scholarly journals Vision Improvement after Osimertinib Treatment in Paraneoplastic Optic Neuropathy Associated with Lung Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Masaomi Kubota ◽  
Nobumasa Tamura ◽  
Takaaki Hayashi ◽  
Euido Nishijima ◽  
Haruhiko Yanagisawa ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Optic Neuropathy ◽  
Kinase Inhibitor ◽  
Metastatic Cancer ◽  
Resistance Mutation ◽  
Growth Factor Receptor ◽  
Visual Field Loss ◽  
Underlying Disease ◽  
Pattern Reversal ◽  
Egfr Tki

Treatments for paraneoplastic optic neuropathy (PON), a tumor-related autoimmune disease, include immunosuppression, plasma exchange, and immunoglobulin therapies, as well as treatment of the underlying disease. Herein, we describe the clinical course of an older adult patient with PON whose loss of vision improved after switching between epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatments for cancer. A 76-year-old woman, who had been treated with gefitinib for lung adenocarcinoma for two years, presented with acute bilateral visual disturbances. Her decimal best-corrected visual acuity (BCVA) was 0.3 in the right eye (RE) and 0.7 in the left eye (LE). Slit-lamp examination and funduscopy showed no abnormal findings. Two weeks later, her BCVA decreased to 0.2 in the RE and 0.01 in the LE. Goldman’s perimetry showed a defect in the lower nasal RE and extensive visual-field loss in the LE. Single-flash electroretinograms showed normal amplitudes. Magnetic resonance imaging revealed left optic neuritis and showed neither metastatic cancer nor multiple sclerosis. Pattern-reversal visual evoked potentials showed decreased P100 amplitudes in both eyes (BE). Based on a diagnosis of PON from clinical findings, methylprednisolone pulse treatment was administered. However, her BCVA became no light perception in BE two months after the first visit. Because the tumor tissue was found to be positive for the EGFR T790M resistance mutation by bronchoscopy, the EGFR-TKI treatment was changed to osimertinib, decreasing the size of the lung cancer lesions. Her BCVA improved to hand motion in BE. Her final BCVA was 0.01 in the RE, counting fingers 10 cm in the LE. She died at the age of 79 years. To our knowledge, no reports have shown improvement in BCVA in patients with PON after changing EGFR-TKI treatments. This report indicates that some patients may develop severe visual dysfunction without early treatment for the primary tumor.

Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21082-e21082
Author(s):  
Yue Mei Sun ◽  
Ming Xiu Zhou ◽  
Ming Zeng
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Mutant ◽  
Egfr Tki

e21082 Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone

scholarly journals Lung adenocarcinoma in a patient with Li–Fraumeni syndrome bearing a novel germ-line mutation, TP53R333Vfs*12

2020 ◽  
Vol 50 (10) ◽  
pp. 1214-1217 ◽  
Author(s):  
Shodai Takahashi ◽  
Kazuhiro Shimazu ◽  
Koya Kodama ◽  
Koji Fukuda ◽  
Taichi Yoshida ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Germ Line ◽  
Growth Factor Receptor ◽  
Triple Mutant ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni ◽  
Egfr Tki

Abstract Germline mutations of TP53 are responsible for Li–Fraumeni syndrome in its 60–80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.

scholarly journals DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Sk. Kayum Alam ◽  
Yongchang Zhang ◽  
Li Wang ◽  
Zhu Zhu ◽  
Christina E. Hernandez ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Clinical Problem ◽  
Oncogenic Signaling ◽  
Before And After ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-refractory lung adenocarcinoma (LUAD) progression is a major clinical problem. New approaches to predict and prevent acquired resistance to EGFR TKIs are urgently needed. Here, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 (HER3) to EGFR to mediate switching from EGFR homodimers to EGFR:ERBB3 heterodimers to bypass EGFR TKI-mediated inhibition by potentiating ERBB3-dependent activation of oncogenic signaling. In paired LUAD patient-derived specimens before and after EGFR TKI-refractory disease progression, we reveal that DARPP-32 and kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired resistance. In mice, DARPP-32 ablation sensitizes gefitinib-resistant xenografts to EGFR TKIs, while DARPP-32 overexpression increases gefitinib-refractory LUAD progression in gefitinib-sensitive lung tumors. We introduce a DARPP-32-mediated, ERBB3-dependent mechanism the LUAD cells use to evade EGFR TKI-induced cell death, potentially paving the way for the development of therapies to better combat therapy-refractory LUAD progression.

Activity of osimetrinib/AZD9291 in pretreated patients (pts) with epidermal growth factor receptor mutant (EGFRmt) non-small cell lung cancer (NSCLC), according to EGFR mutations detected in circulating plasma DNA (ctDNA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20608-e20608
Author(s):  
Emmanouil Kontopodis ◽  
Jordana Nuria ◽  
Aliki Ntzifa ◽  
Panayiotis Katsaounis ◽  
Charalambos Haris Charalambous ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Resistance Mutation ◽  
Growth Factor Receptor ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Plasma Dna ◽  
T790m Mutation ◽  
Egfr Tki ◽  
Egfr Tkis

e20608 Background: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI), selective for EGFR TKI-sensitizing mutations and the T790M resistance mutation. We sought to determine the activity of osimertinib after progression on EGFR TKIs in pts with T790-negative ctDNA. Methods: A multicenter phase II study ( clinicaltrials.gov NCT02771314) of osimertinib (80 mg daily) was conducted in pts with metastatic EGFRmt NSCLC, who had progressed after previous treatment with EGFR TKIs. Serial serum and/or plasma samples were drawn for ctDNA analysis at enrollment, 1 month and every 3 months of treatment, until disease progression. Efficacy outcomes in pts without the T790M mutation in ctDNA at baseline are reported. Results: Thirty-seven NSCLC patients with undetectable baseline T790M in the plasma have been enrolled. Median age was 67 years, 21.6% were male, and histology was adenocarcinoma in 100%. More frequent adverse events (grade 1/2) included diarrhea (12.5%), fatigue (12.5%), anorexia (12.5%) and acneiform rash (10.4%). The overall response rate (ORR) was 40.5% (95% CI, 24.7-56.4%) and the disease stabilization rate 37.8%; the median progression-free survival (PFS) was 8.9 months (range, 1.6-30), and the estimated median overall survival (OS) 26 months (range, 2.2-30). At enrollment, EGFR mutations del19 and L858R were detected in ctDNA in 9 and 3 pts, respectively. After one month of treatment with osimertinib, EGFR mutations in ctDNA were not detectable in 4/9 and 2/3 of pts with del19 and L858R at baseline, respectively. Pts without detectable EGFRm ctDNA at baseline remained negative throughout the study. Efficacy according to baseline ctDNA status was as follows: Clinical trial information: NCT02771314. Conclusions: Osimertinib was effective in EGFR TKI pretreated pts without EGFR T790M mutation in plasma. Pts with detectable del19 or L858R mutations in ctDNA before treatment had worse clinical outcomes, despite the elimination of EGFRmt ctDNA.[Table: see text]

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Suzhi Li ◽  
Chen Kan ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Cxcl8 Secretion ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), which is the thorny challenge to propel the treatment of lung adenocarcinoma (LUAD) forward. In the tailored targeting era, the strategy of EGFR-TKI combined regimen was considered the promising approach to conquer the big aforesaid question. The mechanism of SHP2 involved in the cell proliferation, cytokine production, stemness maintenance and drug resistance of LUAD was not yet fully explored.Methods: To determine the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing were performed to explore the mechanism of SHP2 promoted stemness.Results: This study demonstrated that high SHP2 indicates poor outcome of LUAD patients, and enriched in Osimertinib resistant LUAD cells. Moreover, SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. Furthermore, SHP2 facilitates the CXCL8 secretion of EGFR T790M mutant LUAD which derived from a CXCL8-CXCR1/2 positive feedback loop that promoted the stemness and tumorigenesis. Finally, we found SHP2 inhibited ERK-AKT-NFκB and GSK3β-β Catenin pathways in EGFR T790M mutant LUAD cells, inactivation of NF-κB confers to a blockage of CXCL8-CXCR1/2 loop, and stemness limited by restricting GSK3β/β-Catenin signaling.Conclusions: Our data revealed that inhibition of SHP2 enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may provide an alternative option to promote the efficacy of osimertinib in clinic of EGFR T790M mutant LUAD.

scholarly journals Early serum tumor marker levels after fourteen days of tyrosine kinase inhibitor targeted therapy predicts outcomes in patients with advanced lung adenocarcinoma

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0240736
Author(s):  
Hung-Jen Chen ◽  
Chih-Yen Tu ◽  
Kuo-Yang Huang ◽  
Chun-Ru Chien ◽  
Te-Chun Hsia
Keyword(s):  
Targeted Therapy ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Ca 125 ◽  
Mutation Status ◽  
Anaplastic Lymphoma

Objective Image evaluation strategy for lung cancer patients has difficulty obtaining the appropriate quantity of diffuse lung nodules and bone metastases. The study was to demonstrate whether early variations in the levels of serum 4-tumor markers (4-TMs)(carcinoembryonic antigen [CEA], cancer antigen [CA]125, CA19-9, and CA15-3) after TKI targeted therapy were associated with treatment response in patients with lung adenocarcinoma. Methods Patients with stage IIIB-IV lung adenocarcinoma taking epidermal growth factor receptor (EGFR) TKIs or anaplastic lymphoma kinase (ALK) inhibitors were enrolled prospectively from June 2012 to February 2015. According to the variations of the percentage of change in 4-TM levels (4-TMpc), we divided patients into ascending (increases in 4-TMpc over the 7th- 14th day) and descending (decreases in 4-TMpc over the 7th- 14th day) groups. Results 184 patients were enrolled, and 89% had at least one of the pre-treatment evaluable TMs and were further analyzed. An excellent response to the TKI targeted therapy was accurately predicted in the descending group, as determined using receiver operating characteristic curve analysis (an area under the curve, 0.83). Multivariate Cox hazards model analyses demonstrated that the type of 4-TMpc and mutation status were the strongest predictors of progression-free survival (PFS)(descending versus ascending, hazard ratios [HR] 0.30, 95% confidence interval [CI], 0.19–0.47; sensitive mutation versus wide type, HR 0.30, 95% CI, 0.19–0.48). Conclusions Type of 4-TMpc 14 days after TKI targeted therapy is associated with an image response and PFS, without regarding mutation status, in patients with advanced lung adenocarcinoma.

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