Abstract
BackgroundThere is a need for improved selection of patients for adjuvant chemotherapy after resection of non-metastatic colorectal cancer (CRC). Regulator of chromosome condensation 2 (RCC2) is a potential prognostic biomarker. We report on the establishment of a robust protocol for RCC2 expression analysis and prognostic tumour biomarker evaluation in patients who did and did not receive adjuvant chemotherapy.Materials and methodsRCC2 was analysed in 2916 primary CRCs from the QUASAR2 randomised trial and two single-hospital Norwegian series. A new protocol using fluorescent antibody staining and digital image analysis was optimised. Biomarker value for 5-year relapse-free survival was analysed in relation to tumour stage, adjuvant chemotherapy and the molecular markers microsatellite instability, KRAS/BRAFV600E/TP53 mutations and CDX2 expression.ResultsLow RCC2 expression was scored in 41% of 2696 evaluable samples. Among patients with stage I–III CRC who had not received adjuvant chemotherapy, low RCC2 expression was an independent marker of inferior 5-year relapse-free survival in multivariable Cox models including clinicopathological factors and molecular markers (HR 1.45, 95% CI 1.09 to 1.94, p=0.012, N=521). RCC2 was not prognostic in patients who had received adjuvant chemotherapy, neither in QUASAR2 nor the pooled Norwegian series. The interaction between RCC2 and adjuvant chemotherapy for prediction of patient outcome was significant in stage III, and strongest among patients with microsatellite stable tumours (pinteraction=0.028).ConclusionsLow expression of RCC2 is a biomarker for poor prognosis in patients with stage I–III CRC and seems to be a predictive biomarker for effect of adjuvant chemotherapy.
Highlights
Colorectal cancer (CRC) is a global health challenge with more than 850 000 registered deaths each year.[1]
What is already known about this subject? ►► Low expression of regulator of chromosome condensation 2 (RCC2) has been reported to be associated with a poor prognosis in colorectal cancer. ►► High expression of Regulator of chromosome condensation 2 (RCC2) has been linked to resistance against chemotherapeutics in cancer cell lines
What does this study add? ►► The association between low expression of RCC2 and poor patient prognosis is validated in an independent series of colorectal cancer patients, but only in those patients who were not treated with adjuvant chemotherapy. ►► A statistically significant interaction was found between RCC2 expression and chemotherapy with respect to relapse-free survival in stage III colorectal cancer
Summary
Colorectal cancer (CRC) is a global health challenge with more than 850 000 registered deaths each year.[1]. ►► A statistically significant interaction was found between RCC2 expression and chemotherapy with respect to relapse-free survival in stage III colorectal cancer. ►► The association between low expression of RCC2 and poor patient prognosis is validated in an independent series of colorectal cancer patients, but only in those patients who were not treated with adjuvant chemotherapy. How might this impact on clinical practice? Among patients with stage I–III CRC who had not received adjuvant chemotherapy, low RCC2 expression was an independent marker of inferior 5-year relapse-free survival in multivariable Cox models including clinicopathological factors and molecular markers (HR 1.45, 95% CI 1.09 to 1.94, p=0.012, N=521). Conclusions Low expression of RCC2 is a biomarker for poor prognosis in patients with stage I–III CRC and seems to be a predictive biomarker for effect of adjuvant chemotherapy
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