Cancer Research, Statistics, and Treatment

: 2021  |  Volume : 4  |  Issue : 1  |  Page : 187--188

Authors' reply to Devakumar et al., Katte et al., and Batra et al.

Suresh Kumar Bondili, Vanita Noronha, Anuradha Chougule, Kumar Prabhash 
 Department of Medical Oncology, Mumbai, Maharashtra, India

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra

How to cite this article:
Bondili SK, Noronha V, Chougule A, Prabhash K. Authors' reply to Devakumar et al., Katte et al., and Batra et al..Cancer Res Stat Treat 2021;4:187-188

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Bondili SK, Noronha V, Chougule A, Prabhash K. Authors' reply to Devakumar et al., Katte et al., and Batra et al.. Cancer Res Stat Treat [serial online] 2021 [cited 2021 May 9 ];4:187-188
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We thank Devakumar et al.,[1] Katte et al.,[2] and Batra and Nathany[3] for their interest and valuable suggestions for our manuscript titled, “Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer.”[4]

Our patient had epidermal growth factor receptor (EGFR)-mutant metastatic adenocarcinoma of the lung and received gefitinib and osimertinib in the first and second lines, respectively. Post disease progression on osimertinib, a next-generation sequencing (NGS)-based analysis of the ascitic fluid cell block revealed a mutation in the CTNNB1 gene along with the EGFR C797S mutation. Devakumar et al.[3] have pointed out that despite the availability of a targetable genomic alteration, we used conventional chemotherapy alone for the treatment. This was because the patient had a considerable disease burden and a borderline performance status of 2, thus necessitating the use of chemotherapy to control the symptom burden. Additionally, information about the type of C797S mutation (cis or trans conformation) was requested from the molecular laboratory, but was not available at the time of treatment initiation. Lastly, since the proposed targeted treatment options did not have sufficient evidence and as the patient had a high disease burden, we preferred the standard treatment option of chemotherapy first and reserved the experimental approaches to a later line after the exhaustion of all the standard treatment options. We agree with Devakumar et al. that EA1045, brigatinib plus cetuximab, and BLU-945 are the treatment options when C797S is in cis with T970M and gefitinib with osimertinib when they are in trans, however, most of these drugs are inaccessible in the Indian setting. Moreover, the combination of gefitinib and osimertinib, albeit tolerable, was not preferred in our patient due to limited evidence of its benefit. In the case reports by Arulananda et al. and Wang et al. on patients treated with the combination of EGFR tyrosine kinase inhibitors (TKIs) and osimertinib, the progression-free survival was modest, at 6 weeks and 3 months, respectively.[5],[6]

CTNNB1, which is a part of the Wnt/beta-catenin pathway, is frequently mutated in several cancers including colorectal cancer, melanoma, mesothelioma, etc. It is also frequently found to be mutated in adenocarcinoma of the lung and is one of the mechanisms of resistance to EGFR TKIs.[7] We agree with Devakumar et al. that trametinib and bevacizumab can be used to target the CTNNB1 mutations, as shown in a preclinical study and a small phase-I clinical trial, respectively. Therefore, these agents can be considered after exhausting standard therapies.[8],[9] The evidence is more for niclosamide, and it is already being evaluated in a phase-II clinical trial in metastatic colorectal cancer (NCT02519582) and in combination with abiraterone and prednisolone (NCT02807805) in castration-resistant prostate cancer. We concur with Devakumar et al. on their proposed approach [Figure 1],[1] however, more clinical research is required to generate sufficient data for it to be incorporated into routine clinical practice.

We agree with Batra and Nathany,[3] that using techniques with higher sensitivities like digital droplet polymerase chain reaction can identify T790M mutations in the plasma cfDNA much before the actual radiological progression. As the ascitic fluid cell block on progression revealed adenocarcinoma, the possibility of a small cell transformation appeared unlikely. Additionally, we would like to clarify that the NGS panel used included TP53 mutations but not mutations in the RB1 gene. We agree that incorporation of the RB1 gene in the NGS panel could give us a better idea about the possibility of a small cell transformation which might otherwise be missed because of tumor heterogeneity.

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