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.

Clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20588-e20588
Author(s):  
Linping Gu ◽  
Bei Zhang ◽  
Ding Zhang ◽  
Hong Jian
Keyword(s):  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
De Novo ◽  
Egfr Mutations ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Genetic Characteristics ◽  
Egfr Mutant ◽  
Lung Adenocarcinomas ◽  
Egfr T790m

e20588 Background: Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the resistance mechanism of EGFR tyrosine kinase inhibitors. However, the clinical course of transformed SCLC and the difference of genomic profiling between de novo SCLC patients and transformed SCLC patients are still poorly characterized. Methods: Patients from our hospital diagnosed with SCLC were enrolled retrospectively in this study, including de novo SCLC patients and SCLC patients transformed from EGFR-mutant lung adenocarcinomas. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples by next generation sequencing (NGS). In statistical analysis, fisher ‘exact test was used. All tests were bilateral, with P<0.05 indicating significant statistical difference. Results: In total, 16 patients with SCLC transformed from EGFR-mutant lung adenocarcinomas and 230 de novo SCLC patients were included in our study. Transformed SCLC patients were more in younger (p=0.007), female (p<0.001) and non-smokers (p<0.001) than de novo SCLC patients. In transformed SCLC patients, 12 patients (75%) occurred SCLC transformation within 2 years after the lung adenocarcinomas diagnosis. Median transformation time was 20 months. During the treatment of adenocarcinomas, the overall response rate (ORR) was 75% and the median progression-free survival was 12 months. After the initiation of SCLC therapy, the ORR of 1st line chemotherapy was 40%. For the genomic profiling, EGFR mutations, including exon 19 deletion (56%), L858R (38%), and others (6%), were detected. 11 patients with acquired resistance were received EGFR T790M test, 82% of patients had acquired EGFR T790M mutation. 11 patients after transformation to SCLC had NGS test, 100% maintained their founder EGFR mutation, and other recurrent mutations included TP53, RB1 and EGFR amplification. Compared with the genetic alterations in de novo SCLC patients, TP53 mutations were significantly decreased (p=0.006) while EGFR mutations were significantly elevated (p<0.001) in transformed SCLC patients. However, no significant difference on RB1, ALK and ROS1 mutations were observed. Interestingly, a 60-year-old woman in our transformed SCLC cohort harbored EGFR 19 del mutant at allele frequency of 50.39%，she received osimertinib plus epirubicin/cyclophosphamide as 1st line treatment and reached partial response, with survival of 4 years to date. Conclusions: We demonstrated the clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC and found one patient still benefited from EGFR-TKI. Our study suggested that SCLC patients with EGFR mutation who transformed from lung adenocarcinoma may be potential benefit population using EGFR inhibitors.

A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) for patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8036-8036 ◽  
Author(s):  
Melissa Lynne Johnson ◽  
Eric M Hart ◽  
Alfred Rademaker ◽  
Bing Bing Weitner ◽  
Alexandra Urman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Hsp90 Inhibitor ◽  
Stage Ii ◽  
Egfr Mutations ◽  
Egfr Mutant ◽  
Egfr T790m ◽  
Egfr Tkis

8036 Background: AUY922 is a synthetic HSP90 inhibitor that degrades client onco-proteins including EGFR. Preclinical studies demonstrate HSP90 inhibitors are effective agents against models of AR in EGFR-mutant lung cancer cell lines and xenografts harboring the “gatekeeper” mutation EGFR T790M. Pts with EGFR mutations who develop AR often continue E with 2nd-line therapies to avoid “disease flare” associated with discontinuing TKI. This phase II study combines AUY922 and E for the treatment of pts with EGFR-mutant lung cancer and RECIST-progression on 1st-line EGFR TKIs. Methods: Eligible pts had EGFR mutations and developed AR (Jackman, JCO 2010) after treatment with EGFR TKIs. Pts underwent tumor biopsies after developing AR and prior to study entry. Pts received AUY922 70 mg/m2 IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment occurred at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR+PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (≥2 responses needed to proceed to stage II), stage II: 9 pts; α=10%, β=10%, p0=10%, p1=30%). Tumor tissue from re-biopsy at study entry was analyzed for EGFR T790M. Results: Sixteen pts have been treated (10 women, median age 58 [range 47-76]). The median time on EGFR-TKI prior to the development of AR was 12 mo (range 2-42 mo). Seven pts had EGFR T790M confirmed by tumor re-biopsy. ORR was 2/16 (13%, 95% CI 2-37%). Both pts with PR had EGFR T790M. Four other pts had stable disease for at least 8 wks, two remain on study after more than 12 wks. Adverse events reported in ≥20% of pts were diarrhea, fatigue, myalgias, nausea, and transient flashing lights or night blindness. One pt each experienced grade 3 diarrhea and cardiac abnormalities. Conclusions: AUY922 and E is a well-tolerated regimen for pts with EGFR-mutant lung cancer and AR to EGFR TKIs. Two pts remain on study and 9 additional pts will be accrued in stage II; final response rate and survival outcomes will be reported. Supported by Novartis, Inc. Clinical trial information: NCT01259089.

scholarly journals O.01: Acquired Resistance to EGFR-TKIs in EGFR-Mutant Lung Adenocarcinoma Among Hispanics (RBIOP-CLICaP)

2016 ◽  
Vol 11 (10) ◽  
pp. S168 ◽  
Author(s):  
Andrés F. Cardona ◽  
Oscar Arrieta ◽  
Martín I. Zapata ◽  
Leonardo Rojas ◽  
Beatriz Wills ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Acquired Resistance ◽  
Egfr Mutant ◽  
Egfr Tkis

Incidence, characteristics, and survival of patients with EGFR-mutant lung cancers with EGFR T790M at diagnosis identified in the lung cancer mutation consortium (LCMC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8085-8085
Author(s):  
Mark G. Kris ◽  
Geoffrey R. Oxnard ◽  
Bruce E. Johnson ◽  
Lynne D Berry ◽  
Heidi Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Stage Iv ◽  
Egfr Mutations ◽  
Lung Cancers ◽  
Exon 20 ◽  
Egfr Mutant ◽  
Egfr T790m ◽  
Exon 19

8085 Background: Somatic T790M mutations are detected in 62% of EGFR-mutant lung cancers with acquired resistance to EGFR TKIs, and have rarely been identified in the tumor at diagnosis and/or within the germline DNA. Multiplexed genotyping by the LCMC permitted us to evaluate the incidence of T790M at diagnosis, co-mutations, and survival of patients with this driver. Methods: The 14 member LCMC prospectively tested tumors of patients with lung adenocarcinomas in CLIA laboratories for mutations in EGFR and 9 other genes. We assayed T790Mby Sequenom, Snapshot, or Sanger sequencing. Germline DNA was not collected. Results: In the 987 tumors tested, 209 had mutations in EGFR alone: 25 T790M (2.5%) , 157 sensitizing EGFR mutations (exon 19 del, L858R, L861Q, G719X) without T790M, 23 exon 20 ins, 4 other mutations. 13 additional cases harbored mutations in EGFR and another driver; 2 with both T790M and PIK3CA. In each of the 27 EGFR-mutant cases with T790M, a coincident EGFR mutation was detected (18 exon 19 del, 9 L858R, 1 exon 20 ins). EGFR T790M was found more often than EGFR exon 20 ins or mutations in HER2 (1.9%), BRAF (1.6%), or PIK3CA (0.7%). Patients with T790M: 77% women, 81% never smokers, median age 55 (range 38-79), stage IV at diagnosis 81%, PS 0/1 100%. Characteristics did not differ from persons with sensitizing mutations and no T790M. Median survival from the diagnosis of metastatic disease for patients with EGFR-mutant lung cancers was 3.5 yrs with T790Mand 4.0 yrs without (p=0.926). Conclusions: T790M mutations were detected at diagnosis in 3% of adenocarcinomas and always coincident with another EGFR mutation. Cases with T790M represent 13% of all cases of EGFR- mutant lung cancer. Characteristics and survival for patients with EGFR- mutant lung cancers with T790M at diagnosis were similar to individuals with sensitizing mutations and no T790M. The observed incidence of T790M exceeded that of the other actionable targets HER2, BRAF, and PIK3CA. Trials should study this unique population identified by routine multiplexed genotyping. Supported by 1RC2CA148394-01 and the National Lung Cancer Partnership. Clinical trial information: NCT01014286.

Quantification of circulating free and circulating tumor DNA in pretreated EGFR mutant NSCLC to inform patient outcomes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9080-9080
Author(s):  
Alexandra Pender ◽  
Curtis Hughesman ◽  
Elaine Law ◽  
Amadea Kristanti ◽  
Kelly McNeil ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Limit Of Detection ◽  
Resistance Mutation ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Egfr Mutations ◽  
Mutational Status ◽  
Egfr Mutant ◽  
Egfr T790m

9080 Background: EGFR T790M testing is standard of care for EGFR mutant (EGFRm) NSCLC progressing on 1st/2nd generation TKIs to select patients for osimertinib. Circulating free DNA (cfDNA) levels are measured prior to circulating tumour DNA (ctDNA) testing using droplet digital PCR (ddPCR) to measure activating/resistant EGFR mutations. We reviewed cfDNA levels and ctDNA mutational status to determine the influence on patient outcome. Methods: Following extraction of cfDNA from plasma using the QIAamp Circulating Nucleic Acid Kit, cfDNA levels are measured with a Qubit 2.0 Fluorometer. Custom ddPCR assays were used to test for the appropriate EGFR activating mutation and the EGFR T790M resistance mutation using the Bio-Rad QX200 system. The custom designed ddPCR assays have a limit of detection of < 0.1% variant allele fraction. All patients undergoing ctDNA testing from February-December 2018 were identified. Baseline characteristics and follow up data were collected retrospectively. OS was calculated from date of metastatic diagnosis to death/last follow-up. Results: 142 patients with EGFR mutant adenocarcinoma had EGFR ctDNA testing: results 52% indeterminant, 32% T790M, 16% activating EGFRm only. At the time of testing: median age 66, 64% female, 57% never smokers 53% Asian; systemic treatment (tx) 62% first line only, 25% two lines and 13% ≥ three lines. First TKI therapy: 32% afatanib, 66% gefitinib, 2% erlotinib. Median cfDNA concentration was 5.65 ng/ml (range 0.50-217.72). The 5 yr OS was 72% below cfDNA median and 25% above the median. Tx after ctDNA testing for below and above cfDNA median: 52 vs 33% original TKI, 34 vs 55% osimertinib, 14 vs 12% other systemic tx. Multivariate analysis shows that even accounting for age, sex and ctDNA mutation result, cfDNA concentration remains an independent predictor of outcome (HR 2.36, 95% CI 1.08-5.18, p = 0.032). Conclusions: cfDNA concentration can predict patient outcome in patients with EGFR mutant NSCLC progressing on TKI regardless of ctDNA testing results. Clinicians may consider switching to chemotherapy for patients with high cfDNA and without detectable EGFR T790M ctDNA to avoid missing the window for therapy instead of awaiting repeat EGFR T790M testing

Transformation of advanced lung adenocarcinoma to acquired T790M resistance mutation adenosquamous carcinoma following tyrosine kinase inhibitor: a case report

2020 ◽  
pp. 030089162097326
Author(s):  
Qinghan Liu ◽  
Lin Wu ◽  
Suning Zhang
Keyword(s):  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Adenosquamous Carcinoma ◽  
Acquired Resistance ◽  
Tumor Resection ◽  
Resistance Mutation ◽  
Egfr Mutations ◽  
Type Conversion ◽  
Next Generation Sequencing Technology

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended for patients with non-small cell lung cancer with EGFR mutations. However, acquired resistance to EGFR-TKIs seems inevitable and the mechanism of drug resistance has not been fully defined. There is no effective treatment for patients with advanced lung adenocarcinoma who are resistant to TKIs owing to pathologic type conversion. Case presentation: We report a patient who was initially diagnosed with lung adenocarcinoma. At first, she was sensitive to the first-generation TKI icotinib. After 17 months of treatment, the patient acquired resistance to icotinib. Moreover, after tumor resection, immunohistochemical analysis showed pathologic change from adenocarcinoma to adenosquamous carcinoma, and next-generation sequencing technology discovered EGFR exon19 p.745-750 del, exon20 p.T790M, and KMT2C exon 18 p.R973G mutations. After video-assisted tumor resection, the patient is receiving osimertinib (AZD 9291). Current overall survival is 60 months. Conclusions: Surgical intervention may prolong survival time in patients with acquired TKI resistance, especially when there is no evidence of metastasis.

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

scholarly journals 439O Tracking spatiotemporal T790M heterogeneity in patients with EGFR-mutant advanced NSCLC after acquired resistance to EGFR TKIs

2016 ◽  
Vol 27 ◽  
pp. ix140
Author(s):  
Y.-C. Zhang ◽  
C. Pi ◽  
E.-E. Ke ◽  
Z.-H. Chen ◽  
J. Su ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Acquired Resistance ◽  
Egfr Mutant ◽  
Egfr Tkis

High PD-L1 expression correlates with primary resistance to EGFR-TKIs in treatment naïve advanced EGFR-mutant lung adenocarcinoma patients

Lung Cancer ◽  
2019 ◽  
Vol 127 ◽  
pp. 37-43 ◽  
Author(s):  
Kuo-Hsuan Hsu ◽  
Yen-Hsiang Huang ◽  
Jeng-Sen Tseng ◽  
Kun-Chieh Chen ◽  
Wen-Hui Ku ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Primary Resistance ◽  
Treatment Naïve ◽  
Egfr Mutant ◽  
Egfr Tkis

scholarly journals The combination of fibrinogen concentrations and the platelet-to-lymphocyte ratio predicts survival in patients with advanced lung adenocarcinoma treated with EGFR-TKIs

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110040
Author(s):  
Qiong He ◽  
Yamin Li ◽  
Xihong Zhou ◽  
Wen Zhou ◽  
Chunfang Xia ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Characteristic Curve ◽  
Performance Status ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Platelet To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Egfr Mutant ◽  
Egfr Tkis

Objective This study aimed to identify a predictive marker of response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant advanced lung adenocarcinoma. Methods A cohort of 190 patients with EGFR-mutant advanced lung adenocarcinoma was analyzed. Receiver operating characteristic curve analysis was used to evaluate the optimal cutoffs for fibrinogen levels, the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) for predicting progression-free survival (PFS). Univariate and multivariate survival analyses were performed to identify factors correlated with PFS and overall survival (OS). Results High NLR was associated with worse performance status. In univariate analysis, fibrinogen levels, NLR, and PLR were correlated with OS and PFS. In multivariate analysis, all three variables remained predictive of OS, whereas only fibrinogen levels and PLR were independent prognostic factors for PFS. Furthermore, the combination of fibrinogen levels and PLR (F-PLR score) could stratify patients into three groups with significantly different prognoses, and the score was independently predictive of survival. Conclusion The F-PLR score predicted the prognosis of patients with EGFR-mutant advanced lung adenocarcinoma who received EGFR-TKIs, and this score may serve as a convenient blood-based marker for identifying high-risk patients.

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