KRAS mutation testing in clinical practice

Abstract

Activating mutation of KRAS plays a significant role in the pathogenesis of common human malignancies and molecular testing of KRAS mutation has emerged as an essential biomarker in the current practice of clinical oncology. The presence of KRAS mutation is generally associated with clinical aggressiveness of the cancer and reduced survival of the patient. Therapeutically, KRAS mutation testing has maximum utility in stratifying metastatic colorectal carcinoma and lung cancer patients for treatment with targeted therapy. Diagnostically, KRAS mutation testing is useful in the workup of pancreaticobiliary and thyroid cancers, particularly using cytological specimens. In the era of precision medicine, the role of KRAS mutation testing is poised to expand, likely in a setting of combinatorial therapeutic strategy and requiring additional mutation testing of its upstream and/or downstream effectors.

Keywords:

• clinical oncology
• KRAS
• mutation testing

Acknowledgement

The authors thank M Talmor for her outstanding technical assistance in the preparation of this work.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Key issues

• Activating mutations in the RAS family GTPases that lock the RAS proteins in the GTP bound ‘on’ state are associated with 20–30% of all human malignancies with KRAS mutations accounting for a disproportionate majority.

• A variety of molecular methods including Sanger sequencing, high-resolution melting analysis, single-strand conformation polymorphism analysis and allele-specific PCR methods that target mutation hotspots in KRAS exons 2 and 3 are currently employed in clinical testing of KRAS mutations and have shown good general concordance in comparative studies.

• National Comprehensive Cancer Network guidelines recommend KRAS mutation testing in the clinical work-up of metastatic colorectal cancer where multiple clinical trials have shown that wild-type KRAS status is associated with a better response to anti-EGFR therapy.

• Diagnostically, KRAS mutation is useful in the work-up of cytology specimens like pancreatobiliary brush specimens and thyroid fine-needle aspiration material where it can increase the positive predictive value for malignancy.

• Novel methods such as next-generation sequencing and mass spectrometry genotyping assays have been shown to increase clinical sensitivity of KRAS mutation testing in clinical samples and are likely to replace current methods in the era of targeted combinatorial therapy.

Notes