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 »  Abstract
 » Introduction
 » Case Report
 » Discussion
 » Conclusion
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  Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 54  |  Issue : 5  |  Page : 65-66
 

Importance of repeat tissue biopsy and tissue-based epidermal growth factor receptor T790M testing in progressed nonsmall cell lung carcinoma patients upon negative plasma genotyping for selection of third-generation tyrosine kinase inhibitor therapy: A case study


1 Director-Oncology & Consultant Surgical Oncology, Surgical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai, Maharashtra, India
2 Senior Clinical Associate, Surgical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai, Maharashtra, India

Date of Web Publication29-Dec-2017

Correspondence Address:
Dr. R Mistry
Director-Oncology & Consultant Surgical Oncology, Surgical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_545_17

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 » Abstract 


Resistance to 1st or 2nd generation epidermal growth factor receptor (EGFR) - tyrosine kinases (TKIs) develops predominantly due to an acquired mutation, EGFR T790M. Third-generation EGFR-TKIs have demonstrated potent activity against TKI resistance mediated by EGFR T790M. Thus, it become critical to identify T790M mutation on disease progression. Analysis of tumor tissue biopsy material is considered as gold standard for mutation detection. However, lung re-biopsy in a progressed patient involves several challenges – access to tumor, patient's willingness, safety, cost. Minimally invasive plasma circulating tumor DNA (ctDNA) evolved as an alternative for detection of EGFR T790M mutation when tumor genotyping is not feasible. Although a positive T790M result from ctDNA analysis is actionable, caution should be exercised in interpreting negative plasma results. A negative result may imply the absence of a mutation or merely that a patient's tumor is not shedding ctDNA at detectable levels, thus necessitating a confirmatory tissue biopsy to rule out a false negative plasma result. In this case report, we described a 78-year-old female who underwent a reflexed tumor biopsy and tissue based testing upon negative plasma genotyping. Our case report exhibited the importance to follow proposed T790M plasma testing algorithm to screen eligible patients for 3rd generation TKI therapy.


Keywords: Anaplastic lymphoma kinase gene rearrangement, epidermal growth factor receptor mutation, exon 19, plasma (ctDNA) genotyping


How to cite this article:
Mistry R, Patil A. Importance of repeat tissue biopsy and tissue-based epidermal growth factor receptor T790M testing in progressed nonsmall cell lung carcinoma patients upon negative plasma genotyping for selection of third-generation tyrosine kinase inhibitor therapy: A case study. Indian J Cancer 2017;54, Suppl S1:65-6

How to cite this URL:
Mistry R, Patil A. Importance of repeat tissue biopsy and tissue-based epidermal growth factor receptor T790M testing in progressed nonsmall cell lung carcinoma patients upon negative plasma genotyping for selection of third-generation tyrosine kinase inhibitor therapy: A case study. Indian J Cancer [serial online] 2017 [cited 2019 Dec 16];54, Suppl S1:65-6. Available from: http://www.indianjcancer.com/text.asp?2017/54/5/65/221926





 » Introduction Top


Epidermal growth factor receptor (EGFR) T790M mutation is the most common cause of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs).[1] Third generation EGFR TKIs are uniquely designed for use in patients whose tumors harbor the T790M resistance mutation.[2] However, clinical uptake of these targeted therapeutics is hindered by challenges in obtaining tissue for molecular analysis in the secondary resistance setting.[3] Several studies and clinical trials showed utility of minimally invasive plasma based circulating tumor DNA (ctDNA) for detection of EGFR T790M mutation.[4],[5]

Here we present a case of an old lady presented with progressed lung adenocarcinoma post EGFR TKI therapy. In this case we described the importance of reflexed tumor T790M genotyping in case of negative T790M result with plasma ctDNA testing.


 » Case Report Top


A 78-year-old female presented with exertional dyspnea since February 2016. Chest X-ray was performed and left upper lobe lung lesion and left pleural effusion was detected. Pleural tapping was done to remove fluid from the space between the lining of the outside of the lungs and the wall of the chest. Cytology-based testing confirmed adenocarcinoma; positron emission tomography-computed tomography (PET-CT) confirmed left upper lobe anterior segment lesion, multiple pleural lesions, pleural effusion, and liver lesion. The lung biopsy was performed and sample sent for epidermal growth factor receptor (EGFR) mutation analysis and anaplastic lymphoma kinase (ALK) gene rearrangement. The molecular analysis detected EGFR mutation; however, ALK gene rearrangement was negative. She was prescribed erlotinib, 150 mg daily and responded to the therapy. However, after 15 months on erlotinib, the patient presented with cough and breathlessness and X-ray revealed an increase in lung lesion. A PET-CT scan confirmed disease progression.

With the availability of targeted treatment for T790M mutation, we decided to detect EGFR T790M mutation. The patient was an old woman, and due to challenges with tissue biopsy, minimally invasive plasma-based testing was advised before selection of therapy. The plasma (ctDNA) genotyping performed by digital droplet polymerase chain reaction (PCR) in August 2017 was negative for T790M resistance mutation. The exon 19 EGFR sensitizing mutation – E746-A750 deletion – was positive with mutant allele fraction 0.6. A month later, she exhibited worsening of symptoms. Following the proposed plasma T790M testing algorithm, CT-guided biopsy was performed from lung lesion and subsequently tested for T790M mutation by ARMS PCR. The T790M mutation has been detected and the patient started receiving osimertinib (80 mg daily) at the time of this communication.


 » Discussion Top


Acquired resistance to first- or second-generation tyrosine kinase inhibitors (TKIs) is caused by exon 20 T790M EGFR mutation in >60% of progressed nonsmall cell lung carcinoma (NSCLC) patients, after a median of 10–12 months.[1] The resultant change of amino acid from threonine to a bulkier methionine impairs the binding of first- and second-generation EGFR kinase inhibitors to the adenosine triphosphate (ATP)-binding pocket of mutant EGFR.[1] The third-generation EGFR TKI, osimertinib has shown exhibited a response rate of 60% and median progression-free survival of 9.6 months in patients tested for T790M positive versus T790M negative by tumor genotyping.[2] Analysis of tumor tissue biopsy material (generally a formalin-fixed paraffin-embedded tissue block) is considered the conventional standard sample for mutation detection. Obtaining sufficient tumor tissue for mutational analysis from patients with advanced NSCLC who progressed during a previous therapy is invasive and time and resource intensive, and such biopsies are associated with a higher risk for complications to the patient.[3] Moreover, detection of disease-relevant mutations from the biopsy of a single tumor lesion may not be reflective of the patient's complete disease burden, especially in heterogeneous cancers.[4] In a retrospective analysis of patients, samples of phase I cohorts of AURA trial demonstrated 70% concordance of plasma genotyping with tumor genotyping.[5] The study also suggested that upon availability of validated plasma-based T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. The 30% false-negative rate of plasma genotyping indicates that those with T790M-negative plasma results still need a tumor biopsy to determine the status of T790M mutation.[5] Oxnard et al. also proposed an algorithm for plasma genotyping for EGFR T790M testing [Figure 1]. The pooled data of AURA extension and AURA2 demonstrated that the plasma test did not detect the T790M mutation in plasma ctDNA of approximately 40% of patients with a T790M-positive tissue test result.[6] The false negative is not a limit of platform sensitivity but rather the biologic features of NSCLC that affects the ability to identify plasma mutations.[7] The authors also suggested that some NSCLC patients, even on disease progression, may only shed very low quantities of DNA into the systemic circulation.[7] To mitigate the risk for a false-negative plasma test result, it is advised that, where possible, any plasma T790M-negative test result be explored further with a contemporaneous biopsy and tissue test.[6] Jenkins et al. also suggested that detection of the original sensitizing mutation in plasma could act as an internal control for plasma testing; accordingly, a plasma sample with no detectable sensitizing mutation can be considered uninformative.
Figure 1: A proposed algorithm for plasma genotyping for EGFR T790M mutation.[5]

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Detection of EGFR T790M resistance mutation is critical for the selection of targeted therapy for the progressed NSCLC patients. Plasma genotyping is an attractive proposition as it is a minimally invasive and representative of multiple metastatic sites. Our case illustrates that the negative plasma genotyping should be tested with tissue testing as recommended by Oxnard et al. In the present case, the patient was T790M negative by plasma testing; in case of failure to follow the plasma testing algorithm, we may have missed to identify an eligible patient for T790M-specific targeted therapies.


 » Conclusion Top


This case demonstrates that clinicians should be cautious while interpreting a negative plasma genotyping result and should ask for a tissue biopsy and tissue-based T790M genotyping, in a suspected case.

Acknowledgment

The authors would like to thank Dr. Subhankar Basak, National Diagnostics Head, AstraZeneca Pharma India Limited, for reviewing this manuscript.

Financial support and sponsorship

Financial support to authors - Nil.

The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Sacher AG, Oxnard GR. Personalizing therapy for acquired resistance to EGFR kinase inhibitors in advanced NSCLC. Am J Hematol Oncol 2016;12:5-8.  Back to cited text no. 1
    
2.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.  Back to cited text no. 2
    
3.
Overman MJ, Modak J, Kopetz S, Murthy R, Yao JC, Hicks ME, et al. Use of research biopsies in clinical trials: Are risks and benefits adequately discussed? J Clin Oncol 2013;31:17-22.  Back to cited text no. 3
    
4.
Thress KS, Brant R, Carr TH, Dearden S, Jenkins S, Brown H, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 2015;90:509-15.  Back to cited text no. 4
    
5.
Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, et al. Association between plasma genotyping and outcomes of treatment with Osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016;34:3375-82.  Back to cited text no. 5
    
6.
Jenkins S, Yang JC, Ramalingam SS, Yu K, Patel S, Weston S, et al. Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol 2017;12:1061-70.  Back to cited text no. 6
    
7.
Karlovich C, Goldman JW, Sun JM, Mann E, Sequist LV, Konopa K, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a Phase I Study of Rociletinib (CO-1686). Clin Cancer Res 2016;22:2386-95.  Back to cited text no. 7
    


    Figures

  [Figure 1]

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