Anaplastic Lymphoma Kinase Gene Research Articles

Genomic ALK alterations in primary and relapsed neuroblastoma

BackgroundGenomic alterations of the anaplastic lymphoma kinase gene (ALK) occur recurrently in neuroblastoma, a pediatric malignancy of the sympathetic nervous system. However, information on their development over time has remained sparse.MethodsALK alterations were assessed in neuroblastomas at diagnosis and/or relapse from a total of 943 patients, covering all stages of disease. Longitudinal information on diagnostic and relapsed samples from individual patients was available in 101 and 102 cases for mutation and amplification status, respectively.ResultsAt diagnosis, ALK point mutations occurred in 10.5% of all cases, with highest frequencies in stage 4 patients <18 months. At relapse, ALK alteration frequency increased by 70%, both in high-risk and non-high-risk cases. The increase was most likely due to de novo mutations, frequently leading to R1275Q substitutions, which are sensitive to pharmacological ALK inhibition. By contrast, the frequency of ALK amplifications did not change over the course of the disease. ALK amplifications, but not mutations, were associated with poor patient outcome.ConclusionsThe considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.

Optimal first-line treatment for metastatic ALK+ non-small cell lung cancer-a narrative review.

First-line treatment options for patients with advanced non-small cell lung cancer (aNSCLC) whose tumors harbour anaplastic lymphoma kinase (ALK) gene rearrangements have rapidly evolved from chemotherapy, to the first in class ALK-targeted tyrosine kinase inhibitor (TKI) crizotinib in 2011, and now include no fewer than five Food and Drug Administration (FDA)-approved ALK inhibitors. However, while superiority to crizotinib has been established, head-to-head clinical trials comparing newer generation ALK inhibitors are lacking, and decisions on optimal first-line treatment must be based on analysis of the relevant trials, with attention to systemic and intracranial efficacy, toxicity profile as well as consideration of patient factors and preferences. Here we aim to synthesise findings from review of these trials and to describe options for optimal first-line treatment for ALK+ NSCLC. A literature review of relevant randomised clinical trials was undertaken using Embase database. There were no limitations to time frame or language applied. Crizotinib was established as the standard of care first-line treatment for patients with ALK+ aNSCLC in 2011. Since this time, alectinib, brigatinib, ensartinib and lorlatinib have all demonstrated superiority as first-line treatments compared to crizotinib, based on progression free survival, intra-cranial efficacy, and side-effect profiles. Options for optimal first-line treatment for ALK+ aNSCLC include alectinib, brigatinib and lorlatinib. This review serves as a resource summarizing data from key clinical trials with ALK inhibitors to aid in decision making when tailoring treatment for patients. Future research in the field includes real world analysis of efficacy and toxicity of next-generation ALK-inhibitors, identification of mechanisms of tumor persistence and acquired resistance, development of novel ALK inhibitors, and use of ALK-TKIs in earlier stage disease.

Therapeutic Targeting of ALK in Neuroblastoma: Experience of Italian Precision Medicine in Pediatric Oncology.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Patients with relapsed/refractory disease have a poor prognosis, and additional therapeutic options are needed. Mutations and amplifications in the ALK (Anaplastic Lymphoma Kinase) gene constitute a key target for treatment. Our goal, within the Italian project of PeRsonalizEdMEdicine (PREME), was to evaluate the genomic status of patients with relapsed/refractory NB and to implement targeted therapies in those with targetable mutations. From November 2018 to November 2021, we performed Whole Exome Sequencing or Targeted Gene Panel Sequencing in relapsed/refractory NB patients in order to identify druggable variants. Activating mutations of ALK were identified in 8(28.57%) of 28 relapsed/refractory NB patients. The mutation p.F1174L was found in six patients, whereas p.R1275Q was found in one and the unknown mutation p.S104R in another. Three patients died before treatment could be started, while five patients received crizotinib: two in monotherapy (one with p.F1174L and the other with p.S104R) and three (with p.F1174L variant) in combination with chemotherapy. All treated patients showed a clinical improvement, and one had complete remission after two cycles of combined treatment. The most common treatment-related toxicities were hematological. ALK inhibitors may play an important role in the treatment of ALK-mutated NB patients.

Epithelioid Fibrous Histiocytoma with CARS-ALK Fusion: First Case Report

Epithelioid fibrous histiocytoma (EFH) is a type of uncommon skin tumor mostly harboring Anaplastic Lymphoma Kinase (ALK) gene rearrangement, with different fusion partners reported. Whether this tumor is a separate entity or has a relationship with conventional fibrous histiocytomas is still a matter of debate. Benign course is the rule after complete surgical excision. A rare subtype of EFH with fusiform cells has been described, with specific fusion partners. Inflammatory myofibroblastic tumor (IMT) is a type of soft tissue tumor rarer than EFH, and it can display distant metastases. Some cases of primary cutaneous IMT included two with Cysteinyl-tRNA Synthetase 1 (CARS)-ALK rearrangement. IMT can have the same fusion partners as EFH, such as DCTN1, TMP3 or EML4 genes. We report the case of a 42-year-old woman presenting EFH with fusiform morphology harboring CARS-ALK fusion and discuss similarities and differences with IMT.

Investigation of EGFR and ALK mutation frequency and treatment results in advanced non-small cell lung cancer.

Lung cancer has opened a new era in cancer treatment by elucidating the tumor's molecular structure and identifying the targetable mutations. Identifying the targeted mutations in lung cancer constitutes one of the main steps of treatment planning. The frequency of EGFR (epidermal growth factor receptor gene) and ALK (anaplastic lymphoma kinase gene) mutations in non-small cell lung cancer (NSCLC) also varies in populations depending on ethnicity, gender, smoking, and histopathological subtype. In general, limited data are available regarding the frequency and regional distribution of these mutations in the Turkish population. Our study aimed to determine the frequency of EGFR and ALK mutations in patients with advanced-stage NSCLC and compare the clinical characteristics, treatment, and survival results of cases with mutations with the group without mutations. In our study, 593 patients with advanced-stage NSCLC diagnosis and mutational analyses were evaluated retrospectively. Demographic characteristics, tumor stages (tumor, node, metastasis, TNM), EGFR and ALK analysis results, treatments applied, and survival of the cases were recorded. EGFR analysis, exon 18, 19, 20, and 21 mutations were studied with real-time PCR (RT-PCR) Rotor-Gene system from patients' samples. For ALK analysis, the ALK Break Apart kit (Zytovision GmbH; Germany) was used with the fluorescent in situ hybridization (FISH) method. In our study, EGFR mutation was detected in 63 patients (10.6%) and ALK mutation in 19 patients (3.2%) out of 593 patients. EGFR mutation was observed more frequently in women and non-smokers (P = 0.001, P = 0.003). No correlation was found between the presence of EGFR mutation and metastases regions and recurrence (P > 0.05). ALK mutation was observed more frequently in non-smokers and females (P = 0.001, P = 0.003). Patients with ALK mutations were younger than other groups (P = 0.003). There was also no significant relationship between ALK mutation and metastates regions and recurrence after treatment (P > 0.05). Patients with EGFR or ALK mutations had a longer life span than other cases (P = 0.474). Those who had ALK mutations and received targeted therapy had a longer average life expectancy (P < 0.05). No difference was observed in those who had EGFR mutations and received targeted treatment in terms of survival (P > 0.05). In our study, conducted in the Aegean region of Turkey, the positivity rates of EGFR and ALK mutations were found to be at similar rates with the Caucasian race across the world. EGFR mutation was more common in women, non-smokers, and patients with adenocarcinoma histology. ALK mutation was also detected more frequently in younger patients, women, and non-smokers. Patients with EGFR and ALK mutations had a longer life expectancy than those without the mutation. It was observed that testing patients diagnosed with advanced-stage NSCLC for genetic mutations of the tumor in the first step of the treatment and initiating treatment in patients with mutations provided a significant survival advantage.

Recent Developments and Challenges in Molecular-Targeted Therapy of Non-Small-Cell Lung Cancer

Treatment of lung cancer with conventional therapies, which include radiation, surgery, and chemotherapy results in multiple undesirable adverse or side effects. The major clinical challenge in developing new drug therapies for lung cancer is resistance, which involves mutations and disturbance in various signaling pathways. Molecular abnormalities related to epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) Kirsten rat sarcoma virus (KRAS) mutations, translocation of the anaplastic lymphoma kinase (ALK) gene, mesenchymal-epithelial transition factor (MET) amplification have been studied to overcome the resistance and to develop new therapies for non-small cell lung cancer (NSCLC). But, inevitable development of resistance presents limits the clinical benefits of various new drugs. Here, we review current progress in the development of molecularly targeted therapies, concerning six clinical biomarkers: EGFR, ALK, MET, ROS-1, KRAS, and B-RAF for NSCLC treatment.

STRN-ALK rearranged malignant peritoneal mesothelioma—Presenting with bilateral extensive pelvic masses in a young woman: Mimicking low-grade serous ovarian carcinoma

Malignant peritoneal mesothelioma (MPM) is an exceptionally rare tumor type. Although some somatic/germline genetic alterations including BAP1 loss have been identified in some cases, the molecular properties of MPMs are remained poorly understood. In recent years, anaplastic lymphoma kinase (ALK) gene rearrangement was revealed in a subset of (3.4%) MPMs. Low-grade serous carcinomas (LGSCs) are a rare subtype of ovarian carcinoma and have some morphologic and immunophenotypic overlapping features with MPMs and this may cause misdiagnosis in daily practice. Here, we report a case of 18-year-old women with STRN-ALK-rearranged MPM and no previous exposure to asbestos. This case was presented with bilateral pelvic masses and histologically was displaying pure papillary morphology with mild-to-moderate nuclear atypia, psammoma bodies, and diffuse PAX8 expression as LGSCs. With the detection of ALK alteration in some of the MPMs, a targeted treatment option has emerged for these unusual tumor types.

USP6-associated neoplasm as a tentative subset of postoperative spindle cell nodule.

Postoperative spindle cell nodule (PSCN) is a pseudosarcomatous proliferative lesion of unclear molecular genetic origins. We examined seven patients with PSCN, using routine haematoxylin-eosin (H&E) slide preparations and a series of immunostains. The latter targeted keratin, vimentin, α-smooth muscle actin (SMA), anaplastic lymphoma kinase (ALK [D5F3]), and other proteins. Ubiquitin-specific peptidase 6 (USP6) and anaplastic lymphoma kinase (ALK) gene rearrangements were also analysed by fluorescence insitu hybridization (FISH). There were histories of prior surgical intervention (n=6) or trauma (n=1) in all seven patients. All lesions were highly cellular and mitotically active spindle cell proliferations, with no cytologic atypia, nuclear pleomorphism, or aberrant mitoses. Immunohistochemical (IHC) staining disclosed focal, weak keratin positivity in two lesions, whereas vimentin (diffuse, strongly positive) and SMA (tram-track pattern) were present in each instance, and ALK (D5F3) was entirely negative. FISH analysis confirmed USP6 gene rearrangements in all seven cases, showing no ALK gene rearrangements. RNA sequencing results showed an MYH9::USP6 gene fusion in only one lesion (No. 6). A subset of PSCN is marked by USP6 gene rearrangements, a genetic feature of nodular fasciitis (NF). Given its similarity to NF, a designation as USP6-associated neoplasm (UAN) seems reasonable, signifying a transient clonal neoplastic lesion.

Coexistence of anaplastic lymphoma kinase rearrangement in lung adenocarcinoma harbouring epidermal growth factor receptor mutation: A single-center study.

Accumulating evidences confirm that epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement have coexisted in lung adenocarcinoma (LUAD). However, Its biological mechanism, clinicopathological features, and optimization of targeted drugs have not yet been completely elucidated. To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes, with hopes of scientifically guiding similar patients towards selected, targeted drugs. Two hundred and thirty-seven LUAD patients were enrolled. EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique, while the expression of ALK rearrangement was screened by the 5'/3' imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis. The clinicopathological features of these patients were analysed retrospectively, and the follow-up data were collected. There were six cases with co-mutations of EGFR and ALK genes, which were more common in women, non-smoking and stage IV LUAD patients with bone metastasis, hence a positive rate of 2.53% (6/237). EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were their preferred drugs for targeted therapy in these patients, with progression-free survival ranging from two months to six months. In Gannan region, the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high, and the co-mutations are more common in women, non-smoking and stage IV patients with bone metastasis. These patients prefer EGFR-TKIs as their preferred targeted drugs, but the therapeutic effect is not good. EGFR/ALK dual-TKIs may be more effective targeted drugs, which needs further study.

Effective and Safe Immune Checkpoint Blockade Induces Complete Responses in Murine PTCL Model of ALCL

Anaplastic large cell lymphoma (ALCL) is a rare T-cell non-Hodgkin lymphoma. In the majority of cases the disease is driven by a chromosomal translocation t(2;5)(p23;35) leading to the fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin gene (NPM), constitutively activating ALK kinase. In the last decade immunotherapy turned out to be a real game-changer in cancer treatment, especially in the field of solid tumors. Regarding T-cell lymphomas (TCL), the significance of immune checkpoint inhibition is still highly debated. The outcomes in preclinical models as well as clinical trials are ranging from response to hyperprogression. Consequently, to provide a better understanding of the role and underlying mechanisms of targeting immune checkpoint axes, preclinical models of TCL are urgently needed to identify patients that benefit from immunotherapy as well as potential biomarkers. To examine disease biology and therapy effects of ALCL in vivo, we use a syngeneic retroviral bone marrow transplantation mouse model of ALK+ ALCL that closely resembles the disease in humans. In order to study the effect of blocking the PD-1/PD-L1-axis in ALCL in vivo, serial transplantations of lymphoma cells from a murine thymus were performed. We further investigated both spontaneous and immunotherapy-induced immune responses and characterized the interaction of innate and adaptive immune master players with flow cytometry, cytokine analysis, histology and transcriptome analysis. In our mouse model of ALK+ ALCL we confirmed the upregulation of PD-L1 on ALK+ lymphoma cells in vivo. Immune checkpoint inhibition of PD-L1 in vivo leads to high complete response rates, prolonged survival and significantly reduced lymphoma burden of treated animals. Flow cytometry analysis revealed that PD-L1 blockade reverses Treg-mediated immunosuppression and causes augmented circulation of CD8+ effector T-lymphocytes. Treatment with depletion antibodies of lymphocyte subpopulations unveils CD4+ T-cells and NK-cells but not CD8+ T-cells as master players of checkpoint-mediated immune response to ALK+ ALCL. Accordingly, we identified exhausted CD4+ T-cells in non-responders to checkpoint inhibition underlining the central role of CD4+ T-cells in ALCL immune surveillance and response. These results are contributing to a broader understanding of the immune surveillance and response in ALCL, with the outmost goal of better identifying patients that benefit from immunotherapy.

More than one-third of advanced non-small-cell lung cancer patients do not receive immunochemotherapy due to intolerance.

Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown. We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020. After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was < 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%). Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.

Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related death. Despite advances in chemotherapy and immunotherapy, the prognosis for advanced patients remains poor. The discovery of oncogenic driver mutations, such as anaplastic lymphoma kinase (ALK) mutations, means that a subset of patients has opportunities for targeted therapy. With the improvement of genetic testing coverage, more and more ALK fusion subtypes and ALK partners have been discovered, and more than 90 rare ALK fusion subtypes have been found in NSCLC. However, unlike the common fusion, echinoderm microtubule-associated protein-like 4 (EML4)-ALK, some rare ALK fusions such as striatin (STRN)-ALK and huntingtin interacting protein 1 (HIP1)-ALK, etc., the large-scale clinical data related to its efficacy are still immature. The clinical application of ALK-tyrosine kinase inhibitors (ALK-TKIs) mainly depends on the positivity of the ALK gene, regardless of the molecular characteristics of the fusion partner. Recent clinical studies in the ALK-positive NSCLC population have demonstrated differences in progression-free survival (PFS) among patients based on different ALK fusion subtypes. This article will introduce the biological characteristics of ALK fusion kinase and common detection methods of ALK fusion and focus on summarizing the differential responses of several rare ALK fusions to ALK-TKIs, and propose corresponding treatment strategies, so as to better guide the application of ALK-TKIs in rare ALK fusion population.

Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors.

Chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene have been observed in approximately 4% of patients with non-small cell lung cancer (NSCLC). Although these patients clinically benefit from treatment with various ALK tyrosine kinase inhibitors (ALK-TKIs), none of these can inhibit the development of resistance mutations. Considering inevitable drug resistance and the variety of available ALK-TKIs, it is necessary to predict the pattern of drug-resistance mutations to determine the optimal treatment strategy. We aimed to establish a polymerase chain reaction (PCR)-based system to predict the development of resistance mutations against ALK-TKIs and identify therapeutic strategies using the upcoming ALK-TKIs repotrectinib (TPX-0005) and ensartinib (X-396) following recurrence on first-line alectinib treatment for ALK-positive NSCLC. An error-prone PCR-based method for predicting drug resistance mutations was established and the half-maximal inhibitory concentration (IC50) values of the predicted ALK mutations were evaluated in a Ba/F3 cell-based assay. We predicted several resistance mutations against repotrectinib and ensartinib, and demonstrated that the next-generation ALK-TKI TPX-0131, was active against repotrectinib-resistant mutations and that the FLT3 inhibitor gilteritinib was active against ensartinib-resistant mutations. We developed a PCR-based system for predicting drug resistance mutations. When this system was applied to repotrectinib and ensartinib, the results suggested that these drugs can be used for the second-line treatment of ALK-positive NSCLC. Predicting resistance mutations against TKIs will provide useful information to aid in the development of effective therapeutic strategies.

The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives.

Simple SummaryIn recent years, prognosis of non-small cell lung cancer (NSCLC) patients significantly improved thanks to the introduction of tyrosine kinase inhibitors (TKIs) in clinical practice. ALK-rearranged NSCLC patients benefit from treatment with ALK inhibitors (ALK-i), which have shown a greater efficacy and a better intracranial activity than chemotherapy. Comparative studies between next-generation ALK-i are still lacking and clinicians are looking for reliable tools to determine which drug suits best for each patient. The aim of this review is to deepen the role of clinical and pathological characteristics influencing patients’ prognosis during treatment with ALK-i and to provide an overview of molecular mechanisms of ALK-i resistance. In this setting, liquid biopsy may play an important role in predicting tumor response and monitoring resistance mutations. We will summarize ongoing trials developing new ALK-i or combinations between ALK-i and other agents, which may represent future scenarios in the field of NSCLC research.During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3–5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients’ subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients’ prognosis during treatment with ALK-i.

Acute kidney injury and long-term renal effects of alectinib in anaplastic lymphoma kinase-positive non-small cell lung carcinoma: a case report

BackgroundTargeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are available on the renal effects of alectinib. We report on a case of acute kidney injury in a patient using alectinib for less than 2 weeks and on serum sodium and creatinine during long-term use of alectinib.Case presentationA 70-year-old Asian woman was diagnosed with metastasized non-small cell lung carcinoma (cT4N3M1c, stage IV) with echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase gene rearrangement and received alectinib, in two daily doses of 600 mg. Eleven days after the initiation of therapy, she was seen at the emergency department with acute kidney injury. Renal biopsy showed lesions in the proximal tubular epithelial cells. Nine days after alectinib cessation, renal function recovered quickly and reintroduction of alectinib in a reduced dose was tolerated, while withholding metformin, enalapril, and naproxen. In seven other patients, data on estimated glomerular filtration rate showed decreased kidney function at 3 months with stabilization at 6 months. Serum sodium at 3 months increased during alectinib treatment and increased further at 6 months.ConclusionsOur data suggest direct or indirect toxic (proximal) tubulopathy due to alectinib with a good prognosis after cessation. Adverse acute renal effects of alectinib may be prevented by avoiding other medication influencing renal hemodynamics, in particular nonsteroidal anti-inflammatory drugs. Without these co-medications, alectinib could be reintroduced in our patient.

A Large Inflammatory Myofibroblastic Tumor of the Urinary Bladder in a Parturient Treated by Partial Cystectomy: Case Report and Literature Review

Inflammatory myofibroblastic tumor (IMT) is a rare type of tumor composed mainly of fibroblastic and myofibroblastic spindle cells, with an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils. IMT may arise from different organs and sites, but it is infrequent to arise from the urinary bladder and usually manifests as hematuria. We report a case of a 24-year-old pregnant woman who presented to our hospital with gross hematuria. After further workup, we concluded that she had this extremely rare tumor, which was resected eventually with a partial cystectomy. Although the diagnosis of these kinds of tumors is usually made by anaplastic lymphoma kinase (ALK) using immunohistochemistry and detecting ALK gene translocation using fluorescence in situ hybridization (FISH), they were negative in our study; hence, we relied mainly on the morphological features of the tumor for the diagnosis.

Ovarian metastases from ALK-positive lung adenocarcinoma: a case report and review of the literature

BackgroundOvarian metastasis is an extremely rare condition in patients with lung adenocarcinoma. Lung adenocarcinoma patients with ovarian metastases were difficult to distinguish from primary ovarian cancer. Anaplastic lymphoma kinase (ALK) gene rearrangement is only found in 3–7% of patients with lung cancer. It is worth noting that the incidence of lung cancer with ovarian metastasis is extremely low, however, ALK rearrangement is often reported in these cases. Here we reported a young woman, aged 23 years, with ALK-positive lung adenocarcinoma and ovarian metastasis.Case DescriptionThe patient underwent laparoscopic bilateral ovarian tumor resection after discovering an abdominal mass accidentally. A series of lung adenocarcinoma-specific immunohistochemical features were detected postoperatively by immunohistochemistry (IHC) analysis. Then extensive-stage metastatic masses of different sizes were identified by 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) positron emission tomography combined with low-dose computed tomography (PET/CT), among which the largest nodule was 1.7 cm × 1.4 cm located in the middle lobe of the right lung. Genetic testing of the paraffin tissue DNA revealed the fusion mutation of EML4_ALK (E14:A20) gene. The patient was pathologically diagnosed with lung adenocarcinoma with bilateral ovarian metastasis, administered with oral alectinib [600 mg twice daily (bid)] and followed-up quarterly. Currently, the patient responded to alectinib stably, with a progression-free survival (PFS) of more than 12 months, and experienced no significant adverse events. In addition, we reviewed the publications associated with the characteristics of ALK-positive lung cancer with ovarian metastases and the identification of primary and secondary ovarian tumors.ConclusionsThis case provides a meaningful reference for the possibility of adnexal metastases from lung cancer, particularly for ALK-rearranged young female patients. In addition, this case highlights the advantages of IHC together with genetic testing for identifying origin sites of ovarian metastases and provides a promising treatment option.

EP14.01-007 Next-Generation Sequencing to Dynamically Detect Mechanisms of Resistance to ALK Inhibitors in ALK-positive SCLC Patient: A Case Report

Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) significantly improve quality of life and survival in non-small cell lung cancer (NSCLC) with ALK fusion. However, ALK fusion is extremely rare in small-cell lung cancer (SCLC), and there is no standard treatment at present, and the mechanism of resistance of ALK-TKIs in SCLC is unknown.

Diagnostic work-up and systemic treatment for advanced non-squamous non-small-cell lung cancer in four Southeast Asian countries

BackgroundLung cancer is the second most common cancer and leading cause of cancer mortality worldwide. Recent advances in molecular testing and targeted therapy have improved survival among patients with metastatic non-small-cell lung cancer (NSCLC). We sought to quantify and describe molecular testing among metastatic non-squamous NSCLC cases in selected Southeast Asian countries and describe first-line therapy chosen.Patients and methodsA retrospective study was conducted based on incident lung cancer cases diagnosed between 2017 and 2019 in Lampang (Thailand), Penang (Malaysia), Singapore and Yogyakarta (Indonesia). Cases (n = 3413) were defined using the International Classification of Diseases for Oncology third edition. In Singapore, a clinical series obtained from the National Cancer Centre was used to identify patients, while corresponding population-based cancer registries were used elsewhere. Tumor and clinical information were abstracted by chart review according to a predefined study protocol. Molecular testing of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangement, ROS1 gene rearrangement and BRAF V600 mutation was recorded.ResultsAmong 2962 cases with a specified pathological diagnosis (86.8%), most patients had non-squamous NSCLC (75.8%). For cases with staging information (92.1%), the majority presented with metastatic disease (71.3%). Overall, molecular testing rates in the 1528 patients with stage IV non-squamous NSCLC were 67.0% for EGFR, 42.3% for ALK, 39.1% for ROS1, 7.8% for BRAF and 36.1% for PD-L1. Among these patients, first-line systemic treatment included chemotherapy (25.9%), targeted therapy (35.6%) and immunotherapy (5.9%), with 31% of patients having no record of antitumor treatment. Molecular testing and the proportion of patients receiving treatment were highly heterogenous between the regions.ConclusionsThis first analysis of data from a clinically annotated registry for lung cancer from four settings in Southeast Asia has demonstrated the feasibility of integrating clinical data within population-based cancer registries. Our study results identify areas where further development could improve patient access to optimal treatment.

Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC).

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.