Triple probe FISH approach for detecting EML4-ALK gene rearrangement in Chinese patients with NSCLC.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21080-e21080
Author(s):  
Weimin Mao ◽  
Mark Han ◽  
Zhiqiang Ling ◽  
Wenyong Sun ◽  
Gu Zhang ◽  
...  
Keyword(s):  
Chinese Patients ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Unselected Patient ◽  
Dual Color ◽  
Alk Positive ◽  
Novel Target ◽  
Nsclc Patients ◽  
First Time

e21080 Background: The echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion represents a novel target for the therapy of a subset of non-small cell lung cancer (NSCLC). ALK rearrangement has been found in approximately 1.6–11.6% of NSCLC in unselected patient populations, but the frequency also varied when different diagnostic approach was used. We, for the first time, investigated frequency of EML4-ALK rearrangement in unselected Chinese patients with NSCLC using recent developed fluorescence in situ hybridization (FISH) triple color break-apart probe. Methods: One hundred-thirty one FFPE specimens from NSCLC patients were collected for the investigation. Fusion between 3’ portion of ALK gene and the 5’ portion of EML4 gene was detected using FISH tri-check probe (ZytoVision, Germany). Positive cells were defined as having any signal A ( distance more than two-time the ALK signal size) or signal B ( distance between one- and two-time the ALK signal size plus EML4 translocation signal) or any isolated ALK 3’ signal. Total 100 nuclei for each specimen were counted. Specimen was as classified as EML4-ALK rearrangement when the proportion of positive cells was over 15%. ALK/EML4 signals over 6 in over 10% nuclei were classified as gene amplification. Results: Of 131 specimens, frequency of ALK rearrangement was 10.7% (14/131) when positive cells were counted by signal A and isolated ALK 3’ signal (dual color). Frequency of EML4-ALK rearrangement was 13.0% (17/131) when positive cells were counted by signal A, B and isolated ALK 3’ signal (triple color), in which 21% (17/14) more cases were classified as EML4-ALK rearrangement comparing dual color enumeration. ALK and EML4 amplification were observed in 2.3% (3/131) specimens, respectively, in which two were co-amplified and none of them had EML4-ALK rearrangement. Conclusions: Present result showed that frequency of EML4-ALK rearrangement in unselected Chinese patients with NSCLC was 13.0% determined by FISH tri-check probe. This study suggested that counting both ALK inversion and EML4 translocation may contribute to defining EML4-ALK positive cells.

Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker females with pulmonary adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10527-10527
Author(s):  
Xiaoxia Chen ◽  
Shengxiang Ren ◽  
Peng Kuang ◽  
ChunXia Su ◽  
Jiayu Li ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mrna Expression ◽  
Egfr Mutation ◽  
Excision Repair ◽  
Egfr Mutations ◽  
Mrna Levels ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Alk Positive ◽  
Nsclc Patients

10527 Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement was found not only predict the efficacy of targeted drugs, but also associate with the efficacy of chemotherapy drugs in non-small cell lung cancer (NSCLC) patients. We investigated the relationship of EGFR mutation status or ALK rearrangement and DNA repair or synthesis genes, such as excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a potential explanation for these observations. Methods: In this surgical series, 104 resected lung adenocarcinomas from nonsmoker females were analyzed concurrently for the EGFR mutation, ALK rearrangement status and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR mutation detection was performed by the method of ADx-ARMS, ALK rearrangement was detected by PCR and the mRNA expression of different genes were tested using the method of real-time PCR. Results: 73 (70.2%) patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. The ERCC1 mRNA level in patients with EGFR mutation was 3.44±1.94×10-3 , which is significantly lower than in the patients with ALK positive and both negative(4.60±1.95×10-3 and 4.95±2.33×10-3 respectively, P=0.010). While the TS mRNA levels were significantly lower in the patients with EGFR mutation(1.15±1.38×10-3 VS 2.69±3.97×10-3, P=0.006) or ALK positive (1.21±0.78×10-3VS 2.69±3.97×10-3, P=0.020) than in patients with both negative. Conclusions: NSCLC specimens harboring activating EGFR mutations are more likely to express low ERCC1 and TS mRNA levels, while NSCLC patients with ALK rearrangement are more likely to express low TS mRNA levels, which could be helpful to select a proper chemotherapy regimen for NSCLC patients with known EGFR mutation or ALK fusion status.

scholarly journals EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib

2021 ◽  
Vol 14 (4) ◽  
pp. e240295
Author(s):  
Hironari Matsuda ◽  
Munechika Hara ◽  
Shin-Ichiro Iwakami ◽  
Kazuhisa Takahashi
Keyword(s):  
Skeletal Muscle ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Stable Condition ◽  
Japanese Woman ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Resistance To Treatment ◽  
Alk Positive ◽  
The Right

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

scholarly journals Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis

2020 ◽  
Vol 13 (11) ◽  
pp. 371
Author(s):  
Maximilian J. Hochmair ◽  
Hannah Fabikan ◽  
Oliver Illini ◽  
Christoph Weinlinger ◽  
Ulrike Setinek ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Real World ◽  
Kinase Inhibitors ◽  
Resistance Mutations ◽  
Real World Data ◽  
Alk Rearrangement ◽  
World Data ◽  
Anaplastic Lymphoma ◽  
Wide Range ◽  
Alk Positive

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.

scholarly journals Success of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer

2018 ◽  
Vol 11 (3) ◽  
pp. 777-783 ◽  
Author(s):  
Sachi Okawa ◽  
Takuo Shibayama ◽  
Atsushi Shimonishi ◽  
Jun Nishimura ◽  
Taichi Ozeki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Anaplastic Lymphoma Kinase ◽  
Whole Brain Radiotherapy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Brain Radiotherapy ◽  
Nsclc Patients

Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case.

First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3007-3007 ◽  
Author(s):  
Ranee Mehra ◽  
D. Ross Camidge ◽  
Sunil Sharma ◽  
Enriqueta Felip ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Tumor Regression ◽  
Duration Of Treatment ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive ◽  
Ecog Ps

3007 Background: LDK378 is a novel, potent and selective small molecule anaplastic lymphoma kinase (ALK) inhibitor (IC50 0.00015 μM), that does not inhibit c-MET (IC50 3.2 μM). Tumor regression has been observed in ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being conducted to determine the MTD and safety profile in patients (pts) with tumors with ALK rearrangement, amplification or mutation. Other objectives were safety, PK and antitumor activity in pts with ALK-driven NSCLC, both naïve to ALK inhibitors and relapsed following previous ALK inhibitor treatment, and other ALK-positive cancers. Methods: Adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy, were given once daily oral LDK378 on a continuous 21-day schedule. Dose escalation, starting at 50 mg/day, was guided by a Bayesian logistic regression model (BLRM) to determine the MTD. Results: At a January 5th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; median age 52 years; 87% ECOG PS 0/1) were enrolled and received LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade (Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia (1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed dose escalation, and there were no DLTs in 4 pts at 500 mg. Median duration of treatment with LDK378 was 7 weeks (range <1–22+). At the cutoff date, 13 (42%) pts discontinued treatment: 1 (3%) due to adverse events (AEs), and 12 (39%) due to disease progression; 18 (58%) pts were still on treatment. The most frequent AEs (all Gr) were nausea (45%), vomiting (36%), and diarrhea (29%). The most frequent Gr 3/4 AEs were diarrhea and dyspnea (2 pts [7%] each). At doses ≥400 mg steady state exposures exceeded efficacious exposures in xenograft models. Of 16 pts with available response data (RECIST, per investigator) there were 4/6 responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZ-naïve pts, of whom 7 were treated below 400 mg. All responses were in NSCLC. Conclusions: Daily oral LDK378 is well tolerated up to 500 mg/day, and escalation continues at 750 mg/day. Preliminary responses have been seen in both CRZ-naïve and CRZ-relapsed pts.

scholarly journals Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2016 ◽  
Vol 23 (3) ◽  
pp. 196 ◽  
Author(s):  
B. Melosky ◽  
J. Agulnik ◽  
R. Albadine ◽  
S. Banerji ◽  
D.G. Bebb ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Alk Positive ◽  
Nonsquamous Nsclc

Anaplastic lymphoma kinase (ALK) is an oncogenic driver in non-small-cell lung cancer (NSCLC). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous NSCLC patients and lead to constitutive activation of the ALK signalling pathway. ALK-positive NSCLC is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis.Targeted inhibition of the ALK pathway prolongs progression-free survival in patients with ALK-positive advanced NSCLC. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population.Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted ALK inhibitor in the first-line setting is recommended. As patients become resistant to first-generation ALK inhibitors, other treatments, including second-generation ALK inhibitors can be considered.

scholarly journals Anaplastic lymphoma kinase rearrangements in non-small cell lung cancer in Jordan

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S151-S151
Author(s):  
M A Sughayer ◽  
B Maraqa ◽  
M Al-Ashhab
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Stage Iv ◽  
Small Cell ◽  
P Value ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Alk Positive ◽  
Nsclc Patients

Abstract Introduction/Objective ALK rearrangement is an important oncogenic driver in a substantial portion of non-small cell lung cancer (NSCLC) patients ranging from 2-7%. Treatment options such as ALK tyrosine kinase inhibitors (TKI) improve progression-free survival and overall survival. Candidates for such treatment are selected based on the identification of the ALK rearrangement. While fluorescence in situ hybridization (FISH) was considered the gold standard method, the availability of a robust FDA-approved companion diagnostic immunohistochemistry (IHC) assay has led to a paradigm shift in ALK testing. The purpose of this study is to determine the prevalence of ALK rearrangement in Jordanian NSCLC patients along with their clinicopathological characteristics and to compare the results of IHC and FISH methods for detecting ALK rearrangements. Methods/Case Report A retrospective study was conducted on 449 Jordanian King Hussein Cancer Center patients with NSCLC whose biopsy samples were tested for ALK rearrangement using FISH and or IHC (clone D5F3) in the period between 2018 and 2020. Results (if a Case Study enter NA) During the study period, the rate of ALK positivity by either IHC or FISH method was 4 percent (18 ALK positive cases out of 449 cases of non-small cell lung cancer). Seven cases were positive for both IHC and FISH, and nine cases were positive for IHC with no confirmation by FISH method; one case was ALK positive by IHC and negative by FISH with a significant response to ALK TKI; one case was IHC negative but FISH positive, with no ALK TKI therapy. The calculated sensitivity of ALK D5F3 immunostain compared to FISH results in the current study is 87.5% while the specificity is 96%. ALK positive patients were significantly younger than those with negative results (p-value=0.051), and women were three times more likely than men to have the rearrangement (p-value=0.013). Rearrangement was more likely to be found in nonsmokers/light or ex-smokers (p-value= 0.013). All patients had clinical stage IV or III disease at presentation with stage IV found in tow thirds of the patients. Conclusion ALK rearrangement is found in 4% of all NSCLC in Jordan. Patients are more likely to be younger, females and light or nonsmokers with an advanced stage disease at presentation. IHC is an acceptable alternative to FISH for ALK testing with reasonable sensitivity and specificity in addition to its advantages in terms of robustness, turnaround time and cost savings

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