Microsatellite, Mutation Status Evaluation Proposed for Testing In Adjuvant Colon Cancer Trials

Microsatellite instability and BRAF and KRAS mutation interaction impacts clinical outcomes in colon adenocarcinoma

medwireNews: A post hoc analysis of the PETACC-8 trial suggests that the prognostic effect of the KRAS exon 2 and BRAFV600E mutations varies according to the microsatellite status of the tumour in stage III colon cancer patients given adjuvant FOLFOX-based chemotherapy.

Therefore, the researchers suggest: “Microsatellite, KRAS, and BRAFV600E status assessment should be mandatory to stratify adequately in future adjuvant trials and must be discussed in our daily practice.”

Tumour microsatellite status could be assessed for 1791 of 2559 patients with nonmetastatic, stage III colon adenocarcinoma enrolled in the randomised PETACC-8 trial, which compared adjuvant FOLFOX4 alone or with cetuximab . And specimens from 1776 and 1643 of these patients were successfully genotyped for KRAS exon 2 and BRAFV600E mutations, respectively.

Almost 10% of evaluated patients demonstrated the microsatellite instability (MSI) phenotype, while KRASmutations were detected in 33.1% and the BRAFV600E mutation in 9.0%, report Julien Taieb, from European Georges Pompidou Hospital and Paris Descartes University in France, and colleagues in JAMA Oncology.

Multivariate analysis in the overall study population showed that the presence of KRAS mutations was the only factor associated with a shorter disease-free survival (DFS; hazard ratio [HR]=1.55) and overall survival (OS; HR=1.56), while the MSI phenotype and the BRAFV600E mutation were not linked to either outcome.

However, in patients with microsatellite stable tumours, DFS was significantly shorter both in patients with mutated versus wild-type KRAS tumours and in those harbouring tumours with versus without the BRAFV600E mutation (HR=1.64 and 1.74, respectively). Moreover, the presence compared with the absence of KRAS and BRAF mutations similarly predicted significantly worse OS (HR=1.71 and 1.84, respectively) in this subgroup.

By contrast, among participants with tumours demonstrating MSI, KRAS status was not significantly associated with clinical outcome, and the BRAFV600E mutation was a significant predictor of improved DFS (HR=0.23) but not OS.

The authors believe that the lack of stratification by microsatellite status could explain the discrepancies among previous studies assessing the prognostic value of KRAS mutations. And they conclude that microsatellite status “should be taken into account in future prognostic studies involving KRAS and BRAF V600E mutations”.

In an accompanying comment, Dirk Klingbiel, from the Swiss Group for Clinical Cancer Research in Bern, Switzerland, and Sabine Tejpar, from Leuven University Hospital in Belgium, commend the authors for “studying such an important question in a large trial population” and agree with their conclusion.

But they also highlight some limitations, such as the low power in the BRAF-mutant and MSI-positive subgroups to reliably identify the presence or absence of effects, and the incomplete assessment of RAS status, which “limits the immediate clinical interpretation”.

Dirk Klingbiel and Sabine Tejpar conclude that in light of the many highly correlated variables, “a pooled analysis with a carefully designed statistical analysis plan of individual patient data (full RAS status, MSI status, sidedness, and so forth) on stage II and III colon cancer from as many trials as possible would be timely and relevant.”

References

Taieb J, Zaanan A, Le Malicot K, et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab. A post hoc analysis of the PETACC-8 trial. JAMA Oncol 2016; Advance online publication 14 January. doi:10.1001/jamaoncol.2015.5225

Klingbiel D, Tejpar S. Microsatellite instability and BRAF and KRAS mutations in stage III colon cancer. Requirements for accurate prognosis assessment. JAMA Oncol 2016; Advance online publication 14 January. doi:10.1001/jamaoncol.2015.5226

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