Approximately 25% of cancer-related deaths in the United States are attributed to lung cancer.1 With the advent of first-line targeted therapies, however, there have been improvements in the survival of select patients with lung adenocarcinoma.2 Many biomarkers have been discovered that predict response to targeted therapies; one of the most predominant biomarkers in lung cancer is epidermal growth factor receptor (EGFR).
EGFR mutations have been reported in approximately 50% of Asian patients as well as in 10% to 20% of white patients with non–small-cell lung cancer (NSCLC).3 These mutations are more common in women, patients with adenocarcinoma, and never-smokers.4 Exon 19 deletions (del19) and exon 21 L858R substitutions are the most frequently observed sensitizing EGFR mutations, occurring in up to 90% of patients harboring an EGFR mutation.5,6
Clinical trials of the tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib have demonstrated an improvement in progression-free survival in patients who harbor sensitizing EGFR mutations compared with patients receiving conventional cytotoxic chemotherapy.7-9 In these studies, disease progression occurred on average between 9 and 13 months of treatment.7-9 The most common mechanism of resistance is the presence of an acquired mutation in exon 20 at position 790 with a threonine-to-methionine substitution (T790M).10,11
Typically, EGFR T790M mutations are diagnosed after initiating an oral TKI treatment for NSCLC that is associated with an EGFR mutation.12
The current clinical practice guidelines recommend osimertinib, a third-generation, small-molecule, oral TKI, as first-line therapy for newly diagnosed patients with a sensitizing EGFR mutation.13 This recommendation is based on the results of the FLAURA study, which demonstrated improved progression-free survival with osimertinib compared with the first-generation TKIs erlotinib and gefitinib.14
Unlike first- or second-generation TKIs (eg, afatinib, dacomitinib), osimertinib targets del19, L858R, as well as the acquired EGFR T790M mutation.15 Before the FLAURA clinical trial results were published, osimertinib was reserved for patients whose disease progressed after receiving a first- or a second-generation TKI, if the patient harbored the acquired EGFR T790M mutation.16
We present a case of a patient with lung adenocarcinoma and EGFR T790M mutation before exposure to therapy.
A 72-year-old white man presented with newly diagnosed stage IV NSCLC. The patient had a medical history of stage IIB (pT2pN1Mx) breast cancer, for which he had a right partial mastectomy, chest wall radiation, adjuvant chemotherapy with doxorubicin and cyclophosphamide, and 5 years of treatment with tamoxifen. Over the subsequent 10 years, he had no evidence of breast cancer recurrence.
The patient’s additional comorbidities included gastroesophageal reflux disease (GERD), aortic insufficiency, benign prostatic hyperplasia, hemorrhoids, osteoarthritis, macular degeneration, hypertension, palpitations, hypothyroidism, seborrheic keratoses, and erectile dysfunction.
He was receiving several maintenance medications, including lisinopril 15 mg orally daily, bisoprolol 2.5 mg orally daily, omeprazole 20 mg orally twice daily, levothyroxine 50 mcg orally daily, and sodium chloride 1-gram tablets orally 3 times daily. The patient also received vitamin D3 and a multivitamin, and used clobetasol 0.05% cream twice daily. Ondansetron, acetaminophen, and calcium carbonate antacids were available, as needed. The patient was allergic to ciprofloxacin, which caused headache and fever.
Before his NSCLC diagnosis, the patient was initially evaluated for symptoms of GERD, weight loss, and anemia. An esophagogastroduodenoscopy revealed patchy, mildly erythematous mucosa, without bleeding in the stomach. An abdominal computed tomography (CT) scan showed signs of lung and liver metastases. A dedicated chest CT scan revealed multiple pulmonary masses, with a dominant right upper-lobe spiculated mass measuring up to 4 cm with mediastinal, hilar, and supraclavicular adenopathy. Bilateral adrenal masses and a right thyroid mass were also visualized.
In addition to the concern for a new primary lung cancer, the suspicion of recurrent breast cancer was high, given the elevations in his cancer antigens 15-3 (507 units/mL) and cancer antigen 19-9 (84.1 units/mL) at the time. The patient was a never-smoker, although he was exposed to heavy secondhand smoke throughout his childhood.
A follow-up PET/CT scan detected a 2.9-cm lesion in the left frontal lobe of the brain, consistent with metastatic disease. 18F-fluorodeoxyglucose–avid activity was also noted in his adrenal glands, bone, thyroid, and liver, as well as in the subcarinal, hilar, paratracheal, retrocrural, mesenteric, pelvic, and retroperitoneal lymph nodes. Subsequent brain magnetic resonance imaging (MRI) revealed 9 lesions within the white matter and subcortical white matter, with the largest (measuring 2.9 × 2.9 cm) in the temporal lobe.
Based on the MRI results, whole-brain radiation was initiated with dexamethasone treatment. The patient received 30 Gy in 10 fractions of 3 Gy once daily for 13 days, followed by a 15-day dexamethasone taper. Biopsies of his cervical and thyroid masses revealed adenocarcinoma of pulmonary origin. Programmed cell death ligand 1 (PD-L1) assay (22C3 pharmDX) revealed a PD-L1 tumor proportion score of 65% (Table 1).
Additional pathology analysis of the patient’s thyroid tissue using next-generation sequencing (NGS) showed an EGFR exon 21 L858R (13.5%) mutation (Table 2). Although the patient had not been previously exposed to an EGFR TKI, he also had an EGFR T790M (13.5%) mutation at diagnosis (Table 2).
After radiation and the dexamethasone taper were complete, the patient started receiving osimertinib 80-mg tablet once daily to target the EGFR driver mutations, and to penetrate his central nervous system (CNS) for the treatment of the brain metastasis.
After 2 months of treatment, a repeated CT scan of the chest, abdomen, and pelvis showed a decrease in the right upper-lobe mass and the bilateral adrenal lesions. The right upper-lobe mass decreased from 3.9 × 3.3 cm to 3.3 × 2.4 cm, and the left adrenal mass decreased from 5.1 cm to 3.3 cm. A right adrenal mass measuring 3.1 × 2 cm was also seen (previous size was not described in the CT report). Diminution of the left pelvic and retroperitoneal adenopathy was noted. The patient reported increased energy and decreased malaise.
Treatment with osimertinib was continued at 80 mg orally once daily. Approximately 1 month after the initiation of osimertinib, the patient had anorexia and low-grade nausea. During the subsequent 2 months, he began to lose weight and had additional nausea.
A repeated CT of the chest and abdomen showed progressive disease, with a new large pleural effusion in the hemithorax. In the chest, a new right upper-lobe mass was noted measuring 7.1 × 7.6 × 6.1 cm, and new mediastinal adenopathy was also seen. The left adrenal mass remained consistent in size, but the right adrenal lesion grew to 5.7 × 3 cm.
The effusion was drained, and the osimertinib treatment was discontinued because of disease progression. Less than 1 month later, the supporting treatment measures were withdrawn because of the patient’s rapid decline in health, resulting in his death.
The frequency of pretreatment EGFR T790M mutations is currently unknown. The incidence of EGFR T790M mutations varies widely in the literature, depending on the patient population being evaluated, as well as the means of mutation detection.17,18 For example, studies using direct sequencing detected de novo EGFR T790M in 0.4% to 4% of all patients with NSCLC.12,19,20 The rate increased to 1% to 8% among patients with EGFR-positive disease.12,20
In studies using polymerase chain reaction (PCR), the detection rate of EGFR T790M mutations among patients with EGFR-positive NSCLC ranged from 0% to 35%.19,21,22 In the study in which an EGFR T790M mutation was not detected in any of the samples using PCR, 79% of the same samples tested positive for the EGFR T790M mutation when colony hybridization was used.21
Dong and colleagues discussed the use of droplet digital PCR (ddPCR) testing as another ultrasensitive method for the detection of de novo EGFR T790M mutations.23 In their study, the ddPCR assay identified a higher percentage of de novo EGFR T790M than amplification refractory mutation system-PCR (19.6% vs 2.2%, respectively; P = .04).23 Lee and colleagues emphasize the importance of the use of ddPCR to confirm the presence of de novo EGFR T790M mutations.24 The study showed that 68.6% of EGFR-positive tumor samples harbored an EGFR T790M mutation when reexamined with ddPCR.24
Ye and colleagues conducted a study to detect the presence of de novo EGFR T790M mutations in patients with NSCLC.25 The detection methods used included digital PCR, which detected EGFR T790M mutations in 42 of 109 (38.5%) pretreatment samples. The investigators concluded that the use of digital PCR is a sensitive and pragmatic method for the detection of EGFR mutations.25 Further support for digital PCR is provided by 2 studies that showed detection rates of 79.9% and 100% for EGFR T790M mutation.26,27
Highly sensitive assays are more likely to detect small numbers of cells with an EGFR T790M mutation within a heterogeneous tumor-cell population.18 The clinical significance of these subclones is unknown, especially when the high false-positive rate of ultra-high sensitive detection methods is considered.18 Molecular studies of our patient demonstrated EGFR exon 20 T790M (13.5%) and EGFR exon 21 L858R (13.5%) mutations.
In addition to somatic mutations, de novo germline EGFR T790M mutations have been rarely reported.28,29 The National Comprehensive Cancer Network’s evidence-based clinical practice guidelines for NSCLC recommend genetic counseling for patients with pretreatment EGFR T790M mutation, because it may indicate a predisposition for familial lung cancer.13
Pretreatment EGFR T790M mutations coexist with EGFR L858R mutations more often than with del19, which was the case with our patient.6,24,30 EGFR T790M mutations alter the binding affinity of the receptor in favor of adenosine triphosphate (ATP) over TKI, leading to relative drug resistance.31 In addition, the affinity for ATP promotes EGFR phosphorylation, leading to enhanced downstream-signaling pathways and ultimately to disease progression.32 These factors may have an impact on a patient’s prognosis.33
Data from a meta-analysis reveal shorter progression-free survival (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.44-3.45; P <.001) and shorter overall survival (HR, 1.55; 95% CI, 1.16-2.07; P = .003) in patients with de novo EGFR T790M mutations in all treatment lines than in patients without EGFR T790M mutations.33 Progression-free survival was also shorter in response to first-line treatments in the patients with EGFR T790M mutations versus patients without EGFR T790M mutations (HR, 1.91; 95% CI, 1.23-2.97; P = .004). Liu and colleagues reported some heterogeneity in the data pooled for this meta-analysis.33 In addition, the detection method for EGFR varied among the studies, and the patient characteristics were asymmetrical.33
The data are limited regarding the management of de novo EGFR T790M–positive NSCLC. The clinical trials combined in the meta-analysis by Liu and colleagues evaluated gefitinib and erlotinib.33 Progression-free survival and overall survival were shorter in patients with de novo EGFR T790M than in patients with acquired EGFR T790M after treatment with these agents.33 The studies, however, were conducted before the FDA’s approval of osimertinib.
Case reports of patients with NSCLC and de novo EGFR T790M mutations are few, and the treatment for this patient population remains difficult. In reports of patients with NSCLC and de novo EGFR T790M mutations, first-generation TKIs, such as erlotinib and gefitinib, were initiated but ultimately resulted in disease progression.17,33,34 In these evaluations, progression occurred within 2 to 6 months.17,33,34
In the AURA3 study by Mok and colleagues of patients with EGFR T790M–positive NSCLC and CNS metastases, treatment with osimertinib produced stability in disease symptoms and a partial response to therapy.16 Senoo and colleagues presented the report of a patient with carcinomatous meningitis of lung adenocarcinoma who received chemoradiotherapy.35 The patient started treatment with osimertinib for more than 1 year, which led to improvements in her condition. A PCR analysis showed that the EGFR T790M mutation was essentially depleted in the cerebrospinal fluid; this is the first known report to confirm the ability of osimertinib to clear the EGFR T790M mutation from the cerebrospinal fluid.35
A case report presented by Noguchi and colleagues further demonstrated the effect of osimertinib in the treatment of de novo EGFR T790M mutations in a patient with lung cancer and brain metastases.36 After initiating treatment with osimertinib, MRI scans revealed a partial response to therapy, with decreased brain metastases.36
Our patient had metastatic disease in the brain and completed whole-brain radiation treatment in addition to receiving treatment with corticosteroids. Our patient discontinued therapy because of disease progression, and further testing results were not collected.
The European BELIEF clinical trial was a phase 2, single-arm study that evaluated the efficacy and safety of erlotinib plus bevacizumab in patients with advanced EGFR mutation–positive adenocarcinoma of the lung.22 Pretreatment EGFR T790M mutation was detected using peptide nucleic acid probe-based 5-nuclease real-time PCR. The primary outcome of progression-free survival was analyzed in the intention-to-treat population and was stratified according to pretreatment EGFR T790M status. De novo EGFR T790M mutation was present in 37 (34%) of the 109 patients enrolled in the study.22
The results revealed longer progression-free survival in patients with pretreatment EGFR T790M mutation than in those without this mutation (16.0 months; 95% CI, 12.7-not estimable vs 10.5 months; 95% CI, 9.4-14.2; P = .016). Rosell and colleagues propose that the longer progression-free survival in the patients with EGFR T790M mutation is because of enhanced vascular endothelial growth factor activity that results from signaling through the EGFR T790M mutation plus another activating EGFR mutation.22
Wang and colleagues conducted a retrospective investigation of TKI therapy in patients with de novo and acquired EGFR T790M mutations.30 EGFR mutations were detected by a direct sequencing and amplification refractory mutation system. Of the 5685 patients diagnosed with NSCLC and EGFR mutation, 61 (1.1%) had de novo EGFR T790M mutations. Of these patients, 18 received treatment with osimertinib. The progression-free survival and overall survival in these patients were compared with the survival of 72 patients who received osimertinib for acquired EGFR T790M–resistant disease.30
The results showed longer progression-free survival in the patients with de novo EGFR T790M than in those with acquired disease (17 months; 95% CI, 14-20 vs 10 months; 95% CI, 8.6-11.4; P = .022).30 The overall survival, however, was significantly shorter in the population with de novo EGFR T790M mutation versus those with acquired EGFR T790M (29.9 months; 95% CI, 19-40.8 vs 50.4 months; 95% CI, 37.8-63; P = .016). This difference may be partially explained by the initial response to first-line therapy in patients with acquired resistance. As expected, the median progression-free survival was only 2 months in those with de novo EGFR T790M mutation who received first-generation TKI treatment compared with 14 months in those with the acquired EGFR T790M mutation (P <.001).30
Ye and colleagues compared the outcomes of osimertinib therapy in a patient with a de novo EGFR T790M mutation versus a patient who did not harbor the EGFR T790M mutation at baseline.25 The patient with de novo EGFR T790M mutation received treatment with osimertinib for 18 months before disease progression. The patient without an EGFR T790M mutation received treatment with osimertinib and continued to respond to treatment at 33 months.25
A total of 12 patients received osimertinib as second-line therapy because of disease progression after taking a first-generation TKI. Before initiating treatment with osimertinib, tumor and blood samples revealed that all 12 patients had an EGFR T790M mutation. The median progression-free survival with osimertinib as second-line treatment was 15.4 months.25
The results of the phase 2 AZENT clinical trial may help to clarify the role of osimertinib in the management of NSCLC with de novo EGFR T790M mutation.37 This study evaluated the objective response rate to osimertinib in treatment-naïve patients with advanced NSCLC who harbor sensitizing EGFR and EGFR T790M mutations. Although the study was terminated early, patients with NSCLC and de novo EGFR T790M mutation who received first-line osimertinib therapy had an overall response rate of 73.3% and an overall progression-free survival of 23.1 months.37
Additional research is needed to determine the optimal treatment for patients with metastatic NSCLC and EGFR T790M mutation. Treatment with osimertinib produced a short-lived response of approximately 4 months in our patient.
The frequency of de novo EGFR T790M mutation varies broadly, because of the different detection methods available. Evidence suggests that the most sensitive methods to detect de novo EGFR T790M mutations include direct sequencing, PCR, colony hybridization, and ddPCR. The optimal detection of EGFR mutations has yet to be determined to ensure that potentially treatable subclones are known before treatment selection.
As pharmacotherapy continues to develop and becomes more targeted, determining resistance patterns on a molecular level, as well as detecting de novo EGFR T790M mutations, remain important points to consider when selecting treatment regimens. Further research is needed to determine if there is a link between familial lung cancer and male breast cancer, which may affect outcomes in this patient population.
Author Disclosure Statement
Dr Boshar is an employee of and has stocks in Sanofi; Dr Katiaj, Dr Cooper, and Dr Gehr have no conflicts of interest to report.
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- Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol. 2020;61:167-179.
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- Chen LY, Molina-Vila MA, Ruan SY, et al. Coexistence of EGFR T790M mutation and common activating mutations in pretreatment non-small cell lung cancer: a systematic review and meta-analysis. Lung Cancer. 2016;94:46-53.
- Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.
- Rosell R, Carcereny E, Gervais R, et al; for the Spanish Lung Cancer Group in collaboration with the Groupe Français de Pneumo-Cancérologie and the Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239-246.
- Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.
- Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786-792.
- Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247.
- Su KY, Chen HY, Li KC, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non–small-cell lung cancer. J Clin Oncol. 2012;30:433-440. Erratum in: J Clin Oncol. 2015;33:2124.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer. Version 5.2022. September 26, 2022. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed November 29, 2022.
- Soria JC, Ohe Y, Vansteenkiste J, et al; for the FLAURA investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113-125.
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- Mok TS, Wu YL, Ahn MJ, et al; for the AURA3 investigators. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629-640.
- Saxena A, Nagasaka M, Li Z, et al. Double trouble: a case of concurrent de novo T790M and L858R EGFR mutations in treatment-naive advanced non–small-cell lung cancer. Oncology (Williston Park). 2014;28:526,528,530,534.
- Yu HA, Arcila ME, Hellmann MD, et al. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol. 2014;25:423-428.
- Inukai M, Toyooka S, Ito S, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non–small cell lung cancer. Cancer Res. 2006;66:7854-7858.
- Wu JY, Yu CJ, Chang YC, et al. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutation of unknown clinical significance in non–small cell lung cancer. Clin Cancer Res. 2011;17:3812-3821.
- Fujita Y, Suda K, Kimura H, et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J Thorac Oncol. 2012;7:1640-1644.
- Rosell R, Dafni U, Felip E, et al; for the BELIEF collaborative group. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017;5:435-444. Erratum in: Lancet Respir Med. 2018;6:e57.
- Dong Y, Zhou Z, Wang J, et al. Origin of the T790M mutation and its impact on the clinical outcomes of patients with lung adenocarcinoma receiving EGFR-TKIs. Pathol Res Pract. 2019;215:946-951.
- Lee SH, Kim EY, Kim A, Chang YS. Clinical implication and usefulness of de novo EGFR T790M mutation in lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutation. Cancer Biol Ther. 2020;21:741-748.
- Ye L, Ardakani NM, Thomas C, et al. Detection of low-level EGFR c.2369 C > T (p.Thr790Met) resistance mutation in pre-treatment non-small cell lung carcinomas harboring activating EGFR mutations and correlation with clinical outcomes. Pathol Oncol Res. 2020;26:2371-2379.
- Watanabe M, Kawaguchi T, Isa SI, et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non–small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res. 2015;21:3552-3560.
- Iwama E, Takayama K, Harada T, et al. Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR. Oncotarget. 2015;6:20466-20473.
- Oxnard GR, Miller VA, Robson ME, et al. Screening for germline EGFR T790M mutations through lung cancer genotyping. J Thorac Oncol. 2012;7:1049-1052. Erratum in: J Thorac Oncol. 2012;7:1206.
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- Sakashita S, Shiba-Ishii A, Murata Y, et al. Case report of three EGFR TKI naïve lung adenocarcinoma containing double EGFR mutations (L858R/T790M or exon 19 deletion/T790M); comparing genetic information and histology. Pathol Res Pract. 2018;214:1224-1230.
- Liu Y, Sun L, Xiong ZC, et al. Meta-analysis of the impact of de novo and acquired EGFR T790M mutations on the prognosis of patients with non-small cell lung cancer receiving EGFR-TKIs. Onco Targets Ther. 2017;10:2267-2279.
- Lammers PE, Lovly CM, Horn L. A patient with metastatic lung adenocarcinoma harboring concurrent EGFR L858R, EGFR germline T790M, and PIK3CA mutations: the challenge of interpreting results of comprehensive mutational testing in lung cancer. J Natl Compr Canc Netw. 2014;12:6-11; quiz 11.
- Senoo S, Ohashi K, Nishii K, et al. Osimertinib depletes EGFR T790M in the spinal fluid of patients with carcinomatous meningitis of lung adenocarcinoma harboring de novo EGFR T790M. J Thorac Oncol. 2018;13:e140-e142.
- Noguchi S, Kawachi H, Fukao A, et al. Osimertinib administration as the primary epidermal growth factor receptor tyrosine kinase inhibitor therapy for brain metastasis of de novo T790M-positive lung cancer. Intern Med. 2019;58:3029-3031.
- Majem M, Sullivan I, Viteri S, et al. First-line osimertinib in patients with epidermal growth factor receptor–mutant non–small-cell lung cancer and with a coexisting low allelic fraction of Thr790Met. Eur J Cancer. 2021;159:174-181.