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Response to letter entitled: Re: ‘Inadequacy of PCR genotyping in advanced non-small cell lung cancer: EGFR L747_A755delinsSS exon 19 deletion is not detected by the real-time PCR IdyllaTM EGFR mutation test but is detected by ctDNA NGS and responds to osimertinib'

Not looking back
Published:August 07, 2022DOI:https://doi.org/10.1016/j.ejca.2022.06.040
      We thank Bennett et al. for their correspondence, in which they suggest that our case report [
      • O'Sullivan H.
      • d'Arienzo P.D.
      • Yousaf N.
      • Cui W.
      • Popat S.
      Inadequacy of PCR genotyping in advanced non-small cell lung cancer: EGFR L747_A755delinsSS exon 19 deletion is not detected by the real-time PCR Idylla™ EGFR mutation test but is detected by ctDNA next generation sequencing and responds to osimertinib.
      ] may cause undue alarm in non-small cell lung cancer (NSCLC) patients who have been genotyped by polymerase chain reaction (PCR)-based assays alone. Our intention is not to cause unwarranted concern but to stress to clinicians the limitations of PCR-based genotyping. Indeed, when PCR-based assays do identify an actionable genetic alteration, their benefit is proven. However, the issue is when such assays are reported as “negative” and the inability to differentiate false negatives from true negatives. Given the paucity of NSCLC tissue, we argue to do the best test first: next-generation sequencing (NGS). Bennett et al. reference their work which analysed the NGS reports of 2796 UK NSCLC patients over a 3-year period. This study found that 12% of driver EGFR mutations detected in this population would have been missed by commercial EGFR PCR assays [
      • Moore D.A.
      • Balbi K.
      • Ingham A.
      • Hendrik-Tobias A.
      • Bennett P.
      Analysis of a large cohort of non-small cell lung cancers submitted for somatic variant analysis demonstrates that targeted next-generation sequencing is fit for purpose as a molecular diagnostic assay in routine practice.
      ]. We wonder whether this is an acceptable false-negative rate for EGFR.
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