Genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma
Genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma

ALK (Anaplastic lymphoma kinase) fusion proteins are oncogenic and have been seen in various tumors. PPP1CB-ALK fusions are rare but have been reported in a few patients with low- or high-grade gliomas. However, little is known regarding the mechanism of fusion formation and genomic break points of this fusion. We performed genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma. The PPP1CB-ALK consists of exons 1–5 of PPP1CB and exons 20–29 of ALK. The genomic translocation breakpoints were determined by real-time quantitative PCR (RT-qPCR) and Sanger sequencing of genomic DNA. Next generation sequencing, RT-qPCR and fluorescence in situ hybridization analyses demonstrated PPP1CB-ALK amplification. Copy number analyses of genes between PPP1CB and ALK using RT-qPCR suggest that the PPP1CB-ALK is likely the result of local chromothripsis followed by episomal amplification. Transcriptome sequencing demonstrated high-level SOX2 expression and predicted WNT/β-catenin pathway activation, suggesting possible therapeutic approaches. READ ARTICLE

Cancer Genetics DOI:10.1016/j.cancergen.2020.12.005

Authors: Yiming Zhong, Fumin Lin, Feng Xu, Jeff Schubert, Jinhua Wu, Luanne Wainwright, Xiaonan Zhao, Kajia Cao, Zhiqian Fan, Jiani Chen, Shih-Shan Lang, Benjamin C. Kennedy, Angela N. Viaene, Mariarita Santi, Adam C. Resnick, Phillip B. Storm and Marilyn M. Li

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Case StudyKirk SmithPPP1CB-ALK fusion, Gene amplification, Glioblastoma, NGS, WNT/β-catenin pathway
Circulating tumor cells as a response biomarker in alk-positive metastatic inflammatory myofibroblastic tumor
Circulating tumor cells as a response biomarker in alk-positive metastatic inflammatory myofibroblastic tumor

Case report of a 19-year-old boy with an ALK-positive IMT of the bladder, proximal osteolytic and multiple bilateral lung lesions, who received ALK inhibitor entrectinib postoperatively and underwent longitudinal CTC analysis during treatment. Antitumor activity of entrectinib was demonstrated and was accompanied by regression of lung lesions, elimination of CTCs from the blood and no development of relapses afterwards. Therapy continued without any clinical sign of progression and 24 months since the initiation of treatment the patient remains symptom-free and disease-free. READ ARTICLE

Frontiers in Pediatrics DOI:10.3389/fped.2021.652583

Authors: Paolo Bonvini, Elisabetta Rossi, Angelica Zin, Mariangela Manicone, Riccardo Vidotto, Antonella Facchinetti, Lucia Tombolan, Maria C. Affinita, Luisa Santoro, Zamarchi Rita, Gianni Bisogno.

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Case StudyKirk SmithALK, MET amplification, resistance mechanism, next-generation sequencing, NGS
First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report
First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report

This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient’s preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.02.005

Authors: Giovanna Scarfone, Monica Fumagalli, Martina Imbimbo, Tommaso Ceruti, Fulvia Milena Cribiù, Eugenia Di Loreto, Maurizio D’Incalci, Federica Facchin, Camilla Fontana, Marina C. Garassino, Fedro A. Peccatori, Nicola Persico, Diego Signorelli, Massimo Zucchetti

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Case StudyKirk SmithALK rearrangement, Lung cancer, alectinib, Pregnancy
First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report
First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report

This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient’s preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.02.005

Authors: GiovannaScarfone, Monica Fumagalli, Martina Imbimbo, Tommaso Ceruti, Fulvia Milena Cribiù, Eugenia Di Loreto, Maurizio D’Incalci, Federica Facchin, Camilla Fontana, Marina C. Garassino, Fedro A. Peccatori, Nicola Persico, Diego Signorelli and Massimo Zucchetti

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Case StudyKirk SmithALK rearrangement, Lung cancer, Alectinib, Pregnancy
Lorlatinib Should Not be Considered as the Preferred First-Line Option in Patients With Advanced ALK Rearranged NSCLC
Lorlatinib Should Not be Considered as the Preferred First-Line Option in Patients With Advanced ALK Rearranged NSCLC

In theory, you might think there should be no debate over whether lorlatinib should be the preferred first-line ALK inhibitor. If the CROWN study data are viewed in isolation, lorlatinib seems to have the best-in-class differential progression-free survival (PFS) benefit over crizotinib (hazard ratio [HR] = 0.28, 95% confidence interval [CI]: 0.19–0.41). 1 In contrast, other next-generation ALK inhibitors alectinib, brigatinib, and ensartinib with comparable head-to-head trials versus crizotinib generated PFS HRs ranging from 0.51 to 0.37. 2 , 3 , 4 , 5 , 6 , 7 Whereas, admittedly, for the lowest of these estimates (from the J-ALEX study [alectinib versus crizotinib in a Japanese population]), the CIs of the PFS HR (0.37, 95% CI: 0.26–0.52) overlap with those of the CROWN study, there is a clear delineation between the upper limit of CROWNs HR CIs and the lower limit of the HR CIs for the other studies. Yet, here we are in a pro and con debate, because, frankly, there is something abou..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.12.022

Authors: David Ross Camidge

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EditorialKirk SmithLorlatinib, First-Line, ALK-Rearranged NSCLC
Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC
Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC

Since the discovery of ALK-positive (ALK+) fusion in NSCLC in 2007, 1 ,2 we now know patients with ALK+ NSCLC can live up to 9 years after stage 4 diagnosis 3 , 4 , 5 but are constantly overshadowed by an unrelenting cumulative incidence of brain metastasis with time (>60% by year 6). 6 At the molecular level, the two most common EML4-ALK fusion variants, variant 1 (v1) and variant 3 (v3), have differential responses to ALK tyrosine kinase inhibitors (TKIs) 7 ,8 with the recalcitrant solvent-front ALK G1202R mutation arising more often from the background of EML4-ALK variant 3. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.12.021

Authors: Misako Nagasaka, Sai-Hong Ignatius Ou

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EditorialKirk Smithlorlatinib, First-Line, ALK-Rearranged, NSCLC
EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.
EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.

Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods:Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal)..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-07905-6

Authors: Miyanaga A, Matsumoto M, Beck JA, Horikawa I, Oike T, Okayama H, Tanaka H, Burkett SS, Robles AI, Khan M, Lissa D, Seike M, Gemma A, Mano H, Harris CC

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Pre-ClinicalKirk SmithEML4-ALK, lung cancer, Senescence, anchorage-independent growth, DNA damage, hTERT
High discrepancy in thrombotic events in non-small cell lung cancer patients with different genomic alterations
High discrepancy in thrombotic events in non-small cell lung cancer patients with different genomic alterations

NSCLC patients with ALK/ROS1 rearrangements are more likely to develop thrombosis than patients with other oncogenic alterations. Thrombosis may also be associated with an inferior response and PFS after TKI therapy. READ ARTICLE.

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1290

Authors: Yiwei Liu, Wanying Wang, Fengying Wu, Guanghui Gao, Jian Xu, Xuefei Li, Chao Zhao, Shuo Yang, Shiqi Mao, Yingying Pan, Keyi Jia, Chuchu Shao, Bin Chen, Shengxiang Ren, Caicun Zhou

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Real-World OutcomesKirk Smith
Comparison of ALK detection by FISH, IHC and NGS to predict benefit from crizotinib in advanced non-small-cell lung cancer
Comparison of ALK detection by FISH, IHC and NGS to predict benefit from crizotinib in advanced non-small-cell lung cancer

Purpose: Anaplastic lymphoma kinase (ALK) is now a validated kinase target in non-small cell lung cancer (NSCLC). We implemented three ALK laboratory methodologies: fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and next-generation sequencing (NGS) to detect EML4-ALK fusions and compared the predictive value for Crizotinib efficacy in ALK-positive patients. Conclusion: FISH present a certain false-negative rate although considered the gold standard. Ventana-D5F3 IHC is qualified as a screening tool, while NGS positive may predict clinical benefit of Crizotinib more accurately, allowing efficient test for specific variants and concurrent genomic alterations. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.03.018

Authors: Chen Lin, Xun Shi, Shao Yang, Jun Zhao, Qiong He, Ying Jin, Xinmin Yu,

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Case StudyKirk SmithALK, Fluorescence in situ hybridization (FISH), Immunohistochemistry (IHC), Next-generation sequencing (ngs), Non-small cell lung cancer (NSCLC)
Successful management of a lung cancer patient harbouring both EGFR mutation and EML4-ALK fusion gene with disseminated intravascular coagulation
Successful management of a lung cancer patient harbouring both EGFR mutation and EML4-ALK fusion gene with disseminated intravascular coagulation

Lung cancer patients harbouring driver oncogene alterations are markedly responsive to molecular target agents, such as epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor (TKI), and echinoderm microtubule-associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK)-TKI. We encountered an exceptionally rare case, harbouring both EGFR mutation and EML4-ALK fusion gene, and suffering from severe disseminated intravascular coagulation. In this case report, we present two notable points. First, our patient was successfully treated with a third-generation EGFR-TKI, osimertinib. Second, osimertinib could manage severe conditions, such as disseminated intravascular coagulation. Third-generation EGFR-TKIs may be a viable option for patients harbouring both EGFR mutations and EML4-ALK fusion genes, even in severe conditions. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2021.101393

Authors: Kohei Fujita, Megumi Naka, Takanori Ito, Osamu Kanai, Koichi Maekawa, Koichi Nakatani, Tadashi Mio

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Case StudyKirk Smithalectinib, EGFR mutation, EML4-ALK rearrangement, Lung adenocarcinoma, NSCLC, osimertinib, TKI
Feasibility and challenges for sequential treatment in ALK-rearranged non-small-cell lung cancer
Feasibility and challenges for sequential treatment in ALK-rearranged non-small-cell lung cancer

Despite absence of regulatory obstacles and no requirement for specific acquired mutations, 25-30% of ALK+ NSCLC patients forego subsequent systemic therapy due to rapid clinical deterioration, in several cases (approximately 1/3) associated with an ineffective first next-line choice. These results underline the need for closer patient monitoring and broader profiling in order to support earlier and better directed use of available therapies. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.670483

Authors: Mei Elsayed, Farastuk Bozorgmehr, Daniel Kazdal, Anna-Lena Volckmar, Holger Sültmann, Jürgen Fischer, Mark Kriegsmann, Albrecht Stenzinger, Michael Thomas, Petros Christopoulos

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Real-World OutcomesKirk SmithALK-rearranged, NSCLC, TKI, chemotherapy, Sequential therapies, overall survival
PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer
PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

Study Proposes proposes PI3Kβ as a novel regulator of ALKi resistance in ALK-rearranged lung cancer cells, showing efficacy even in aggressive TP53 mutant and mesenchymal cells. Given that multiple salvage signals are activated upon resistance to ALKi, the co-targeting of PI3Kβ may provide a promising therapy option as PI3Kβ acts as a common effector of multiple salvage pathways, including EGFR, autophagy and GPCRs. Importantly, we found that co-targeting of PI3Kβ showed reduced toxicity in normal lung epithelial cells when compared with co-targeting of EGFR, possibly providing for a relatively safe clinical direction to treat ALK-rearranged tumors. READ ARTICLE

BioRxIV DOI:10.1101/2021.03.18.435801

Authors: Sarang S. Talwelkar, Mikko I. Mäyränpää, Julia Schüler, Nora Linnavirta, Annabrita Hemmes, Simone Adinolfi, Matti Kankainen, Wolfgang Sommergruber, Anna-Liisa Levonen, Jari Räsänen, Aija Knuuttila, Emmy W. Verschuren, Krister Wennerberg

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Pre-Print, Pre-ClinicalKirk SmithPI3Kβ inhibition
Case Report: Neoadjuvant and Adjuvant Crizotinib Targeted Therapy in Stage IIIA-N2 ALK-Positive Non-Small-Cell Lung Cancer
Case Report: Neoadjuvant and Adjuvant Crizotinib Targeted Therapy in Stage IIIA-N2 ALK-Positive Non-Small-Cell Lung Cancer

Case report of systemic treatment with ALK inhibitor crizotinib before surgery showing it may provide the potential to cure the initially inoperable tumor. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.655856

Authors: Xiao-Hong Xie, Ze-Jiang Zhan, Yin-Yin Qin, Ju-Hong Jiang, Wei-Qiang Yin, Rong-Hui Zheng, Shi-Yue Li, Cheng-Zhi Zhou

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Case StudyKirk SmithNeoadjuvant, Adjuvant, crizotinib, NSCLC
Efficacy and safety of crizotinib plus bevacizumab in ALK/ROS-1/c-MET positive non-small cell lung cancer: an open-label, single-arm, prospective observational study
Efficacy and safety of crizotinib plus bevacizumab in ALK/ROS-1/c-MET positive non-small cell lung cancer: an open-label, single-arm, prospective observational study

This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive ALK rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in ALK/ROS-1/c-MET positive NSCLC patients. READ ARTICLE

American Journal of Translational Research DOI:10.1016/j.cllc.2021.06.011

Authors: Huang Z., Xiong Q., Cui Z., Tao H., Zhang S., Wang L., Cui P., Chen S., Huang D., Yang B., Hu Y.

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Clinical TrialsKirk Smithcrizotinib, bevacizumab, ALK, ROS-1, c-MET, brain metastasis
Complex genetic alterations contribute to rapid disease progression in an ALK rearrangement lung adenocarcinoma patient: a case report
Complex genetic alterations contribute to rapid disease progression in an ALK rearrangement lung adenocarcinoma patient: a case report

Concurrent genetic alterations, including loss-of-function mutations in FBXW7 and MLL3, may mainly contribute to poor prognosis in the patient. It highlighted the molecular profiling by using NGS can be useful in identifying the heterogeneity across lesions and the resistance mechanism of targeted treatments. READ ARTICLE

Translational Cancer Research DOI:10.21037/tcr-20-3473

Authors: Xiang Long, Hao Wu, Chenglin Yang, Fang Li, Min Zhang, Xuan Wu

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Case StudyKirk SmithALK, MET amplification, resistance mechanism, next-generation sequencing, NGS
Crizotinib in Patients With MET-Amplified NSCLC
Crizotinib in Patients With MET-Amplified NSCLC

Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.02.010

Authors: D. Ross Camidge, Gregory A. Otterson, Jeffrey W. Clark, Sai-Hong Ignatius Ou, Jared Weiss, Steven Ades, Geoffrey I. Shapiro, Mark A. Socinski, Danielle A. Murphy, Umberto Conte, Yiyun Tang, Sherry C. Wang, Keith D. Wilner, Liza C. Villaruz

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Case StudyKirk SmithALK fusion, ALK rearrangement, concomitant mutation, crizotinib, NSCLC, next-generation sequencing, NGS