The Clinical Characteristics and Prognosis of Different Age Patients with Lung Cancer
The Clinical Characteristics and Prognosis of Different Age Patients with Lung Cancer

Cancer is closely related to age, and the incidence of cancer increases with age. However, there are few studies on the relationship between age and clinical characteristics of lung cancer. We collected all the consecutive lung cancer cases from 2012 to 2017 in our hospital and divided them into 6 groups according to their ages: ≤ 40 y/o, 41∼ 50 y/o, 51∼ 60 y/o, 61∼ 70 y/o, 71∼ 80 y/o and > 80 y/o. There were more non-smokers (p< 0.01), stage IV (p< 0.01) and anaplastic lymphoma kinase (ALK) fusion (p< 0.01) patients but less stage I patients in ≤ 40 y/o group compared with other age groups. It seemed that older patients were more likely had co-exist driver gene mutations (p=0.04). There are some differences in clinical characteristics and prognosis among different age groups. The reasons behind the phenomenon are largely unclear. The age should be taken into account when we develop clinical trials...... READ ARTICLE

Cancer Management and Research DOI:10.2147/CMAR.S240318

Authors: Chen X, Han X, Zhou H, Liang Y, Huang Z, Li S, Lin Y, Huang X, Wu J, Su W, Lai Z and Yang Z

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Real-World OutcomesKirk Smithage, lung cancer, clinical characteristics, clinical trials
Pseudosarcomatous myofibroblastic proliferations of the urinary bladder are neoplasms characterized by recurrent FN1–ALK fusions
Pseudosarcomatous myofibroblastic proliferations of the urinary bladder are neoplasms characterized by recurrent FN1–ALK fusions

Pseudosarcomatous myofibroblastic proliferation is a descriptive term that designates a group of clinically indolent genitourinary lesions that most commonly arise in the urinary bladder. Given that pseudosarcomatous myofibroblastic proliferation may show morphologic overlap with inflammatory myofibroblastic tumor, the relationship, if any, between the two entities has been unclear. Moreover, pseudosarcomatous myofibroblastic proliferations are known to be positive for ALK immunohistochemistry in a subset of cases, although an inconsistent association with ALK rearrangement (ranging from 0 to 60%) has been reported. The objectives of this study were to determine the frequency of ALK rearrangement and to identify fusion partners using fluorescence in situ hybridization (FISH) and targeted RNA sequencing studies in a contemporary series of 30 pseudosarcomatous myofibroblastic proliferations of the urinary bladder, as well as to investigate ROS1 status by immunohistochemistry. ALK immunoh..... READ ARTICLE

Modern Pathology DOI:10.1038/s41379-020-00670-0

Authors: Andres M. Acosta, Elizabeth G. Demicco, Paola Dal Cin, Michelle S. Hirsch, Christopher D. M. Fletcher & Vickie Y. Jo

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Real-World OutcomesKirk Smithpseudosarcomatous myofibroblastic proliferation, FN1-ALK fusion
Spheroacanthocytes secondary tonoveltyrosine kinase inhibitors
Spheroacanthocytes secondary tonoveltyrosine kinase inhibitors

A 64‐year‐old male with ALK‐positive nonsmall cell lung carcinoma on oral therapywith alectinib presented with pleural effusion. ...Peripheral blood film displayed marked acanthocytes and spheroacanthocytes..Alectinib is a novel tyrosine kinase inhibitor approved for use in patients with nonsmall cell lung cancer. Alectinib is known to cause anemia but the striking acanthocytes and spheroacanthocytes have only been reported in a few case series. Spheroacanthocytes are commonly associated with end‐stage liver disease; however, hematopathologists should recognize alectinib as an alternate cause for acanthocytes and spheroacanthocytes on a peripheral blood film. READ ARTICLE

eJHaem DOI:10.1002/jha2.104

Authors: Michael Ashby, Michael Sze Yuan Low

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Kirk Smith
22 COMPARATIVE EFFICACY OF ALK-INHIBITORS IN ALK INHIBITOR-NAIVE ALK+ LUNG CANCER BRAIN METASTASES: A NETWORK META-ANALYSIS
22 COMPARATIVE EFFICACY OF ALK-INHIBITORS IN ALK INHIBITOR-NAIVE ALK+ LUNG CANCER BRAIN METASTASES: A NETWORK META-ANALYSIS

Lung cancer has been the leading cause of cancer death for both men and women worldwide. Non-small-cell lung cancer (NSCLC) displays an array of molecular abnormalities most commonly involving ALK and EGFR pathways. NSCLC with ALK rearrangements comprises around 5% of cases. Over the years, several ALK inhibitors (ALKI) have been approved with notable activity in brain metastases. However, there have been limited comparative studies exploring their relative efficacies. This analysis was conducted to compare the relative efficacy of ALKIs against ALKI-naïve ALK+ lung cancer brain metastases.This network meta-analysis is the first to compare and rank ALKIs used in treating metastatic ALK+ lung cancer. It indicates that BRG, CER, and ALC are better therapeutic options for patients with ALK-naive ALK+ lung cancer brain metastases when compared to CRZ. READ ARTICLE

Neuro-oncology Advances DOI:10.1093/noajnl/vdaa073.012

Authors: Philip Haddad, Dalia Hammoud, Kevin Gallagher

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Real-World OutcomesKirk SmithNon-small cell lung cancer, NSCLC, ALK, EGFR
EGFR mutations and ROS1 and ALK rearrangements in a large series of non-small cell lung cancer in South India
EGFR mutations and ROS1 and ALK rearrangements in a large series of non-small cell lung cancer in South India

Aim of this study was to analyse the frequency of epidermal growth factor receptor (EGFR) mutations, ALK and ROS1 rearrangements and their association with age and gender in non-small cell lung cancer reported from a tertiary care center in South India. The study found EGFR mutations are more common than ALK and ROS1 rearrangements. They are more common in females. Patients less than 36 years have reduced frequency of EGFR mutations. Exon 19 deletion and L858R are most common and are more prevalent in lung adenocarcinomas. Rare EGFR mutations are seen in patients aged more than 50 years. READ ARTICLE

Cancer Reports DOI:10.1002/cnr2.1288

Authors: Anil Tarigopula, Gayathri Ramasubban, Vani Chandrashekar, Perumal Govindasami, hitra Chandran

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Real-World OutcomesKirk SmithALK, EGFR, non-small cell lung carcinoma, ROS1
ALK Inhibitors Do Not Increase Sensitivity to Radiation in EML4-ALK Non-small Cell Lung Cancer
ALK Inhibitors Do Not Increase Sensitivity to Radiation in EML4-ALK Non-small Cell Lung Cancer

ALK inhibitors like Crizotinib, Ceritinib and Alectinib are targeted therapies used in patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC). Since in this tumor entity radiotherapy is employed sequentially or concomitantly, potential synergistic effects were investigated, which may support the hypothesis of induced radiosensitization by using ALK inhibitors. Two cell lines expressing wild-type (WT) or echinoderm microtubule-associated protein-like 4 (EML4)-ALK were treated with ALK inhibitors, followed by irradiation. Cell survival, cell death, cell cycle and phosphorylation of H2A histone family, member X (H2AX) were examined. Combined treatment with ALK-inhibitors plus 10 Gy-irradiation led to effects similar to those of sole radiotherapy, but was more effective than sole drug treatment. There is no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors. READ ARTICLE

Anticancer Research DOI:10.21873/anticanres.14497

Authors: Kathrin Fleschutz, Lisa Walter, Tumo Leistner, Lucie Heinzerling

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Pre-ClinicalKirk SmithNSCLC, ALK inhibitors, Ceritinib, Crizotinib Alectinibanaplastic lymphoma kinase, radiation
Sustained Response to Crizotinib After Resistance to First-Line Alectinib Treatment in Two Patients With ALK-Rearranged NSCLC
Sustained Response to Crizotinib After Resistance to First-Line Alectinib Treatment in Two Patients With ALK-Rearranged NSCLC

... Here, we describe the sustained response to second-line crizotinib in two patients with echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged advanced NSCLC after failure of the first-line alectinib therapy with no secondary ALK mutations... We speculate that the sustained response to crizotinib in our cases was primarily owing to the absence of ALK resistance mutations. However, we cannot completely rule out the activation of other alternative pathways, as tumor rebiopsies were not performed after developing resistance to alectinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.01.003

Authors: Jing Zheng, Wenjia Sun, Wenhong Chen, Jianying Zhou, Jianya Zhou

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Case StudyKirk SmithCrizotinib, Alectinib, ALK, NSCLC
A case of one lung adenocarcinoma patient harboring a novel FAM179A-ALK (F1, A19) rearrangement responding to lorlatinib treatment
A case of one lung adenocarcinoma patient harboring a novel FAM179A-ALK (F1, A19) rearrangement responding to lorlatinib treatment

The FAM179A gene has recently been screened as a new fusion partner fusing to the anaplastic lymphoma kinase gene (ALK) in plasma cell-free DNA (cfDNA) of patients with non-small-cell lung cancer (NSCLC). However, the response of patients with NSCLC harboring the FAM179A–ALK fusion to ALK inhibitors remains unknown. In this study we report a novel FAM179A–ALK rearrangement variant (F1, A19) identified by next-generation sequencing in an NSCLC patient with multiple brain metastases (M1c). This patient responded sensitively to lorlatinib as evaluated by brain MRI and chest CT, followed up using plasma cfDNA. The conclusion is that we found a novel FAM179A–ALK rearrangement variant (F1, A19) and provided evidence of its sensitivity to ALK inhibitors. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.06.026

Authors: Jing Yan, Xijian Zhou, Dejian Pan

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Case StudyKirk SmithALK, NSCLC, Lorlatinib, Brain metastases
Les réarrangements moléculaires : cibles thérapeutiques en cancérologie thoracique Fusion transcripts: Therapeutic targets in thoracic oncology
Les réarrangements moléculaires : cibles thérapeutiques en cancérologie thoracique Fusion transcripts: Therapeutic targets in thoracic oncology

Five to ten percent of lung adenocarcinoma harbor chromosomal rearrangements affecting the ALK, ROS1, NTRK and RET genes. These rearrangements are associated with the production of fusion transcripts that lead to the synthesis of chimeric proteins with constitutive kinase activity. These abnormal proteins induce an oncogenic dependency that may be targeted by tyrosine kinase inhibitors. In this review, we will summarize the clinical and molecular epidemiology of chromosomal rearrangements affecting ALK, ROS1, NTRK and RET genes. We will describe the mechanisms of resistance to tyrosine kinase inhibitors that have been reported. We will present the molecular techniques that can be used to detect these rearrangements and the strategies set-up by the molecular oncology laboratories to diagnose these genetic alterations. READ ARTICLE

Bulletin du Cancer DOI:10.1016/j.bulcan.2020.05.008

Authors: Audrey Mansuet-Lupo, Simon Garinet, Diane Damotte, Marco Alifano, Hélène Blons, Marie Wislez, Karen Leroy

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Review PaperKirk SmithRearrangement, Fusion, ALK, ROS1, RET, NTRK
Efficacy and safety of ceritinib 450 mg-fed vs 750 mg-fasted in Asian patients (pts) with ALK+ non-small cell lung cancer (NSCLC) in the ASCEND-8 trial
Efficacy and safety of ceritinib 450 mg-fed vs 750 mg-fasted in Asian patients (pts) with ALK+ non-small cell lung cancer (NSCLC) in the ASCEND-8 trial

Asian pts with ALK+ advanced/metastatic NSCLC treated with ceritinib 450 mg-fed showed numerically higher efficacy and less GI toxicity compared to 750 mg-fasted pts. READ ARTICLE

ESMO (European Society for Medical Oncology) Abstract DOI: 10.1016/j.annonc.2020.08.1662

Authors: B.C. Chul Cho, D-W. Kim, U. Batra, K. Park, S-W. Kim, C.T. Yang, V. Pie Jye, V. Sriuranpong, K.G. Babu, K. Amin, Y. Wang, L. Wang, M. Bhering, S. Lucien Geater

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Clinical TrialsKirk SmithASCEND-8, ceritinib
Clinical Utility of Reflex Ordered Testing for Molecular Biomarkers in Lung Adenocarcinoma
Clinical Utility of Reflex Ordered Testing for Molecular Biomarkers in Lung Adenocarcinoma

Introduction: In order to standardize and expedite molecular biomarker testing, we implemented reflex ordered testing of targeted gene alterations in newly diagnosed lung adenocarcinomas within our hospital system... Conclusions: Reflex ordered testing of molecular biomarkers in lung adenocarcinoma led to significantly decreased TAT within our hospital system and higher detection rates of targeted gene alterations. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.007

Authors: Kartik Anand, Thuy L. Phung, Eric H. Bernicker, Philip T. Cagle, Randall J. Olsen, Jessica S. Thomas

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Review PaperKirk SmithALK fusion, EGFR mutation, NSCLC, ROS1 fusion, Turnaround time
Development of complex renal cysts: A complication associated with Crizotinib therapy
Development of complex renal cysts: A complication associated with Crizotinib therapy

Crizotinib is a tyrosine kinase inhibitor that has been found to be effective in the treatment of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer. This targeted cancer therapy agent has been shown to have superior efficacy over standard chemotherapy in this small subset of lung cancer patients. An adverse effect of this drug therapy is the development of complex renal cysts. Here, we present a case of a 68-year-old patient with non-small cell lung cancer on Crizotinib therapy who developed complex bilateral renal cysts. It is important to recognize this drug-related complication in order to avoid mistaking it for disease progression, primary renal malignancy, or renal infection. READ ARTICLE

Clinical Imaging DOI:10.1016/j.clinimag.2020.03.011

Authors: Frank Chen, Neema J. Patel, Jordan D. Legout, Melanie P. Caserta

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Case StudyKirk SmithCT, Crizotinib, Complex renal cyst, Lung cancer
Expression Profiling of Driver Genes in Female Never-smokers With Non-adenocarcinoma Non–small-cell Lung Cancer in China
Expression Profiling of Driver Genes in Female Never-smokers With Non-adenocarcinoma Non–small-cell Lung Cancer in China

Background: Although smoking is a primary cause of lung cancer, females are overrepresented among never-smokers with the disease. The mutational landscape of adenocarcinoma in never-smoking females has been extensively profiled; however, there is little knowledge about genomic alterations in non-adenocarcinoma non–small-cell lung cancer (NA-NSCLC). In the study, we reviewed the status of oncogenic drivers of NA-NSCLC in these populations... Conclusion: Female never-smokers with NA-NSCLC in this study had a high frequency of currently known or potentially actionable oncogenic alterations and could benefit from targeted therapy. Our study also provides evidence for the recommendation of molecular analysis in never-smoking female SQCC. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.02.005

Authors: Yiming Zhao, Yu Dong, Ruiying Zhao, Bo Zhang, Shuyuan Wang, Lele Zhang, Minjuan Hu, Qingnan He, Wei Zhang, Baohui Han

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Real-World OutcomesKirk SmithDriver gener, Female, Genome, Never-smokers, Non-small cell lung cancer
Treatment Algorithm for Advanced ALK-Rearranged NSCLC: Reply
Treatment Algorithm for Advanced ALK-Rearranged NSCLC: Reply

... We agree that crizotinib will still have a role in the treatment of patients with advanced ALK-rearranged NSCLC, however, probably only as a supplementary drug. In cell lines, crizotinib has been reported to be active in Ba/F3 cells harboring EML4-ALK resistance 1198F mutations or E1210K mutations... Finally, we agree with Urbanska et al. that comprehensive molecular profiling is also very important for treatment-naive patients, which may help identify potentially “detrimental” factors, such as TP53 mutations or BIM deletion polymorphisms.11,12 Nevertheless, a deeper understanding of the underlying biology mechanisms of acquired resistance to ALK inhibitors will help us further complement the therapeutic algorithm for patients with advanced ALK-rearranged NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.06.005

Authors: Fei Zhou, Caicun Zhou

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EditorialKirk SmithALK, NSCLC
1301P Blood first assay screening trial (BFAST) in patients (pts) with 1L NSCLC: ALK+ cohort updated biomarker analyses
1301P Blood first assay screening trial (BFAST) in patients (pts) with 1L NSCLC: ALK+ cohort updated biomarker analyses

Clinical trial identification: NCT03178552. Background: BFAST (NCT03178552) is a global, multi-cohort study evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations in circulating tumour DNA and activity of targeted therapies/immunotherapy in pts with 1L advanced NSCLC. In the ALK+ cohort, investigator-assessed objective response rate (ORR) was 87.4% and 12-month progression-free survival (PFS) rate was 78.4% with alectinib. We present updated ALK+ cohort biomarker analyses (median follow-up: 18.2 months)... Conclusions: Molecular heterogeneity in ALK+ NSCLC may influence clinical efficacy of ALK inhibitors such as alectinib. Larger, more mature datasets are needed to identify and validate additional biomarkers predictive of limited benefit from ALK inhibitors. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.08.1615

Authors: S. M. Gadgeel, M. Yan, S. M. Paul, M. Mathisen, S. Mocci, Z. J. Assaf, R. Patel, E. S. Sokol, T. Mok, S. Peters, L. Paz-Ares, R. Dziadziuszko

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Review PaperKirk Smith1301P Blood first assay screening trial (BFAST), NSCLC, ALK
ALK Inhibitors in ALK-positive NSCLC with Central Nervous System Metastases
ALK Inhibitors in ALK-positive NSCLC with Central Nervous System Metastases

In anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer, brain metastases occur in 22–33% of cases at diagnosis and could reach up to 70% after crizotinib failure. Next-generation ALK inhibitors (ngALKi) have superior intracranial activity and prolonged responses compared with crizotinib and chemotherapy, as was shown in treatment-naïve or crizotinib pre-treated patients, irrespective of prior brain irradiation. Nevertheless, central nervous system relapse is also seen with ngALKi. Tailored treatment is necessary to obtain long-term survival without detrimental effects on cognition. Possible options include profiling secondary mutations to select sequential ngALKi, stereotactic radiotherapy and/or surgery, with the aim to avoid/deter whole brain irradiation. READ ARTICLE

touchONCOLOGY DOI:10.17925/EOH.2020.16.1.18

Authors: Mihaela Aldea, Benjamin Besse, Lizza EL Hendriks

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EditorialKirk SmithNon-small cell lung cancer, anaplastic lymphoma kinase, brain metastases, personalised treatment
Anaplastic Lymphoma Kinase-Positive Lung Cancer with Mucoepidermoid Carcinoma Differentiation: A Case Report
Anaplastic Lymphoma Kinase-Positive Lung Cancer with Mucoepidermoid Carcinoma Differentiation: A Case Report

Mucoepidermoid carcinoma (MEC) of the lung is an extremely rare tumor, and a standard chemotherapy has not been established. Furthermore, little work has been conducted on the genetic characteristics of MEC. We herein report the case of a 42-year-old nonsmoking male patient who was referred to our hospital due to cough. Chest computed tomography demonstrated infiltration and atelectasis in the right lower lobe. He was eventually diagnosed with non small cell lung cancer (NSCLC) with MEC differentiation corresponding to clinical stage IVA (cT4N2M1a[PLE]). Genetic testing for EGFR mutations was negative, but positive for anaplastic lymphoma kinase (ALK) fusion gene. After 2 weeks of first-line treatment with alectinib, the tumor decreased in size and his symptoms improved. Advanced MEC is a rare tumor, and reports on the treatment of ALK-positive NSCLC with MEC differentiation are rare. READ ARTICLE

Case Reports in Oncology DOI:10.1159/000510042

Authors: Sakatani T., Masuda Y., Morikawa T., Usui K

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Case StudyKirk SmithMucoepidermoid carcinoma, MEC, nonsmoking, male, ALK positive, alectinib
Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with ..... READ ARTICLE

Journal of Personalized Medicine DOI:10.3390/jpm10030107

Authors: László Urbán, Róbert Dóczi, Barbara Vodicska, Dóra Kormos, László Tóth, István Takács, Edit Várkondi, Dóra Tihanyi,Dóra Lakatos, Anna Dirner, István Vályi-Nagy, István Peták

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Real-World OutcomesKirk SmithNSCLC, ALK rearrangement, TP53 mutation, TKI, personalized treatment
EML4-ALK, a potential therapeutic target that responds to alectinib in ovarian cancer
EML4-ALK, a potential therapeutic target that responds to alectinib in ovarian cancer

Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK. READ ARTICLE

Japanese Journal of Clinical Oncology DOI:10.1093/jjco/hyaa156

Authors: Beina Hui, Jingping Zhang, Xiaobo Shi, Fangfang Xing, Yang W Shao, Yuanyuan Wang, Xiaozhi Zhang, Shuwen Wang

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Case StudyKirk SmithOvarian cancer, EML4-ALK fusion gene, targeted therapy, alectinib, next generation sequencing (ngs)