analysis nor did they serve as independent factors in the multivariate analysis. CONCLUSIONS: TATI and TAT-2 as well as CRP significantly, but not independently, served as prognostic factors in our cohort of colorectal cancer patients. Further research is needed to fully understand their clinical role in colorectal cancer.

CA125: A superior prognostic biomarker for colorectal cancer compared to CEA, CA19-9 or CA242.

OBJECTIVES: The tumor stage represents the single most important prognostic factor for colorectal cancer (CRC), although more accurate prognostics remain much needed. Previously, we identified CA125 as an independent significant prognostic factor, which we have further validated along with CEA, CA19-9, and CA242 in a large cohort of CRC patients. METHODS: Using enzyme-linked immunosorbent assays, we analyzed preoperative serum samples in 322 CRC patients operated on between 1998 and 2003. RESULTS: Using the Spearman's rho model, we calculated the correlation between our previous findings on MUC16 and CA125, for which the correlation coefficient was 0.808 (p < 0.001). The Cox regression analysis of the linear and logarithmic values of CEA, CA125, CA242, and CA19-9 identified only CA125 (hazard ratio [HR] 1.03; 95% confidence interval [95% CI] 1.02-1.04; p < 0.001) as significant when using the linear values. Survival among CRC patients with a high CA125 level was poor compared with CRC patients with a low CA125 level (HR 2.48; 95% CI 1.68-3.65; p < 0.001). In subgroup analyses, patients with high CA125 levels and aged ≤67 or >67, with stage I-II or III-IV, and both colon and rectal cancer exhibited poor prognoses. In the multivariate analysis, we used clinical pathological variables in the model, where age, gender, and stage served as the background characteristics. We dichotomized CA125 using the Youden maximal cutoff point, and the median values for CEA, CA19-9, and CA242. CA125 emerged as the only marker remaining significant and independent together with stage, location, and age (HR 1.91; 95% CI 1.24-2.95; p 0.003). CONCLUSIONS: CA125 represents a significant and independent prognostic factor in CRC patients, superior to CEA. Furthermore, CA242 served as a better prognostic marker than both CEA and CA19-9. We recommend including both CA125 and CA242 in prognostic clinical trials among CRC patients.

A prognostic model for colorectal cancer based on CEA and a 48-multiplex serum biomarker panel.

Mortality in colorectal cancer (CRC) remains high, resulting in 860,000 deaths annually. Carcinoembryonic antigen is widely used in clinics for CRC patient follow-up, despite carrying a limited prognostic value. Thus, an obvious need exists for multivariate prognostic models. We analyzed 48 biomarkers using a multiplex immunoassay panel in preoperative serum samples from 328 CRC patients who underwent surgery at Helsinki University Hospital between 1998 and 2003. We performed a multivariate prognostic forward-stepping background model based on basic clinicopathological data, and a multivariate machine-learned prognostic model based on clinicopathological data and biomarker variables, calculating the disease-free survival using the value of importance score. From the 48 analyzed biomarkers, only IL-8 emerged as a significant prognostic factor for CRC patients in univariate analysis (HR 4.88; 95% CI 2.00-11.92; p = 0.024) after correcting for multiple comparisons. We also developed a multivariate model based on all 48 biomarkers using a random survival forest analysis. Variable selection based on a minimal depth and the value of importance yielded two tentative candidate CRC prognostic markers: IL-2Ra and IL-8. A multivariate prognostic model using machine-learning technologies improves the prognostic assessment of survival among surgically treated CRC patients.

Mucin 16 and kallikrein 13 as potential prognostic factors in colon cancer: Results of an oncological 92-multiplex immunoassay.

Colon cancer represents one of the most common cancers in the world. Despite improved treatment, mortality remains high. In order to improve the assessment of prognosis for colon cancer patients, identifying new prognostic markers remains necessary. We analyzed preoperative serum samples from 148 colon cancer patients surgically treated at Helsinki University Hospital from 1998 through 2002 using a multiplex proximity extension assay (Oncology II panel, Olink Bioscience, Uppsala, Sweden), a panel constituting 92 immunological and oncological markers. We performed univariate and multivariate analyses on these patients and calculated the disease-specific survival among patients using the log-rank test for Kaplan-Meier estimates. In the univariate survival analysis of 92 biomarkers, 26 resulted in p < 0.1. Among these, eight biomarkers emerged as statistically significant (p < 0.05). Patients with low levels of kallikrein 13 had a poor prognosis. Moreover, patients with high levels of amphiregulin, carcinoembryonic antigen-related adhesion molecule 5, interleukin 6, mucin 16, syndecan 1, transforming growth factor alpha, and vimentin also had a poor prognosis. In the multivariate analysis, kallikrein 13 and mucin 16 emerged as independent prognostic markers. The role of kallikrein 13, a member of the serine protease kallikrein biomarker family, in tumorigenesis remains unclear. Mucin 16 is also known as carbohydrate antigen 125, a well-known ovarian cancer biomarker. Patients with low levels of kallikrein 13 (hazard ratio: 0.36; 95% confidence interval: 0.14-0.92; p = 0.033) and high levels of mucin 16 (hazard ratio: 3.15; 95% confidence interval: 1.68-5.93; p < 0.005) had a poor prognosis. Mucin 16 and kallikrein 13 represent independent prognostic markers for colon cancer. Furthermore, the clinical utility of mucin 16 and kallikrein 13 serum tests warrants additional investigation.