Entrectinib expands the range of treatment options for advanced NTRK+ solid tumours and ROS1+ NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases. READ ARTICLE
Drugs DOI:10.6084/m9.figshare.14150207
Authors: James E Frampton
Anaplastic lymphoma-kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is prone to developing heterogeneous, only partly known mechanisms of resistance to ALK-tyrosine-kinase-inhibitors (ALK-TKIs). We present a case of a 38-year old male, who never smoked with disseminated ALK-rearranged (EML4 (20) – ALK (20) fusion variant 2) lung adenocarcinoma, who received four sequentially different ALK-TKIs and two lines of chemotherapy in-between. We observed significant clinical benefit by the first three ALK-TKIs (Crizotinib, Ceritinib, Alectinib) and chemotherapy with Pemetrexed, resulting in overall survival over 3 years. Longitudinal assessment of progressions by rebiopsies from hepatic metastases showed different mechanisms of resistance to each ALK-TKI, including secondary ALK-mutations and the downstream p.V600E BRAF-mutation that had not been linked to second-generation ALK-TKIs before. Ultimately, in connection with terminal rapid progression and resistance to Alectinib and Lor..... READ ARTICLE
International Journal of Molecular Sciences DOI:10.3390/ijms21082847
Authors: Urbanska, E.M.; Sørensen, J.B.; Melchior, L.C.; Costa, J.C.; Santoni-Rugiu, E.
To assess EBUS-TBNA biopsy adequacy for ALK, EGFR and PD-L1 testing, we conducted a prospective study of 279 consecutive NSCLC patients referred to a tertiary EBUS-TBNA centre in South West England. One hundred eight-four (62.6%) patients were found to have adenocarcinoma, 83 (28.2%) had squamous cell carcinoma, and 27 (9.2%) were identified as NSCLC-not otherwise specified. EGFR testing was successful in 166 of 168 patients (98.8%), ALK testing in all 115 and PD-L1 testing in 43 of 49 patients (88.2%). Previous EGFR and ALK testing did not affect biopsy PD-L1 testing success. PD-L1 testing failures occurred in three of five (60.0%) of 22G needle biopsies, one of five (20.0%) of 21G needle biopsies and two of 39 (5.1%) of 19G needle biopsies, P = .016. EBUS-TBNA biopsies are mostly suitable for PD-L1 testing. Larger needle size may improve PD-L1 (but not EGFR and ALK) testing success but requires further study in a controlled trial...... READ ARTICLE
Asia-Pacific Journal of Clinical Oncology DOI:10.1111/ajco.13549
Authors: Joanna Hardy, Nidhi Bhatt, Andrew R L Medford
Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. READ ARTICLE
Cell DOI:10.1016/j.cell.2021.03.031
Authors: Asmin Tulpule, Juan Guan, Dana S Neel, Hannah R Allegakoen, Yone Phar Lin, David Brown, Yu-Ting Chou, Ann Heslin, Nilanjana Chatterjee, Shriya Perati, Shruti Menon, Tan A Nguyen, Jayanta Debnath, Alejandro D Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Suraj Makhija, Bo Huang, Trever G Bivona
Brigatinib is a novel potent tyrosine kinase inhibitor as third-generation therapy for anaplastic lymphoma kinase (ALK) rearrangement positive non-small cell lung cancer (NSCLC). Clinical trials show that brigatinib is potent choice of treatment for the first line and further lines of treatment of ALK rearranged NSCLC with highly potent anti-tumor effect on brain metastasis. The adverse effects of brigatinib are tolerable and managable. However, there is limited data about effects on immune system. The most possible serious adverse effect of brigatinib on immune system might be brigatinib associated grade 3-4 lymphopenia. Here we report a brigatinib-induced tuberculosis reactivation patient who is using third-line brigatinib for metastatic NSCLC and have partial response. READ ARTICLE
Current Problems in Cancer DOI:10.1016/j.currproblcancer.2021.100738
Authors: Volkan Keş, Osman Sütcüoğlu, Fatih Gürler, Ozan Yazıcı, Ahmet Özet
Here, we describe a case study with confirmed EGFR wild-type and ALK-rearranged lung adenocarcinoma who developed complex renal cysts combined with hemorrhage during crizotinib treatment, with no abnormal clinical symptoms or kidney functions observed. Interestingly, without crizotinib treatment termination or reduction, the complex hemorrhagic renal cysts regressed with self-limiting and healing. The combined usage of ultrasound, CT and MRI techniques in the presented case allowed proper monitoring of the internal changes within complex renal cysts. The patient provided written informed consent authorizing publication of clinical case. Thus, better understanding of the imaging features of crizotinib-related renal cysts combined with hemorrhage would avoid misdiagnoses as a new metastatic renal mass or the aggravation of the primary disease, therefore avoiding further invasive investigation. READ ARTICLE
Cancer Treatment Research Communications DOI:10.1016/j.ctarc.2021.100373
Authors: Ling Yang, Jianing Gu, Xiaomin Niu
This paper focuses on automatic Cholangiocarcinoma (CC) diagnosis from microscopic hyperspectral (HSI) pathological dataset with deep learning method. The first benchmark based on the microscopic hyperspectral pathological images is set up. Particularly, 880 scenes of multidimensional hyperspectral Cholangiocarcinoma images are collected and manually labeled each pixel as either tumor or non-tumor for supervised learning. Moreover, each scene from the slide is given a binary label indicating whether it is from a patient or a normal person. Different from traditional RGB images, the HSI acquires pixels in multiple spectral intervals, which is added as an extension on the channel dimension of 3-channel RGB image. This work aims at fully exploiting the spatial-spectral HSI data through a deep Convolution Neural Network (CNN). The whole scene is first divided into several patches. Then they are fed into CNN for the tumor/non-tumor binary prediction and the tumor area regression. The furthe..... READ ARTICLE
Methods DOI:10.1016/j.ymeth.2021.04.005
Authors: Li Sun, Mei Zhou, Qingli Li, Menghan Hu, Ying Wen, Jian Zhang, Yue Lu, Junhao Chu
Lorlatinib can cause visual and auditory hallucinations. And, it is necessary to keep in mind that hallucinations can persist even after discontinuation in patients who develop hallucinations while receiving lorlatinib. READ ARTICLE
Clinical Case Reports
Authors: Jun Hakamata, Hideo Nakada, Hiroshi Muramatsu, Keita Masuzawa, Hideki Terai, Shinnosuke Ikemura, Koichi Fukunaga, Tohru Aomori
Read MoreBackground: National Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing as the first step in the management of patients with advanced non-small cell lung cancer (aNSCLC). We assessed anaplastic lymphoma kinase (ALK) testing rates and factors related to underuse in community medical systems between 2012 and 2019 to understand guideline adoption. Conclusion: 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:doi.org/10.1002/onco.13779
Authors: Eric H. Bernicker,Yan Xiao,Anup Abraham,Baiyu Yang,Denise A. Croix,Stella Redpath,Julia Engstrom-Melnyk,Roma Shah,Jaya Madala,Timothy C. Allen
Comprehensive genomic profiling is needed to know and then target the genes causing resistance in ALK rearranged patients [ [9] ]. We report one such novel deletion p.(Q1188_L1190del) in the ALK tyrosine kinase domain which responded to Lorlatinib. READ ARTICLE
Cancer Genetics DOI:10.1016/j.cancergen.2021.03.006
Authors: Moushumi Suryavanshi, Krushna Chaudhari, Shrinidhi Nathany, Vineet Talwar
PURPOSE Liquid biopsy specimen genomic profiling is integrated in non–small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK/ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. CONCLUSION Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy. READ ARTICLE
JCO Precision Oncology DOI:10.1200/PO.19.00281
Authors: Laura Mezquita, Aurélie Swalduz, Cécile Jovelet, Sandra Ortiz-Cuaran, Karen Howarth, David Planchard, Virginie Avrillon, Gonzalo Recondo, Solène Marteau, Jose Carlos Benitez, Frank De Kievit, Vincent Plagnol, Ludovic Lacroix, Luc Odier, Etienne Rouleau, Pierre Fournel, Caroline Caramella, Claire Tissot, Julien Adam, Samuel Woodhouse, Claudio Nicotra, Edouard Auclin, Jordi Remon, Clive Morris, Emma Green, Christophe Massard, Maurice Pérol, Luc Friboulet, Benjamin Besse, and Pierre Saintigny
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of MYCN. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the pathogenesis of neuroblastoma and other malignancies where it cooperates with N-Myc. We previously identified the first case of ALK F1174C-activating mutation in a patient with de novo NEPC who responded to the ALK inhibitor, alectinib. Here, we show that coactivation of ALK and N-Myc (ALK F1174C/N-Myc) is sufficient to transform mouse prostate basal stem cells into aggressive prostate cancer with neuroendocrine differentiation in a tissue recombination model. A novel gene signature from the ALK F1174C/N-Myc tumors was associated with poor outcome in multiple human prostate cancer datasets. ALK F1174C and ALK F1174C/N-Myc tumors displayed activat..... READ ARTICLE
Cancer Research DOI:10.1158/0008-5472.CAN-20-3351
Authors: Kenji Unno, Zachary R. Chalmers, Sahithi Pamarthy, Rajita Vatapalli, Yara Rodriguez, Barbara Lysy, Hanlin Mok, Vinay Sagar, Huiying Han, Young A. Yoo, Sheng-Yu Ku, Himisha Beltran, Yue Zhao and Sarki A. Abdulkadir
Dr. Ben Levy has a casual conversation with ALK Positive patients and caregivers. Nurse Practitioner, Rasheda Persinger talks about the imperative role of advanced practice nurses in a Multi-D setting. WATCH VIDEO
ALK Positive Inc.
Authors: Ben Levy, Rasheda Persinger
Targeted Oncology Video series: ALK+ mNSCLC: Advancements Made and What’s Next. WATCH VIDEO
Targeted Oncology
Authors: Karen Reckamp
Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer. READ ARTICLE
Journal of Thoracic Oncology, Clinical and Research Reports DOI:10.1016/j.jtocrr.2021.100157
Authors: Amanda J. W. Gibson, Adrian Box, Michelle L. Dean, Anifat A. Elegbede, Desiree Hao, Randeep Sangha, D. Gwyn Bebb
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
Multiple genetic mutations are associated with the outcomes of patients with non-small cell lung cancer (NSCLC) after using tyrosine kinase inhibitor, but the cost for detecting multiple genetic mutations is high. Few studies have investigated whether multiple genetic mutations can be simultaneously detected based on image features in patients with NSCLC. We developed a machine learning-derived radiomics approach that can simultaneously discriminate the presence of EGFR, KRAS, ERBB2, and TP53 mutations on CT images in patients with NSCLC. These findings suggest that machine learning-derived radiomics may become a noninvasive and low-cost method to screen for multiple genetic mutations in patients with NSCLC before using next-generation sequencing tests, which can help to improve individualized targeted therapies. READ ARTICLE
Cancers DOI:10.3390/cancers13081814
Authors: Tiening Zhang, Zhihan Xu, Guixue Liu, Beibei Jiang, Geertruida H. de Bock, Harry J. M. Groen, Rozemarijn Vliegenthart, Xueqian Xie
Most ALK variants are described as VUS, limiting the
impact of precision oncology. ALK fusions occur in 2.6%% of the lung adenocarcinomas, with EML4 being the most common upstream partner.
Meanwhile, G1202R mutations occur only among 0.07% of the ALK alterations. Heat shock protein and Neuregulin-1 pathway may present additional opportunities for combination targeted therapies in the future for ALK-positive NSCLC. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/S1556-0864(21)01863-3
Authors: A. Desai, T. Mohammed, S. Rakshit, J. Krull
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
The effectiveness of targeted therapies with tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) depends on the accurate determination of the genomic status of the tumour. For this reason, molecular analyses to detect genetic rearrangements in some genes (ie, ALK, ROS1, RET and NTRK) have become standard in patients with advanced disease. Since immunohistochemistry is easier to implement and interpret, it is normally used as the screening procedure, while fluorescence in situ hybridisation (FISH) is used to confirm the rearrangement and decide on ambiguous immunostainings. Although FISH is considered the most sensitive method for the detection of ALK and ROS1 rearrangements, the interpretation of results requires detailed guidelines. In this review, we discuss the various technologies available to evaluate ALK and ROS1 genomic rearrangements using these techniques. Other techniques such as real-time PCR and next-generation sequencing have been developed recently to evaluat..... READ ARTICLE
Journal of Clinical Pathology DOI:10.1136/jclinpath-2021-207490
Authors: Esther Conde, Federico Rojo, Javier Gómez, Ana Belén Enguita, Ihab Abdulkader, Ana González, Dolores Lozano, Nuria Mancheño, Clara Salas, Marta Salido, Eduardo Salido-Ruiz, Enrique de Álava
