Epidermal growth factor receptor (EGFR) mutation rate in advanced ovarian cancer (AOC): Results of a prospective study in Caucasian patients (pts)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13127-13127
Author(s):  
A. Mustea ◽  
D. Koensgen ◽  
R. Zeillinger ◽  
D. C. Castillo-Tong ◽  
P. Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Descriptive Analysis ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Kinase Domain ◽  
Rank Test ◽  
P Value ◽  
Egfr Gene

13127 Background: The EGFR is over expressed in 55% to 98% of advanced epithelial ovarian carcinoma. Different studies demonstrated EGFR status as an independent prognostic factor for OC. Recent studies in non small cell lung cancer suggest that the presence of the clinical response to tyrosine kinase inhibitors (e.g. ZD 1839) correlates with the somatic mutations in the kinase domain of EGFR, exons 18–21. For pts with OC data are not available on EGFR gene mutation. Methods: Shock-frozen samples from 32 patients (pts) with primary of ovarian cancer were stratified in two groups according to disease-free interval: ≤6 months (17 pts.) and <6 months (15 pts.). All pts were prospectively collected within Tumor bank Ovarian Cancer Project. Patient collective consisted only from west European Caucasian women. Additionally, 9 commercial available ovarian cancer cell lines (TOV-90, TOV-112D, TOV-21G, OVCAR-3, A2780, A2780 ADR, ES-2, SK-OV-3, and Caov-3) and 32 established ovarian cancer lines were analysed. Exon sequencing of genomic DNA was used to detect L858R deletion mutations of EGFR within exons 21 of the kinase domain. PCR and capillary electrophoresis (Chip-Format) were used to analyse 15 bp deletion in Exon 19. We focused on descriptive analysis. The Log-Rank test was applied to confirm statistically significance (p-value of <0.05). Results: Overall, 74.6% of the pts. were diagnosed FIGO stage III-IV. Median follow-up period was: 14.17 month (range: 2–42 months). Whether in cell lines, nor in tumor samples, stratified to response of platinum therapy any mutation of EGFR gene was observed. Conclusions: Our study indicates that the prevalence of mutation in the kinase domain of EGFR, exons 19 and 21 seems to be very low in pts. with AOC. Further studies should investigate other ethical groups of pts. No significant financial relationships to disclose.

Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer

2005 ◽  
Vol 23 (11) ◽  
pp. 2445-2459 ◽  
Author(s):  
José Baselga ◽  
Carlos L. Arteaga
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Gene ◽  
Epidermal Growth ◽  
Egfr Tkis ◽  
Receptor Family

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.

scholarly journals ERβ1 Expression Patterns Have Different Effects On EGFR TKIs Treatment Response in EGFR Mutant Lung Adenocarcinomas.

2020 ◽  
Author(s):  
Lijuan Zhang ◽  
Meng Tian ◽  
Jiamao Lin ◽  
Jianbo Zhang ◽  
Haiyong Wang ◽  
...  
Keyword(s):  
Western Blot ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Expression Patterns ◽  
Estrogen Therapy ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Pathway Activation ◽  
Egfr Tkis

Abstract Background: Estrogen receptor β (ERβ) can regulate cellular signaling through non-genomic mechanisms, potentially promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanisms underlying the ERβ-mediated resistance to EGFR TKIs remain poorly understood. Methods: qRT-PCR was performed to investigate ERβ1 and ERβ5 expression levels in cell lines. The localization of ERβ and ERβ1 within cells was assessed using immunocytochemistry and immunofluorescence. The effect of estradiol and/or gefitinib on EGFR signaling pathways was determined by western blot. Cell viability and colony formation assays were used to assess gefitinib response for different cell lines. The apoptosis was verified by tunel and western blot. Immunohistochemistry was used to assess the expression of ERβ1 in lung adenocarcinoma tissues. Patient survival was estimated using the Kaplan-Meier method, and comparisons between groups were conducted using log-rank tests. Results: PC9 cell lines stably overexpressing ERβ1 or ERβ1/ERβ5 were established successfully. Immunofluorescence revealed that ERβ5 overexpression partly retained ERβ1 in the cytoplasm. Immunoblotting analyses revealed that EGFR pathway activation levels were higher in PC9/ERβ1/5 cells than those in PC9/ERβ1 or control PC9 cells. In the presence of estradiol, PI3K/AKT/mTOR pathway activation levels were higher in ERβ1/5-expressing cells than those in ERβ1-expressing cells. Additionally, PC9/ERβ1/5 cells were less prone to the cytotoxic and pro-apoptotic effects of gefitinib compared with PC9/ERβ1 or control PC9 cells. Conclusion: Cytoplasmic ERβ1 was associated with poor progression-free survival in lung cancer patients treated with EGFR TKIs. These results suggest that anti-estrogen therapy might reverse EGFR TKI treatment resistance to some extent in selected patients.

Incorporation of Pazopanib in Maintenance Therapy of Ovarian Cancer

2014 ◽  
Vol 32 (30) ◽  
pp. 3374-3382 ◽  
Author(s):  
Andreas du Bois ◽  
Anne Floquet ◽  
Jae-Weon Kim ◽  
Joern Rau ◽  
Josep M. del Campo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Line Chemotherapy

PurposePazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy.Patients and MethodsNine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators.ResultsMaintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%).ConclusionPazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).

Epidoxorubicin versus no treatment as consolidation therapy in advanced ovarian cancer: results from a phase II study

2006 ◽  
Vol 16 (Suppl 1) ◽  
pp. 74-78 ◽  
Author(s):  
G. Bolis ◽  
S. Danese ◽  
S. Tateo ◽  
E. Rabaiotti ◽  
G. D'Agostino ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Figo Stage ◽  
Pathologic Response ◽  
Rank Test ◽  
Complete Pathologic Response ◽  
First Line ◽  
Histologic Diagnosis ◽  
Treatment Groups ◽  
First Line Therapy

To compare the effect of epidoxorubicin given for 4 months versus no treatment in the survival of patients with advanced ovarian cancer and complete pathologic response after first-line surgery and chemotherapy with platinum-based schedules, we conducted a multicenter randomized clinical trial. Patients with histologic diagnosis of epithelial ovarian cancer FIGO stage III or IV at first diagnosis; complete pathologic response at second-look laparotomy/laparoscopy or complete clinic response; and those who have had first-line therapy including surgery and one regimen containing cisplatin or carboplatinum were eligible for the study and were randomly allocated to epidoxorubicin 120 mg/sqm or no treatment. A total of 64 women were allocated to epidoxorubicin and 74 to no treatment. There were 20 and 19 deaths, respectively, in the epidoxorubicin and no-treatment groups. The 3-year percent overall survival was 79.0% and 78.7%, respectively, in the no-treatment and epidoxorubicin groups (log-rank test, P= 0.93).

Carboplatin (C) plus paclitaxel (P) versus carboplatin plus pegylated liposomal doxorubicin (PLD) in patients with advanced ovarian cancer (AOC): Final analysis of the MITO-2 randomized multicenter trial.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA5033-LBA5033 ◽  
Author(s):  
S. Pignata ◽  
G. Scambia ◽  
A. Savarese ◽  
R. Sorio ◽  
E. Breda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Response Rate ◽  
Multivariable Analysis ◽  
Advanced Ovarian Cancer ◽  
Final Analysis ◽  
Phase Iii ◽  
P Value ◽  
First Line ◽  
Significant Difference ◽  
Line Chemotherapy

LBA5033 Background: CP is standard first-line chemotherapy for AOC. MITO-2 (Multicentre Italian Trials in Ovarian Cancer) is an academic multicenter randomized phase III study, testing whether C-PLD is more effective than CP. Methods: AOC chemo-naïve patients (pts), stage IC-IV, aged≤75, ECOG PS≤2, were randomized to CP (C AUC5 + P 175 mg/m2,d1q3w) or to C-PLD (C AUC5 + PLD 30 mg/m2,d1q3w), both for 6 cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate, toxicity and quality of life (QoL). To have 80% power in detecting a 0.80 HR in PFS, with 2-sided α error 0.05, 632 events were needed and 820 pts were planned. Response rate and toxicity have been reported at ASCO 2009 (abs #LBA5508). All analyses are based on intention to treat. Results: From Jan ’03 to Nov ’07, 820 pts were randomized, 410 to each arm. Median age was 57 yrs (range 21-77). Stage III (60%) and IV (21%) were prevalent. A plateau in PFS events was reached before obtaining the planned number. Thus, following an IDMC recommendation, the final analysis was done with 556 events occurred as of December 31, 2009. This size is consistent with HR to be detected equal to 0.79, with 80% power. With a median follow-up of 40.2 months, median PFS was 19.0 and 16.8 months with C-PLD and CP, respectively (HR 0.95, 95%CI 0.81-1.13, log-rank p value=0.58). Lack of significant difference was confirmed (HR 0.96, 95%CI 0.81-1.14) at multivariable analysis adjusted by stage, PS, residual disease, age and size of the institution. There was no heterogeneity of treatment effect among major subgroups. With 313 deaths recorded, median OS was 61.6 and 53.2 months with C-PLD and CP, respectively (HR 0.89, 95%CI 0.72-1.12, log-rank p value=0.32). QoL data will be presented at the meeting. Conclusions: In the MITO-2 trial, C-PLD was not found to be superior to CP, which remains the standard first-line chemotherapy for AOC.However, given the observed confidence interval and the different toxicity profile, C-PLD could be considered an alternative to standard therapy. Study was partially supported by Schering-Plough. [Table: see text]

The regulation effect of EGFR signaling pathway on PD-L1 expression on esophageal squamous cell carcinoma cell lines.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15577-e15577
Author(s):  
Ran Lin Wang ◽  
Tao Li ◽  
Jianming Huang ◽  
Jiahua Lv
Keyword(s):  
Mrna Expression ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Radiotherapy Alone ◽  
Pcr Method ◽  
Egfr Tki

e15577 Background: To explore the effect of radiation combined with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKI) on the expression of PD-L1 in ESCC cell lines, and to provide theoretical support for radiotherapy combined with EGFR-TKI for esophageal cancer. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) method was used to assess EGFR and PD-L1 mRNA expression on ESCC cell lines when different doses of X-ray irradiation were conducted on ESCC cell lines TE-1 and ECA-109 combining with EGFR-TKI or not. Results: In ESCC cell lines TE-1 and ECA-109, the expression of EGFR and PD-L1 mRNA was increased significantly by the activation of EGFR signaling pathway and decreased after the use of gefitinib (P > 0.01). Both EGFR (P < 0.01) and PD-L1(P < 0.01) mRNA expression of ESCC cell lines TE-1 and ECA-109 were increased by radiotherapy alone. EGFR-TKI could block the increase of both EGFR mRNA (P < 0.01) and PD-L1 mRNA (P < 0.01) which was induced by radiation. Conclusions: EGFR signaling pathway is involved in the regulation of PD-L1 expression in ESCC cell lines. Radiation could up-regulate the expression of EGFR and PD-L1 mRNA in ESCC cells which could be blocked by the use of EGFR-TKI.

Prognostic Value of Human Epidermal Growth Factor Receptor 2 (Her-2)/neu in Patients With Advanced Ovarian Cancer Treated With Platinum/Paclitaxel as First-Line Chemotherapy: A Retrospective Evaluation of the AGO-OVAR 3 Trial by the AGO OVAR Germany

2009 ◽  
Vol 19 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Jacobus Pfisterer ◽  
Andreas Du Bois ◽  
Eva-Katrin Bentz ◽  
Friedrich Kommoss ◽  
Philipp Harter ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Prognostic Value ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Advanced Stage ◽  
First Line ◽  
Her 2 ◽  
Epidermal Growth ◽  
Line Chemotherapy

Objectives:Results on the prognostic value of human epidermal growth factor receptor 2 (HER-2)/neu in ovarian cancer are inconsistent. This exploratory analysis evaluates Her-2/neu as a prognostic factor in a large cohort of patients with advanced-stage ovarian cancer treated with platinum/paclitaxel as first-line chemotherapy within a prospective randomized trial.Methods:Her-2/neu expression was assessed by immunohistochemistry in 359 patients (46%) treated within the AGO-OVAR 3 trial (n = 783). Patients received either cisplatin/paclitaxel or carboplatin/paclitaxel according to the study protocol. Immunohistochemistry results were scored according to the Dako score.Results:Her-2/neu Dako scores of 0 or 1+ was found in 337 patients (94%) and a score of 2+ or 3+ in 22 patients (6%). Her-2/neu overexpression (2+/3+) was associated with a higher International Federation of Gynecology and Obstetrics stage and larger postoperative residual disease. There were no significant differences in response to chemotherapy between the Her-2/neu score subgroups and in progression-free survival time. In a multivariate analysis, the Her-2/neu score had no significant impact on overall survival time.Conclusions:In the present study, Her-2/neu overexpression in patients with advanced-stage ovarian cancer was rare and provided no evidence for a prognostic value of Her-2/neu in patients with advanced ovarian cancer treated with platinum/paclitaxel.

scholarly journals Lung Adenocarcinoma Patient Harboring EGFR-KDD Achieve Durable Response to Afatinib: A Case Report and Literature Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Lingling Zhao ◽  
Zhen Wang ◽  
Haiwei Du ◽  
Songan Chen ◽  
Pingli Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Case Reports ◽  
Rapid Development ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Kinase Domain ◽  
Durable Response ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tkis

The rapid development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations including but not limited to exon 19 deletions (19 del) and point mutation L858R in exon 21. However, the efficacy of EGFR-TKIs in patients with rare mutations, such as EGFR-kinase domain duplication (KDD), remains elusive. EGFR-KDD often results from in-frame tandem duplication of EGFR exons 18–25, causing subsequent constitutive activation of EGFR signaling. Several case reports have revealed the efficacies of EGFR-TKIs in advanced lung adenocarcinoma (LUAD) with EGFR-KDD but yielded variable antitumor responses. In the present study, we report a 61-year-old male patient diagnosed with T1N3M0 (stage IIIB) LUAD harboring EGFR-KDD involving exons 18–25. He was treated with afatinib and achieved partial response (PR) with progression-free survival (PFS) of 12 months and counting. Our work, confirming EGFR-KDD as an oncogenic driver and therapeutic target, provides clinical evidence to administer EGFR-TKIs in patients with advanced LUAD harboring EGFR-KDD.

scholarly journals Landscape of drug-resistance mutations in kinase regulatory hotspots

2020 ◽  
Author(s):  
Pora Kim ◽  
Hanyang Li ◽  
Junmei Wang ◽  
Zhongming Zhao
Keyword(s):  
Drug Resistance ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Systematic Investigation ◽  
Drug Binding ◽  
Data Sets ◽  
Resistance Mutations ◽  
Cancer Data

Abstract More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase’s secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.

Mutational analysis of the EGFR gene in lung cancer with acquired resistance to gefitinib

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7074-7074 ◽  
Author(s):  
T. Mitsudomi ◽  
T. Kosaka ◽  
H. Endoh ◽  
K. Yoshida ◽  
T. Hida ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Mutational Analysis ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Ras Gene ◽  
T790m Mutation ◽  
Egfr Gene ◽  
Activating Mutations

7074 Background: Non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) gene is usually highly sensitive to EGFR tyrosine kinase inhibitors (TKI), gefitinib or erlotinib. However, it is common to develop acquired resistance to TKI after presenting an initial striking response. It has been reported that secondary mutation of threonine to methionine at codon 790 (T790M) of the EGFR gene is related to this acquired resistance. Methods: We sequenced exons 18–21 of the EGFR gene in 14 NSCLC patients exhibiting acquired resistance to gefitinib following the initial good response. This region of the EGFR gene corresponds with that of the ABL gene where various secondary mutations have been reported in patients with chronic myelogenous leukemia (CML) with acquired resistance to imatinib. To raise sensitivity of the assay, we also subcloned the PCR products into plasmids and sequenced, or we used CyCleave method (real-time PCR combined with fluorescence labeled mutant specific probe) in addition to usual sequencing. We also searched for secondary K-ras mutations. Results: All the 14 patients had activating mutations of the EGFR gene (9 with exon 19 deletions, 5 with L858R). In addition, we found that 7 of 14 patients had a T790M mutation, but there were not any other novel secondary mutations. In these seven patients, T790M mutant bands were smaller than wild-type bands. Patients with T790M tended to be never smoking female, but there was no difference in the period of gefitinib administration by the presence or absence of T790M. We could not detect any T790M in tumors before gefitinib treatment at the sensitivity of 1%. There were no patients with acquired mutation of the K-ras gene. Conclusions: Secondary T790M mutation of the EGFR gene accounted for half of the cases with acquired resistance to gefitinib. Unlike the cases with CML, various kinds of secondary mutations were not likely to exist in the EGFR gene as a mechanism of acquired resistance. No significant financial relationships to disclose.

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