Factor Receptor-tyrosine Kinase Inhibitor Therapy Research Articles

Analysis of tumor abnormal protein expression and epidermal growth factor receptor mutation status in non-small cell lung cancer

BackgroundThe level of tumor abnormal protein (TAP) level has a significant impact on tumor growth, recurrence, and metastasis. Previous studies have highlighted the influence of the mutations in exons 19 and 21 of the epidermal growth factor receptor (EGFR), particularly the sensitivity displayed by tumor cells to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Our study is centered on exploring the clinical relevance of TAP and EGFR mutations in patients with non-small cell lung cancer (NSCLC).Material and methodsIn this study, tissue samples were collected from a total of 176 patients diagnosed with non-small cell lung cancer (NSCLC). Real-time PCR technology was utilized to detect mutations within exons 19 and 21 of the epidermal growth factor receptor (EGFR) gene in these samples. This approach enables precise identification of EGFR mutations associated with NSCLC. Furthermore, the study investigated the impact of various tumor markers, including tumor abnormal protein (TAP) and carcinoembryonic antigen (CEA), on EGFR mutation status. Established assays were employed to evaluate TAP and CEA levels, aiming to ascertain their potential correlation with EGFR mutation in NSCLC patients.ResultsEGFR exhibited mutation rates of 23.86% and 12.50% in exons 19 and 21, respectively. EGFR mutations were more prevalent in younger women (< 60 years old) and in cases with pleural invasion, vessel invasion, CEA > 6.5 ng/mL, and TAP > 228 µm2 for both genders. Increased TAP levels independently predicted EGFR mutations (P = 0.001 for males; P = 0.000 for females). An area under the curve (AUC) of 0.833 indecated EGFR mutation prediction with sensitivity and specificity of 79.7% and 87.0%, respectively. For females, the sensitivity increased to 89.7% and specificity increased to 93.8%.ConclusionsTAP effectively predicts EGFR mutations in NSCLC patients with moderate accuracy, particularly benefiting diagnosis in females with high sensitivity and specificity. Integrating TAP assessment into EGFR mutation testing can significantly enhance diagnostic precision, especially in female NSCLC cases.

Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1β. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Overall signature of acquired KRAS gene changes in advanced non-small cell lung cancer patient with EGFR-TKI resistance.

Numerous scattered case studies continue to demonstrate a strong correlation between acquired KRAS mutations and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in non-small cell lung cancer. However, the comprehensive understanding of the KRAS pathway following the failure of epidermal growth factor receptor-tyrosine kinase inhibitor therapy remains limited. We conducted a retrospective evaluation of the next generation sequencing data from 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations after experiencing progression with epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our analysis specifically focused on the acquired changes to the KRAS gene. Among the 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations who experienced resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy, 14 individuals (4.3%) developed resistance due to acquired KRAS alterations. Of these 14 patients, 10 cases (71.4%) were due to KRAS missense mutations, 1 case (7.2%) was due to KRAS gene fusion and 3 cases (21.4%) were due to KRAS amplification. Notably, we identified one newly demonstrated KRAS gene fusion (KRAS and LMNTD1), one KRAS G13D and one KRAS K117N. The emergence of acquired KRAS alterations was often accompanied by novel mutations and high tumor mutation burden, with TP53, CNKN2A, PIK3CA, MYC, STK11, CDK4, BRCA2 and ERBB2 being the most frequently observed concurrent mutations. The median progression-free survival and overall survival for the 14 patients were 5.2 and 7.3months, respectively. Acquired KRAS missense variants were associated with significantly worse progression-free survival compared with other KRAS variant subtypes (P<0.028). This study provides significant evidence of the role of acquired KRAS variants in the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our results contribute to the growing body of knowledge on the mutational profiles associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Furthermore, our study highlights the KRAS gene change as a significant mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Upfront Use of First-/Second-Generation EGFR-TKI Followed by Osimertinib Shows Better Prognosis than Upfront Osimertinib Therapy in Japanese Patients with Non-small-cell Lung Cancer with Exon 19 Deletion: A Single-Center Retrospective Study.

Clinical evidence on the increased efficacy of sequential epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is limited. This study aimed to compare the efficacy of upfront use of first-/second-generation TKI followed by osimertinib with upfront osimertinib therapy for each representative EGFR mutation in Japanese patients with NSCLC. Patients with EGFR-mutated NSCLC were classified into two groups: first-/second-generation TKI followed by osimertinib (sequential TKI group) and upfront osimertinib groups. The total time to treatment failure (TTF) of TKI therapies, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated. Of the 74 patients included in the analysis, 38 and 34 patients had exon 19 deletion and L858R, respectively, and other two patients had minor mutations. The sequential TKI group had a significantly longer TTF than the upfront osimertinib group in overall patients (33.2 vs. 11.2 months; p = 0.007) and in the subgroup of exon 19 deletion (36.7 vs. 10.0 months; p = 0.004), but not in the subgroup of L858R (22.6 vs. 15.6 months; p = 0.37). The similar tendency was observed in PFS. OS of the sequential TKI group was significantly longer compared with the upfront osimertinib group in overall patients, the subgroup of exon 19 deletion, and the subgroup of L858R. The upfront use of first-/second-generation TKI followed by osimertinib is one of the feasible and effective strategies in Japanese patients with EGFR-mutated NSCLC, especially in patients with exon 19 deletion.

Regional differences in epidermal growth factor receptor-tyrosine kinase inhibitor therapy in lung cancer treatment using a national database in Japan

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are extensively used in the treatment of non-small cell lung cancer (NSCLC); hence, equal access to them is important. Therefore, this study aimed to identify regional differences in the prescription of EGFR-TKIs and the factors contributing to these differences. In this ecological study, we collected data using the National Database Open Data and the National Cancer Registry. The standardized claim ratio (SCR) was used as an indicator of the number of EGFR-TKI prescriptions. Additionally, we examined the association between SCR and various factors to identify the factors associated with this difference. The average SCR for the top three provinces was 153.4, while the average for the bottom three provinces was 61.6. Multivariate analysis used for evaluating the association of SCR with variables revealed that the number of designated cancer hospitals and radiation therapies were independent factors associated with the SCR of EGFR-TKIs. There were significant regional differences in the prescriptions of EGFR-TKIs in Japan based on the number of coordinated designated cancer hospitals and the number of patients receiving radiotherapy alone. These findings emphasize the need to implement policies to increase the number of hospitals to reduce regional differences.

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study.

The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis

BackgroundMucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising...

Enhanced Sensitivity of Nonsmall Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors to Phenformin: The Roles of a Metabolic Shift to Oxidative Phosphorylation and Redox Balance

Background Although the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR- TKI) therapy has been proven in non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs presents a serious clinical problem. Hence, the identification of new therapeutic strategy is needed to treat EGFR-TKI-resistant NSCLC. Methods Acquired EGFR-TKI-resistant lung cancer cell lines (HCC827, H1993, and H292 cells with acquired resistance to gefitinib or erlotinib) were used for cell-based studies. IncuCyte live cell analysis system and XFp analyzer were used for the determination of cell proliferation and energy metabolism, respectively. In vivo anticancer effect of phenformin was assessed in xenografts implanting HCC827 and gefitinib-resistant HCC827 (HCC827 GR) cells. Results HCC827 GR and erlotinib-resistant H1993 (H1993 ER) cells exhibited different metabolic properties compared with their respective parental cells, HCC827, and H1993. In EGFR-TKI-resistant NSCLC cells, glycolysis markers including the glucose consumption rate, intracellular lactate level, and extracellular acidification rate were decreased; however, mitochondrial oxidative phosphorylation (OXPHOS) markers including mitochondria-driven ATP production, mitochondrial membrane potential, and maximal OXPHOS capacity were increased. Cell proliferation and tumor growth were strongly inhibited by biguanide phenformin via targeting of mitochondrial OXPHOS complex 1 in EGFR-TKI-resistant NSCLC cells. Inhibition of OXPHOS resulted in a reduced NAD+/NADH ratio and intracellular aspartate levels. Recovery of glycolysis by hexokinase 2 overexpression in erlotinib-resistant H292 (H292 ER) cells significantly reduced the anticancer effects of phenformin. Conclusion Long-term treatment with EGFR-TKIs causes reactivation of mitochondrial metabolism, resulting in vulnerability to OXPHOS inhibitor such as phenformin. We propose a new therapeutic option for NSCLC with acquired EGFR-TKI resistance that focuses on cancer metabolism.

Changes of Brain Structure in Patients With Metastatic Non-Small Cell Lung Cancer After Long-Term Target Therapy With EGFR-TKI.

PurposeEpidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the routine treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring positive EGFR mutations. Patients who undergo such treatment have reported cognitive decline during follow-up. This study, therefore, aimed to evaluate brain structural changes in patients receiving EGFR-TKI to increase understanding of this potential symptom.MethodThe medical records of 75 patients with metastatic NSCLC (without brain metastasis or other co-morbidities) who received EGFR-TKI therapy from 2010 to 2017 were reviewed. The modified Scheltens Visual Scale and voxel-based morphometry were used to evaluate changes in white matter lesions (WML) and gray matter volume (GMV), respectively.ResultsThe WML scores were higher at the 12-month [8.65 ± 3.86; 95% confidence interval (CI), 1.60–2.35; p < 0.001] and 24-month follow-ups (10.11 ± 3.85; 95% CI, 2.98–3.87; p < 0.001) compared to baseline (6.68 ± 3.64). At the 24-month follow-up, the visual scores were also significantly higher in younger patients (3.89 ± 2.04) than in older patients (3.00 ± 1.78; p = 0.047) and higher in female patients (3.80 ± 2.04) than in male patients (2.73 ± 1.56; p = 0.023). Additionally, significant GMV loss was observed in sub-regions of the right occipital lobe (76.71 voxels; 95% CI, 40.740–112.69 voxels), left occipital lobe (93.48 voxels; 95% CI, 37.48–149.47 voxels), and left basal ganglia (37.57 voxels; 95% CI, 21.58–53.57 voxels) (all p < 0.005; cluster-level false discovery rate < 0.05).ConclusionsAn increase in WMLs and loss of GMV were observed in patients with metastatic NSCLC undergoing long-term EGFR-TKI treatment. This might reflect an unknown side-effect of EGFR-TKI treatment. Further prospective studies are necessary to confirm our findings.

Meta-Analysis of Aidi Injection and First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapy in Treating Advanced Non-Small Cell Lung Cancer.

The combination of Aidi injection (ADI) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in treating non-small cell lung cancer (NSCLC) has been reported, but the effects of this therapy have not been systematically assessed. Randomized controlled trials (RCTs) published before June 2020 were searched from 6 databases. Two reviewers independently assessed the methodological quality of 8 RCTs involving 667 patients diagnosed with stage III-IV NSCLC. We found that ADI combined with EGFR-TKI increased the objective response rate (ORR) significantly (relative risk [RR]: 1.60; 95% confidence interval [CI]: 1.28-1.99, P < 0.0001). There was also improvement in the disease control rate (DCR) (RR: 1.25; 95% CI: 1.11-1.40, P = 0.0002) as compared with EGFR-TKI alone. This therapy also increased the percentage of CD3+ cells (weighted mean difference [WMD]: 9.86; 95% CI: 4.62-15.10), CD4+ cells (WMD: 6.10; 95% CI: 1.67-10.53), and the CD4+/CD8+ (WMD: 0.35; 95% CI: 0.28-0.43). With regard to drug toxicity, the occurrence of rash was significantly reduced by ADI combined with EGFR-TKI (RR: 0.78, 95% CI: 0.63-0.97, P = 0.03); however, we did not find a significant reduction in the occurrence of dry skin, nausea and vomiting, as well as diarrhea between the 2 therapies. ADI combined with first-generation EGFR-TKIs may be more effective in improving tumor response, reducing the occurrence of rash, and enhancing immune function in NSCLC than EGFR-TKI alone.

Chemotherapy should be performed in epidermal growth factor receptor mutation-positive lung adenocarcinoma patients who had progressive disease to the first epidermal growth factor receptor-tyrosine kinase inhibitor.

After the failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, some non-small cell lung cancer patients desire to receive switching with another EGFR-TKI (TKI-switching), although cytotoxic chemotherapy has been recommended as second-line therapy. It is unclear who should not receive TKI-switching in these patients. We retrospectively evaluated overall survival (OS) from the initiation of first EGFR-TKI (first-TKI) therapy in advanced lung adenocarcinoma patients with active EGFR mutations (deletion of exon 19 or L858R in exon 21) who received TKI-switching according to the best response of the first-TKI. There was no difference in the OS between patients receiving TKI-switching (n = 35) and patients receiving additional chemotherapy between the first-TKI and second-TKI therapy (n =10) (P = 0.614). Among patients receiving TKI-switching, the OS in cases with progressive disease to the first-TKI (n = 9) was shorter than that in cases with disease control to the first-TKI (n = 26) (12.7 months vs. 49.4 months, P < 0.001). Five of the nine progressive disease cases who received TKI-switching missed an opportunity to receive chemotherapy. Their OS tended to be shorter than that in patients who received chemotherapy during the whole period of anticancer therapy (12.2 months vs. 20.3 months, P = 0.060). The multivariate analysis showed that disease control to the first-TKI therapy (P = 0.005) or the presence of chemotherapy (P = 0.087) decreased the risk of mortality. Chemotherapy should be performed in patients with progressive disease to the first-TKI.

Statins use and its impact in EGFR-TKIs resistance to prolong the survival of lung cancer patients: A Cancer registry cohort study in Taiwan.

Statins have been shown to be a beneficial treatment as chemotherapy and target therapy for lung cancer. This study aimed to investigate the effectiveness of statins in combination with epidermal growth factor receptor‐tyrosine kinase inhibitor therapy for the resistance and mortality of lung cancer patients. A population‐based cohort study was conducted using the Taiwan Cancer Registry database. From January 1, 2007, to December 31, 2012, in total 792 non‐statins and 41 statins users who had undergone EGFR‐TKIs treatment were included in this study. All patients were monitored until the event of death or when changed to another therapy. Kaplan‐Meier estimators and Cox proportional hazards regression models were used to calculate overall survival. We found that the mortality was significantly lower in patients in the statins group compared with patients in the non‐statins group (4‐y cumulative mortality, 77.3%; 95% confidence interval (CI), 36.6%‐81.4% vs. 85.5%; 95% CI, 78.5%‐98%; P = .004). Statin use was associated with a reduced risk of death in patients the group who had tumor sizes <3 cm (hazard ratio [HR], 0.51, 95% CI, 0.29‐0.89) and for patients in the group who had CCI scores <3 (HR, 0.6; 95% CI, 0.41‐0.88; P = .009). In our study, statins were found to be associated with prolonged survival time in patients with lung cancer who were treated with EGFR‐TKIs and played a synergistic anticancer role.

Feasibility of Surgical Resection After Induction Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor Therapy for N2 Lung Adenocarcinomas

Prognosis of patients with stage IIIA-N2 lung adenocarcinoma is still not optimistic. The aim of this study was to evaluate safety, feasibility, and outcomes of surgery after induction epidermal growth factor receptor-tyrosine kinase inhibitor therapy in a clinical trial setting. Fourteen patients with IIIA-N2 lung adenocarcinoma and epidermal growth factor receptor mutation received erlotinib induction followed by surgery in a phase II clinical trial. Perioperative outcomes and survival results were compared with a control group of 15 patients receiving neoadjuvant chemotherapy during the same time period. Thirteen patients showed partial response toinduction, whereas 16 patients remained stable. Serum carcinoembryonic antigen level in the erlotinib group was significantly higher than in the chemotherapy groupbefore treatment but was reduced to similar levels after induction. Operation time, blood loss, resection extents, complete resection rates, postoperative drainage, complication rates, and length of hospital stay were allcomparable between the 2 groups. Thoracoscopic resection was accomplished in 78.6% of patients in theerlotinib group and 80.0% of patients in the chemotherapy group (P= .924) but was higher in patientswho responded to induction than those who did not (92.3% vs 68.8%, P= .119). A resection extent greater than lobectomy and incomplete resections wereonly seen in stable disease after induction. Nosignificant difference was detected in 1-year and 3-yearoverall or disease-free survivals between the 2groups. Pulmonary resection is safe and feasible after induction treatment with erlotinib for stage IIIA-N2 lung adenocarcinomas. Better surgical and oncologic outcomes may be expected in patients who respond to effective induction therapies.

Circulating plasma lncRNAs as novel markers of EGFR mutation status and monitors of epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

BackgroundEpidermal growth factor receptor (EGFR) gene mutations predict tumor response to EGFR tyrosine kinase inhibitors (EGFR‐TKIs) in non‐small cell lung cancer (NSCLC). However, even patients with EGFR‐sensitive mutations in NSCLC have limited efficacy with EGFR‐TKI. Studies have shown that long noncoding RNA (lncRNA) is related to diagnosis and prognosis with NSCLC. This study aimed to explore the correlation between lncRNA in NSCLC patients with EGFR mutation status and EGFR‐TKI efficacy.MethodsThe amplification‐refractory mutation system method was used to test the EGFR mutation status in tumor tissues and pleural effusions of NSCLC patients. Three EGFR‐mutant patients and three EGFR wild‐type patients were selected. Differential lncRNA was performed on the pleural effusions of the two selected groups of patients using Clariom D Human chip technology. Five lncRNAs significantly associated with EGFR mutation status were screened by FC value and GO analysis, and then evaluated by real‐time quantitative polymerase chain reaction in NSCLC patients' pleural effusions. Three were further analyzed in NSCLC patients' plasma.ResultsThere were 61 significant differences in lncRNA between EGFR mutation‐positive and wild‐type patients. Among them, SCARNA7, MALAT1, NONHSAT017369, NONHSAT051892, and FTH1P2 were significantly associated with EGFR mutation status. SCARNA7, MALAT1, and NONHSAT017369 showed consistent results with plasma in pleural effusions compared to EGFR wild‐type, all upregulated in the EGFR mutation group.ConclusionThis study shows that lncRNAs can be used not only as potential biomarkers for predicting the mutation status of EGFR and the efficacy of EGFR‐TKI, but also for monitoring the efficacy of EGFR‐TKI.

Metformin Prolongs Survival in Type 2 Diabetes Lung Cancer Patients With EGFR-TKIs.

Background: Metformin use reportedly reduces cancer risk and improves survival in lung cancer patients. This study aimed to investigate the effect of metformin use in patients with diabetes mellitus (DM) and lung cancer receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Methods: A nationwide, population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. From January 1, 2004, to December 31, 2012, a total of 373 metformin and 1260 non-metformin lung cancer cohorts with type 2 DM and EGFR-TKI treatment were studied. Results: Metformin use was significantly associated with a reduced risk of death (hazard ratio: 0.73, 95% confidence interval [CI]: 0.62-0.85, P < .001), as well as a significantly longer median progression-free survival (9.2 months, 95% CI: 8.6-11.7, vs 6.4 months, 95% CI: 5.9-7.2 months, P < .001) and median overall survival (33.4 months, 95% CI: 29.4-40.2, vs 25.4 months, 95% CI: 23.7-27.2 months, P < 0.001). Conclusions: In conclusion, metformin may potentially enhance the therapeutic effect and increase survival in type 2 DM patients with lung cancer receiving EGFR-TKI therapy.

Non–Small Cell Lung Cancer with Resistance to EGFR-TKI Therapy: CT Characteristics of T790M Mutation–positive Cancer

Purpose To evaluate the clinical and CT characteristics of T790M mutation-positive non-small cell lung cancer (NSCLC) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy failure. Materials and Methods A retrospective study of 304 patients with NSCLC who underwent rebiopsy after first-line EGFR-TKI therapy was conducted. Rebiopsy methods included CT- or fluoroscopy-guided lung biopsies (n = 105), endobronchial US- or bronchofibroscopy-guided biopsies (n = 66), pleural fluid analysis (n = 47), other solid organ biopsies (n = 43), US-guided axillary or supraclavicular lymph node biopsies (n = 31), and cerebrospinal fluid analysis (n = 12). CT findings at the initial diagnosis and rebiopsy were analyzed. Progression-free survival, the duration from the start of TKI therapy to rebiopsy, and survival were calculated. Results At rebiopsy, 144 (47.4%) patients were T790M mutation positive. The percentages of T790M mutation-positive NSCLCs were similar in 106 patients with rebiopsy of the lungs (53 [50%] of 106) and in 77 patients with rebiopsy of the primary lung lesions (36 [47%] of 77). T790M mutation positivity was associated with peripheral tumors (odds ratio [OR], 2.6; P = .01), pleural tag (OR, 5.0; P < .001), and air bronchogram (OR, 4.0; P = .006) at CT after TKI failure. The duration from the start of TKI therapy to rebiopsy was longer in T790M mutation-positive than in T790M mutation-negative patients (20.5 vs 13.6 months; P < .001). Cumulative survival from the time of rebiopsy to the last follow-up was significantly longer in patients with T790M mutation-positive lung cancers (P = .014). However, median survival time after rebiopsy was not statistically different between patients with and those without T790M mutation. Conclusion Peripheral tumor location with vascular convergence, the presence of a pleural tag, and air bronchogram of lung lesions at CT at the time of rebiopsy were significantly associated with T790M mutation in patients with non-small cell lung cancer after first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy failure. © RSNA, 2018 Online supplemental material is available for this article.

T790M Correlates with Longer Progression-free Survival in Non-small Cell Lung Carcinomas Harboring EGFR Mutations.

The aim of this study was to evaluate the relationship between T790M status and the characteristics of non-small cell lung cancer (NSCLC) patients undergoing rebiopsy after initial epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and whether the site of rebiopsy has an effect on the detection rate for T790M in these patients. We retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who had initially received EGFR-TKI at our Center from January 2009 to December 2016. Overall, 129 patients were included. The median age at EGFR-TKI therapy initiation was 73 years and 110 showed progressive disease. The presence of T790M mutation was associated with significantly longer progression-free survival (PFS) and EGFR mutation status. The participants' characteristics and rebiopsy site did not affect the T790M detection rate. It is highly recommended that patients with exon 19 deletions and long PFS undergo screening for T790M.

Current progress and outcomes of clinical trials on using epidermal growth factor receptor-tyrosine kinase inhibitor therapy in non-small cell lung cancer patients with brain metastases

Non-small cell lung cancer (NSCLC) continues to be one of the major causes of cancer-related deaths worldwide, and brain metastases are the major cause of death in NSCLC patients. With recent advances in understanding the underlying molecular mechanism of NSCLC development and progression, mutations in epidermal growth factor receptor (EGFR) have been recognized as a key predictor of therapeutic sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Using EGFR-TKI alone or in combination with standard treatments such as whole-brain radiotherapy and surgery has been an effective strategy for the management of brain metastasis. Particularly, a newer generation of EGFR-TKIs, including osimertinib and AZD3759, has been developed. These new EGFR-TKIs can cross the blood–brain barrier and potentially treat EGFR-TKI resistance and improve prognosis. In this article, current progress and outcomes of clinical trials on the use of EGFR-TKIs for treating NSCLC patients with brain metastasis will be reviewed.

Histone deacetylation, as opposed to promoter methylation, results in epigenetic BIM silencing and resistance to EGFR TKI in NSCLC.

Drug resistance remains a major challenge in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Bcl-2-like protein 11 (BIM), a B-cell lymphoma 2 family pro-apoptotic protein, is a prime target for specific anti-cancer therapeutics. However, the epigenetic regulation of BIM in non-small cell lung cancer (NSCLC) cell lines and patients with NSCLC in association with EGFR-TKI resistance requires investigation. Methylation-specific PCR (MSP), pyrosequencing, and nested quantitative (q)-MSP were conducted to explore the methylation status of BIM in NSCLC cell lines. In addition, the methylation profile of BIM in patients with NSCLC was assessed by nested q-MSP using circulating free DNA. Cell lines, treated with methylation inhibitor 5-Aza-2'-deoxycytidine (AZA) or histone deacetylation inhibitor trichostatin A (TSA) prior to gefitinib treatment, were examined for BIM gene expression and resistance to gefitinib. All cell lines used in the present study presented with hypo-methylated BIM. Treatment with AZA had no effect on BIM RNA expression in PC9 cells or the gefitinib-resistant cell lines PC9/R and PC9/G2, nor did it reverse their resistance to gefitinib. In contrast, TSA treatment produced the opposite result. In the present study, 25 (78.1%) patients with hypo-methylated BIM and 7 patients (21.9%) with partial or hyper-methylated BIM were identified. The clinicopathological data revealed a random hypo-methylated BIM distribution amongst patients with NSCLC. In the overall study group and EGFR mutant group, hypo-methylated BIM carriers presented with no significant differences in progression free survival compared with patients with partial or hyper-methylated BIM. All cell lines in the present study and the majority of patients with NSCLC carried hypo-methylated BIM. Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing of BIM and lead to EGFR TKI resistance in NSCLC.

Adverse Prognostic CT Findings for Patients With Advanced Lung Adenocarcinoma Receiving First-Line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapy.

The purpose of this study is to investigate adverse prognostic CT findings in patients with advanced-stage lung adenocarcinoma who are receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy as first-line therapy. We included 199 patients (71 men and 128 women; mean ± SD age, 64.3 ± 11.2 years) with stage IIIB or IV lung adenocarcinoma who received first-line EGFR-TKI therapy between January 2009 and December 2015. Clinical findings and imaging parameters on CT images obtained before TKI therapy were analyzed, including tumor size, TNM category according to the seventh edition of the American Joint Committee on Cancer lung cancer TNM staging system, tumor type, the presence of cavity or necrosis, pleural effusion, and metastasis to pleura, lung, and distant organs. Response evaluation was performed according to the Response Evaluation Criteria in Solid Tumor version 1.1 guidelines. Correlation of clinical and radiologic findings with durations of progression-free survival (PFS) and overall survival (OS) was evaluated using a Cox proportional hazard model. Pleural effusion (hazard ratio [HR], 2.095; 95% CI, 1.394-3.147; p < 0.001) and an N2 or N3 tumor category (HR, 2.145; 95% CI, 1.280-3.594; p = 0.004) were significantly associated with a short PFS duration in multivariate analysis. Older age (HR, 1.040; 95% CI, 1.014-1.067; p = 0.002), an N2 or N3 tumor category (HR, 2.427; 95% CI, 1.068-5.518; p = 0.034), pleural effusion (HR, 1.903; 95% CI, 1.105-3.276; p = 0.020), and distant metastasis (HR, 2.795; 95% CI, 1.356-5.765; p = 0.005) were associated with a short OS duration in multivariate analysis. Pre-TKI therapy CT findings of pleural effusion and high N-category tumors are associated with short durations of PFS and OS in patients with lung adenocarcinoma who are receiving EGFR-TKI therapy.