LGR5 rs17109924 is a predictive genetic biomarker for time to recurrence in patients with colon cancer treated with 5-fluorouracil-based adjuvant chemotherapy.

We recently found variants in cancer stem cell genes (CD44, ALCAM and LGR5) significantly associated with increased time to recurrence (TTR) in patients with stage III and high-risk stage II colon cancer treated with 5-fluorouracil (5-FU)-based chemotherapy. In this study, we validated these genetic biomarkers in a large and independent patient cohort (n=599). Patients who received 5-FU-based adjuvant chemotherapy (n=391) carrying at least one C allele in LGR5 rs17109924 had a significantly increased TTR compared with patients carrying the homozygous T/T variant (HR 0.38, 95%CI 0.19-0.79; P=0.006). In patients treated with surgery alone (n=208), no association between LGR rs17109924 and TTR was found (P=0.728). In the multivariate Cox-analysis, LGR5 rs17109924 remained statistically significant (HR 0.38, 95%CI 0.18-0.78; P=0.008) for patients who received adjuvant chemotherapy. We confirmed in a large and independent study cohort that LGR5 rs17109924 is a predictive genetic biomarker for TTR in patients with colon cancer treated with 5-FU-based adjuvant chemotherapy.

The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer.

BACKGROUND: Inflammation has a critical role in the pathogenesis and progression of cancer. The lymphocyte to monocyte ratio (LMR) could be shown to be prognostic in haematologic neoplasia. In this study, we analysed the LMR with clinical outcome in stage II and III colon cancer patients. METHODS: Three hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS). RESULTS: Including all patients, the elevated preoperative LMR was significantly associated with increased TTR and OS in multivariate analysis (HR: 0.47, 95%CI: 0.29-0.76, P=0.002; HR: 0.51, 95%CI: 0.31-0.83, P=0.007; respectively). In subanalyses, the association was limited to patients with stage III (HR: 0.40, 95%CI: 0.22-0.72, P=0.002), in contrast to patients with stage II (HR: 0.40, 95%CI: 0.28-1.66, P=0.397). When the subgroup of patients with 'high-risk' LMR≤2.83 was analysed, no benefit of adjuvant 5-FU-based chemotherapy could be found (HR: 0.99; 95%CI: 0.60-1.63; P=0.953). CONCLUSION: The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients. Our results further suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.

Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients.

BACKGROUND: Recent evidence indicates that the host inflammatory response has an important role in the tumour progression. Elevated C-reactive protein (CRP) levels have been previously associated with poor prognosis in several cancer types including small-scale studies in pancreatic cancer (PC) patients. The purpose of the present study was to validate the prognostic impact of plasma CRP levels at date of diagnosis on cancer-specific survival (CSS) in a large cohort of PC patients. METHODS: Data from 474 consecutive patients with adenocarcinoma of the pancreas, treated between 2004 and 2012 at a single centre, were evaluated retrospectively. CSS was analysed using the Kaplan-Meier method. To evaluate the prognostic significance of plasma CRP levels, univariate and multivariate Cox analyses were applied. RESULTS: High plasma CRP levels at diagnosis were significantly associated with well-established prognostic factors, including high tumour stage and tumour grade and the administration of chemotherapy (P<0.05). In univariate analysis, we observed that a high plasma CRP level was a consistent factor for poor CSS in PC patients (hazard ratio (HR)=2.21; 95% confidence interval (CI)=1.68-2.92, P<0.001). In multivariate analysis, tumour stage, grade, administration of chemotherapy, a high neutrophil-lymphocyte ratio and the highest quartile of CRP levels (HR=1.60, 95% CI=1.16-2.21; P=0.005) were identified as independent prognostic factors in PC patients. CONCLUSION: In conclusion, we confirmed a significant association of elevated CRP levels with poor clinical outcome in PC patients. Our results indicate that the plasma CRP level might represent a useful marker for patient stratification in PC management.

A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients.

BACKGROUND: Inflammation has a critical role in the pathogenesis and progression of cancer. Recently, the derived neutrophil to lymphocyte ratio (absolute count of neutrophils divided by the absolute white cell count minus the absolute count of neutrophils; dNLR) has been shown to influence clinical outcome in various cancer entities. In this study, we analysed the dNLR with clinical outcome in stage II and III colon cancer patients. METHODS: Three-hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan-Meier curves and multivariate Cox proportion analyses were calculated for time to recurrence (TTR) and overall survival (OS). RESULTS: In univariate analysis, the elevated preoperative dNLR was significantly associated with decreased TTR (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.57-3.6, P<0.001) and remained significant in multivariate analysis. Patients with dNLR >3 had a median TTR of 83 months, and patients with dNLR ≤ 3 showed a median TTR of 132 months. In OS analysis, a dNLR >2.2 was significantly associated with decreased OS in univariate (HR 1.85, 95% CI 1.11-3.08, P=0.018) and multivariate analysis. Patients with dNLR >2.2 showed a median OS of 121 months, and patients with dNLR ≤ 2.2 had a median OS of 147 months. CONCLUSION: The dNLR may be an independent prognostic marker for TTR and OS in patients with stage II and III colon cancer. Independent validation of our findings is warranted.

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer.

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer.

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.