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How close are we to standardised extended RAS gene mutation testing? The UK NEQAS evaluation
Susan D Richman1, Jennifer Fairley2, Rachel Butler3
1Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James University Hospital, Leeds, UK.
Aims:
Since 2008, KRAS mutation status in exon 2 has been used to predict response to anti-EGFR therapies. Recent evidence has demonstrated that NRAS status is also predictive of response. Several retrospective 'extended RAS' analyses have been performed on clinical trial material. Despite this, are we really moving towards such extended screening practice in reality?
Methods:
Data were analysed from four consecutive UK National External Quality Assessment Service for Molecular Genetics Colorectal cancer External Quality Assessment schemes (during the period 2014-2016), with up to 110 laboratories (worldwide) participating in each scheme. Testing of four or five tumour samples is required per scheme. Laboratories provided information on which codons were routinely screened, and provided genotyping and interpretation results for each sample.
Results:
At least 85% of laboratories routinely tested KRAS codons 12, 13 and 61. Over the four schemes, an increasing number of laboratories routinely tested KRAS codons 59, 117 and 146. Furthermore, more laboratories were introducing next generation sequencing technologies. The pattern of 'extended testing' was reassuringly similar for NRAS, although fewer laboratories currently test for mutations in this gene. Alarmingly, still only 36.1% and 24.1% of participating laboratories met the ACP Molecular Pathology and Diagnostics Group and American Society of Clinical Oncology guidelines, respectively, for extended RAS testing in the latest assessment.
Conclusions:
Despite recommendations in the UK and USA on extended RAS testing, there has clearly been, based on these results, a delay in implementation. Inadequate testing results in patients being subjected to harmful treatment regimens, which would not be the case, were routine practice altered, in line with evidence-based guidelines.
Insights
Extended RAS testing, including NRAS mutations, is recommended for colorectal cancer patients but implementation lags. Many labs still don't follow guidelines, potentially leading to inappropriate anti-EGFR therapy.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- KRAS mutation status in exon 2 has guided anti-EGFR therapy selection since 2008.
- Emerging evidence highlights NRAS mutation status as also predictive of anti-EGFR therapy response.
- Retrospective analyses support 'extended RAS' testing, encompassing more than just KRAS exon 2.
Purpose of the Study:
- To assess the current real-world adoption of extended RAS (KRAS and NRAS) mutation screening in clinical practice.
- To evaluate laboratory adherence to established guidelines for extended RAS testing.
- To identify potential barriers and consequences of delayed implementation of extended RAS testing.
Main Methods:
- Analysis of data from four UK National External Quality Assessment Service for Molecular Genetics Colorectal cancer External Quality Assessment schemes (2014-2016).
- Inclusion of up to 110 participating laboratories worldwide per scheme.
- Collection of information on routinely screened codons, genotyping, and interpretation results for tumor samples.
Main Results:
- Over 85% of laboratories routinely tested KRAS codons 12, 13, and 61; increasing numbers tested additional KRAS codons (59, 117, 146).
- Similar trends observed for NRAS testing, though fewer laboratories performed it.
- Alarmingly, only 36.1% and 24.1% of labs met guidelines for extended RAS testing from ACP and ASCO, respectively.
Conclusions:
- There is a significant delay in implementing recommended extended RAS testing in routine practice, despite UK and US guidelines.
- Inadequate testing practices may lead to patients receiving ineffective or harmful anti-EGFR therapies.
- Altering routine practice to align with evidence-based guidelines is crucial for optimizing patient treatment.