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IHC screening for EGFR mutations may be useful lung adenocarcinoma diagnosis
Immunohistochemical screening was linked to a similar predictive value as standard molecular methods in identifying epidermal growth factor receptor mutations that would respond to tyrosine kinase inhibitor therapy in a cohort of patients with lung cancer.
The researchers said EGFR mutation status is the optimal predictor of response to TKIs among patients with primary lung adenocarcinoma.
Given that more than two-thirds of lung cancers are diagnosed in advanced stages using small biopsies and cytological specimens, the researchers aimed to evaluate specific antibodies to detect mutations in two major forms of EGFR: exon 21 L858R and exon 19 deletion (15 bp). They used immunohistochemistry (IHC) to obtain the results in cytology and small specimens..
There were 145 lung adenocarcinomas included in the analysis. Specimens included cytology material, core biopsy and decalcified bone biopsy.
The following scale was used to score stains: negative=0; weak and focal=1+; moderate intensity and focal=2+; and strong and diffuse=3+.
The stain results were correlated with mutation status that was determined using standard molecular methods.
“Validation using clinical material showed deletions in exon 19 were detected in 35% and L858R mutation in 17.6% of all cases by standard molecular methods,” the researchers wrote. IHC results indicated that the cutoff value used for positive was 2+. None of the wild-type cases observed were found to be immunoreactive.
A 100% positive predictive value and specificity were associated with both antibodies. The performance of the antibodies was strong in cytology, core biopsies and decalcified bone biopsies.
The researchers concluded that immunostaining for specific mutations in EGFR may be a clinically useful tool for identifying patients for TKI therapy.
Perspective
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EGFR genotype is a powerful biomarker in the care of patients with non–small cell lung cancer because it can predict which patients will respond to EGFR kinase inhibitors like erlotinib. However, not all patients have enough biopsy tissue available for DNA extraction and EGFR genotyping, and many clinicians struggle with how to manage such patients. In my practice, when I see a patient with a small biopsy specimen — such as from a bronchoscopy or bone biopsy — I generally refer them for a new biopsy in order to have adequate tissue for genotyping. Yet not all lung cancer patients are well enough to postpone treatment so they can get a new biopsy and have it genotyped, such that some go without genotyping and end up receiving empiric chemotherapy.
The research by Hasanovic and colleagues suggests that an IHC assay for detecting EGFR mutations may be a new option for these patients. When using 2+ IHC staining as a cut-off, they found that this assay had 100% specificity (no false positives), though it was not sensitive enough to eliminate the need for EGFR genotyping in patients who are IHC negative. This means that IHC could potentially be used by clinicians as a positive screen, particularly in patients at high risk of having an EGFR mutation in their lung cancer. If an oncologist sees a never-smoker with lung adenocarcinoma, but with a biopsy too small for genotyping, instead of ordering a new biopsy they first could have IHC performed for detection of an EGFR mutation. If this were positive, an oncologist might be able to initiate treatment with erlotinib and postpone the confirmatory biopsy and genotyping until later in their care.
There are several important caveats. First, the investigators only studied two IHC assays — one for L858R and one for 15 base-pair exon 19 deletions — so they were not able to detect other exon 19 deletion variants and other less common EGFR mutations. This means that IHC would not be able to replace a sensitive EGFR genotyping assay testing for all sensitizing mutations. Secondly, IHC is a somewhat subjective tool. If a pathologist overcalls a 1+ case as 2+, this could lead to a false-positive result and lead to an oncologist giving erlotinib to a patient who is better off receiving chemotherapy. Before I would use such an IHC assay to guide the care of my lung cancer patients, I would want to see the findings validated prospectively with blinded review of the IHC. But I am optimistic that such an assay eventually will have a role in simplifying the care of patients with non-small cell lung cancer and small biopsy specimens.