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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 692-701

Impact of epidermal growth factor receptor T790M testing in relapsed non-small cell lung cancer: A narrative review of the T790M reflex testing algorithm

1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, Delhi, India

Date of Submission20-Jul-2021
Date of Decision30-Aug-2021
Date of Acceptance17-Oct-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_169_21

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Reflex testing for the T790M mutation is important in patients with non-small cell lung cancer (NSCLC) who progress on first- or second-generation tyrosine kinase inhibitors (TKIs). Reflex testing, initiated by the treating medical oncologist, allows for the faster identification of patients who are eligible to receive a third-generation TKI such as osimertinib, which is the only TKI to report favorable outcomes in patients with T790M mutation. International guidelines and the Indian consensus guidelines recommend tissue rebiopsy as the gold standard to source genetic material for the testing of molecular biomarkers. As a result of its non-invasiveness, although liquid profiling is currently preferred as a starting point for diagnosing T790M mutations, in the case of inconclusive results, repeat tissue biopsy and reflex tissue-based T790M testing are deemed essential because of higher diagnostic certainty. Medical oncologists along with interventional radiologists and pathologists play a critical role in ensuring the feasibility of repeat tissue biopsy in patients with advanced NSCLC. Reflex tissue testing has the potential to identify acquired T790M mutation in patients with lung cancer at progression. We conducted a literature search in Embase and PubMed for the relevant articles to be included in this review. We also referred to the international and local guidelines to develop the testing algorithm. This narrative review provides a practical algorithm for reflex tissue testing and explains the significance of tissue rebiopsy in improving treatment outcomes in patients with NSCLC post-disease progression.

Keywords: Liquid profiling, non-small cell lung cancer, reflex testing, T790M, tissue rebiopsy

How to cite this article:
Prabhash K, Batra U. Impact of epidermal growth factor receptor T790M testing in relapsed non-small cell lung cancer: A narrative review of the T790M reflex testing algorithm. Cancer Res Stat Treat 2021;4:692-701

How to cite this URL:
Prabhash K, Batra U. Impact of epidermal growth factor receptor T790M testing in relapsed non-small cell lung cancer: A narrative review of the T790M reflex testing algorithm. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Aug 19];4:692-701. Available from: https://www.crstonline.com/text.asp?2021/4/4/692/334177

  Introduction Top

Lung cancer is the most commonly diagnosed cancer, constituting 11.6% of all cancers, and a leading cause of cancer-related mortality worldwide accounting for 18.4% (1.76 million) of all cancer-related deaths.[1] In India, lung cancer is one of the most common cancers with an incidence varying from 2 to 45/100,000 individuals, depending on the geography.[2] According to the GLOBOCAN estimates, India recorded 72,510 (5.5%) new cases of lung cancer in 2020.[3] Nearly 85% of all lung cancers in India are reported to be non-small cell lung cancers (NSCLC), with adenocarcinomas constituting approximately 50% and squamous cell carcinomas constituting up to 35% of the cases.[4],[5],[6],[7]

The discovery of targetable oncogenic driver mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, mesenchymal epithelial transition factor (MET), human epidermal growth factor receptor 2 (HER2), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), and programed death-ligand 1 (PD-L1) has effectively changed the treatment paradigm for NSCLC.[4] The incidence of EGFR-mutated NSCLC is much higher in Indians than in Caucasians (23%–44% vs. 10%–20%) and is closer to the incidence observed in the East Asian countries (27%–62%).[8],[9],[10] In an analysis from a tertiary care center in India, the prevalence of EGFR mutations was reported to be higher in non-smokers, women, and patients with distant metastasis.[11]

Several prognostic and predictive molecular biomarkers have been recognized for NSCLC.[4],[12] Introduction of EGFR tyrosine kinase inhibitors (TKIs) has improved the overall survival and progression-free survival (PFS) in patients with EGFR-mutant NSCLC.[13] Hence, guidelines recommend molecular testing for mutations at the time of NSCLC diagnosis, irrespective of the stage of the disease, and initiation of appropriate molecular targeted therapy such as TKIs for eligible patients.[14],[15],[16] However, precision therapy with TKIs requires complex diagnostic testing. The time required for molecular testing can vary depending on who initiates the request. Reflex testing is initiated by pathologists based on a diagnosis fulfilling the inclusion criteria, while bespoke testing is an on-demand testing approach and is initiated by the treating clinician or a multidisciplinary team when required, such as after receiving the pathology report confirming lung cancer diagnosis.[17] Patients can be started on appropriate targeted therapies after molecular testing. For patients with EGFR mutations, options for first-line therapy include TKIs. However, patients receiving first-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) EGFR TKIs develop resistance because of alterations in the target EGFR gene. Resistance usually develops within 8–16 months of therapy, necessitating the use of alternate TKIs or change in the course of therapy in these patients.[18] The resistance mutation that is most frequently (>50% of patients) acquired by patients is T790M in EGFR exon 20.[18],[19],[20] Patients with T790M mutation have shown favorable outcomes to targeted therapy with osimertinib, a third-generation TKI. To ensure targeted treatment after NSCLC progression, all patients who progress on first- and second-generation EGFR TKIs are recommended to undergo testing to determine the presence of the acquired T790M resistance mutation in the tumor.[21],[22] For detection of EGFR mutations, liquid biopsy-based profiling is a minimally invasive procedure to collect circulating biomarkers such as circulating tumor cells and nucleic acids, including cell-free RNA, micro-RNA, and circulating tumor DNA (ctDNA).[23] However, liquid biopsy-based profiling may produce false-negative results, thus limiting their validity, possibly due to the variation in the sensitivity of the kits used for testing, gene fusions with cell-free DNA (cfDNA), and lack of consensus on the methodology used.[24],[25],[26] Several methods are available for cfDNA analysis, such as polymerase chain reaction (PCR)-based sequencing and next-generation sequencing-based methods; currently, PCR-based sequencing is most commonly used.[27] Therefore, the concept of reflex tissue testing can be adopted in plasma genotyping negative cases, as this would allow clinicians to make an informed decision regarding the further course of treatment.[22] In this review, we elaborate on the impact of EGFR T790M testing through a reflex testing algorithm at progression on treatment outcomes in patients with NSCLC.

  Methods Top

This narrative review aims to elaborate on the significance of reflex tissue testing in patients with NSCLC post-disease progression and also to provide a practical algorithm for the same. We searched for the relevant published literature in PubMed and Embase databases using the following keywords – “NSCLC,” “metastatic,” “reflex testing,” “T790M mutations,” “tissue rebiopsy,” “liquid profiling,” etc. Instead of following a systematic literature review methodology (using checklists and systematic screening), we focused on our specific area of interest. Conference abstracts and available results from the clinicaltrials.gov database were hand searched. International and local guidelines were also manually searched and referenced to develop the testing algorithm. The references cited in all the above-retrieved publications were also reviewed for relevance and were included, when applicable.

  Guidelines for Epidermal Growth Factor Receptor T790M Testing Top

The emergence of effective targeted therapies for specific molecular targets has led to the development of guidelines for testing and stratifying patients in whom targeted therapies can result in clinical improvement. Guidelines aim to minimize inappropriate practice variation and provide a reference for medical education along with criteria for self-evaluation and indicators and criteria for external quality review, in order to improve patient outcomes. Multiple guidelines on molecular testing and appropriate treatment strategies for patients with advanced NSCLC have been published and are summarized in [Table 1].[15],[22],[28],[29]
Table 1: Guidelines for T790M testing

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All guidelines stress on the importance of testing for EGFR-activating mutations, as a part of reflex testing at the time of the first biopsy, along with testing for other common mutations. In addition, upon disease progression in patients with EGFR mutations, T790M mutation testing using a reflex testing algorithm should be an integral part of the battery of tests conducted. Although tissue biopsy is considered the gold standard, in cases where it is not feasible, liquid biopsy-based profiling is preferred. However, in the case of negative results from liquid biopsy-based profiling, tissue or cytology sample-based T790M testing is warranted for further evaluation.[15],[22],[28],[29]

  Current Scenario of Epidermal Growth Factor Receptor T790M Testing in India Top

Recognizing the importance of biomarker testing, an expert group of medical oncologists, molecular pathologists, and pathologists came together and drafted the Indian consensus recommendations in March 2018.[4] This consensus considered the current international guidelines on the topic and incorporated them in the Indian scenario, as several logistic considerations limit the application of international guidelines in the Indian setup. The key recommendations for molecular testing in NSCLC in India are mentioned in [Table 2]. Testing for T790M resistance mutation (along with mutations in other genes such as HER2 and MET) in patients with NSCLC progression is also an important recommendation. Testing of these resistance mutations can be performed by tissue rebiopsy or liquid biopsy-based profiling; however, tissue rebiopsy remains the gold standard for the detection of the T790M resistance mutation.[18],[22],[30]
Table 2: Indian consensus recommendations for T790M reflex testing

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  Role of Liquid Profiling Top

Liquid biopsy-based profiling is a noninvasive method of biomarker testing in cancer and is gaining importance because of its ease of use. It involves testing for cell-free nucleic acids, usually cfDNA in the peripheral blood/plasma samples.[31] This technique can be applied to other body fluids such as cerebrospinal fluid, urine, and ascitic fluid.[32],[33] While cfDNA refers to the total DNA shed from both normal and tumor cells, ctDNA refers specifically to the DNA originating from tumors. The release of ctDNA into the bloodstream is influenced by the tumor type, stage, metastasis, aggressiveness, location, size, and vascularity.[34],[35]

Analysis of tumor tissue biopsy is the standard method for mutation detection. However, tissue rebiopsy is invasive, time and resource intensive, and associated with a higher risk of complications in patients, in addition to the challenge of tumor heterogeneity during rebiopsy.[36] Hence, several guidelines including the Indian consensus guidelines recommend liquid biopsy as a preferred specimen for EGFR mutation testing at disease progression. The minimally invasive ctDNA testing is considered an alternative to tissue biopsy for the detection of EGFR T790M mutation when tumor genotyping by tissue biopsy is not feasible.[37]

An important technical difference between tissue and liquid biopsy is that in tissue biopsy a pathology review is performed to confirm the adequacy of the specimen, and genotyping is not performed if the tumor content is low (5%–10%), whereas for liquid biopsy, this review is not performed.[38] Nevertheless, highly sensitive assays are required for the detection of the mutation of interest in ctDNA, as it constitutes a very small fraction of the total cfDNA. In some cases, no ctDNA may be detected, rendering the entire molecular biomarker testing process futile.[39] Thus, liquid biopsy-based profiling offers high specificity, but has a low negative predictive value.[23],[24] The sensitivity of plasma genotyping for the detection of T790M mutation has been reported to be 70%, suggesting that the remaining 30% false-negative cases will need a tumor biopsy to determine the presence or absence of the T790M mutation.[40]

The logistic challenges in conducting liquid biopsy-based profiling include appropriate blood collection procedures, sample processing, transport, and storage, which can affect the mutation detection rate. In addition, as more time elapses between blood collection and processing, the DNA released from the lysis of white blood cells reduces the mutant allele fraction, causing it to fall below the limit of detection.[23] Therefore, appropriate collection and processing of samples for liquid biopsy-based profiling are very critical for the detection of ctDNA. The Indian consensus on molecular testing suggests that ethylenediaminetetraacetic acid (EDTA) tubes can be used in settings where laboratories are available intramurally.[4] In addition, if whole blood is collected in EDTA tubes, the plasma should be separated immediately using the double centrifugation method. Use of heparinized tubes can interfere with the PCR-based genotyping techniques, and hence should be avoided for the collection of blood for molecular analysis. In case mutation testing is to be outsourced to other laboratories, Streck/Paxgene tubes should be used for sample collection. These specialized tubes contain preservatives for preventing cell lysis, improving cell stability, and avoiding contamination of ctDNA in the blood sample with DNA from the lysed leukocytes.[4],[41],[42]

  Role of Repeat Tissue Biopsy Top

Disease progression post-treatment with EGFR TKIs necessitates a repeat tissue biopsy or a cytology sample assay to determine the resistance mechanism. A close collaboration between oncologists, pulmonologists, interventional radiologists, and pathologists can ensure adequate tissue samples for cytological and histological examinations. Factors that limit the feasibility of repeat biopsy and molecular analysis include the amount of tissue sample that can be recovered during bronchoscopy, lack of access to tumor sites, and the invasive nature of the sampling methods.[43]

Success rates for repeat biopsy in acquiring tissue for molecular testing and its subsequent impact on therapy vary from 73% to 95%.[44] An Indian study reported a 77% chance of undergoing repeat tissue biopsy in the clinical trial subgroup (114 out of 148; 95% confidence interval 69.4%–83.5%). The major reasons for not undergoing repeat tissue biopsy were patient reluctance (15 [44.1%] cases), technical difficulties in tissue sampling (10 [29.4%] cases), and poor performance status (6 [17.6%] cases). The same study reported that EGFR T790M mutation testing was performed in 42 patients, and the mutation was detected in 28.6% of the patients.[45]

In another prospective study of 90 Indian patients with NSCLC who had progressed on first-line EGFR TKIs, T790M mutation was detected in 47 (52.2%) out of the 90 patients, by repeat tissue biopsy in 39 (82.9%) and liquid biopsy in 8 (17%) patients. The incidence of T790M mutation was similar for tissue and liquid biopsy-based profiling (50.6% and 52.9%, respectively). At progression, tissue rebiopsy was feasible in 77 (85%) out of the 90 patients. In a small number of patients who declined a tissue biopsy or in whom a tissue biopsy was not technically feasible, liquid biopsy-based profiling could identify the T790M mutation.[46] Although guidelines recommend liquid biopsy-based profiling followed by tissue biopsy for the detection of T790M at progression, in this single-center analysis, the gold-standard tissue biopsy was preferred because of logistic convenience.[46]

In another study on 102 patients with EGFR-mutated NSCLC, 55 patients underwent repeat biopsy after developing acquired resistance to EGFR TKIs. Pre-existing activating EGFR mutations were found in all rebiopsy samples, with 25 of 55 (45.5%) patients being T790M-positive; 30 (54.5%) patients were T790M-negative on the first rebiopsy, of which 21 underwent additional rebiopsies following interval therapy. Of the 21 patients, 12 (57.1%) were T790M positive on the second/third rebiopsy.[47] This study highlights the efficiency of repeat tissue biopsy for the detection of the T790M mutation.[30] Thus, several studies from India and other countries have demonstrated that tissue rebiopsy is feasible in patients with NSCLC, who experience disease progression. Evidence suggests that EGFR mutation detection rates are higher in tissue samples than that in plasma samples.[48] Interventional radiologists, treating medical oncologists, and pathologists play a very critical role in making tissue rebiopsy possible. [Table 3] summarizes the comparison between tissue biopsy and liquid biopsy-based profiling.[24]
Table 3: Comparison of tissue biopsy and liquid biopsy-based profiling in the detection of mutation in molecular pathological assays[24]

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  Role of Cytology Top

Studies have shown that cytological samples have equivalent or higher sensitivity and accuracy for identifying EGFR mutations in NSCLC when compared with surgical specimens. Cytological samples obtained directly from tumors can provide higher sensitivity for the detection of the EGFR T790M mutation than liquid biopsy-based profiling because of the higher tumor DNA load.[49] About 40% of all lung cancers can be diagnosed using cytology samples without concurrent biopsy material.[50] Several studies have demonstrated that cytology samples are appropriate for EGFR mutation testing.[51],[52],[53] In a study by Satouchi et al., the EGFR T790M mutation detection rate in tumor biopsy and cytology samples was 42.5% and 37.5%, respectively. The overall agreement between the tissue biopsy and cytology samples was 91.7%.[54] Cytological diagnosis of lung cancer is typically based on endobronchial ultrasound-guided fine-needle aspiration (FNA), bronchial cytology, pleural effusions, and FNA from distant metastases [Table 4].[54],[55],[56],[57],[58]
Table 4: Techniques used for acquiring cytological samples

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In the Phase I dose-expansion component of the AURA study, cytology samples were used for the detection of T790M mutation in 28 Japanese patients.[49] The most commonly used cytology sample was bronchoalveolar lavage in approximately 43% of the patients. The median PFS in these patients was 8.3 months, which is similar to the PFS in other AURA studies (AURA 1, AURA 2, and AURA 3).[49],[59],[60],[61] Based on the trial, it is evident that cytology samples are feasible for EGFR T790M mutation detection.

  Impact of T790M Reflex Testing on Clinical Outcomes Top

Testing for the T790M mutation is requested at the time of clinical or radiological progression in patients with EGFR-mutated NSCLC receiving first- or second-generation TKIs.[22] Pathologists can perform reflex testing for specific EGFR activating mutations requested by the treating medical oncologist. Thus, implementation of T790M testing through a reflex testing algorithm may help identify patients with activating mutations and hasten their receipt of appropriate therapy.

Although there are limited data on T790M detection using a reflex testing algorithm, the impact of the implementation of reflex testing in patients with NSCLC at diagnosis has been evaluated in several studies. Some of the important studies for T790M reflex testing and its impact on treatment outcomes are described in [Table 5].[37],[46],[62]
Table 5: T790M reflex testing and impact on treatment outcomes

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In patients with disease progression, the T790M mutation is observed in more than 60% of the cases.[18],[19],[40],[63] This mutation mediates resistance to first- and second-generation TKIs because of the reduced binding affinity of the drugs for the ATP-binding pocket. In patients harboring the T790M mutation, osimertinib has shown a high response rate with significant improvement in PFS.

Tissue biopsy remains the gold standard for detection of the T790M mutation.[18],[22],[30] However, because of the need for an adequately large specimen, invasiveness, poor patient performance status, and the high risk involved, tissue biopsy can be challenging. In such cases, the minimally invasive liquid biopsy-based profiling is preferred.[32],[64] However, several published case reports have described patients who are negative for T790M on liquid biopsy-based profiling, but positive on tissue biopsy. These patients received osimertinib and showed appropriate clinical response.[37],[63] Thus, testing for T790M through a reflex testing algorithm at disease progression can play an important role in identifying patients who might benefit from third-generation TKIs.[65] An algorithm for T790M reflex testing of patients with advanced NSCLC in the Indian scenario is proposed [Figure 1], taking into account the recommendations from other guidelines.
Figure 1: Testing Algorithm for T790M Reflex Testing in Patients with Advanced NSCLC. (Acronyms: EGFR = epidermal growth factor receptor; NSCLC = non-small cell lung cancer; TKI = tyrosine kinase inhibitor)

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  Role Of Medical Oncologists in Driving T790M Reflex Testing – Indian Scenario Top

In a survey conducted across 111 centers to understand the pattern of EGFR mutation testing in the Indian scenario, 26 centers reported that they had in-house EGFR testing facilities, while 85 centers sent the samples to external facilities for testing. Medical oncologists examined a strikingly large number of patients with lung cancer (143 patients per oncologist per month), of which, three quarters were in the advanced stages and more than half had adenocarcinomas. Among patients who had progressed on first-line TKIs, only 25% could undergo a repeat biopsy. The major reason for not performing a tissue rebiopsy in this study was poor performance status and rapid disease progression.[10] Other Indian studies have reported a higher rate of tissue rebiopsy at disease progression, ranging from 43% to 80%.[45],[66]

This wide disparity in the proportion of patients in whom repeat tissue biopsy is feasible, has primarily been attributed to the inadequacy of tissue sample and patient reluctance. Patient reluctance may be related to the lack of knowledge or cost considerations. In the study by Jaiswal et al., 85% of patients underwent repeat tissue biopsy and in-house tissue-based T790M testing, suggesting that tissue sampling was preferred over liquid biopsy sampling.[46] However, there are certain limitations to tissue-based profiling, such as longer turnaround time, increased risk of procedural complications, and greater chances of sampling error due to tumor heterogeneity as compared to liquid-biopsy based profiling.[67],[68] In a prospective validation study for rapid plasma genotyping, a delay of 24 days was reported while awaiting the results of the tissue genotyping for the initiation of therapy with osimertinib, leading to loss of crucial time, which was primarily important for patient management.[42]

The high rate of repeat tissue biopsies in larger institutions may be because of the implementation of a sequential workflow along with the recommendation of appropriate T790M testing through a reflex testing algorithm followed in the case of disease progression. Medical oncologists play an important role along with interventional radiologists and pathologists in ensuring the feasibility of a repeat tissue biopsy, followed by a successful tissue-based T790M testing. An increase in patient education and proper counseling with regard to the need and benefits of T790M testing through a reflex testing algorithm in NSCLC cases at progression may increase the proportion of patients undergoing repeat tissue biopsy, when required. A multidisciplinary team involving medical oncologists, interventional radiologists, pulmonologists, and pathologists can play a critical role in facilitating repeat tissue biopsy, and obtaining cytological samples, when a tissue biopsy is not feasible.

The multidisciplinary team needs to drive the concept that once a T790M test is ordered, the algorithm for testing should be followed in the case of inconclusive T790M test results.

  Conclusion Top

International guidelines as well as the Indian consensus guidelines have recommended T790M testing in all patients who progress on EGFR TKIs using different sampling methods – tissue, cytology, or plasma ctDNA. As plasma ctDNA-based testing is minimally invasive, the adoption rate is higher than that for invasive tissue or cytology-based T790M testing. Although liquid biopsy-based T790M testing has demonstrated high specificity, it is reported to have a low negative predictive value.[22],[24] International guidelines recommend the use of liquid biopsy as the starting material for mutation profiling in patients with NSCLC at progression, but its feasibility needs to be assessed at the institutional level; likewise, its pros and cons should be considered before recommending the test. Sensitivity of plasma genotyping for the detection of T790M mutation has been reported to be 70%.[38] Tissue biopsy thus remains the gold standard for obtaining conclusive results in patients with negative/inconclusive plasma T790M genotyping results.[38] In patients with poor performance status or nonfeasibility of tissue sampling, cytological assay of bronchoalveolar lavage, bronchial brushings, or other body fluids/effusions may be considered. Medical oncologists play a crucial role in recommending a T790M test at disease progression and in counseling patients about the importance of different sampling methods in the case of a negative test result. With the availability of newer targeted therapies for NSCLC, T790M testing through a reflex testing algorithm is necessary, as it can help in taking the right treatment decision, and for improving the overall survival and quality of life in Indian patients with NSCLC who demonstrate disease progression.


The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Ms. Prajakta Nachane (M. Pharm.) from Labcorp Scientific Services & Solutions Private Limited in accordance with the GPP3 guidelines (http://www. ismpp.org/gpp3).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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