|LETTER TO EDITOR
|Year : 2021 | Volume
| Issue : 1 | Page : 182-183
Path beyond tyrosine kinase inhibitors: Full of riddles and puzzles
Ullas Batra, Shrinidhi Nathany
Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
|Date of Submission||28-Feb-2021|
|Date of Decision||04-Mar-2021|
|Date of Acceptance||04-Mar-2021|
|Date of Web Publication||26-Mar-2021|
Department of medical oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Batra U, Nathany S. Path beyond tyrosine kinase inhibitors: Full of riddles and puzzles. Cancer Res Stat Treat 2021;4:182-3
We read with interest the article by Bondili et al. titled, “Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer.” Following the results of the FLAURA trial, with osimertinib being approved in the first line for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer, new challenges have emerged with respect to newer resistance mechanisms. The improved progression-free survival may be related to the improved penetration of the blood–brain barrier or suppression of the pretreatment EGFR T790M clones. However, the status of the pretreatment T790M mutation was not evaluated in patients enrolled in the FLAURA trial. The case discussed in Bondili et al.'s article is interesting with respect to the disease course. However, whether pretreatment EGFR T790M clones were present cannot be ascertained as the patient underwent real-time polymerase chain reaction-based tissue genotyping, which usually has a 5% detection limit.
In addition, reports from the literature suggest that T790M mutations can be detected using plasma cell-free DNA (cfDNA)-based genotyping at a median time of approximately 2 months before the actual progression as determined using the Response Evaluation Criteria in Solid Tumors. Even though, in the case discussed by Bondili et al., T790M was not detected in the plasma cfDNA, other platforms with higher sensitivities could have detected it in the plasma, thus eliminating the need for a repeat omental biopsy. Post osimertinib resistance, the C797S mutation was detected along with an activating mutation in CTNNB1 gene, which is a part of the Wnt signaling pathway. This was further confirmed by immunohistochemistry that revealed an abnormal nuclear localization of the beta catenin protein. However, whether C797S was in cis or trans with T790M has not been reported in this case. This information could have been easily obtained from the raw next-generation sequencing (NGS) data by evaluating the presence of these two mutations in the positive and negative strand reads using the Integrative Genomics Viewer (Broad Institute, USA) software. It has been described that patients harboring C797S in trans with T790M may benefit from combination therapy. Therefore, this information is crucial.
In addition, there is evidence in the literature that the CTNNB1-activating mutations co-exist with mutations in the TP53 and RB1 genes. The NGS panel used in this case sequences 42 genes for the detection of DNA-based alterations. Therefore, it is important to note whether these genes were included in the panel. As transformation to small cell carcinoma may follow osimertinib therapy, it is important to take into account the possible intratumor heterogeneity owing to which this transformation may have been missed. In this regard too, the presence/absence of TP53 or RB1 gene mutations is important, as they are commonly implicated in histological transformation to small cell carcinoma.
EGFR resistance mechanisms can be both primary and secondary, encompassing both EGFR-dependent and -independent mechanisms,, which require a broader panel-based testing for detection, as seen here. The CTNNB1 activation would have otherwise been missed on sequential single-gene testing. Discussing the activation of the WNT signaling pathway as a resistance mechanism also necessitates the mention of the activation of YAP1, which has been reported anecdotally post osimertinib therapy.
Finally, polymorphism in the B-cell lymphoma-2-like 11 (BCL2L 11) gene, a crucial mediator of apoptosis, which has been reported in 12% of the East Asians, is important to detect. However, most of the times, it is not included in the NGS panels as it is a big deletion of ~2900 bp. The use of BH3 mimetics to decrease this is being evaluated in preclinical studies.
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Conflicts of interest
There are no conflicts of interest.
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