scholarly journals HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFRT790M Mutation

2012 ◽  
Vol 2 (10) ◽  
pp. 922-933 ◽  
Author(s):  
Ken Takezawa ◽  
Valentina Pirazzoli ◽  
Maria E. Arcila ◽  
Caroline A. Nebhan ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Potential Mechanism ◽  
Her2 Amplification ◽  
Lung Cancers ◽  
Egfr Inhibition ◽  
Egfr Mutant

Occurrence of HER2 amplification in EGFR-mutant lung adenocarcinoma with acquired resistence to EGFR-TKIs.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8047-8047 ◽  
Author(s):  
Giuseppe Altavilla ◽  
Carmela Arrigo ◽  
Chiara Tomasello ◽  
Mariacarmela Santarpia ◽  
Patrizia Mondello ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Egfr Mutations ◽  
Rapid Progression ◽  
Her2 Amplification ◽  
Egfr Inhibition ◽  
Egfr Mutant ◽  
Egfr T790m ◽  
Egfr Tkis

8047 Background: Patients with EGFR-mutant lung adenocarcinoma develop progression of disease on TKIs therapy after a median of 12 months;this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30% and a SCLC transformation in some pts. Recently, Takezawa and colleagues pointed out that HER2 amplification is a mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers without EGFR T790M mutation. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 41 lung adenocarcinomas pts. (20 male, 21 female, median age 55 years) with EGFR mutations at 19 or 21 exons received TKIs as first line of treatment. 31 pts. (75%) showed a clinical response and relapsed after a mTTP of 12 months. At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR, MET and HER-2 amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all 31 pts. retained their original activating EGFR mutations, 16 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 5, 4 pts. developed MET amplification, 3 pts. were found to have a diagnosis of small cell lung cancer. HER2 amplification was observed in four pts. (13%), with dramatic progression and a median OS of 5 months after treatment with CDDP + pemetrexed. Notably all 4 cases were EGFR T790M negative. Conclusions: Among pts. with acquired resistence to EGFR TKIs the presence of HER2 amplification defines a clinical subset with a more adverse prognosis and rapid progression. Interestingly, recent data suggest that afatinib combined with cetuximab could have promising activity in pts. with acquired resistance due to HER2 amplification.

Abstract 955: Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors

2014 ◽  
Author(s):  
Matthew J. Niederst ◽  
Lecia V. Sequist ◽  
Elizabeth L. Lockerman ◽  
Angel R. Garcia ◽  
Carlotta Costa ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Egfr Inhibitors ◽  
Lung Cancers ◽  
Egfr Mutant

scholarly journals P1.14-06 Tissue-Based Molecular and Histologic Landscape of Acquired Resistance to Osimertinib in Patients with EGFR-Mutant Lung Cancers

2019 ◽  
Vol 14 (10) ◽  
pp. S554
Author(s):  
A. Schoenfeld ◽  
J. Chan ◽  
H. Rizvi ◽  
R. Somwar ◽  
D. Kubota ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Lung Cancers ◽  
Egfr Mutant

Monitoring of plasma pro-GRP level during EGFR-TKI treatment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10604-10604
Author(s):  
Yuko Kawano ◽  
Atsushi Horiike ◽  
Azusa Tanimoto ◽  
Toshio Sakatani ◽  
Ryota Saito ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Receptor Gene ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Patient Characteristics ◽  
T790m Mutation ◽  
Lung Cancers ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

10604 Background: Lung cancers harboring mutations in the epidermal growth factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but drug resistance invariably emerges. The major acquired mechanisms of resistance are the EGFR T790M mutation or MET gene amplification. Transformation from NSCLC into small-cell lung cancer (SCLC) has been recently identified in acquired resistance to EGFR-TKI. However, it is difficult to predict the transformation during EGFR-TKI treatment because obtaining serial and sufficient specimens for biopsy is difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels could predict SCLC transformation in resistance to EGFR-TKI. Methods: From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC who received EGFR-TKI treatment were enrolled. Plasma was obtained from these patients before EGFR-TKI treatment and when EGFR-TKI treatment failed. Pro-GRP and CEA levels were measured and compared before and after treatment. Results: Patient characteristics for 49 patients (15 men, 34 women) were as follows: median age, 62 years (41–81 years); histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 patients had received EGFR-TKI treatment (45 with gefitinib and 4 with erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the Pro-GRP levels had increased after treatment, but the CEA level did not increase. Objective responses to cytotoxic chemotherapy were noted in all 3 patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma Pro-GRP during EGFR-TKI treatment may be useful for early detection of SCLC transformation in resistance to EGFR-TKI.

HER2 amplification in EGFR mutant NSCLC after acquired resistance (AR) to EGFR-directed therapies.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 9049-9049 ◽  
Author(s):  
Bing Xia ◽  
Anna Wurtz ◽  
Scott N. Gettinger ◽  
Roy S. Herbst ◽  
Anne C. Chiang ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Her2 Amplification ◽  
Egfr Mutant

Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR-mutant lung cancers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9028-9028 ◽  
Author(s):  
Adam Jacob Schoenfeld ◽  
Joseph Minhow Chan ◽  
Hira Rizvi ◽  
Natasha Rekhtman ◽  
Yahya Daneshbod ◽  
...  
Keyword(s):  
Initial Treatment ◽  
Tumor Tissue ◽  
Cell Transformation ◽  
Chromosomal Rearrangements ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Resistance Mutations ◽  
Mechanisms Of Resistance ◽  
Lung Cancers ◽  
Egfr Mutant

9028 Background: Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after developing acquired resistance to initial EGFR inhibitor. Further, studies of osi resistance to date have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements. Methods: To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had next-generation sequencing performed on tumor tissue after developing acquired resistance to osi. Results: From January 2016 to December 2018, post-osi tumor tissue was collected from 71 patients (42 with paired pre-treatment specimens). See mechanisms of resistance below. Histologic transformation was identified in 19% of initial cases and 14% of all cases. When osi is given as initial treatment, with median follow up of 17 months, early emerging MOR rarely included on-target resistance mechanisms (1/16 cases of acquired EGFR G724S). Acquired alterations representing potential resistance mechanisms included CCNE1 and MYC amplifications, and mutations in MTOR and MET H1094Y. We confirmed in preclinical studies that an amino acid substitution at MET H1094 can reduce sensitivity to osi. Conclusions: In this analysis of MOR identified on NGS from tumor tissue, we found a different spectrum of resistance mechanisms to initial and later-line osi, with histologic transformation (including squamous cell transformation) a dominant MOR, particularly in the first-line setting, that cannot be identified on plasma testing. Subsequent studies are needed to assess patients with a longer time on initial osi as there may be a temporal bias to MOR, with off-target MOR emerging earlier and on-target resistance mutations later. [Table: see text]

Managing Resistance to EFGR- and ALK-Targeted Therapies

2017 ◽  
pp. 607-618
Author(s):  
Christine M. Lovly ◽  
Puneeth Iyengar ◽  
Justin F. Gainor
Keyword(s):  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Mechanisms Of Resistance ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ablative Therapies ◽  
Egfr Mutant

Targeted therapies have transformed the management of non–small cell lung cancer (NSCLC) and placed an increased emphasis on stratifying patients on the basis of genetic alterations in oncogenic drivers. To date, the best characterized molecular targets in NSCLC are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Despite steady advances in targeted therapies within these molecular subsets, however, acquired resistance to therapy is near universal. Recent preclinical models and translational efforts have provided critical insights into the molecular mechanisms of resistance to EGFR and ALK inhibitors. In this review, we present a framework for understanding resistance to targeted therapies. We also provide overviews of the molecular mechanisms of resistance and strategies to overcome resistance among EGFR-mutant and ALK-rearranged lung cancers. To date, these strategies have centered on the development of novel next-generation inhibitors, rationale combinations, and use of local ablative therapies, such as radiotherapy.

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