This report illustrates the importance of careful interpretation of aberrant FISH findings and subsequent use of orthogonal methods to clarify the presence of genomic alterations to successfully determine potential treatment targets. READ ARTICLE
Case Reports in Oncology DOI:10.1159/000512187
Authors: Sara Akhavanfard, Erik Nohr, Mohammad AlNajjar, Mollie Haughn, Sayaka Hashimoto, Carol Deeg, Ruthann Pfau, Marie-Anne Brundler, Shalini C Reshmi
This analysis of real-world data shows increasing test use by year; however, one fifth of patients eligible for ALK testing still remain untested and potentially missing therapeutic options. READ ARTICLE
The Oncologist DOI:10.1002/onco.13779
Authors: Eric H Bernicker, Yan Xiao, DrPH, Anup Abraham MPH, Baiyu Yang, Denise Croix, Stella Redpath, Julia Engstrom-Melnyk, Roma Shah MPH, Jaya Madala MS, Timothey Craig Allen, JD
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
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.
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
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
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,
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
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
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
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
We demonstrated that IHC positive test, in these cases, must be interpreted with caution. FISH analysis has to be recommended to confirm IHC results in case of unusual phenotype, such as smoker or lung cancer other than adenocarcinoma. Although lung carcinoma with ALK rearrangement seems to be not sensitive to ICI, further investigations should be conducted on other types of ALK molecular alterations. ALK amplifications, as observed in the present case, should not be an impediment to taking into account the PD-L1 marking for the initiation of treatment by immunotherapy. READ ARTICLE
Lung Cancer DOI: 10.1016/j.lungcan.2020.12.022.
Authors: Gendarme S, Matton L, Antoine M, Kerrou K, Ruppert AM, Epaud C, Cadranel J, Fallet V.
Read MoreEGFR mutation and ALK rearrangement were considered mutually exclusive mutations in non-small cell lung cancer. Upfront comprehensive mutation screening, like next-generation sequencing, enabled the discovery of simultaneous mutations. We describe a case of a woman with stage IV lung adenocarcinoma with 2 synchronous mutations at diagnosis, the EGFR p.(Leu858Arg) mutation, and an ALK rearrangement. The patient is on gefitinib for 16 months, maintaining this strategy currently. Co-occurrence of 2 targetable mutations is a particular challenge when choosing first-line treatment. We discuss the treatment options and results in patients with both mutations, which were generally associated with a poor prognosis in multiple studies comparing with one single mutation. READ ARTICLE
Porto Biomedecial Journal DOI: 10.1097/j.pbj.0000000000000124
Authors: Élia Cipriano, Helena Magalhães, Catarina Tavares, João Pinto, Luís Cirnes, Fernanda Estevinho
Read MoreWe present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses – 300 mg and 600 mg twice daily – across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of A..... READ ARTICLE
Cancer Treatment and Research Communications DOI:10.1016/j.ctarc.2021.100319
Authors: Danielle Benedict Sacdalan and Josephine Anne Luceroc
Anaplastic lymphoma kinase (ALK)-translocations are present in up to 5% of non-small cell lung cancer (NSCLC), most of them being adenocarcinomas. Even though the availability of five potent ALK-inhibitors for the treatment of ALK-positive NSCLC patients, there is no consensus about the ideal therapy sequence. Alectinib has been so far successfully and routinely used as first-line therapy, especially in patients presenting central nervous system lesions; however, with the very recent European approval of brigatinib in the first line, a new treatment option is now available for ALK+ patient collective. In this case series, efficient systemic and intracranial responses to alectinib late-line treatment following brigatinib therapy are reported. This therapeutic sequence is going to gain therefore more importance in a near future READ ARTICLE
Anti-Cancer Drugs DOI:10.1097/CAD.0000000000000989
Authors: Hochmair, Maximilian Johannesa; Prosch, Helmutb; Krenbek, Dagmarc; Weinlinger, Christopha; Fabikan, Hannaha; Valipour, Arschang
Report reveals the efficacy of lorlatinib in targeting ALK G1202L and can serve as an option for the clinical management of patients with ALK-rearranged lung adenocarcinoma after acquiring G1202L-mediated resistance from prior ALK inhibitor therapy. Furthermore, it demonstrates the sequential use of crizotinib, brigatinib, and lorlatinib in a patient with advanced ALK-rearranged lung adenocarcinoma with an overall progression-free survival of 33.3 months for the sequential ALK inhibitor regimens. His overall survival was 41.5 months inclusive of all regimens. READ ARTICLE
Cancer Biology & Therapy DOI: 10.1080/15384047.2020.1836947
Authors: Zhaoting Meng, Ting Li, Pei Wang, Analyn Lizaso, Dingzhi Huang
Read MoreTyrosine kinase inhibitors are the first-line treatment for Anaplastic Lymphoma Kinase-positive lung adenocarcinomas. However, chemotherapy is still an option in patients who are unresponsive or intolerant of tyrosine kinase inhibitors. There is a high likelihood of brain metastasis in patient with lung adenocarcinomas with Anaplastic Lymphoma Kinase rearrangement. Surveillance brain imaging may have a role in clinical follow up. Brigatinib and lorlatinib are two tyrosine kinase inhibitors with excellent intracranial penetrance. READ ARTICLE
Cancer Treatment and Research Communications DOI:10.1016/j.ctarc.2020.100291
Authors: Oranus Mohammadi, Kayla Haines, Mohammad Jahanzeb,
We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions. READ ARTICLE
International Journal of Molecular Science DOI: 10.3390/ijms21249705
Authors: Tashiro T, Imamura K, Tomita Y, Tamanoi D, Takaki A, Sugahara K, Sato R, Saruwatari K, Sakata S, Inaba M, Ushijima S, Hirata N, Sakagami T
Read MoreThe knowledge of oncogene addiction in non small cell lung carcinoma (NSCLC) involving EGFR, ALK and ROS1 genes has changed the therapeutic and prognostic landscape of NSCLC. ALK rearranged NSCLC accounts for 10% of these cases, and with the development and approval of ALK TKIs (tyrosine kinase inhibitors) like crizotinib, it is imperative to detect the same. Various ALK variants are known to occur resulting in differential sensitivities to TKIs because of different protein stabilities. The precise characterization hence is important which can be achieved only by high throughput next generation sequencing (NGS) based assays. Immunohistochemistry and FISH (fluorescence in situ hybridization) although considered gold standards cannot define the breakpoints and length of the fusion transcripts. We herein report a novel EML4-ALK variant in a case of advanced NSCLC which plausibly is inherently resistant to crizotinib because of the breakpoints involved. READ ARTICLE
Current Problems in Cancer DOI:doi.org/10.1016/j.cpccr.2020.100040
Authors: Ullas Batra, Shrinidhi Nathany, Mansi Sharma, Satyajeet Soni, Parveen Jain, Sunil Pasricha, Abhishek Bansal, Anurag Mehta
Renal cell carcinoma (RCC) with anaplastic lymphoma kinase (ALK) rearrangement is rare, and the genetic profiles of the tumor have not been elucidated. Here, we report a case with recurrent papillary RCC and lung metastasis after nephrectomy for nearly 7 years. The patient first received sunitinib, whereas the drug toxicity was intolerable. Combined Immunohistology (IHC) and fluorescence in situ hybridization (FISH) revealed the patient has an ALK rearrangement, and the patient then was treated with crizotinib. The patient had good tolerance, and a partial response in the target lesions was achieved. In order to further understand the benefit of crizotinib in ALK-rearranged RCC, the patient was detected with whole exome sequencing (WES) to study her genetic profiles. Compared those of RCC cases without ALK rearrangement (nALK-RCC), the patient and nine RCC cases with ALK rearrangement (ALK-RCC) revealed unique genetic characteristics: 1) The common mutations that occurred in RCC were n..... READ ARTICLE
Translational Andrology and Urology DOI: 10.21037/tau-20-1343
Authors: Zhou S, Sun G, Wang J, Zhang H.
Read More
