The management of patients with epidermal growth factor receptor (EGFR)-mutant, metastatic non–small-cell lung cancer (NSCLC) who become resistant to EGFR inhibitors remains challenging given the presence of complex and heterogeneous resistance mechanisms. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.009
Authors: Yan Yan, Guozhong Jiang, Weijie Ma, Tianhong Li, Liping Wang
We report a patient with stage IV anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (primary lung signet ring cell adenocarcinoma) who received serial crizotinib, chemotherapy, and lorlatinib over more than 4 years. The patient discontinued crizotinib after approximately 4 months due to crizotinib-associated hepatotoxicity. Twenty-five days later, when transaminases had normalized, crizotinib was resumed. However, the patient’s liver enzymes rapidly increased again, and crizotinib was discontinued. After 6 cycles of platinum-based chemotherapy, lorlatinib was initiated. Hepatotoxicity did not recur with lorlatinib, a next-generation ALK inhibitor, but grade 4 hypertriglyceridemia and acute pancreatitis were induced by lorlatinib after 4 months. To our knowledge, this is the first case report of acute pancreatitis with lorlatinib. Additionally, stereotactic body radiation therapy (SBRT) was performed for residual small primary lesions in the lung without stopping lorlatinib. Given the rarity of radiation pneumonitis, especially with the relatively small fields treated by SBRT, we suspect that lorlatinib enhanced the pulmonary toxicity. Physicians should be aware that ALK inhibitors, such as lorlatinib and crizotinib, have potentially lethal side effects. READ ARTICLE
Case Reports in Oncology DOI: 10.1159/000512829
Authors: Ibrahim Yildiz
Read MoreCombined small cell lung cancer (c-SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non-small cell carcinoma (NSCLC). Standard chemotherapy for patients with c-SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c-SCLC. However, little is known about ana-plastic lymphoma kinase (ALK) rearrangement in c-SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK-positive c-SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR- or ALK-positive c-SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component READ ARTICLE
Thoracic Cancer DOI:10.1111/1759-7714.13716
Authors: Takayuki Niitsu, Takayuki Shiroyama, Kotaro Miyake, Yoshimi Noda, Kansuke Kido, Reina Hara,Takatoshi Enomoto, Yuichi Adachi, Saori Amiya,YasuhikoSuga, Kiyoharu Fukushima,Shohei Koyama, Kota Iwahori, Haruhiko Hirata, Izumi Nagatomo, Yoshito Takeda, Atsushi Kumanogoh
We report a case wherein a combination of crizotinib and hematopoietic stem cell transplantation (HSCT) cured a 20-year-old woman with relapsed and refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-positive ALCL). Although she received cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) as the first-line chemotherapy from the beginning, the disease progressed rapidly with the emergence of bone marrow invasion and hemophagocytic syndrome. Vincristine, idarubicin, l-asparaginase, and prednisone (VILP) chemotherapy was not effective. Therefore, the patient received off-label use of crizotinib (an ALK inhibitor) and her condition improved rapidly. Subsequently, she received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and achieved complete remission (CR) a month later. Later, crizotinib was used as a maintenance treatment for 3 months and discontinued because of adverse reactions. Our patient has been in CR for 3 years.
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Indian Journal of Cancer DOI:10.4103/ijc.IJC_961_19
Authors: Xue Sun, Xiaosheng Fang, Yujie Jiang
We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes. READ ARTICLE
OncoTargets and Therapy DOI: 10.2147/OTT.S270481
Authors: Chenlu Zhang, Zhiming Wang, Rongyuan Zhuang, Xi Guo, Yi Feng, Feng Shen, Wenshuai Liu, Yong Zhang, Hanxing Tong, Wending Sun, Jun Liu, Guan Wang, Chun Dai, Weiqi Lu and Yuhong Zhou
Read MoreThe expression of anaplastic lymphoma kinase (ALK), a target of tyrosine kinase is altered in several kinds of cancer, including in non-small cell lung cancer (NSCLC). For this reason, the use of crizotinib to treat locally advanced or metastatic ALK-positive NSCLC was approved by the US Food and Drug Administration in 2011. The reported adverse events during clinical trials with crizotinib included esophageal disorders in 11% of the patients, although none of them experienced severe events. Drug-induced esophagitis or more severe ulcerations are considerably rare according to the available case reports. We report a patient who presented with severe esophageal ulcers after 2-year treatment with crizotinib for metastatic, ALK-positive NSCLC. These clinical conditions improved after education on proper eating habits and an additional prescription of a proton pump inhibitor. Several months later, the patient developed colitis with severe diarrhea, which was successfully controlled with me..... READ ARTICLE
Advances in Digestive Medicine DOI:10.1177/1078155220961549
Authors: Wei-Wen Su,Hui-Ting Hsu,Po-Ke Hsu
However, the concurrent two ALK rearrangements within the same patient have rarely previously been reported. Here, we describe a novel CCNY-ALK (C1:A20) and ATIC-ALK (A7:A20), coexisting in the same case with poorly differentiated NSCLC and providing evidence of its sensitivity to ALK inhibitors. The newly identified rearrangement partners can be added to the list of ALK rearrangements that occurred in ALK-positive NSCLC, as it could lead to prolonged disease control. Also, while different ALK rearrangement variants might bring differing clinical outcomes, we discuss the impact of the co-mutations of these two ALK rearrangements on the sensitivity to ALK inhibitors. However, the impact of co-mutations on the pathogenesis of NSCLC should be further studied to supply more theoretical insight that co-mutations present for personalized anti-cancer therapy. READ ARTICLE
Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1049
Authors: Xuan Wu, Hanqiong Zhou, Zhen He, Zhe Zhang, Wen Feng, Jiuzhou Zhao3, Haiyang Chen, Shuai Wang, Wei Wang, Qiming Wang
Read MoreObjectives: The molecular profiles and prognosis of anaplastic lymphoma kinase (ALK) fusion and resectable non-small cell lung cancer (NSCLC) remain unclear. This study aimed to explore the distribution of ALK fusion variants and prognostic factors in patients with surgically resected NSCLC. Conclusions: This study illustrated the patterns of EML4-ALK fusion variants and gene profiles in patients with resected NSCLC. Advanced T stage and EML4-ALK variant 3 were associated with worse prognosis. The role of TP53 mutations in prognosis is worthy of further study. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.09.012
Authors: Hong Tao, Liang Shi, Aoxue Zhou, Hongxia Li, Fei Gai, Zhan Huang, Nanying Che, Zhe Liu
... 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
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
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
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
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
Functional profiling of a cancer patient’s tumor cells holds potential to tailor personalized cancer treatment. Here we report the utility of Fresh Uncultured Tumor-derived EpCAM+ epithelial Cells (FUTC) for ex vivo drug response interrogation. Analysis of murine Kras mutant FUTCs demonstrated pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. Applying FUTC profiling on non-small cell lung cancer patient samples, we generated robust drug response data in 18 of 19 cases, where the cells exhibited targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling was used to guide compassionate treatment. FUTC profiling identified selective sensitivity to disulfiram and the combination of carboplatin plus etoposide and the patient received substantial clinical benefit from the treatment with these agents. We conclude that FUTC profiling..... READ ARTICLE
BioRxiv DOI:10.1101/2020.08.12.247817
Authors: Sarang S. Talwelkar, Mikko I. Mäyränpää, Lars Søraas, Swapnil Potdar, Jie Bao, Annabrita Hemmes, Nora Linnavirta, Jon Lømo, Jari Räsänen, Aija Knuuttila, Krister Wennerberg, Emmy W. Verschuren
Primary lung cancer with gastric metastasis is rare to see in the world, little is known about its characteristics. Here, we describe the first case of primary lung adenocarcinoma with gastric and skin metastases along with a review of literature to help clinical decision making. A 49-year-old woman admitted to our department for abdominal distension. The immunohistochemistry staining for the biopsy in the gastric fundus, back and lung showed positive for CK5/6, TTF-1, Napsin A and CK7, but negative for CK20, which strongly indicated all of them were homologous and might originate from lung adenocarcinoma. Chromosome mutation analysis presented an EML4-ALK fusion gene. Brain metastases occurred after 6 months with crizotinib treatment. More than two months later, intracranial lesions became more and larger as she persisted in taking crizotinib plus whole-brain radiotherapy (WBRT). Hence, alectinib was performed due to the continuous growth of brain lesions. When reexamined three months..... READ ARTICLE
National Library of Medicine DOI:10.21037/apm-20-1025
Authors: Xueqin Duan, Xinhan Zhao, Shuhong Wang
Read MoreAs far as we are aware, this present clinical case is the first to report an acquired exon14 MET mutation
mediated resistance to alectinib in a patient with ALK rearrangement NSCLC. We had chosen to treat
our patient at the time of progression under alectinib with crizotinib with a short time efficacy, three and a
half months. READ ARTICLE
JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100082
Authors: Catherine Daniel, Celine Callens, Samia Melaabi, Ivan Bieche, Nicolas Girard,
Objectives: ... Here, we reported a case of lung adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)–ALK fusion which the breakpoints was (S6,A20). To our knowledge, this case is the first report showed clinical evidence of SRBD1-ALK fusion responding to crizotinib. Conclusion: To our knowledge, our case is the first case of SRBD1-ALK fusion with excellent response to crizotinib. This case merits further follow-up and provides valuable information on the response to crizotinib of NSCLC patients with SRBD1-ALK fusion. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.04.031
Authors: Yao, Chen, Xiaochen Zhang, Qi Jiang, Bo Wang, Yina Wang, Yan Junrong
Objectives: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC. Conclusions: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.05.019
Authors: Jose Luis Leal, Geoffrey Peters, Marcin Szaumkessel, Trishe Leong, Khashayar Asadi, Gareth Rivalland, Hongdo Do, Clare Senko, Paul L.Mitchell, Chai Zi Quing, Alexander Dobrovic, Bibhusal Thapa, Thomas John
The frequency of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) is approximately 3%–5% [ [1] ], and the administration of ALK tyrosine kinase inhibitors has achieved impressive outcomes. Apart from EML4–ALK, various ALK fusion partner genes have recently been identified [ [2] ]. In this case, we report a novel PNPT1 (polyribonucleotide nucleotidyl transferase 1)–ALK fusion responding to crizotinib in a patient with lung adenocarcinoma. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.05.014
Authors: Linling Jin, Yanli Wang, Si Li, Dongsheng Chen, Xin Zhao
