Abstract
BackgroundRecent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR-mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing.MethodsWe examined 132 patients with EGFR-mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR-positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide.ResultsThe positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection.ConclusionsCobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.
Highlights
Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR-mutated non-small cell lung cancer (NSCLC)
The following clinicopathological factors were obtained from medical charts and analysed: age, sex, detected EGFR mutation, smoking status, stage [8], 1st line EGFR-TKI therapy and the best response to the therapy according to the Response Evaluation Criteria in Solid Tumours, and progression free survival (PFS) calculated from the initiation of the TKI therapy until the date of disease progression
Among the patients that had detectable EGFR mutations with the cobas method, we observed consistent EGFR mutation profiles using PCR clamp except for one who carried both L858R and T790 M mutations identified by PCR clamp, but only the L858R mutation was identified with the cobas test (Table 2)
Summary
Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR-mutated non-small cell lung cancer (NSCLC). Osimertinib has been shown to exert remarkable effects against untreated EGFR mutation-positive advanced NSCLC as well as those with EGFR-TKI-sensitizing and EGFR T790 M resistance mutations [4] This third generation TKIs can bind irreversibly to the EGFR kinase by targeting the cystine-797 residue in the ATP binding site via covalent bond formation and a phase 3 trial revealed prolonged progression-free survival with a similar safety profile and lower rates of serious adverse events compared to standard EGFR-TKIs [5]. No study has clarified the efficacy of this dissection and not a few facilities are incapable of routinely performing this dissection in the real world
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