|Year : 2022 | Volume
| Issue : 5 | Page : 11-18
CONCORDANCE: A real-world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non-small cell lung cancer
Kumar Prabhash1, Bivas Biswas2, Sachin Khurana3, Ullas Batra4, Ghanashyam Biswas5, Suresh Hariram Advani6, Prabrajya N Mohapatra7, Senthil Rajappa8, Ajay Sharma9, Shekhar Patil10, Palanki Satya Dattatreya11, Rakesh Roy12, Sachin Almel13, Gautam Goyal14, Narayanankutty Warrier15
1 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha Block, Parel, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Medical Center Trust, 14 MAR(EW), New Town, Kolkata, West Bengal, India
3 Department of Medical Oncology, All India Institute of Medical Sciences, Ansari Nagar East, Delhi, India
4 Department of Medical Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Rohini, New Delhi, India
5 Department of Medical Oncology, Sparsh Hospitals and Critical Care (P) Ltd, Bhubaneswar, Odisha, India
6 Department of Medical Oncology, Sushrut Hospital, Chembur East, Mumbai, Maharashtra, India
7 Department of Medical Oncology, Apollo Gleneagles Hospitals 58, Kolkata, West Bengal, India
8 Department of Medical Oncology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Banjara Hills, Hyderabad, Telangana, India
9 Department of Medical Oncology, Action Cancer Hospital, New Delhi, India
10 Department of Medical Oncology, Healthcare Global Enterprises Ltd, Bengaluru, Karnataka, India
11 Department of Medical Oncology, Omega Hospitals, Banjara Hills, Hyderabad, Telangana, India
12 Department of Medical Oncology, Saroj Gupta Cancer Centre & Research Institute, Thakurpukur, Kolkata, West Bengal, India
13 Department of Medical Oncology, P.D. Hinduja Hospital & Medical Research Centre, 908 9th floor Research Department Veer Savarkar Marg Mahim, Mumbai, Maharashtra, India
14 Department of Medical Oncology, Max Super Speciality Hospital, Room No 143 Basement 2 Phase 6 Sahibzada Ajit Singh Nagar, Chandigarh, Punjab, India
15 Department of Medical Oncology, MVR Cancer Centre & Research Centre, Vellalaserry NIT Poolacode Choolur, Kozhikode, Kerala, India
|Date of Submission||20-Apr-2021|
|Date of Acceptance||14-Feb-2022|
|Date of Web Publication||24-Mar-2022|
Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha Block, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Molecular tissue testing in non-small cell lung cancer (NSCLC) is done for the assessment of epidermal growth factor receptor (EGFR) mutation. EGFR mutation status is the basis for deciding the targeted treatment option for patients with metastatic NSCLC. The nonavailability of tissue samples and contraindications for biopsy pose a significant challenge. Hence, circulating tumor DNA (ctDNA) by liquid biopsy can be a viable alternative for NSCLC patients.
Methods: This study was conducted at 15 sites across India. EGFR mutation testing from plasma was done as part of the study at the central laboratory by the next-generation sequencing (NGS) method, and EGFR mutation test results from tissue samples (done as part of routine practice) were recorded for all the patients.
Results: Out of the total patients enrolled (N = 245), the majority (64.5%, n = 158) were men. The median age of patients was 58.0 (range: 26–84) years. The concordance between plasma and tissue testing was found to be 82.9% (95% confidence interval [CI]: 77.55, 87.45). The sensitivity and specificity of NGS were 68.4% (95% CI: 56.92, 78.37) and 90.1% [95% CI: 84.36, 94.21), respectively. Plasma testing detected 1.2% (n = 3) and tissue sample testing detected 2.4% (n = 6) positive status of exon 20 T790M EGFR mutation. Out of the total number of patients enrolled, 25 were tissue positive and plasma negative, while 16 were plasma positive and tissue negative.
Conclusions: This real-world study in Indian patients suggests that plasma testing for EGFR mutation analysis is a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. The noninvasive plasma procedure in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies by providing clinicians with valuable insights into the patient's tumor mutation status.
ClinicalTrials.gov Identifier: NCT03562819
Keywords: ctDNA, EGFR mutation, next-generation sequencing (NGS) and TKI, NSCLC
Cancer detection via “Liquid biopsy-ctDNA detection” is rapidly advancing in real world practice. This is the first Indian study on large sample size on considerations on plasma testing for EGFR mutation analysis as a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. In our study, the concordance between plasma and tissue testing was found to be 82.9 % for all EGFR mutation subtypes in NSCLC patients
|How to cite this article:|
Prabhash K, Biswas B, Khurana S, Batra U, Biswas G, Advani SH, Mohapatra PN, Rajappa S, Sharma A, Patil S, Dattatreya PS, Roy R, Almel S, Goyal G, Warrier N. CONCORDANCE: A real-world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non-small cell lung cancer. Indian J Cancer 2022;59, Suppl S1:11-8
|How to cite this URL:|
Prabhash K, Biswas B, Khurana S, Batra U, Biswas G, Advani SH, Mohapatra PN, Rajappa S, Sharma A, Patil S, Dattatreya PS, Roy R, Almel S, Goyal G, Warrier N. CONCORDANCE: A real-world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non-small cell lung cancer. Indian J Cancer [serial online] 2022 [cited 2022 Dec 5];59, Suppl S1:11-8. Available from: https://www.indianjcancer.com/text.asp?2022/59/5/11/340524
| » Introduction|| |
Worldwide, lung cancer remains the leading cause of cancer incidence and mortality, with 20,93,876 cases and 17,61,007 deaths reported in 2018. As per the comprehensive report of Global Cancer Incidence, Mortality & Prevalence(GLOBOCAN) 2018, India reported 67,795 new cases and 63,475 deaths of lung cancer across age groups and genders. In non-small cell lung cancer (NSCLC), the epithelial growth factor receptor (EGFR) is often mutated and abruptly activated. The most common activating mutations of EGFR in NSCLC fall within the tyrosine kinase binding domain. EGFR tyrosine kinase mutations occur in approximately 10%–15% of NSCLC adenocarcinomas in Caucasian patients. Studies from India reported a much higher frequency of EGFR mutations (23%–44%.), A recent study conducted on EGFR-mutated NSCLC patients (n = 483) reported that 68.1% of patients had exon 19 deletion mutation, followed by 26.9% with exon 21 L858R. The presence of EGFR mutation is a robust predictor of EGFR tyrosine kinase inhibitor (TKI) responsiveness.
Guidelines from the College of American Pathologists recommended testing of tumor sample DNA from patients with non-squamous advanced NSCLC to confirm appropriateness for EGFR TKI treatment, where the tissue sample is limited or hard to obtain. However, small tissue samples may not always be sufficient for EGFR mutational assessment to select patients for TKI therapy. In patients without tissue availability, the analysis of cell-free DNA (cfDNA) or circulating tumor DNA* (ctDNA) derived from liquid biopsy samples, particularly from plasma, represents an alternative to provide EGFR mutational testing for arriving at a treatment decision.
Additionally, (liquid biopsy: cfDNA) has the potential to detect resistance mechanisms at an initial stage, such as the EGFR T790M mutation in case of EGFR TKI use. Several studies have established the predictive and prognostic value of measuring ctDNA concentration in the blood.,, “Liquid biopsy”-ctDNA detection has great potential in cancer diagnosis, monitoring, and predicting survival. Liquid biopsy can serve as a marker(s) of disease in patients with a solid tumor, where the tumor is genome specific and one or more driver mutation(s) remain preserved throughout the disease course. In lung cancer, these requirements are met by EGFR-mutated adenocarcinomas, which contain an activating/sensitizing mutation that persists in the tumor cells during therapy and at relapse.
A ctDNA mutational analysis is a clinically congruent way to check the presence of EGFR mutations and predict its counter effect to EGFR TKIs. As the sensitivity and specificity of ctDNA analysis are technically challenging, it is vital to assess its accuracy, suitability, and feasibility of mutation analysis. An open-label Efficacy, Safety, Tolerability of Gefitinib as 1st Line in Caucasian Patients With EGFR Mutation Positive Advanced NSCLC (IFUM) study in (n = 652) Caucasian patients with EGFR mutation-positive NSCLC established a 94% concordance between tissue/cytologic and plasma (ctDNA) samples. A similar study conducted in a real-world setting (ASSESS) among European and Japanese patients showed 89% concordance. However, this data is unavailable in the Indian population. Therefore, the present prospective observational study was conducted to improvise diagnostic practices for mutation detection, which would enable broader access to EGFR mutation testing. It would also provide the opportunity for more patients to receive therapies personalized to their mutational status in the Indian setting.
| » Patients and Methods|| |
The multicenter, prospective, diagnostic, observational study was conducted at 15 sites from different geographic regions across India. Newly diagnosed, histologically confirmed, treatment-naïve patients (i.e., no chemotherapy or EGFR-TKI) with metastatic adenocarcinoma of the lung (stage IV NSCLC) and age 18 years and older were included in the study. Patients with any medical condition that, in the opinion of the investigator, would interfere with the outcome and those on any other interventional clinical study/trial were excluded from the study. This was a single-visit study where no medication was administered as part of the study procedure.
The study was performed in accordance with the ethical principles of Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use – Good Clinical Practice (ICH-GCP), Good Pharmacoepidemiology Practices (GPP), regulatory guideline for observational studies, and sponsor's policy on bioethics and human biological samples. The final version protocol and the informed consent form were approved by the institutional review board (IRB). Before the start of the study, written approval of the IRB and written informed consent of the patients were obtained. The study duration was approximately 12 months, with a recruitment period of 6 months. EGFR mutation test was performed as per the routine practice for both tissue- and plasma-based detection. Histopathology examination was done for all enrolled patients.
The study was registered at Clinicaltrials.gov (NCT03562819) and Clinical Trials Registry India (CTRI/2018/08/015290).
Two hundred and fifty-four patients were required to assess the level of concordance of EGFR mutation status obtained by ctDNA and tissue testing, assuming a 5% level of significance. The expected level of concordance in EGFR mutation status by ctDNA and tissue testing was 89%, with a precision of 3.85%. Approximately 268 patients were planned to be enrolled, considering a 5% dropout rate. Any sample failure (testing/destroyed) during transportation and handling was included in the rate of 5%.
Descriptive statistics were used for primary and secondary analyses; frequency and percentages of patients with EGFR mutation and its subtypes were calculated. For the primary objective, the concordance rate, sensitivity, specificity, positive and negative predictive values (NPV and PPV), and their two-sided 95% confidence interval (CI) for comparing the mutational status between tumor and plasma samples were calculated for the evaluable population.
| » Results|| |
Demographic and Baseline Characteristics
A total of 245 patients were enrolled in the study and they completed the study. The study flow chart is presented in [Figure 1].
|Figure 1: Study flow chart. EGFR = epidermal growth factor receptor, NSCLC = non-small cell lung cancer|
Click here to view
Out of the total participants, majority (n = 158, 64.5%) were men, and the median age was 58.0 (26–84) years. Majority (n = 164, 66.9%) of the patients were reported to be nonsmokers, and 21.2% were ex-smokers. Median number of cigarette/bidi packs per year was 35.2 (3.2–90.2). Detailed demographic information and baseline characteristics are provided in [Table 1]. All eligible patients were assessed at baseline for vital signs, physical examination, and current medications. Mean (standard deviation [SD]) systolic blood pressure, diastolic blood pressure, and heart rate were 127.9 (17.37) (95% CI: 125.8, 130.1), 79.8 (9.33) (95% CI: 78.6, 80.9), and 91.1 (14.92) (95% CI: 89.2, 93.0), respectively.
Also, 42% of patients had a history of medical illnesses. The most prevalent medical history was hypertension (43 [41.7%]), followed by diabetes mellitus (15.5%) and cough (14.6%). Appendectomy (n = 3 [2.9%]), hysterectomy (n = 3 [2.9%]), and biopsy (2 [1.9]) were the most prevalent surgeries.
Level of Concordance Between EGFR Mutation Status Obtained from Tissue and Plasma Testing
Analysis of primary outcome measures showed 82.9% (95% CI: 77.55, 87.45) concordance, 68.4% (95% CI: 56.92, 78.37) sensitivity, 90.1% (95% CI: 84.36, 94.21) specificity, 77.1% (95% CI: 65.55, 86.33) PPV, and 85.3% (95% CI: 79.06, 90.25) NPV of EGFR mutation between tissue and ctDNA (plasma)-based testing for all three subtypes [Table 2].
|Table 2: Summary of concordance, sensitivity, specificity, PPV, and NPV of EGFR mutation subtypes between ctDNA and tissue testing|
Click here to view
In an analysis of secondary outcome measure, plasma sample testing detected 1.2% (n = 3) of exon 20 T790M, 16.7% (n = 41) of exon 19 deletions, 11.4% (n = 28) of exon 21 L858R, and 30.6% (n = 75) multiple mutations, whereas tissue sample testing detected 2.4% (n = 6) of exon 20 T790M, 19.2% (n = 47) of exon 19 deletions, 11.0% (n = 27) of exon 21 L858R, and 34.3% (n = 84) multiple mutations with positive mutation status in all enrolled patients [Table 3]. A total of 98.8% (n = 242) of TKI treatment-naïve NSCLC patients had negative T790M mutation status with plasma sample testing. On the other hand, 97% (n = 238) of TKI treatment-naïve NSCLC patients had negative T790M mutation status with tissue sample testing [Table 4].
|Table 3: Summary of individual EGFR mutation types (including multiple mutations)|
Click here to view
As this is an observational study, no proactive safety data collection was conducted. Only spontaneously mentioned safety events were reported, as required by the post-marketing pharmacovigilance regulations.
| » Discussion|| |
Due to the discovery of diagnostic procedures to detect EGFR, the management of NSCLC has improved over the years.,, Tissue sample testing was considered as a gold standard. However, factors like invasiveness and inaccessibility, contraindication of the test in many patients, and nonavailability of neoplastic tissue in many patients due to technical infeasibility are major disadvantages of tissue-based EGFR mutation detection method. ctDNA-based mutation detection overcame these disadvantages and emerged as a capable technique with advantages like noninvasiveness, accessibility, and repeated sampling. Targeted therapies like EGFR TKIs are available for the treatment of lung carcinoma. EGFR TKIs have proved superior to doublet chemotherapy in patients with metastatic NSCLC in terms of efficacy.
As sensitivity and specificity of ctDNA analysis are technically challenging, it is important to assess the accuracy, suitability, and feasibility of the use of ctDNA for mutation analysis. An open-label IFUM study enrolling 652 Caucasian patients with EGFR mutation-positive NSCLC established a concordance of 94% between tissue/cytologic and plasma (ctDNA) samples.
This large, multicenter, observational, diagnostic study investigated the utility of ctDNA for EGFR mutation testing with next-generation sequencing in a real-world diagnostic setting in Indian patients. The study reported a concordance of around 83% between plasma and tissue testing.
The majority (66.9%) of patients enrolled were nonsmokers. Supporting the demographic and disease characteristics of our study, two studies depicted similar demographics and baseline characteristics: an observational, multi-institutional study performed from January 2016 to July 2019 in a Chinese population with age ranging from 33 to 94 years, where more than 55% of patients were nonsmokers in chemotherapy-naïve patients, and a comparison study of EGFR mutation status between plasma and tissue, where the mean age was 58 years and approximately 50% of patients were nonsmokers.
In our study, patients showed multiple mutations and a concordance of 82.9% between ctDNA (plasma) and tissue-based EGFR mutation test for all three subtypes. Similar results were reported across the globe. A study with 1288 patients (mean [±SD] age 66.5 [±9.8] years) conducted in a real-world setting (ASSESS) reported 89% concordance, and a Phase III, First-line Asian Sequential Tarceva and Chemotherapy Trial (FASTACT-2) reported an overall concordance of 88% between tissue and plasma tests., Another study comparing EGFR mutation status between plasma and tissue conducted in 94 NSCLC Chinese patients reported an overall concordance of 80% with sensitivity and specificity of 50% and 100%, respectively. An interventional study conducted in 3382 Asia-Pacific and Russian patients reported a concordance of 80.5% between 2581 matched tissue/cytology and plasma samples. A study with 163 Indian patients (treatment-naïve diagnosed with advanced NSCLC) randomized into two groups based on the availability of tissue and plasma test reported 96.97% concordance between allele-specific real-time polymerase chain reaction (on tumor tissue DNA) and ctDNA (plasma) for EGFR mutation detection (exon 19 and exon 21 mutations). Data from various parts of the world showed that our results were comparable on ctDNA (plasma) versus tissue biopsy in NSCLC patients.,,,
Along with overall concordance between plasma and tissue tests, sensitivity, specificity, PPV, and NPV were also analyzed. The sensitivity of the test determines the likelihood to accurately detect the EGFR mutation. The present study showed low sensitivity of plasma test; however, the sensitivity is similar to the results of EGFR mutation (62%–67%) reported in a recently performed meta-analysis. However, high sensitivity (91.1%) of plasma test was shown by a study conducted in an Indian population with 163 patients.
The PPV is the percentage of patients (who actually have a disease) with a positive test. The PPV in our study was 77%, which is on the lower side for a test. The reasons for a low PPV are false-negative tests and heterogeneous data. The PPV for the plasma test has been reported to be between 78% and 100% around the world.,,
In the present study, 75 (30.6%) patients reported multiple mutations, including exon 20 T790M, exon 19 deletions, exon 21 L858R, exon 18, exon 18 G719A, exon 18 G719S, exon 21 L861G, and exon 21 L861Q. The maximum number of mutations was reported for exon 19 deletions (41 [16.7%]), followed by exon 21 L858R (28 [11.4%]).
In Asia-Pacific and Russian patients, the maximum number of mutations was reported for exon 19 deletions (n = 514) and the minimum number for exon 19 deletion + T790 mutation (n = 1). Another study conducted by Reck et al. also demonstrated maximum exon 19 deletions (n = 68). Our results were comparable to the two studies ( and ), taking into account the maximum number of mutations.
In the present study, 1.2% of patients reported positive T790M mutation with the plasma test. The literature revealed that the identification of T790M mutation before exposure to the treatment is rare. The frequency reported was 2.9% and <1% for patients suffering from adenocarcinomas by Inukai et al. and Yu et al., respectively. The reasons can be a difference in the sample size or heterogeneous population and different methods used to assess EGFR mutation. A study was conducted to estimate the frequency of T790M EGFR mutations. Out of 2744 patients with lung cancer, 579 had EGFR mutations. Eleven patients were identified to have EGFR T790M mutations, that is, 2.0% of all EGFR-mutant tumors.
In a study with Indian NSCLC patients (n = 133), the patients were grouped into three different groups: group 1 (EGFR mutation positive, treatment naïve), group 2 (EGFR mutation positive, EGFR-targeted TKI therapy), and group 3 (no known EGFR mutation diagnosed, treatment naïve). Four (10%) patients from group 1 reported positive T790M mutations using droplet digital polymerase chain reaction (ddPCR).
In another study, evaluation of the distribution of EGFR T790M in treatmentnaïve patients was performed. The results reported that 1% (n = 3/394) of patients had somatic T790M mutation.
To make rapid therapeutic progress in the molecular diagnosis and treatment of NSCLC, it is a must to incorporate safe and facile noninvasive methods for sensitive, comprehensive tumor profiling to select patients for personalized therapy. Given the ease of obtaining plasma-based genotyping and the success observed with such a noninvasive approach, our results argue for incorporation of plasma-based genotyping into routine clinical management of patients with NSCLC. Integration of plasma next-generation sequencing (NGS) testing into the routine management of stage IV NSCLC demonstrates a marked increase in the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy (targeted therapy).
Considering the observational nature of the study, randomization and blinding were not included, and furthermore, the study was lacking in controlled selection criteria, which could have led to selection bias (bias in patient, study design selection).
| » Conclusion|| |
The present study is the first report on concordance between EGFR mutation status obtained from tissue- and blood (plasma)-based testing in India. In our study, the concordance between tissue- and plasma-based testing was found to be more than 80% for all EGFR mutation subtypes. The results were similar to the concordance of the tests in other parts of the world. The researchers accepted that Asia-Pacific regions faced challenges in EGFR mutation testing in the past due to a lack of access to these tests. However, with the availability of ctDNA testing, it would be feasible for the clinicians to easily manage the disease at the early stages and its progression effectively with a higher success rate and better patient outcomes.
The authors would like to thank AstraZeneca Pharma India Ltd., and Tech-Observer India Pvt Ltd, New Delhi, the Contract Research Organization for supervising the study, providing administrative support for the development of this manuscript. Medical writing assistance was provided by Dr. Pawandeep Kaur Dhawan MBBS, MD and Mr. Swapnil Tukaram Lanjewar B-Pharm, MBA from Tech-Observer India Pvt Ltd, New Delhi, in accordance with GPP3 guidelines (http://www.ismpp.org/gpp3).
Financial support and sponsorship
AstraZeneca Pharma India Ltd.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]