BACKGROUND BRAF is a gene whose mutation is found in many tumors, including non-small cell lung cancer (NSCLC). Although its frequency is rare, it represents a target for targeted oncological therapy. However, the clinicopathological characteristics of patients with BRAF mutations require further investigation to optimize prognostic stratification and therapeutic management. OBJECTIVES The aim is to outline an “identikit” of patients with non-small cell lung carcinoma (NSCLC) harboring BRAF mutations by comparing their clinicopathological data with a wild-type (WT) control group and with international literature. METHODS The study was conducted on a cohort of patients with NSCLC recruited from five hospital centers in Veneto between 2021 and 2023 who tested positive for BRAF mutations. For each case, demographic, clinical, and pathological data were collected, including disease stage, histotype, performance status, smoking habits, and BRAF mutation status. Wild-type patients were selected as the comparison group. All data were managed and analyzed using appropriate statistical software, considering p-values < 0.05 as significant. RESULTS BRAF gene mutations were found in 5% (54/1100) of patients with non-small cell lung cancer, with 26 out of 47 cases having the V600E subtype. The average age was 70 ± 8.6 years, with a male predominance (69% male). Among these patients, 36 out of 45 (80%) had a history of smoking (42 ± 24 pack-years), 9 out of 39 (23%) had occupational exposure to pneumotoxic substances, 12 out of 37 (32%) had a family history of lung cancer, 7 out of 20 (35%) had a history of previous neoplasia, and 9 out of 41 (22%) had pneumopathy. Compared to the wild-type group, no significant differences were found regarding gender, age, late-stage diagnosis, occupational exposure, and smoking history. A significant difference was observed in PD-L1 expression, which was positive especially in association with BRAF mutations (p = 0.0009). Additionally, patients with BRAF mutations tended to present more frequently as asymptomatic at diagnosis (p = 0.0298). In the BRAF-mutated subgroup, nearly one-third of the patients (13 out of 41, 32%) received targeted therapies (dabrafenib + trametinib). The importance of the BRAF mutation with specific therapy targets is underscored by the fact that, with an average survival of 9 ± 11 months, patients who did not receive any therapy (4 out of 41) died on average in 1.25 ± 1.9 months. CONCLUSIONS: The collected data indicate that patients with BRAF-mutated NSCLC constitute a biologically and clinically distinct subgroup. The frequent expression of PD-L1 and sensitivity to targeted therapies make BRAF a driver of significant clinical interest. Our data help describe the phenotype of this patient category and optimize their diagnostic and therapeutic pathways.
INTRODUZIONE BRAF è un gene la cui mutazione si ritrova in molti tumori tra cui quelli polmonari non a piccole cellule (NSCLC) e che, nonostante la sua fre-quenza sia rara, rappresenta un target per la terapia oncologica mirata. Tutta-via, le caratteristiche clinico-patologiche dei pazienti con mutazione di BRAF necessitano di ulteriori approfondimenti per ottimizzare la stratificazione pro-gnostica e la gestione terapeutica. OBIETTIVI L’obiettivo di delineare un “identikit” dei pazienti affetti da carci-noma polmonare non a piccole cellule (NSCLC) con mutazione di BRAF, con-frontandone i dati clinico-patologici con un gruppo di controllo wild type (WT) e con la letteratura internazionale. METODI: Lo studio è stato condotto su una coorte di pazienti con NSCLC reclu-tati in cinque centri ospedalieri del Veneto tra il 2021 e 2023 e risultati positivi alla mutazione di BRAF. Per ciascun caso sono stati raccolti dati demografici, clinici e anatomopatologici, inclusi stadio di malattia, istotipo, performance status, abitudine tabagica e stato mutazionale di BRAF. I pazienti wild type so-no stati selezionati come gruppo di confronto. Tutti i dati sono stati gestiti e analizzati tramite software statistici appropriati, considerando significativi i va-lori di p < 0,05. RISULTATI: La mutazione del gene BRAF è stata riscontrata nel 5% (54/1100) dei pazienti con tumore polmonare non a piccole cellule (26/47 con sottotipo V600E) con un’età media di 70±8.6 anni e con una predilezione per il genere maschile (M 69%). Tra questi pazienti 36/45 (80%) avevano una storia di fumo (42±24 packs/year), 9/39 (23%) presentavano un’esposizione professionale a sostanze pneumotossiche, 12/37 (32%) avevano familiarità per tumori pol-monari, 7/20 (35%) avevano in anamnesi una pregressa neoplasia e 9/41 (22%) presentavano una pneumopatia. In confronto al gruppo wilde type non sono emerse particolari differenze per quanto riguarda genere, età, stadio tardivo alla diagnosi, esposizione profes-sionale e storia di fumo. Una differenza significativa riguarda l’espressione di PD-L1 che risulta positiva soprattutto in associazione alla mutazione di BRAF con p=0,0009. Inoltre i pazienti con BRAF mutato tendono a presentarsi più frequentemente asintomatici alla diagnosi (p=0,0298). Nel sottogruppo BRAF-mutato, quasi un terzo dei pazienti (13/41, 32%) ha ri-cevuto terapie target (dabrafenib + trametinib). L’importanza della mutazione BRAF con target di terapia specifica si riconosce nel fatto che a fronte di una sopravvivenza media di 9±11 mesi, i pazienti che non hanno avuto accesso a nessuna terapia (4/41) sono morti mediamente in 1,25±1,9 mesi. CONCLUSIONI I dati raccolti indicano che i pazienti con NSCLC BRAF mutato costituiscono un sottogruppo biologicamente e clinicamente distinto. La fre-quente espressione di PD-L1 e la sensibilità alle terapie target fanno di BRAF un driver di notevole interesse clinico. I dati da noi raccolti aiutano a descrivere il fenotipo di questa categoria di pazienti e ottimizarne il percorso diagnostico e terapeutico.
Analisi della mutazione del gene BRAF nei pazienti con tumore del polmone non a piccole cellule
SQUARZONI, GIULIA
2022/2023
Abstract
BACKGROUND BRAF is a gene whose mutation is found in many tumors, including non-small cell lung cancer (NSCLC). Although its frequency is rare, it represents a target for targeted oncological therapy. However, the clinicopathological characteristics of patients with BRAF mutations require further investigation to optimize prognostic stratification and therapeutic management. OBJECTIVES The aim is to outline an “identikit” of patients with non-small cell lung carcinoma (NSCLC) harboring BRAF mutations by comparing their clinicopathological data with a wild-type (WT) control group and with international literature. METHODS The study was conducted on a cohort of patients with NSCLC recruited from five hospital centers in Veneto between 2021 and 2023 who tested positive for BRAF mutations. For each case, demographic, clinical, and pathological data were collected, including disease stage, histotype, performance status, smoking habits, and BRAF mutation status. Wild-type patients were selected as the comparison group. All data were managed and analyzed using appropriate statistical software, considering p-values < 0.05 as significant. RESULTS BRAF gene mutations were found in 5% (54/1100) of patients with non-small cell lung cancer, with 26 out of 47 cases having the V600E subtype. The average age was 70 ± 8.6 years, with a male predominance (69% male). Among these patients, 36 out of 45 (80%) had a history of smoking (42 ± 24 pack-years), 9 out of 39 (23%) had occupational exposure to pneumotoxic substances, 12 out of 37 (32%) had a family history of lung cancer, 7 out of 20 (35%) had a history of previous neoplasia, and 9 out of 41 (22%) had pneumopathy. Compared to the wild-type group, no significant differences were found regarding gender, age, late-stage diagnosis, occupational exposure, and smoking history. A significant difference was observed in PD-L1 expression, which was positive especially in association with BRAF mutations (p = 0.0009). Additionally, patients with BRAF mutations tended to present more frequently as asymptomatic at diagnosis (p = 0.0298). In the BRAF-mutated subgroup, nearly one-third of the patients (13 out of 41, 32%) received targeted therapies (dabrafenib + trametinib). The importance of the BRAF mutation with specific therapy targets is underscored by the fact that, with an average survival of 9 ± 11 months, patients who did not receive any therapy (4 out of 41) died on average in 1.25 ± 1.9 months. CONCLUSIONS: The collected data indicate that patients with BRAF-mutated NSCLC constitute a biologically and clinically distinct subgroup. The frequent expression of PD-L1 and sensitivity to targeted therapies make BRAF a driver of significant clinical interest. Our data help describe the phenotype of this patient category and optimize their diagnostic and therapeutic pathways.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/81356