|Ahead of print
Epidermal growth factor receptor mutated lung cancers: Looking beyond adenocarcinomas
Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
|Date of Submission||30-Jul-2019|
|Date of Decision||16-Oct-2019|
|Date of Acceptance||16-Oct-2019|
|Date of Web Publication||24-Nov-2020|
Department of Internal Medicine, Mayo Clinic, Rochester, MN
Source of Support: None, Conflict of Interest: None
The discovery of mutations in the epidermal growth factor receptor (EGFR) mutations in metastatic non-small cell lung cancer (NSCLC) has been a focal point in changing the treatment landscape of these tumors. There is abundance of data with regard to the prevalence of EGFR mutation and the efficacy of small molecule tyrosine kinase inhibitors (TKIs) in targeting these driver mutations in metastatic adenocarcinomas (ADCs) of the lung. The EGFR mutation rate in ADCs varies substantially with the population under study, with the prevalence being the lowest in the Northern American and European studies ranging from 10 to 15%, to approximately 25% in Indian setting and to an even higher prevalence in studies from Eastern Asia. This marked heterogeneity in the mutation profile across patients with different ethnicities makes it tricky to interpret these data from a non-representative study population and apply them into practice. An even more contentious issue is whether to perform the testing for EGFR mutations in metastatic squamous cell carcinomas (SCC) of the lung, for which the jury is still out. These factors make it imperative to use data from indigenous patient population in making decisions in patients with NSCLCs.
While the EGFR mutation rate in SCCs is definitely much lower compared to their counterpart with ADCs, this still represents a substantial number of patients. A previous Indian study of 639 consecutive metastatic SCCs of the lung that were confirmed by immunohistochemistry (IHC) in addition to the histologic diagnosis of SCCs demonstrated the prevalence of EGFR mutation to be around 4.5% in this patient population. To put this in context, the prevalence of anaplastic lymphoma kinase (ALK) mutations, testing for which is routinely performed in all metastatic ADCs, is not much higher at 4–8%.
However, there is still reluctance among providers to test EGFR mutation in SCCs. Case in point, a recent survey of 111 tertiary care centers from India has suggested that only 40% of the centers recommend EGFR mutation testing in SCCs of lung. This finding is not surprising at all given the skepticism surrounding the data for the frequency of EGFR mutations and the efficacy of TKIs in SCCs. A recent single center study from Northern India looks at EGFR mutations in NSCLCs in both ADC and non-ADC histology. The study included 250 patients (out of a potential 530 patients) with NSCLC in whom EGFR mutation results were available and demonstrated an EGFR mutation rate of ~36% in ADCs and ~15% in SCCs. While the relatively small sample size can certainly lead to wide confidence intervals giving exaggerated numbers, a rate of 15% EGFR-mutated SCCs still seems rather high and can be attributed to the lack of immunohistochemistry (IHC) correlation to confirm pure SCC status in all biopsies, the heterogeneity of the types of specimens itself on which the EGFR testing was performed, and the sensitivity of the EGFR assay in different settings.
Patients with adenosquamous histology need to be excluded from the SCC group while analyzing prevalence of EGFR mutations, which has often been the confounder for high EGFR mutation rates in SCCs in previous similar studies. The Indian study demonstrating a prevalence rate of 4.5% EGFR mutation positivity rate in SCCs did rightly exclude adenosquamous histology and it was of importance to note that only one-third of the cohort had a history of smoking. On the same note, the National Comprehensive Cancer Guidelines recommend EGFR mutation in testing in SCCs that were never smokers or with a scant biopsy specimen, highlighting that missing potential adenosquamous tumors in these situations is a likely possibility.
Going forward it would be prudent to look at the success rates of repeat biopsy upon progression on TKIs and report the frequency of T790M mutations, especially in EGFR-mutated SCCs, for which there is currently very limited data., Collaborative efforts for such rare subsets of patients are the need of the hour and will go a long way in providing valuable information to further improve the care for our patients.
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