Sabine Venderbosch

Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies

Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAFMT) status in metastatic colorectal cancer (mCRC). Experimental Design: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data. Results: The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAFMT. BRAFMT was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P < 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors [HR, 1.33; 95% confidence interval (CI), 1.12–1.57 and HR, 1.35; 95% CI, 1.13–1.61, respectively), and for patients with BRAFMT compared with BRAF wild-type (BRAFWT) tumors (HR, 1.34; 95% CI, 1.17–1.54 and HR, 1.91; 95% CI, 1.66–2.19, respectively). PFS and OS were significantly decreased for patients with BRAFMT within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAFWT or BRAFMT. Conclusions: Prevalence of dMMR and BRAFMT in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAFMT status. Clin Cancer Res; 20(20); 5322–30. ©2014 AACR.

A review on the use of molecular markers of cytotoxic therapy for colorectal cancer, what have we learned?

BACKGROUND Over the past decades, significant progress has been achieved in the cytotoxic treatment of colorectal cancer (CRC) by the use of fluoropyrimidines, irinotecan and oxaliplatin. However, as not all patients do respond to chemotherapy, there is a need for predictive and prognostic factors in order to optimise the treatment for individual patients. Although many potential molecular markers have been studied, none of these have been implemented in the standard of care for colorectal cancer patients. METHOD We performed a review of the data on the prognostic and/or predictive value of molecular markers for cytotoxic drugs in CRC. The following markers were included: dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase, thymidine phosphorylase, thymidylate synthase, mismatch repair deficiency, topoisomerase 1, excision cross-complementing gene and carboxylesterases. RESULTS With the exception of mismatch repair deficiency, these molecular markers showed divergent and inconsistent results on their prognostic and/or predictive value. This underscores the complexity of the role of these markers. CONCLUSIONS We conclude that further retrospective testing of these markers is unlikely to add clinically useful results. More definite results may only be expected when these markers are included in the design of prospective randomised studies.

Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study

We have tested several biomarkers [dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), thymidylate synthase (TS) and excision cross-complementing gene (ERCC1)] for their prognostic and predictive value in relation to the outcome of chemotherapy in tumour tissues of 556 advanced colorectal cancer (ACC) patients who were randomised between sequential treatment and combination treatment in the CApecitabine, IRinotecan, Oxaliplatin (CAIRO) study. DPD expression showed a statistically significant predictive value for combination treatment with capecitabine plus irinotecan with low versus high values resulting in an improved median progression-free survival (PFS) and median overall survival (OS) of 8.9 (95% confidence interval (CI) 8.3-9.9) versus 7.2 months (95% CI 6.5-8.1, p=0.006), and 21.5 months (95% CI 17.9-26.5) versus 16.9 months (95% CI 13.0-19.1, p=0.04), respectively. In the overall patient population a high OPRT expression in stromal cells was a favourable prognostic parameter for OS, with 21.5 months (95% CI 17.9-27.3) versus 17.2 months (95% CI 15.1-18.6, p=0.036), respectively. A similar effect was observed for PFS. In a multivariate analysis that included known prognostic factors these results remained significant and also showed that a high OPRT expression in tumour cells was an unfavourable prognostic parameter for PFS and OS. In conclusion, in this largest study on capecitabine with or without irinotecan to date we found a predictive value of DPD expression. Our results on the prognostic value of OPRT expression warrant further studies on the role of stromal cells in the outcome of treatments. The divergent results of ours and previous studies underscore the complexity of these biomarkers and currently prevent the routine use of these markers in daily clinical practice.

Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer.

PURPOSE Mucinous histology of metastatic colorectal cancer (CRC) has been associated with poor prognosis, however this has never been assessed in large well-defined study populations treated with the current used systemic agents. We investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC. PATIENTS AND METHODS The study population included 1010 metastatic CRC patients who were treated with chemotherapy and targeted therapies in two phase III studies. Patients were classified according to the histology of the primary tumour in mucinous adenocarcinomas (MC) and non-mucinous adenocarcinomas (AC). RESULTS Patients with MC (n=99) were older, had more often a normal serum lactate dehydrogenase (LDH), extrahepatic localisation of metastases, larger primary tumour diameter and a higher T classification compared to patients with AC (n=911). A deficient mismatch repair system and BRAF mutations were observed in 17% and 22% of patients with MC, compared to 3% and 7% in patients with AC, respectively. Clinical outcome was investigated in both studies separately, showing a worse overall survival (OS), progression free survival and overall response rate in patients with MC compared to patients with AC. Patients with MC received less cycles of treatment compared to AC, but did not suffer from a higher incidence of grade 3/4 toxicity. In multivariate analysis, mucinous histology was as an independent negative prognostic factor for OS, resulting in a combined hazard ratio of 1.78 (95%confidence interval (CI) 1.35-2.35). CONCLUSIONS Patients with metastatic mucinous CRC have distinct clinicopathological features and poor response to chemotherapy and targeted agents. The strong negative prognostic value of MC warrants the use of this pathological feature as a stratification factor for clinical trials in metastatic CRC.

Outcome of first line systemic treatment in elderly compared to younger patients with metastatic colorectal cancer: a retrospective analysis of the CAIRO and CAIRO2 studies of the Dutch Colorectal Cancer Group (DCCG)

Abstract Background. Metastatic colorectal cancer (CRC) is predominantly a disease of the elderly, therefore the current standards should be evaluated in this population. Material and methods. We evaluated in different age groups the outcome in terms of median overall and progression-free survival, response rate, disease control rate, relative dose intensity (RDI), tolerability, and global quality of life (QoL) of first-line capecitabine monotherapy (CAP) versus capecitabine + irinotecan (CAPIRI) and capecitabine + oxaliplatin + bevacizumab (CAPOX + BEV) in the CAIRO and CAIRO2 study, respectively. Patients were categorized into three age groups: age > 75, 70–75 and < 70 years. Results. Clinical outcomes were not significantly different among age groups, with the exception of a higher response rate from CAP treatment in the elderly. Elderly patients treated with CAPOX + BEV showed a trend towards a worse median overall survival compared to younger patients. Only treatment with CAP resulted in a higher incidence of grade 3–4 toxicity and a lower RDI in elderly versus younger patients. Treatment with CAP and CAPOX + BEV in elderly patients was significantly more often discontinued due to toxicity instead of progression to disease compared to younger patients. The increase in global QoL was comparable for the three age groups for each treatment regimen. Conclusion. We did not observe significant differences in survival outcomes between elderly and younger metastatic CRC patients with three different first-line systemic treatment regimens. Our data suggest that initial dose reduction of CAP monotherapy may be indicated in elderly patients.

EMAST Is Associated with a Poor Prognosis in Microsatellite Instable Metastatic Colorectal Cancer

Purpose To determine the frequency and prognostic value of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in metastatic colorectal cancer (mCRC) patients in relation to microsatellite instability (MSI) status and MSH3 protein expression. Material and Methods The frequency of EMAST was evaluated in mCRC patients with MSI tumors and microsatellite stable (MSS) tumors. A literature overview was performed to compare the frequency of EMAST in our study with existing data. Immunohistochemistry for MSH3 was compared with EMAST status. Outcome was studied in terms of overall survival (OS) of mCRC patients with MSI and MSS tumors. Results EMAST was evaluated in 89 patients with MSI tumors (including 39 patients with Lynch syndrome) and 94 patients with MSS tumors. EMAST was observed in 45.9% (84 out of 183) of patients, with an increased frequency in MSI tumors (79.8% versus 13.8%, p < 0.001). We found no correlation between EMAST and MSH3 protein expression. There was no effect of EMAST on prognosis in patients with MSS tumors, but patients with MSI / non-EMAST tumors had a significantly better prognosis than patients with MSI / EMAST tumors (OS: HR 3.22, 95% CI 1.25-8.30). Conclusion Frequency of EMAST was increased in mCRC patients with MSI tumors, compared to MSS tumors. Our data suggest that the presence of EMAST correlates with worse OS in these patients. There was no effect of EMAST on the prognosis of patients with MSS tumors. A limitation of our study is the small number of patients in our subgroup analysis.

Abstract 534: MicroRNA-143 is a putative predictive biomarker for 5-FU-based chemotherapy in patients with metastatic colorectal cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Approximately half of the colorectal cancer (CRC) patients develop metastatic disease, either at diagnosis or during follow-up. 5-FU-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. MicroRNAs are short RNAs that post-transcriptionally regulate the gene expression of many genes. MicroRNA levels are frequently altered in cancer, and can affect expression of genes that modulate tumorigenesis. Objective: In this study, we explore the potential of microRNAs, and the microRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity in patients with metastatic colorectal cancer. Methods: We analyzed the levels of a selected panel of 22 miRNAs and the Dicer protein in primary CRC tumors from patients enrolled in the CAIRO study (a phase III study of the Dutch Colorectal Cancer Group). MiRNA levels were determined with Taqman microRNA assays and Dicer level with immunohistochemistry. Correlation between the expression status of microRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. In addition, we evaluated correlations between Dicer and miRNA levels. Results: Variable Dicer intensities were observed among the analyzed samples, but there was no significant association between Dicer levels and PFS. In addition, no clear correlation between Dicer and miRNA levels could be identified. We especially detected higher expression of miR-31 and miR-21 in tumors compared to matched normal tissue, whereas miR-137 and miR-215 were lower expressed. Interestingly, miR-143 expression was reduced in a subset of the primary CRC tumors, and this differential expression showed a relationship with PFS. The group with reduced miR-143 expression showed higher PFS. The median PFS for patients with reduced, neutral and increased miR-143 expression was 261, 167 and 142 days, respectively (p-value log-rank test=0.018). Conclusion: The expression level of miR-143 may have clinical utility as a biomarker for response to 5-FU-based chemotherapy. These findings warrant further studies to investigate the relationship between miR-143 expression and 5-FU. Citation Format: Femke Simmer, Jeroen Dijkstra, Sabine Venderbosch, Claudius Faber, Leonie Mekenkamp, Miriam Koopman, Ton de Haan, Cornelis Punt, Iris Nagtegaal. MicroRNA-143 is a putative predictive biomarker for 5-FU-based chemotherapy in patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 534. doi:10.1158/1538-7445.AM2014-534