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| LETTERS TO EDITOR |
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| Year : 2021 | Volume
: 4
| Issue : 1 | Page : 179-180 |
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Authors' reply to Rasalkar et al.
Ullas Batra, Shrinidhi Nathany, Mansi Sharma
Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| Date of Submission | 15-Feb-2021 |
| Date of Decision | 23-Feb-2021 |
| Date of Acceptance | 23-Feb-2021 |
| Date of Web Publication | 26-Mar-2021 |
Correspondence Address:
Ullas Batra
Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/crst.crst_42_21
How to cite this article:
Batra U, Nathany S, Sharma M. Authors' reply to Rasalkar et al. Cancer Res Stat Treat 2021;4:179-80 |
We thank Rasalkar et al.[1] for their comments on our article titled, “Biomarker testing in non-small cell lung carcinoma – More is better: A case series.”[2] RET-rearranged non-small cell lung cancer (NSCLC) is gaining importance owing to the development of selpercatinib, a kinase inhibitor. RET rearrangements ever since their discovery are detected using break-apart fluorescence in situ hybridization (FISH).[3] However, this method involves technical difficulties, does not allow for the characterization of the fusion partner, and has no standard cutoff for a positive signal[4] (10% vs. 20%), thus leading to errors in signal interpretation that have been well-documented in the literature. FISH may be used as an orthogonal technique to validate the findings of next-generation sequencing (NGS). Schweitzer et al. in the American Society of Clinical Oncology 2015 meeting presented a novel real-time polymerase chain reaction-based method for the identification of RET fusion-positive NCSLC.[5] However, the limitation of this assay is its inability to detect novel or unknown RET fusion partners, thus potentially underestimating the true prevalence of RET rearrangements in NSCLC. In addition, the poor quality of RNA obtained from the formalin-fixed paraffin-embedded tumor blocks can also affect the assay results. Contrary to this, RNA sequencing using the NGS technology, in our opinion, is a robust method for the detection of RET rearrangements as it indicates the likelihood of a fusion by computing 3'/5' balance scores normalized against the assay expression controls. We agree that our sample size was limited, and hence, drawing definitive conclusions with respect to the clinicopathologic associations may not be appropriate. Overexpression of PDL1 in the presence of a targetable biomarker may not carry the same clinical implication as in tumors which are not molecularly driven, as evidenced by our experience with epidermal growth factor receptor-mutant NSCLC.[6],[7],[8] As patients with RET-rearranged NSCLCs have high levels of thymidylate synthase mRNA,[9] an objective response rate of ~40% with a progression-free survival of about 19 months[10] has been reported in those receiving pemetrexed-based chemotherapeutic regimens. A pan-India registry is a good suggestion. In addition, broader panel-based genomic profiling may help identify more cases of RET-rearranged NSCLC which could otherwise be missed on single-gene testing. In conclusion, NGS offers a one-stop solution for the detection of RET rearrangements, both as primary drivers as well as possible co-mutations and resistance mechanisms.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | |  |
| 1. | Rasalkar AA, Bhatia S, Sirigiri DN. RET gene fusions/rearrangements as biomarkers for lung carcinoma. Cancer Res Stat Treat 2021;4:177-8.  [Full text] |
| 2. | Batra U, Sharma M, Nathany S, Soni S, Bansal A, Jain P, et al. Biomarker testing in non-small cell lung carcinoma – More is better: A case series. Cancer Res Stat Treat 2020;3:742-7. [Full text] |
| 3. | Liu Y, Wu S, Zhou L, Guo Y, Zeng X. Pitfalls in RET fusion detection using break-apart FISH probes in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2020:dgaa913. Epub ahead of print. |
| 4. | Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2018;13:27-45. |
| 5. | Schweitzer BL, Smith RB, Skelton R, Vincent R, McMahon F, Handshoe J, et al. Novel qPCR screen for efficient and reliable identification of RET fusion-positive non-small cell lung cancer. J Clin Oncol 2015;33:S15. |
| 6. | Batra U, Sharma M, Jain P, Bothra S, Pasricha S. EGFR & PD L1: An (im) perfect union. Ann Oncol 2019;30:ii51-2. |
| 7. | Kapoor A, Noronha V, Chougule A, Patil VM, Menon N, Joshi A, et al. Molecular tumor board: Case 1-Interplay of EGFR, MET and PD-L1 in non-small cell lung carcinoma. Cancer Res Stat Treat 2019;2:228-31. [Full text] |
| 8. | Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53. [Full text] |
| 9. | Song Z, Yu X, Zhang Y. Clinicopathologic characteristics, genetic variability and therapeutic options of RET rearrangements patients in lung adenocarcinoma. Lung Cancer 2016;101:16-21. |
| 10. | Drilon A, Bergagnini I, Delasos L, Sabari J, Woo KM, Plodkowski A, et al. Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers. Ann Oncol 2016;27:1286-91. |
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