Prognostic Role of KRAS and BRAF in Stage II and III Resected Colon Cancer

Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. The prognostic role of KRAS and BRAF in colon cancer was explained in the Journal of Clinical Oncology by Roth et al. Researchers took advantage of the PETACC-3 trial to evaluate the prognostic value of the above mutations in relation to relapse-free survival (RFS) and overall survival (OS). PETACC-3 is a large, randomized, Phase III trial assessing the role of irinotecan added to fluorouracil (FU)/leucovorm (FA) as adjuvant treatment for stage II and III colon cancer, in which 3,278 patients were accrued.

The BRAF gene encodes a serine/threonine protein kinase belonging to the RAS-RAF-MEK-ERK kinase pathway, regulated by KRAS protein activity and involved in CRC development. KRAS and BRAF mutations have been reported to be mutually exclusive events within tumors. The KRAS and BRAF mutation frequency was similar in stage II and III colon cancer. Survival analyses were based on univariate and multivariate proportional hazard regression models. In a multivariate analysis of the stage, tumor site, nodal status, sex, age, and grade and microsatellite instability (MSI) status, the KRAS mutation was associated with grade, while the BRAF mutation was significantly associated with females and highly significantly associated with right-sided tumors, old age, high grade, and MSI-high tumors. In univariate and multivariate analyses, KRAS mutations did not have a major prognostic value regarding RFS or OS. The BRAF mutation was not prognostic for RFS but was for OS, particularly in patients with MSI-low and MSI-stable tumors. Additional analysis of KRAS and BRAF mutations for molecular prognostic factors is underway and will be helpful in the evaluation of the weightage of these mutations in the evolution of this cancer.

Source: J Clin Oncol

 

DNA Methylation Signatures Identify Biologically Distinct Subtypes in AML

It has been appreciated in recent years that there are chemical codes in addition to the DNA sequence that control the behavior of normal and malignant cells. These additional codes are called “epi”genetic, as they are found outside of the DNA sequence. In a study published in Cancer Cell, Melnick et al. examined a specific epigenetic marker, DNA methylation, which plays a critical role in controlling gene expression. Investigators examined DNA methylation in 344 patients diagnosed with AML. Clustering of these patients by methylation data segregated them into 16 groups. This led to the identification of five methylation signatures with no other common morphologic or molecular features but with distinct clinical outcomes, suggesting that these are unique forms of AML with their own biological characteristics.

In addition, DNA methylation profiles segregated patients with CEBPA (CCAAT/enhancer-binding protein alpha) aberrations from other sub-types of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. The study also identified a robust 15-gene methylation classifier that was predictive of overall survival in an independent patient cohort. Although epigenetic deregulation has been recognized as a hallmark of cancer for some time, the use of epigenomics to further improve an understanding of the biology of these diseases has only recently become feasible in the clinical context. The study showed that DNA methylation profiling is a powerful tool for the clinical stratification of AML and to further explore and define the biology of this disease.

Source: Cancer Cell

 

AstraZeneca and Dako to Develop Companion Diagnostics for Cancer Treatments

AstraZeneca and Dako Denmark have entered into a collaboration agreement to develop companion diagnostic tests for multiple AstraZeneca oncology projects, including biologics and small molecules, in different stages of discovery and development. Under the terms of the agreement, the companies will work together to develop diagnostic tests to help physicians determine the most appropriate cancer treatment for patients. The financial terms of the deal were not disclosed. The collaboration will leverage Dako’s position as a leader in cancer diagnostics and a strong partner in the development of diagnostic tests used in conjunction with drug therapies. AstraZeneca will bring its extensive experience in the development and commercialization of vital oncology products worldwide.

Ruth March, Personalized Healthcare Leader at AstraZeneca said, “For AstraZeneca, today’s announcement marks the continuation of their commitment to Personalized Healthcare as demonstrated by the launch of IRESSA in the EU for patients with activating mutations of EGFR-TK (epidermal growth factor receptor-tyrosine kinase).” The agreement advances Dako’s ongoing strategy to collaborate with strong partners in the pharmaceutical sector to enhance its offering of companion diagnostic assays.

Source: Dako