Cornelis J. A. Punt

Background: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Methods: Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Results: Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model. Conclusions: Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.

The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer. Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response. Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol. The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov ( NCT01273051 )

Background: Methods: Results: Conclusion:

Background: Methods: Results: Conclusion:

Background: Early predictive markers for response are needed for advanced colorectal cancer (ACC) patients. We assessed the value of circulating tumour cells (CTC) in ACC patients treated with chemotherapy plus targeted agents (CAIRO2 phase III trial) and compared the results with computed tomography (CT) imaging. Materials and methods: CTC were determined at baseline and at different time points during treatment. Patients were stratified into low (less than three CTC per 7.5 ml of blood) or high CTC (three or more CTC per 7.5 ml of blood). Results: A total of 467 patients were assessable for CTC analysis. Among them, 129 patients (29%) with high baseline CTC had a significantly decreased progression-free survival [PFS; hazard ratio (HR) 1.5] and overall survival (OS; HR 2.2) compared with 322 patients with low baseline CTC. This difference remained statistically significant during treatment. The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1–2 weeks after the start of treatment 20.0% and 95.1%, respectively. The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone. Conclusions: The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.

Background: Early and correct assessment of treatment-related mortality is highly important in clinical cancer trials. However, no data are available on the quality of safety monitoring. Patients and methods: An on-site review was carried out by the study coordinators of the individual charts of all patients participating in the Capecitabine-Irinotecan-Oxaliplatin (CAIRO) study who had died within 30 days of the last administration of study drugs when death was accompanied by any other event than disease progression. The relationship between treatment and death was categorized as unrelated, remote, possible, or probable and submitted to an independent data monitoring committee (IDMC). These results were then compared with the initial assessment of the local investigator. Results: Forty of 820 patients qualified for review. The relationship between cause of death and study drugs was changed in 26 patients (65%). A major protocol violation (MPV) was identified in 12 of 14 patients with a probable relationship between cause of death and study treatment. Conclusions: There was little agreement between the relation as assessed by the local investigator compared with the IDMC. A quality control improves the assessment of safety results and the observed MPVs underscore the importance of educating medical staff and patients.

We recently found that progression-free survival was shorter among patients with metastatic colorectal cancer treated with chemotherapy, bevacizumab, and cetuximab (CBC regimen) than among patients who received chemotherapy and bevacizumab alone (CB regimen) (Feb. 5 issue).¹ Other investigators have found that the efficacy of cetuximab is limited to patients with wild-type–KRAS tumors.² In a subgroup of 520 patients with available tumor samples, we observed a shorter median progression-free survival among patients with a mutated-KRAS oncogene in the CBC group than among patients with mutated-KRAS tumors who received the CB regimen and among patients with wild-type–KRAS tumors who received the CBC regimen. An activating mutation in the B-type Raf kinase (BRAF) oncogene encoding the BRAF protein, localized directly downstream of RAS, leads to stimulation of the mitogen-activated protein kinase pathway.³ In a recent study, the efficacy of antibody therapy against the epidermal growth factor receptor for wild-type–KRAS tumors appeared to be restricted to wild-type–BRAF tumors.⁴ We performed a retrospective analysis of the BRAF V600E mutation status in 519 tumors that were tested in our study to determine KRAS status. A BRAF mutation was detected in 45 tumors (8.7%) ( Table 1 ). BRAF and KRAS mutations were mutually exclusive. Patients with BRAF-mutated tumors had a significantly shorter median progression-free and median overall survival than patients with wild-type–BRAF tumors, both in the CB group and in the CBC group ( Table 1 ). No difference in response rate was observed. We conclude that a BRAF mutation is a negative prognostic marker in patients with metastatic colorectal cancer and that this effect, in contrast to KRAS mutations, is not restricted to the outcome of cetuximab treatment.

Fluoropyrimidine-based chemotherapy plus the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. We studied the effect of adding the anti–epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer.

Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.