Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report

Anaplastic lymphoma kinase (ALK) rearrangements account for approximately 5–6% of non–small-cell lung cancer (NSCLC) patients. In this study, a case of lung adenocarcinoma harboring a novel MRPS9-ALK fusion is reported. The patient responded well to the first and second generation of ALK-tyrosine kinase inhibitors (ALK-TKIs) (crizotinib then alectinib), as her imaging findings and clinical symptoms significantly improved. At last follow-up, over 21 months of overall survival (OS) has been achieved since ALK-TKI treatment. The progression-free survival (PFS) is already ten months since alectinib. The adverse effects were manageable. The case presented here provides first clinical evidence of the efficacy of ALK-TKIs in NSCLC patients with MRPS9-ALK fusion. READ ARTICLE

Frontiers in Oncology DOI: 10.3389/fonc.2021.670907

Authors: Zhou H., Xu B., Xu J., Zhu G. and Guo Y.

Case Study, group5Kirk SmithJune 8, 2021NSCLC, MRPS9-ALK, next generation sequening (NGS), crizotinib, ALK-TKI

Superficial ALK-rearranged myxoid spindle cell neoplasm: a cutaneous soft tissue tumor with distinctive morphology and immunophenotypic profile

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18–84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2–18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term “superficial ALK-rearranged myxoid spindle cell neoplasm”. READ ARTICLE

Modern Pathology

Authors: Josephine K. Dermawan, Elizabeth M. Azzato, John R. Goldblum, Brian P. Rubin, Steven D. Billings and Jennifer S. Ko

Case Study, group5Kirk SmithJune 4, 2021FLNA-ALK, MYH10-ALK, HMBOX1-ALK, ALK fusions

Enteral lorlatinib after alectinib as a treatment option in anaplastic lymphoma kinase‐positive non‐small cell lung cancer with triple problems

Alectinib treatment is effective in patients with anaplastic lymphoma kinase (ALK) gene rearrangement‐positive non‐small cell lung cancer (NSCLC; hereafter ALK‐positive NSCLC) who exhibit central nervous system (CNS) relapse and poor performance status (PS). Lorlatinib treatment is effective upon failure of other ALK inhibitor‐based treatments. However, much remains unknown about the efficacy of lorlatinib in patients with ALK‐positive NSCLC, who have triple problems, carcinomatous meningitis, poor PS, and dysphagia, after alectinib treatment. Here, we report the remarkable response of a 73‐year‐old patient with ALK‐positive NSCLC showing carcinomatous meningitis due to CNS metastases, poor PS, and dysphagia to lorlatinib. Lorlatinib administration through a nasogastric tube alleviated complications related to consciousness within three days, and the patient survived for 16 months after CNS relapse. Lorlatinib could be a treatment option for patients with ALK‐positive NSCLC showing carcinomatous meningitis, poor PS, and dysphagia upon failure of other ALK inhibitor‐based treatments. READ ARTICLE

Respiratory Case Reports DOI:10.1002/rcr2.796

Authors: Kota Sasaki, Yusuke Yokota, Toshihito Isojima, Mayumi Fujii, Kengo Hasui, Yu Chen, Kensuke Saito, Takenori Takahata, Seiko Kindaichi, and Atsushi Sato

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

Highlights: Upfront LT delay intracranial progression, but do not prolong OS in oncogene-driven NSCLC. Use of stereotactic versus whole-brain radiotherapy and primary tumor TP53 status do not significantly affect brain control. Non-del19 EGFR mutations and ‘short’ EML4-ALK fusions are independent predictors of earlier intracranial failure. Results: Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial..... READ ARTICLE

ESMO Open DOI:10.1016/j.esmoop.2021.100161

Authors: R.A. El Shafie, K. Seidensaal, F. Bozorgmehr, D. Kazdal, T. Eichkorn, M. Elshiaty, D. Weber, M. Allgäuer, L. König, K. Lang, T. Forster, N. Arians, S. Rieken, C.-P. Heussel, F.J. Herth, M. Thomas, A. Stenzinger, J. Debus, P. Christopoulos.

A Novel Nonreciprocal/Reciprocal ALK Translocation Cause ALK+ in NSCLC

The development and clinical application of ALK inhibitors have made a great breakthrough in recent years. It is of great clinical significance to identify the target population suitable for ALK inhibitors by using appropriate ALK detection methods. 5’ALK fusions currently draw the most attention. Nonreciprocal/reciprocal ALK translocations were often thought of nonfunctional or neglected. Here, we identified a rare patient with lung adenocarcinoma in pT1N2M0 stage IIIA. Tumor tissue of the patient harbored a novel nonreciprocal/reciprocal ALK translocation which did not form a 5’ALK fusion. But Tumor tissue did express ALK protein, which is normally not expressed in the lungs. READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2021.05.020

Authors: Xianguo Chen, Bo Xu, Fangni Fu, Ke Cai and Zhaonan Yu

Case StudyKirk SmithMay 20, 2021ALK, Nonreciprocal/reciprocal Translocation, NSCLC, inhibitors

Successful Alectinib Treatment for Carcinoma of Unknown Primary with EML4-ALK Fusion Gene: A Case Report

Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene. READ ARTICLE

Current Oncology DOI: 10.3390/curroncol28030180

Authors: Sugiyama K., Izumika A., Iwakoshi A., Nishibori R., Sato M., Shiraishi K., Hattori H., Nishimura R. and Kitagawa C.

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining sig..... READ ARTICLE

Endocrine-Related Cancer DOI:10.1530/ERC-20-0436

Authors: Mehtap Derya Aydemirli, Jaap D H van Eendenburg, Tom van Wezel, Jan Oosting, Willem E Corver , Ellen Kapiteijn and Hans Morreau

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.05.010

Authors: Kei Kunimasa, Yosuke Hirotsu, Yoji Kukita, Yumi Ueda, Yoshiharu Sato, Madoka Kimura, Tomoyuki Otsuka, Yuichiro Hamamoto, Motohiro Tamiya, Takako Inoue, Takahisa Kawamura, Kazumi Nishino, Kenji Amemiya, Taichiro Goto, Hitoshi Mochizuki, Keiichiro Honma, Masao Omata and Toru Kumagai

Primary resistance to alectinib in a patient with STRN-ALK-positive non-small cell lung cancer: A case report

naplastic lymphoma kinase (ALK) rearrangements are drivers of a subset of non-small cell lung cancer (NSCLC). The rapid progression of ALK inhibitors has significantly prolonged the progression-free survival of patients with ALK gene-sensitive mutations. However, the response of patients with rare ALK rearrangements to tyrosine kinase inhibitors remains unknown. Here, we report a rare case of striatin (STRN)-ALK-positive NSCLC showing primary resistance to first-line therapy alectinib and limited clinical activity of crizotinib in the alectinib-resistant setting. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13983

Authors: Kunyan Sun,Ligong Nie,Lin Nong and Yuan Cheng

Case StudyKirk SmithMay 7, 2021STRN-ALK, NSCLC, alectinib, crizotinib

Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.

Genotyping of sequential post-progression plasma specimens reveals that treatment with sequential first-, second-, and third-generation ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance. READ ARTICLE

Journal of Clinical Oncology DOI: 10.1200/JCO.2021.39.15_suppl.3011

Authors: Gang Hua, Xiaoxi Chen, Ruoying Yu, Hua Bao, Xue Wu and Yang Shao

Case StudyKirk SmithMay 6, 2021ALK, ctDNA

Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma

... We report a case of LCNEC harboring a novel PLB1-ALK rearrangement sensitive to crizotinib by next-generation sequencing (NGS). The patient’s disease responded to crizotinib for > 5 months... NGS demonstrates an additional advantage of being able to concurrently detect different mutations in genetic testing and plays an important role in detecting ALK-rearranged non–small-cell lung cancer. Screening for ALK rearrangement by NGS in patients with LCNEC may help in selecting potential candidates for targeted therapy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.026

Authors: Shuai Wang, Xuan Wu, Jiuzhou Zhao, Haiyang Chen, Zhe Zhang, Mingyue Wang, Cong Xu, Yongsen Wang, Lili Wang, Zhen He, Qiming Wang

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal sero..... READ ARTICLE

The American Journal of Surgical Pathology DOI:10.1097/PAS.0000000000001656

Authors: Argani, Pedram, Lian, Derrick W.Q., Agaimy, Abbas, Metzler, Markus, Wobker, Sara E. Matoso, Andres, Epstein, Jonathan I., Sung, Yun-Shao; Zhang, Lei and Antonescu, Cristina R

Case StudyKirk SmithMay 1, 2021mesothelioma, ALK, translocation, pediatric

Alectinib for Miliary Lung Metastasis in ALK-Positive Lung Adenocarcinoma

We have reported a case of ALK-rearranged NSCLC with a miliary pulmonary metastasis pattern that was sensitive to alectinib and in which the serum amylase level decreased in response to treatment with alectinib. Young patients with miliary pulmonary metastasis should be checked for all driver mutations. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S300229

Authors: Satoh H, Okuma Y, Kashima J, Konnno-Yamamoto A, Yatabe Y, Ohe Y

Case StudyKirk SmithApril 30, 2021alectinib, ALK rearrangement, NSCLC, miliary pulmonary metastasis

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

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. READ ARTICLE

British Medical Journal DOI:10.1136/bcr-2020-240295

Authors: Hironari Matsuda, Munechika Hara, Shin-Ichiro Iwakami, Kazuhisa Takahashi

Case StudyKirk SmithApril 27, 2021post-alectinib, lorlatinib, EML4-ALK

Early Alectinib Resistance From MET Amplification in ALK-Rearranged NSCLC: Response to Crizotinib with Re-Response to Alectinib and Crizotinib

Crizotinib is active as second-line therapy against MET-mediated resistance to alectinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer and can be used in combination.

Repeat molecular analyses including assessment of MET amplification can help guide therapy in ALK-positive non–small-cell lung cancer. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.04.008

Authors: Jingran Ji, Anupam Mitra, D. Ross Camidge, Jonathan W. Riess

Changing ALK-TKI-Resistance Mechanisms in Rebiopsies of ALK-Rearranged NSCLC: ALK- and BRAF-Mutations Followed by Epithelial-Mesenchymal Transition

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.

Brigatinib-induced tuberculosis reactivation: A case report

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

Case StudyKirk SmithApril 10, 2021Immunodeficiency, Lung cancer, Lymphopenia, TKI

Complex renal cysts combined with hemorrhage during crizotinib treatment for ALK-rearranged lung adenocarcinoma

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

Lorlatinib-induced visual and auditory hallucinations: A case report

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

Identification of a Novel resistance ALK p.(Q1188_L1190del) deletion in a Patient with ALK-rearranged Non–small-cell Lung cancer

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

Case StudyKirk SmithApril 4, 2021ALK p, Ceritinib resistance, lorlatinib, ALK, NSCLC, next generation sequencing, NGS