Real-World Analysis of the EGFR Mutation Test in Tissue and Plasma Samples from Non-Small Cell Lung Cancer.
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SUBMITTER: Lee H
PROVIDER: S-EPMC8465683 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeStandard treatment for cases of non-small cell lung cancer (NSCLC) exhibiting acquired drug resistance includes tumor rebiopsy, epidermal growth factor receptor (EGFR) mutation testing (e.g., for T790M mutations), and the subsequent administration of third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, rebiopsies are typically invasive, costly, and occasionally not feasible. Therefore, the present study aimed to assess rebiopsy procedures by analyzing real-world data collected by the ASTRIS study of patients with resistant NSCLC.Materials and methodsThe present study used statistical models to evaluate data collected by the ASTRIS trial (NCT02474355) conducted at Yonsei Cancer Center, including the rebiopsy success rate, incidence of T790M mutations in collected tissue and plasma samples, and association of administered osimertinib treatment efficacy.ResultsIn a total of 188 screened patients, 112 underwent rebiopsy. An adequate tumor specimen was obtained in 95 of these patients, the greatest majority of whom (43.8%) were subjected to bronchoscopy. T790M mutations were detected in 53.3% of successfully EGFR-tested rebiopsy samples. A total of 88 patients received osimertinib treatment, and the objective response rate and median progression-free survival time was 44.3% and 32.7 weeks, respectively, among the treated patients overall, but 57.8% and 45.0 weeks, and 35.2% and 20.4 weeks among patients who exhibited T790M-positive tissue (n=45) and plasma (n=54) samples, respectively.ConclusionApproximately 60% of patients in the analyzed real-world cohort were eligible for tissue rebiopsy upon NSCLC progression. Osimertinib activity was higher in patients in whom T790M mutations were detected in tissues rather than in plasma samples.
| S-EPMC6536394 | biostudies-literature
Project description:Background:The epidermal growth factor receptor (EGFR) gene has been identified as the driving gene of non-small cell lung cancer (NSCLC), and EGFR-tyrosine kinase inhibitor (TKI) has shown efficacy, but acquired resistance is inevitable. It has been confirmed that the secondary EGFR Thr790Met (T790M) mutation accounts for about 50% of the mechanisms of acquired resistance to EGFR-TKI. The third-generation of EGFR-TKI has significantly efficacy in advanced T790M-positive NSCLC patients. Therefore, it is necessary to detect the status of T790M in patients with acquired resistance after first generation EGFR-TKI. The objective of this study was to investigate the positive rate of plasma test T790M mutation and its relationship with different clinical characteristics, and the frequency of T790M mutation in advanced EGFR-mutant NSCLC patients with acquired resistance after firstline EGFR-TKI treatment. Methods:Patients from a single clinical center (Taizhou hospital) were recruited prospectively from September 2017 to June 2018. The eligibility criteria of the trial included the following: (I) aged 18 years or older, histologically confirmed NSCLC stage IIIB/st and EGFR mutation positive; (II) progressive disease (PD) after first generation EGFR-TKI by RECIST v1.1, with PFS>3 months; (III) no third generation TKI treatment. All patients signed informed consent, had 10 mL of blood drawn, and were evaluated for the presence of T790M gene by amplification refractory mutation system (ARMS). The study was approved by the Ethics Committee of Taizhou Hospital (ethical batch number: 201637). Results:A total of 189 patients were included in the analysis. The overall T790M mutation rate of plasma detection was 36.51% (69/189). The positive rate of T790M mutation after the failure of first generation EGFR-TKI treatment was not correlated with the patient's age, sex, and the type of first generation TKI drugs. However, it was related to the mutation type of EGFR in baseline and the mode of progression according to reports by Wu et al. The frequency of T790M mutation among patients with initial exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 45.45%, 26.19% and 33.33%, respectively. The mutation rate of T790M in 19del mutant patients was higher than that of L858R mutation and other mutations (P=0.026). The frequency of T790M mutation in local progression patients was 50% after the first generation TKI was resistant to drug treatment: in gradual progression it was 26.92%, and in dramatic progression it was 38.10%. The frequency of T790M mutation of patients with local progression was significantly higher (P=0.031). Conclusions:The patients with EGFR mutations after the first generation of EGFR-TKI-acquired resistance of NSCLC were evaluated for their plasma EGFR mutation status, and the overall T790M mutation rate of was 36.51%. The frequency of T790M mutation with initial mutation of 19 del was higher than that of L858R mutation and other mutations, and local progression was higher than that in patients with gradual progression and dramatic progression.
| S-EPMC7138969 | biostudies-literature
Project description:PurposeTissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples.Materials and methodsWe conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)-based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305). Sample characteristics and PCR-CGP performance were assessed across all tested samples, including exception samples not meeting minimum input quality control (QC) requirements (< 20% tumor content [TC], < 2 mm2 tumor surface area [TSA], DNA or RNA yield < 1 ng/µL, or specimen age > 5 years). Tests reporting ≥ 1 prioritized alteration or meeting TC and sequencing QC were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting ≥ 1 actionable or informative alteration or meeting TC and sequencing QC were considered actionable.ResultsAmong 31,165 (97.2%) samples where PCR-CGP was attempted, 10.7% had < 20% TC and 59.2% were small (< 25 mm2 tumor surface area). Of 31,101 samples evaluable for input requirements, 8,089 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.5% of exception samples. Positive predictive value of PCR-CGP for ERBB2 amplification in exceptions and/or sequencing QC-failure breast cancer samples was 96.7%. Importantly, 84.0% of tested prostate carcinomas and 87.9% of lung adenocarcinomas yielded results informing treatment selection.ConclusionMost real-world tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for > 94% of samples, potentially expanding the proportion of CGP-testable patients and impact of biomarker-guided therapies.
| S-EPMC8384401 | biostudies-literature
Project description:BackgroundThis prospective, post-marketing observational study in Japanese patients aimed to evaluate the safety and effectiveness of daily afatinib use in general practice.MethodsThis non-interventional study (NCT02131259) enrolled treatment-naïve and pre-treated patients with inoperable/recurrent EGFR mutation-positive NSCLC, eligible for afatinib treatment as per the afatinib label in Japan. Patients received afatinib at the approved dose (20, 30, 40, or 50 mg/day; physician decision), and were observed following treatment initiation for 52 weeks or until premature discontinuation. Primary endpoint was the incidence of adverse drug reactions (ADRs). Secondary endpoints included ADRs of special interest, and objective response rate (ORR). Post hoc Cox multivariate analyses were used to assess prognostic factors associated with the incidence of ADRs.Results1602 patients, at 374 sites (April 2014-March 2015), were included in the analysis; 307 (19%) were aged ≥ 75 years. The most frequently reported ADRs (all/grade 3-4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and nail effects (38%/4%). Serious ADRs resulting in death occurred in 18 patients (1%). 762 patients (48%) had ≥ 1 afatinib dose reduction and 366 (23%) discontinued due to ADRs; the most common reason for both was diarrhea (8.2% and 6.7%, respectively). ORR was 40.1%.ConclusionsReal-world treatment of 1602 Japanese patients with afatinib was associated with a predictable ADR profile. Afatinib showed effectiveness in inoperable/recurrent EGFR mutation-positive NSCLC, especially as first-line treatment. As with other EGFR TKIs, prompt management of adverse events is needed in the Japanese population, to reduce serious events and outcomes, including interstitial lung disease.
| S-EPMC6597604 | biostudies-literature
Project description:BackgroundThe prevalence of EGFR mutations in circulating free tumor-derived DNA (ctDNA) was still unknown in China. This large-scale study (NCT02623257) aimed to explore the prevalence of epidermal growth factor receptor (EGFR) mutations and determine the correlation of EGFR mutation status with clinical characteristics.MethodsPlasma DNA samples from 1,001 patients with stage III/IV NSCLC who received ≤1st line chemotherapy were collected from 65 hospitals. EGFR mutations were tested by amplification refractory mutation system (ARMS) method. The EGFR mutation rate was calculated and the associations between EGFR status and patients' demographic data, disease status as well as treatment pattern were explored.ResultsEGFR mutations were detected in 251 of 1,001 (25.1%) patients, 26.8% in adenocarcinoma and 11.7% in squamous carcinoma. A total of 189 harbored sensitizing mutations alone, 28 had resistance mutations alone, 3 had a combination of activating mutations, and 31 had a combination of activating and resistance mutations. Higher detection rate was observed in chemotherapy-naïve patients than those received 1st line chemotherapy (27.0% vs. 18.0%; P=0.006). Of which, the mutation rate of exon 19 deletion was 9.31% for naïve patients and 7.37% for the 1st chemotherapy patients; while the mutation rate of L858R decreased obviously from 10.20% (naïve) to 3.69% (1st line). We also noticed the mutation rate was 37.1% in patients with ≥2 organ metastases. Multivariate analysis showed female, chemotherapy-naïve, or ≥2 metastatic organs patients had higher EGFR mutation rate.ConclusionsctDNA based EGFR mutation test is feasible and could be a surrogate when tissue biopsy is not available.
| S-EPMC6105939 | biostudies-literature
Project description:BackgroundRandomized phase III trials have established the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line treatment for EGFR mutation-positive advanced non-small-cell lung cancer (EGFR Mut+ NSCLC). This retrospective cohort study examined the management patterns and outcomes of patients with EGFR Mut+ NSCLC in a real-world setting.Materials and methodsData were extracted from the US Flatiron Electronic Health Record-derived database. Adult patients with stage IIIB/IV EGFR Mut+ NSCLC (exon 19 deletion or exon 21 L858R mutation) who had received first-line systemic therapy between 2011 and 2016 were included. Demographic and clinical characteristics were analyzed. Outcomes evaluated were time to next treatment (a surrogate for progression-free survival) and overall survival.ResultsOf the 22,258 patients with advanced NSCLC in the database, 961 met the inclusion criteria. Median age was 69.0 years (range: 61-78) and the majority were female (68.0%), with stage IV (93.9%), non-squamous cell carcinoma (97.4%). EGFR tyrosine kinase inhibitors were the most widely prescribed first-line therapy (72.8%). The likelihood of receiving an EGFR tyrosine kinase inhibitor or chemotherapy was unaffected by the type of medical insurance patients had. Patients treated with an EGFR tyrosine kinase inhibitor had significantly longer time to next treatment than those given other first-line systemic therapies (p < 0.0001). There were no significant differences in overall survival according to treatment type.ConclusionResults from this large US cohort study reflect those obtained in randomized trials of patients with advanced EGFR Mut+ NSCLC and demonstrate their transferability into a real-world setting.
| S-EPMC6319739 | biostudies-literature
Project description:BackgroundThe aims were to compare the consistency of epidermal growth factor receptor (EGFR) mutations in the plasma and tumor tissue of NSCLC patients, and to explore the prognostic significance of plasma EGFR mutation status in tyrosine kinase inhibitors (TKIs)-treated patients with tumor EGFR mutation.MethodsWe evaluated EGFR gene (exons 18, 19, 20 and 21) mutation status in paired plasma and tumor tissue from 94 NSCLC patients before EGFR-TKIs treatments using the Scorpion amplification refractory mutation system (Scorpion-ARMS) method.ResultsOur results demonstrated that the rates for EGFR mutations in 94 NSCLC patients were 20% (19/94, plasma samples) and 40% (38/94, tumor tissue samples), respectively. The consistency of EGFR mutations between plasma and tissue reached 80% (75/94, P<0.001). The sensitivity of tests using plasma samples was 50% (19/38) and the specificity was 100% (49/49) compared with tissue samples. 29 of the 38 patients were treated with TKIs. Among the 29 patients, 14 patients had EGFR mutations in both plasma and tumor tissue, and these patients had a significantly shorter overall survival (OS) than those with EGFR mutations in tumor tissue only by univariate analysis (P=0.019).ConclusionsOur data demonstrated the feasibility and potential utility of plasma cell-free DNA (cfDNA) as a source of specimens for EGFR mutation detection using the Scorpion ARMS method. Moreover, plasma EGFR mutation status before TKIs therapy might be of prognostic significance for TKIs-treated NSCLC patients with tumor tissue EGFR mutation.
| S-EPMC4680457 | biostudies-literature
Project description:BackgroundTargeted agents have improved the outcome of a subset of non-small cell lung cancer (NSCLC). Molecular profiling by next-generation sequencing (NGS) allows screening for multiple genetic alterations both in tissue and in plasma, but limited data are available concerning its feasibility and impact in real-world clinical practice.MethodsPatients with advanced NSCLC consecutively referring to our Institution for potential eligibility to VISION trial (NCT02864992) were prospectively enrolled. They were already screened with standard method, and EGFR/ALK/ROS-1 positive cases were excluded. NGS was performed in plasma and tissue using the Guardant360 test covering 73 genes and the Oncomine Focus Assay covering 59 genes, respectively.ResultsThe study included 235 patients. NGS was performed in plasma in 209 (88.9%) cases; 78 of these (37.3%) were evaluated also in tissue; tissue only was analyzed in 26 cases (11.1%). Half of the tissue samples were deemed not evaluable. Druggable alterations were detected in 13 (25%) out of 52 evaluable samples and 31 of 209 (14.8%) of plasma samples. Improved outcome was observed for patients with druggable alterations if treated with matched targeted agents: they had a longer median overall survival (not reached) compared with the ones who did not start any targeted therapy (9.1 months; 95% confidence interval, 4.6-13.6; p = .046). The results of NGS testing potentially also affected the outcome of patients treated with immunotherapy.ConclusionSystematic real-life NGS testing showed the limit of tissue analysis in NSCLC and highlighted the potentiality of genetic characterization in plasma in increasing the number of patients who may benefit from NGS screening, both influencing the clinical decision-making process and affecting treatment outcome.Implications for practiceGenetic characterization of cancer has become more important with time, having had positive implications for treatment specificity and efficacy. Such analyses changed the natural history of advanced non-small cell lung cancer (aNSCLC) with the introduction of drugs targeted to specific gene alterations (e.g., EGFR mutations, ALK and ROS-1 rearrangements). In the field of cancer molecular characterization, the applicability of the analysis of a wide panel of genes using a high-throughput sequencing approach, such as next-generation sequencing (NGS), is still a matter of research. This study used NGS in a real-world setting to systematically and prospectively profile patients with aNSCLC. The aim was to evaluate its feasibility and reliability, as well as consequent access to targeted agents and impact on clinical outcome whenever a druggable alteration was detected either in tumor tissue samples or through liquid biopsy.
| S-EPMC8108051 | biostudies-literature
Project description:AimsTo evaluate the suitability of malignant pleural effusion (MPE) and plasma as surrogate samples for epidermal growth factor receptor (EGFR) mutation detection, and compare three different detection methods.MethodsMatched tissue and plasma samples were collected from patients with advanced non-small cell lung cancer (NSCLC) (stage IIIB/IV adenocarcinoma/adenosquamous carcinoma), with matched MPE samples collected from a subgroup. DNA was extracted from tissue, MPE cell block, MPE supernatant and plasma before mutation detection by amplification refractory mutation system (ARMS) (all samples), Sanger sequencing and mutant-specific immunohistochemistry (IHC) (tissue and MPE cell blocks only).ResultsSensitivity of MPE cell block, MPE supernatant and plasma versus tissue: 81.8% (9/11), 63.6% (7/11) and 67.5% (27/40); specificity was 80.0% (8/10), 100% (10/10) and 100% (46/46), respectively. Sensitivity of Sanger sequencing versus ARMS: 81.8% (27/33) for tissue, 40% (4/10) for MPE cell blocks; specificity was 100% (36/36 and 12/12) for both. Sensitivity of mutant-specific IHC versus ARMS: 54.8% (17/31) for tissue, 50.0% (6/12) for MPE cell blocks; specificity was 97.1% (34/35) and 100% (14/14), respectively.ConclusionsMPE and plasma are valid surrogates for NSCLC tumour EGFR mutation detection when tissue is not available. ARMS is most suitable for mutation detection in tissue and MPE cell blocks; however, mutant-specific IHC could be a complementary method when DNA-based molecular testing is unavailable.
| S-EPMC3841772 | biostudies-literature
Project description:BackgroundWe investigated the clinical characteristics and treatment outcomes of Korean patients receiving first-line afatinib for advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) in a real-world setting.MethodsElectronic case reports were retrospectively reviewed from patients across 15 sites in South Korea. Outcome measures included baseline characteristics, overall response rate (ORR), time-to-treatment discontinuation (TTD), and overall survival (OS). Subgroups were: presence/absence of brain metastases at baseline, dose reductions, and baseline EGFR mutation category.ResultsAmong 422 patients, 39.8% had brain metastases and 59.0%/25.1%/10.0%/5.0% had Del19/L858R/compound/uncommon EGFR mutations at baseline. ORR was 62.6% overall; responses were observed across all EGFR mutation categories, including against compound mutations. Median TTD was 17.8 months; median OS was not reached (NR). Median TTD and OS were longer in patients without versus with brain metastases (TTD: 22.9 vs. 14.8 months, P=0.001; OS: NR vs. 40.3 months, P=0.0009) and patients with versus without dose reductions (TTD: 22.2 vs. 14.2 months, P=0.0004; OS: NR vs. 40.3 months, P=0.0117). Median OS was 30.5/37.7 months in patients receiving chemotherapy/osimertinib as subsequent therapy. The most common treatment-related adverse events (TRAEs; any grade/grade ≥3) were diarrhea (31.3%/8.5%) and rash (23.0%/8.1%). Overall, 34 patients (8.1%) discontinued afatinib due to AEs.ConclusionsAfatinib was well tolerated with no new safety signals, and efficacy was encouraging in Korean patients with EGFRm+ NSCLC, including those with baseline brain metastases and/or uncommon EGFR mutations. AE management with dose reductions facilitated a long TTD, prolonging the chemotherapy-free period for many patients.
| S-EPMC8743522 | biostudies-literature