Histological transformation of lung adenocarcinoma to small cell lung cancer with mutant C797S conferring acquired resistance to osimertinib

Epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer may initially respond to EGFR tyrosine kinase inhibitors (TKIs), but may subsequently become resistant; however, the resistance mechanisms remain unclear. We report a rare case of acquired resistance to osimertinib associated with transformation to small cell lung cancer (SCLC) with cis-C797S mutation. A man with recurrent lung adenocarcinoma harboring an EGFR exon 19 deletion received erlotinib for 10 months following curative surgery and adjuvant chemotherapy. However, he switched to osimertinib after repeat biopsy showed EGFR exon 19 deletion and T790M mutation leading to erlotinib resistance. His disease progressed after 15 months and repeat biopsy showed SCLC. Next-generation sequencing of peripheral blood detected EGFR exon 19 deletion, T790M mutation, cis-C797S mutation, and RB1 inactivation. The tumor was reduced after four cycles of etoposide and cisplatin and his respiratory symptoms improved. However, computed tomography after six cycles of chemotherapy showed multiple bilateral lung lesions, and single-photon emission computed tomography showed bone metastasis. The patient received paclitaxel plus cisplatin for two cycles with partial response. Because heterogeneous genetic and phenotypic mechanisms of TKI-resistance may occur at different times and locations, histopathological and molecular testing both provide evidence to support appropriate treatment.

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Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

Future Oncology ◽

10.2217/fon-2020-0203 ◽

2020 ◽

Vol 16 (21) ◽

pp. 1537-1547

Author(s):

Fumio Imamura ◽

Madoka Kimura ◽

Yukihiro Yano ◽

Masahide Mori ◽

Hidekazu Suzuki ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitors ◽

Egfr Mutation ◽

Acquired Resistance ◽

Small Cell ◽

Small Cell Lung ◽

T790m Mutation ◽

Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

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The impact of EGFR exon 19 deletion subtypes on clinical outcomes in non-small cell lung cancer

Translational Lung Cancer Research ◽

10.21037/tlcr-19-359 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1149-1158

Author(s):

Chao Zhao ◽

Tao Jiang ◽

Jiayu Li ◽

Yan Wang ◽

Chunxia Su ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Exon 19 Deletion ◽

The Impact ◽

Exon 19

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Immunotherapy Combined with Chemotherapy as a Promising Therapy for a EGFR Exon 19 Deletion with MET Amplification Patient with Non-Small-Cell Lung Cancer: A Case Report

OncoTargets and Therapy ◽

10.2147/ott.s243988 ◽

2020 ◽

Vol Volume 13 ◽

pp. 3039-3044 ◽

Cited By ~ 1

Author(s):

QingTao Ni ◽

Chi Pan ◽

ShengBin Dai ◽

Peng Wang

Keyword(s):

Lung Cancer ◽

Case Report ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Met Amplification ◽

Exon 19 Deletion ◽

Exon 19

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Survival benefit of gefitinib treated non-small-cell lung cancer patients with exon 19 deletion mutations in epidermal growth factor receptor (EGFR), detected by a new sensitive PCR-based method

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10614 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10614-10614

Author(s):

E. Nakajima ◽

M. Sugita ◽

R. Dziadziuszko ◽

M. Tsuboi ◽

H. Kato ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Survival Benefit ◽

Objective Response ◽

Small Cell ◽

Small Cell Lung ◽

Deletion Mutations ◽

Exon 19 Deletion ◽

Exon 19

10614 Background: As for two common types of EGFR mutations, patients with exon 19 deletion mutations have longer survival than those with the L858R point mutations in exon 21 after treatment with EGFR inhibitors. We have developed a simple, polymerase chain reaction (PCR)-based method to detect exon 19 deletion mutations, and evaluated survival benefit of gefitinib treated patients with exon 19 deletion mutations versus patients without these mutations. Patients and methods: Tumor tissue was microdissected under stereoscopic microscopy from formalin-fixed paraffin-embedded sections, and DNA was extracted from tumor cells with DNeasy (Qiagen). Our method consisted of two different semi-nested PCRs with the deletion screening PCR and the common deletion specific PCR. All of the known deletions present in cell lines were detected by this method without direct sequencing. The result was validated by sequencing of exon 19. 73 non-small-cell lung cancer (NSCLC) Japanese patients treated with gefitinib were analyzed with this method. Study group consisted of 28 females (38%), 29 never smokers (40%) and 57 patients with adenocarcinoma (78%). Results: The PCR-based method detected mutations at mutant to wild type DNA copy ratio of 1/600, and in samples as small as 30 ng of purified DNA. Exon 19 deletion mutations were found in 25 (34%) patients. This method was more sensitive than conventional sequencing. The sequencing was performed in 19 patients with mutations and could not detect 3 deletions. Among 60 assessable patients 14 had overall response (23%). Objective response rates to gefitinib were observed in 7/21 patients with exon 19 deletion mutations (33%), and 7/39 patients without exon 19 deletion mutations (17%) (P = .211). Patients with exon 19 deletion mutations survived significantly longer than those without exon 19 deletion mutations (P = .017). Conclusions: The PCR-based method to detect exon 19 deletion mutations is cost effective and very sensitive, compared to previously described methods. We demonstrated survival benefit in NSCLC patients with exon 19 deletion mutations treated with gefitinib, and our PCR-based method is easily applicable for clinical use. No significant financial relationships to disclose.

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Complete Resolution of Sellar Metastasis in a Patient With NSCLC Treated With Osimertinib

Journal of the Endocrine Society ◽

10.1210/js.2019-00217 ◽

2019 ◽

Vol 3 (10) ◽

pp. 1887-1891

Author(s):

WuQiang Fan ◽

Jason Sloane ◽

Lisa B Nachtigall

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Complete Resolution ◽

Small Cell ◽

Deletion Mutation ◽

Illustrative Case ◽

Small Cell Lung ◽

Exon 19 Deletion ◽

Exon 19

Abstract Non–small cell lung cancer with pituitary metastasis (NSCLC-PM) is a devastating disease; however, treatment is being revolutionized by a novel therapy targeting highly specific tumor signals, such as the mutation of epidermal growth factor receptors (EGFRs). Long-term management of hormonal defects in this population has become a unique neuroendocrine clinical challenge. We report the case of a 73-year-old female nonsmoker who was diagnosed with stage IV non–small cell lung cancer. The initial staging evaluation revealed a 7 × 11 × 21-mm sellar lesion abutting the optic chiasm and causing clinical hypopituitarism. The patient received three cycles of chemotherapy with carboplatin and pemetrexed, which was discontinued because of major cumulative side effects of myelosuppression and kidney disease. Eight months later, scans demonstrated evidence of disease progression. A repeated lung nodule biopsy revealed an EGFR exon 19 deletion mutation. EGFR-targeted therapy with osimertinib 80 mg daily was initiated. A complete resolution of the pituitary lesion was evident on a follow-up pituitary MRI 5 weeks later and was sustained 1 year after. However, the panhypopituitarism persisted. This is an illustrative case of NSCLC-PM with EGFR exon 19 deletion mutation, wherein osimertinib, a third-generation EGFR‒tyrosine kinase inhibitor, eradicated the sellar metastasis and prevented the need for radiotherapy. However, the neuroendocrine deficits persisted despite anatomic improvement.

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Secondary T790M mutation and novel G796A mutation in exon20 of EGFR gene in patients with non-small cell lung cancer who show resistance to gefitinib

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7703 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7703-7703

Author(s):

H. Uramoto ◽

K. Sugio ◽

T. Oyama ◽

T. Iwata ◽

T. Onizuka ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Missense Mutation ◽

Cell Lung Cancer ◽

Acquired Resistance ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

T790m Mutation ◽

Egfr Gene

7703 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI. No significant financial relationships to disclose.

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