How close are we to standardised extended RAS gene mutation testing? The UK NEQAS evaluation.
OBJECTIVE
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.
Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James University Hospital, Leeds, UK.
Susan D
SD
Richman
UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK.
Jennifer
J
Fairley
Cardiff and Vale UHB-Medical Genetics University Hospital of Wales, Cardiff, Wales, UK.
Rachel
R
Butler
UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK.
Zandra C
ZC
Deans
D004252:DNA Mutational Analysis / Q000379:methods*; D055317:Evidence-Based Practice; D011905:Genes, ras / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D013997:Time Factors; D006113:United Kingdom
COLORECTAL CANCER; EQA; MOLECULAR PATHOLOGY
Cancer Treat Rev. 2012 Oct;38(6):618-25
22118887
Lancet Oncol. 2008 Oct;9(10):962-72
18804418
Int J Colorectal Dis. 2011 Jul;26(7):823-33
21286919
Ann Oncol. 2015 Jan;26(1):13-21
25115304
J Clin Oncol. 2015 Mar 1;33(7):692-700
25605843
Clin Colorectal Cancer. 2011 Mar 1;10 (1):63-9
21609938
Ann Oncol. 2011 Jul;22(7):1535-46
21228335
J Clin Oncol. 2011 May 20;29(15):2011-9
21502544
J Clin Oncol. 2008 Apr 1;26(10 ):1626-34
18316791
J Clin Oncol. 2010 Nov 1;28(31):4706-13
20921462
Int J Colorectal Dis. 2012 Aug;27(8):997-1004
22358385
Health Technol Assess. 2013 Apr;17 (14 ):1-237
23547747
Genet Test Mol Biomarkers. 2011 Nov;15(11):777-83
21851273
Ann Intern Med. 2011 Jan 4;154(1):37-49
21200037
Ont Health Technol Assess Ser. 2010;10(25):1-49
23074403
Int J Colorectal Dis. 2010 Jun;25(6):713-21
20309588
N Engl J Med. 2013 Sep 12;369(11):1023-34
24024839
Eur J Cancer. 2015 Jul;51(10):1243-52
25937522
J Clin Oncol. 2016 Jan 10;34(2):179-85
26438111
Eur J Cancer. 2010 Oct;46(15):2781-7
20580219
J Clin Oncol. 2010 Nov 1;28(31):4697-705
20921465
Eur J Cancer. 2011 Jun;47(9):1343-54
21550229
J Clin Pathol. 2014 Sep;67(9):751-7
24996433
Int J Colorectal Dis. 2011 Aug;26(8):1025-33
21523374
N Engl J Med. 2009 Apr 2;360(14):1408-17
19339720
Lancet Oncol. 2013 Jul;14 (8):749-59
23725851