RESUMO
Lorlatinib has been FDA-approved as a systemic therapy for ALK/ROS1-positive non-small cell lung cancer (NSCLC) patients. However, it has been associated with an increased frequency of neurocognitive adverse events (NAEs). Therefore, we conducted a systematic review and meta-analysis to assess the NAEs related to lorlatinib therapy in NSCLC patients. PubMed, Scopus, the Cochrane Library, and prominent conference proceedings were searched for eligible studies of lorlatinib in NSCLC patients. NAEs included cognitive, mood, speech, and psychotic effects. A total of 1147 patients from 12 studies were included; 62% had brain metastases. A pooled analysis of NAEs showed frequencies of cognitive effects of 14.57% (95% CI, 8.37 to 24.14, I2 = 84%), mood effects of 11.17% (95% CI, 5.93 to 20.07, I2 = 84%), speech effects of 7.24% (95% CI, 3.39 to 15.20, I2 = 72%), and psychotic effects of 4.97% (95% CI, 3.27 to 7.49, I2 = 21%). Clinical trials reported a significantly higher frequency of mood effects than was indicated by real-world data. These results highlight the importance of educating patients and healthcare professionals about lorlatinib-related NAEs for early detection and management to improve NSCLC patients' quality of life.
RESUMO
RESUMEN Objetivo: Los pacientes con cáncer de pulmón de células no pequeñas positivas a la mutación del gen linfoma anaplásico quinasa (ALK+) que, además, presentan mutaciones en el gen Kirsten rat sarcoma (KRAS), como KRASG12C, están mostrando resistencia tanto a inhibidores del gen linfoma anaplásico quinasa (ALK) como de KRAS. Por ello, se analizó la interacción de los inhibidores de ALK con KRAS, para sugerir una sinergia entre ambos. Materiales y métodos: En el estudio se realizó un modelado por homología de las estructuras KRASwt, KRASG12C y ALKwt. Posteriormente, se realizaron acoplamientos moleculares para determinar la energía de unión de los inhibidores de ALK y de KRAS, y evaluar la posible interacción entre los inhibidores de ALK con KRAS y la estructura KRASG12C. Finalmente, se analizó la expresión en la vía de proliferación celular de las proteínas rat sarcoma/quinasa regulada por señales extracelulares (vía RAS/MEK) mediante la técnica de Western blot. Resultados: Los valores de energía de unión muestran la posibilidad de interacción de los inhibidores de ALKwt, como crizotinib y alectinib, con las estructuras de KRASwt y KRASG12C. Los acoplamientos entre crizotinib con KRASwt y KRASG12C, respectivamente, muestran valores de energía de interacción (42,77 kcal/mol y 46,20 kcal/mol) muy similares a los obtenidos entre crizotinib y ALK (42,37 kcal/mol). A su vez, alectinib se acopló en el mismo sitio que los fármacos específicos de KRAS y KRASG12C, y presentaron valores de energía de interacción (51,74 kcal/mol y 54,69 kcal/mol, respectivamente) superiores a los obtenidos con ALK (44,94 kcal/mol). Finalmente, la expresión de la vía RAS/MEK nos mostró una disminución significativa de la expresión de RAS en líneas celulares de cáncer de pulmón ALK+ y ALKL1196M tratadas con crizotinib y alectinib. Conclusiones: Las técnicas in silico de este estudio muestran la posibilidad de acoplamiento entre los inhibidores de ALK (crizotinib y alectinib) con la estructura de KRAS. Esto permite sugerir una posible terapia combinada entre inhibidores de KRAS y ALK para los casos de coexistencia de ambas mutaciones, que puede evaluarse en posteriores ensayos con líneas celulares.
ABSTRACT Objective: Patients with non-small cell lung cancer positive for the anaplastic lymphoma kinase (ALK+) gene mutation who also have mutations in the Kirsten rat sarcoma (KRAS) gene, such as KRAS G12C, are showing resistance to both anaplastic lymphoma kinase (ALK) gene and KRAS inhibitors. Therefore, the interaction between ALK inhibitors and KRAS was analyzed to suggest a synergy between them. Materials and methods: The study performed homology modeling of the KRASwt, KRAS G12C and ALKwt structures. Subsequently, molecular dockings were carried out to determine the binding energy of ALK and KRAS inhibitors and to evaluate the possible interaction of ALK inhibitors with KRAS and the KRAS G12C structure. Finally, the expression in the RAS/MEK pathway was analyzed using the Western Blot technique. Results: The binding energy values show the potential interaction of ALKwt inhibitors, such as crizotinib and alectinib, with the KRASwt and KRAS G12C structures. The binding of crizotinib to KRASwt and KRAS G12C, respectively, indicates interaction energy values (42.77 kcal/mol and 46.20 kcal/mol) which are very similar to those obtained between crizotinib and ALK (42.37 kcal/mol). In turn, alectinib bound to the same site as drugs targeting KRAS and KRAS G12C, and showed interaction energy values (51.74 kcal/mol and 54.69 kcal/mol, respectively) higher than those obtained with ALK (44.94 kcal/mol). Finally, a significant decrease in RAS expression within the RAS/MEK pathway was observed in ALK+ and ALK 1196M lung cancer cell lines treated with crizotinib and alectinib. Conclusions: In silico techniques of this study demonstrate the potential binding of ALK inhibitors (crizotinib and alectinib) to the KRAS structure. In addition, this allows suggesting a possible combined therapy between KRAS and ALK inhibitors for cases of coexistence of both mutations that can be assessed in subsequent trials with cell lines.
RESUMO
PURPOSE: Despite the generally favourable prognoses observed in patients with ALK-positive non-small cell lung cancer (NSCLC), there remains significant variability in clinical outcomes. The objective of this study is to enhance patient stratification by examining both the specific sites of gene fusion and the presence of co-occurring mutations. METHODS: We collected retrospective clinical and pathological data on ALK-positive patients with locally advanced or metastatic disease. ALK fusion variants and concomitant mutations were identified through next-generation sequencing technology. We then assessed treatment efficacy via tumor response and survival metrics. RESULTS: This study included a total of 59 patients, with 49 harboring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions and 10 presenting with rare fusions. The median follow-up period was 33 months. Clinical outcomes between non-EML4-ALK and EML4-ALK patients were comparable. Among the EML4-ALK cohort, patients with longer variants (v1, v2, v8) demonstrated superior progression-free survival (PFS) (median PFS: 34 months vs. 11 months; hazard ratio [HR]: 2.28; P = 0.05) compared to those with shorter variants (v3, v5). Furthermore, patients treated with second-generation ALK inhibitors (ALKi) displayed a progression-free survival advantage (median PFS: not reached [NR] vs. 9 months; HR: 5.37; P = 0.013). Baseline TP53 co-mutation were linked with a substantially shorter OS (median OS,37 months vs. NR; HR 2.74; P = 0.047). CONCLUSIONS: In ALK+ NSCLC, longer EML4-ALK variants correlate with improved prognosis and enhanced response to second-generation ALKi, while TP53 co-mutations indicate a negative prognosis.
Assuntos
Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Proteínas de Fusão Oncogênica , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Quinase do Linfoma Anaplásico/genética , Estudos Retrospectivos , Idoso , Adulto , Proteínas de Fusão Oncogênica/genética , Proteína Supressora de Tumor p53/genética , Intervalo Livre de Progressão , Prognóstico , China , População do Leste AsiáticoRESUMO
A 56-year-old woman debuted with a palpable painless mass in the anterior thorax wall at the level of the second and third right parasternal intercostal space, which progressively increased in size over 5 months accompanied by localized skin rash, mild dyspnea and chest pain when changing position. Imaging studies showed a soft tissue mass measuring 75 × 62 mm and a density of 34 Hounsfield Units that had caused the lysis of the costal arches and grew expansively towards the anterior mediastinum, without identifying mediastinal adenopathies only by this imaging method. Core biopsy was performed, which was initially diagnosed as histiocytic sarcoma (HS); however, when the diagnostic panel was expanded to include molecular and NGS studies, the final diagnosis was anaplastic large cell lymphoma with ALK::ATIC fusion. Here, we report a very rare neoplasm with unusual clinical presentation, histopathology and molecular features.
Assuntos
Sarcoma Histiocítico , Linfoma Anaplásico de Células Grandes , Humanos , Feminino , Pessoa de Meia-Idade , Sarcoma Histiocítico/patologia , Sarcoma Histiocítico/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/diagnóstico , Quinase do Linfoma Anaplásico/genética , Diagnóstico Diferencial , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/genéticaRESUMO
Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.
Assuntos
Quinase do Linfoma Anaplásico , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases , Neoplasias Gástricas , Humanos , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Rearranjo Gênico , Transdução de Sinais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
INTRODUCTION: ALK tyrosine kinase inhibitors have exhibited promising activity against advanced ALK-rearranged NSCLC. However, co-occurring genetic alterations, such as CDKN2A/B or TP53, may negatively affect the efficacy of targeted therapies. METHODS: From December 2017 to December 2022, this study cohort analyzed next-generation sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin American cancer centers. Clinicopathologic and molecular features were associated with clinical outcomes and risk of brain metastasis (BrM) in patients with and without concurrent somatic alterations. RESULTS: All patients (N = 116) received a second-generation ALK tyrosine kinase inhibitor, and alectinib was selected in 87.2% of cases. Coalterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). The loss of CDKN2A/B was associated with an increased risk of BrM, with a cumulative incidence of 33.3% versus 7.4% in the non-coaltered subgroup. Compared with patients without coalterations, patients with concurrent CDKN2A/B loss (n = 21) had a shorter median progression-free survival (10.2 versus 34.2 mo, p < 0.001) and overall survival (26.2 versus 80.7 mo, p < 0.001). In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer progression-free survival and OS despite the presence of other somatic coalterations, TP53 mutations, BrM, and Eastern Cooperative Oncology Group Performance Status. CONCLUSIONS: This study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was substantially associated with worse outcomes and a higher risk of brain metastases. The evidence presented in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , GenômicaRESUMO
Primary cutaneous anaplastic large cell lymphoma (ALCL) is the second most common cutaneous T-cell lymphoma after mycosis fungoides and belongs to the spectrum of cutaneous CD30+ T-cell lymphoproliferative disorders. Although primary cutaneous ALCL usually presents as a localized nodule or papule with or without ulceration, multifocal lesions may occur in up to 20% of cases. Histologically, primary cutaneous ALCL consists of a diffuse dermal infiltrate of medium to large anaplastic/pleomorphic cells with abundant amphophilic-to-eosinophilic cytoplasm, horseshoe-shaped nuclei, strong and diffuse expression of CD30, and with focal or no epidermotropism. The neoplastic infiltrate may show angiocentric distribution and may extend to the subcutis. Patients with localized or multifocal disease have a similar prognosis with a 10-year overall survival rate of 90%. Approximately 30% of primary cutaneous ALCLs harbor a DUSP22 (6p25.3) gene rearrangement that results in decreased expression of this dual-specific phosphatase, decreased STAT3 activation, and decreased activity of immune and autoimmune-mediated mechanisms regulated by T-cells.
RESUMO
Background and Objective: The therapeutic landscape for non-small cell lung cancer (NSCLC) has evolved considerably in the last few years. The targeted drugs and molecular diagnostics have been developed together at a fast pace. This narrative review explores the evolution of anaplastic lymphoma kinase (ALK) targeting therapies from discovering the ALK protein, molecular tests, present clinical trial data and future perspectives. Since the body of evidence on lung cancer is growing daily, most oncologists need time to implement data in their daily practice. Methods: We developed a narrative review to provide up-to-date help in the clinical decision-making of ALK-altered NSCLC patients. In 2022, the authors reviewed PubMed's published pivotal randomized Phase 3 trial results. Key Content and Findings: The development of ALK inhibitors was a revolution that is still ongoing; second and third-generation ALK inhibitors provided more than 30 months of progression-free survival (PFS) and impressive "brain-control". Brigatinib provided a survival benefit for patients with baseline brain metastases (HR 0.43, 95% CI: 0.21-0.89), and Lorlatinib demonstrated intracranial response rates of 82%, with 71% of complete intracranial responses. Personalized medicine is the new paradigm, from performing broad genetic panels for diagnosis to individual targeted therapy or combinations of different targeted agents. Conclusions: In the future, performing broad molecular panels should be the standard of care in the front line and after each progression to detect arising resistance mechanisms. Longer PFS will substantially convert a deadly condition into an almost chronic disease in the following decades. Treatment sequencing will be the cornerstone for patient survival, and liquid biopsies may replace tissue biopsies.
RESUMO
OBJECTIVE: To assess the utility of the Curaçao criteria by age over time in children with hereditary hemorrhagic telangiectasia (HHT). STUDY DESIGN: This was a single-center, retrospective analysis of patients attending the HHT clinic at the Hospital for Sick Children (Toronto, Canada) between 2000 and 2019. The evaluation of the Curaçao criteria was completed during initial and follow-up visits. Screening for pulmonary and brain arteriovenous malformations was completed at 5 yearly intervals. RESULTS: A total of 116 patients with genetic confirmation of HHT were included in the analysis. At initial screening at a median (IQR) age of 8.4 (2.8, 12.9) years, 41% met criteria for a definite clinical diagnosis (≥3 criteria). In children <6 years at presentation, only 23% fulfilled at least 3 criteria initially. In longitudinal follow-up, 63% reached a definite clinical diagnosis, with a median (IQR) follow-up duration of 5.2 (3.2, 7.9) years (P = .005). Specifically, more patients met the epistaxis and telangiectasia criteria at last visit compared with initial (79% vs 60%; P = .006; 47% vs 30%; P = .02) but not for the arteriovenous malformation criterion (59% vs 57%; P = .65). CONCLUSIONS: In the pediatric population, most patients do not meet definite clinical criteria of HHT at initial presentation. Although the number of diagnostic criteria met increased over time, mainly due to new onset of epistaxis and telangiectasia, accuracy remained low during follow-up visits. Relying solely on clinical criteria may lead to underdiagnosis of HHT in children.