An Inherited Cancer Syndrome Due to a Germline Monoallelic EGFR Mutation with Loss of Heterozygosity in Lung and Breast Tumors

The epidermal growth factor receptor (EGFR) exon-19 deletion is one of the most common mutations detected in lung cancer patients. Although exon-19 deletion is frequently detected in adenocarcinoma, observing this mutation in germline cells is very rare. Besides, the co-occurrence of homozygous and heterozygous mutations in dual primary cancers in a person is very uncommon. This article presents a 53-year-old Iranian woman with no history of smoking who was diagnose with two primary cancers; invasive ductal carcinoma, and primary pulmonary lung adenocarcinoma. The case reported a history of breast cancer in her sister and a history of lung cancer in her father. To select the best choice of treatment the EGFR gene was analyzed with Sanger’s sequencing method from DNA extracted from the patient’s lung tissue sample. Observing two primary cancers in this patient and considering her family pedigree, germline cells were also analyzed using samples recruited from the patient’s peripheral blood to investigate any EGFR mutations in her germline cells. The obtained data revealed that the lung tissue of the patient carried a homozygous form of EGFR exon-19 deletion while her peripheral blood contained a heterozygous form of this mutation, which is exceptionally rare.

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Molecular changes in epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) biopsies at time of progression compared to initial biopsy

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22066 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22066-e22066

Author(s):

G. Speranza ◽

V. Cohen ◽

J. S. Agulnik ◽

G. Chong ◽

F. Meilleur ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Kinase Inhibitors ◽

Genetic Alterations ◽

Egfr Mutations ◽

Missense Mutations ◽

Molecular Changes ◽

Mutational Status ◽

Exon 19 Deletion ◽

Exon 19

e22066 Background: EGFR mutations predict sensitivity and clinical outcome to tyrosine kinase inhibitors (TKI) in NSCLC. The two most commonly described mutations are Exon 19 deletion and Exon 21 L858R missense mutations. Genetic alterations over time have been described in other tumour types, but studies assessing EGFR genotypic changes with lung cancer progression are lacking. We sought to compare EGFR mutational status from lung tumors at time of recurrence or progression with the primary tumor. Methods: Using the Jewish General Hospital lung cancer database, of all patients diagnosed with NSCLC since 1999, those with biopsies at two different points in time were identified. All tumour samples were genotyped for EGFR exons 19 and 21 mutations using denaturing high performance liquid chromatography (dHPLC). Results: 29 patients were identified. Data for 12 patients, whose time of recurrence or progression varied between 4 months and 6 years, are available at this time. Of 12 patients, one had EGFR exon 19 mutation at time of diagnosis. One patient who initially displayed no EGFR mutation was found to have an exon 19 deletion at time of recurrence. The one with exon 19 at time of initial diagnosis continued to express exon 19 in the second biopsy. Conclusions: To our knowledge, this is the only study assessing changes in molecular genotype using dHPLC between primary and recurrent or progressive lung cancer biopsy specimens. Although sample size is small, it is evident that changes in EGFR mutational status can occur. Further prospective studies are required to determine how commonly molecular changes occur. No significant financial relationships to disclose.

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Multicenter prospective trial of customized erlotinib for advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Final results of the Spanish Lung Cancer Group (SLCG) trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8023 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8023-8023

Author(s):

B. Massuti ◽

T. Morán ◽

R. Porta ◽

C. Queralt ◽

F. Cardenal ◽

...

Keyword(s):

Lung Cancer ◽

Negative Impact ◽

Cox Model ◽

Prospective Trial ◽

Complete Response ◽

Egfr Mutations ◽

First Line ◽

Exon 19 Deletion ◽

L858r Mutation ◽

Exon 19

8023 Background: The purpose of the study was to evaluate the efficacy of erlotinib and the feasibility of screening for EGFR mutations in advanced NSCLC p (chemonaive or relapsed after 2 prior chemotherapy regimens). Methods: Exon 19 deletions and L858R mutations in tumor and paired serum DNA were assessed in one central laboratory, using three different techniques. Results: From April 2005 to December 2008, 2507 p were screened. EGFR mutations were detected in 358 p; 217 were entered on the trial: 158 (72.8%) female; 148 (68.2%) never-smokers; 176 (81.1%) adenocarcinoma; 134 (62.3%) exon 19 deletion, 83 (37.7%) L858R mutation; 112 (51.6%) first-line, 104 (48.4%) second-line. Response in 139/197 evaluable p (70.6%); complete response (CR) in 24 p (12.2%). Odds ratio for response: 3 for p with exon 19 deletion (P=0.001). Time to progression (TTP): 14 months (m). Median survival (MS): 27 m. MS according to response shown in table. Cox model for TTP showed that male gender (hazard ratio [HR], 2.3; P=0.001), L858R mutation (HR, 1.8; P=0.008), and mutated EGFR in serum (HR,1.6; P=0.03) had a negative impact. Conclusions: A multicenter study of customized erlotinib, using a central screening laboratory, is feasible and shows the outstanding benefit to p for selecting erlotinib treatment based on EGFR mutation status. The SLCG has initiated a randomized trial of first-line erlotinib vs chemotherapy. [Table: see text] No significant financial relationships to disclose.

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Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: Distinguishing influence of exon 19 deletion on radiographic features

Lung Cancer ◽

10.1016/j.lungcan.2011.12.017 ◽

2012 ◽

Vol 77 (1) ◽

pp. 64-69 ◽

Cited By ~ 60

Author(s):

Akimasa Sekine ◽

Terufumi Kato ◽

Eri Hagiwara ◽

Takeshi Shinohara ◽

Takanobu Komagata ◽

...

Keyword(s):

Lung Cancer ◽

Brain Tumors ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Egfr Mutations ◽

Metastatic Brain Tumors ◽

Small Cell Lung ◽

Exon 19 Deletion ◽

Exon 19

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Identification of non-small-cell lung cancer with activating EGFR mutations in malignant effusion and cerebrospinal fluid: Rapid and sensitive detection of exon 19 deletion E746-A750 and exon 21 L858R mutation by immunocytochemistry

Lung Cancer ◽

10.1016/j.lungcan.2011.02.002 ◽

2011 ◽

Vol 74 (1) ◽

pp. 35-40 ◽

Cited By ~ 47

Author(s):

Akihiko Kawahara ◽

Koichi Azuma ◽

Akiko Sumi ◽

Tomoki Taira ◽

Kazutaka Nakashima ◽

...

Keyword(s):

Lung Cancer ◽

Cerebrospinal Fluid ◽

Small Cell Lung Cancer ◽

Small Cell ◽

Egfr Mutations ◽

Malignant Effusion ◽

Small Cell Lung ◽

Exon 19 Deletion ◽

L858r Mutation ◽

Exon 19

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SpecificEGFRMutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non–Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.6695 ◽

2008 ◽

Vol 26 (16) ◽

pp. 2745-2753 ◽

Cited By ~ 176

Author(s):

Chih-Hsin Yang ◽

Chong-Jen Yu ◽

Jin-Yuan Shih ◽

Yeun-Chung Chang ◽

Fu-Chang Hu ◽

...

Keyword(s):

Lung Cancer ◽

Multivariate Analysis ◽

Response Rate ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

First Line ◽

Exon 19 Deletion ◽

Nsclc Patients ◽

Exon 19

PurposeTo explore predictive factors for time to treatment failure (TTF) in chemotherapy-naive non–small-cell lung cancer (NSCLC) patients receiving gefitinib treatment.Patients and MethodsWe designed a phase II study to test gefitinib antitumor efficacy in advanced-stage, chemotherapy-naive NSCLC patients. Patients were treated with gefitinib 250 mg/d. Tumor assessments were performed every 2 months. Responding or stable patients were treated until progression or unacceptable toxicity. All scans were reviewed independently. EGFR exons 18-21 sequence, K-ras exon 2 sequence, and MET gene copy numbers were examined in available samples. Clinical or molecular predictors of TTF were examined by multivariate analysis.ResultsOne hundred six patients were enrolled. Ninety patients had tumor samples for biomarker tests. Overall response rate was 50.9% (95% CI, 41.4% to 60.4%). Median TTF was 5.5 months, and median overall survival (OS) was 22.4 months. The response rate and median TTF of the patients with exon 19 deletion (n = 20) were 95.0% and 8.9 months, for exon 21 L858R mutation (n = 23) were 73.9% and 9.1 month, and for other types of EGFR mutations (N = 12) were 16.7% and 2.3 months, respectively. In multivariate analysis, the presence of EGFR deletion exon 19 or L858R EGFR mutations in adenocarcinoma patients predicted longer TTF. High copy number of MET seemed to correlate with shorter TTF in patients with gefitinib-sensitive activating EGFR mutations.ConclusionIn this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.

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Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: A randomized phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7519 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7519-7519 ◽

Cited By ~ 1

Author(s):

Si-Yu Wang ◽

Wei Ou ◽

Ning Li ◽

Haibo Sun ◽

Liang Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Adjuvant Chemotherapy ◽

Phase Ii Study ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Stage Iiia ◽

Exon 19 Deletion ◽

Resected Stage ◽

Exon 19

7519 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The BR.19 trial exploring the role of adjuvant gefitinib in resected early stage NSCLC (stage IB 49%, II 38%, III 13%) did not show significant progression-free survival (PFS) or overall survival (OS) improvement in all patients. The efficacy of gefitinib following adjuvant chemotherapy in patients with EGFR mutation is unknown. Methods: In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned to receive pemetrexed (500mg/m2) and carboplatin (AUC=5), administered every 21 days for 4 cycles, followed with (n=30) or without (n=30) gefitinib (250mg per day) for 6 months. The primary end point was PFS. The second end point was OS. Results: From August 2008 toSeptember 2011, 60 patients (35 males and 25 females) were included in our center. Of the 60 patients (56 adenocarcinomas, 2 squamous cell carcinomas, 2 adenosquamous carcinomas), 20 patients (33.3%) had exon 19 deletion mutation, 40 (66.7%) patients had exon 21 L858R point mutation. The most common adverse event was rash (43.3%, 13 of 30) in the pemetrexed and carboplatin (PC)-gefitinib group and the addition of gefitinib to chemotherapy was well tolerated. The PFS was significantly longer among those who received PC-gefitinib than among those who received PC alone (median,39.8 months vs 27.0 months; hazard ratio [HR],0.369; 95% confidence interval [CI], 0.161-0.847; P=0.014). There was no significant difference in OS between the two group(median,41.6 months vs 32.6 months,P=0.066). The rates of 2-year PFS and OS were 78.9% and 92.4% in PC-gefitinib group, and 54.2% and 77.4% in PC alone group, respectively. Conclusions: The addition of gefitinib to pemetrexed and carboplatin adjuvant therapy showed significant improvement in PFS for patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.

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The Profile of Lung Adenocarcinoma Patients with Positive EGFR Mutation

Green Medical Journal ◽

10.33096/gmj.v2i1.37 ◽

2020 ◽

Vol 2 (1) ◽

pp. 8-12

Author(s):

Edward Pandu Wiriansya ◽

Ainun ◽

Puspa Ratu ◽

Andi Muhammad Reza Cesarian Noor

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Medical Records ◽

Egfr Mutation ◽

Clinical Symptoms ◽

Secondary Data ◽

Egfr Mutations ◽

Cross Sectional ◽

History Of ◽

Exon 19

Background: The high mortality rate in pulmonary carcinoma is a problem encountered in various countries, including Indonesia. According to WHO, there are 2.09 million people affected by lung cancer and 1.76 million deaths due to lung cancer worldwide. This study was aimed to determine the profile of lung adenocarcinoma patients with positive EGFR mutation. Methods: The study was descriptive study with cross-sectional approach using secondary data obtained from medical records of lung adenocarcinoma patients. Results: The present study revealed that lung adenocarcinoma was found higher in patients with age >40 years old (93.9%) compared to those with age <40 years old. It was also higher in male (66.7%) than in female patients. Most patient with lung adenocarcinoma were at the IIIB stage (42.4%). It was also reported that higher cases was found in patients with history of smoking more than 15 years (42.4%). Hemoptoe was the most reported clinical symptoms in patients with lung adenocarcinoma (87.9%). Lung adenocarcinoma was also observed higher in patients without family history of pulmonary adenocarcinoma (81.8%). Seventeen of 33 EGFR mutations (51.5%) were observed in exon 19 and fourteen (48.5%) were in exon 21. Conclusion: The most common EGFR mutation lung adenocarcinoma was observed in exon 19.

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Distinct Benefit of Overall Survival between Patients with Non-Small-Cell Lung Cancer Harboring EGFR Exon 19 Deletion and Exon 21 L858R Substitution

Chemotherapy ◽

10.1159/000454944 ◽

2017 ◽

Vol 62 (3) ◽

pp. 151-158 ◽

Cited By ~ 8

Author(s):

Nobuyuki Koyama ◽

Yasutaka Watanabe ◽

Yuki Iwai ◽

Rumi Kawamura ◽

Chihiro Miwa ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Multivariate Analyses ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Exon 19 Deletion ◽

Exon 19

Background: Exon 19 deletion (Del19) and exon 21 L858R substitution (L858R), which account for 90% of epidermal growth factor receptor (EGFR) mutations as common mutations, are associated with favorable outcomes with EGFR-tyrosine kinase inhibitors (TKIs) compared with other uncommon EGFR mutations in non-small-cell lung cancer (NSCLC). However, whether there are differences in overall survival (OS) between patients with these common EGFR mutations remains controversial. Methods: The subjects studied were 74 NSCLC patients with common EGFR mutations treated with gefitinib or erlotinib. Using univariate and multivariate analyses, we retrospectively compared the clinicopahological characteristics of patients harboring Del19 with those harboring L858R. Results: Compared with patients harboring L858R, EGFR-TKIs provided a significant OS benefit in patients harboring Del19 (p = 0.024), as well as favorable therapeutic responses (p = 0.045) and progression-free survival (PFS) benefits (p = 0.031). In multivariate analyses, Del19 was independently associated with PFS (p = 0.029) and OS (p = 0.009), whereas no parameters other than pleural dissemination at the initial treatment were associated with EGFR mutation types. Conclusion: Del19 and L858R have distinct prognostic implications and may require individual therapeutic strategies.

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Genome-wide analysis of microRNA signature in lung adenocarcinoma with EGFR exon 19 deletion

10.1101/032367 ◽

2015 ◽

Author(s):

Lixia Ju ◽

Mingquan Han ◽

Xuefei Li ◽

Chao Zhao

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Genetic Alterations ◽

Egfr Mutations ◽

Wild Type ◽

Lung Cancer Patients ◽

Whole Genome Microarray ◽

Exon 19 Deletion ◽

The Difference ◽

Exon 19

AbstractPurposeThe findings of EGFR mutations and the development of targeted therapies have significantly improved the overall survival of lung cancer patients. Still, the prognosis remains poor, so we need to know more about the genetic alterations in lung cancer. MicroRNAs are dysregulated in lung cancer, and microRNAs can regulate EGFR. So it is very important to predict the candidate microRNAs that target mutated EGFR and to investigate the role of these candidate microRNAs in lung cancer.Materials and methodsIn this study, we investigated the difference of microRNAs expression between lung adenocarcinoma cell lines with EGFR exon 19 deletion (H1650 and PC9) and its wild-type (H1299 and A549) using the Phalanx Human Whole Genome Microarray. Then the expression of individual microRNAs was validated by qRT-PCR assays. Moreover, we have detected the microRNAs expression in serum of lung adenocarcinoma patients with EGFR exon 19 deletion and wild-type.ResultsThe expression of 1,732 microRNAs was evaluated, and we found that microRNAs expression was different between these two groups. Hsa-miR-141-3p, hsa-miR-200c-3p, hsa-miR-203, hsa-miR-3182, hsa-miR-934 were up-regulated and hsa-miR-3196 was down-regulated in the EGFR exon 19 deletion group compared with wild-type group. The detection of circulating microRNAs showed that miR-3196 was down-regulated in lung adenocarcinoma patients with EGFR exon 19 deletion compared with wild-type.ConclusionsIt is suggested that microRNAs associate with EGFR exon 19 deletion and miR-3196 can be further explored for potential predictor and targeted biomarker when it is difficult to get the tumors.

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