Thesis Objective: The objective of this study is to evaluate the use of circulating tumor DNA fraction, calculated from free circulating DNA, as a prognostic indicator for patients with high-grade serous epithelial ovarian carcinoma. Methods:The primary aim of the study was to identify clinical and biological factors capable of stratifying the varying perspectives of progression-free survival (PFS) and overall survival (OS) at the time of diagnosis in patients with stage III/IV epithelial ovarian carcinoma (EOC). A total of 172 patients out of 398 participants in the clinical trial were included in the analysis. Plasma samples collected after debulking surgery and before the initiation of frontline platinum-based treatment were available for analysis. Circulating free DNA (cfDNA) was extracted from plasma using the Maxwell RSC system from Promega, and whole-genome libraries (HyperPlus, Roche) were prepared and sequenced. The IchorCNA algorithm was utilized to determine the percentage of tumor fraction (TF) Results: The tumor fraction was calculated for the 172 patients at various time points, and its correlation with progression-free survival (PFS) and overall survival (OS) was subsequently examined through univariate analysis, revealing statistically significant results. Following this, multivariate analyses were conducted to explore correlations with other variables, demonstrating significant associations with residual disease presence and tumor histology. The same analyses were performed using a "cut-off" value for the tumor fraction, transforming it into a dichotomous variable. This enabled confirmation of previous correlations and comparison of its prognostic value with that of CA125, commonly used as the gold standard, through univariate and multivariate analyses. Conclusions: The retrospective analysis, conducted within the MITO-16A/MaNGO-OV2A clinical trial, demonstrates for the first time that tumor fraction (TF) after surgical intervention is a prognostic marker in advanced stages of high-grade serous epithelial ovarian carcinoma (HGS-EOC). In particular, it has been shown that, using whole-genome somatic sequencing (sWGS), it is possible to predict better than currently considered conventional parameters (residual disease, platinum-free interval, and CA125) the response to frontline chemotherapy and the risk of relapse in patients
Scopo della tesi: L'obiettivo del presente studio è valutare l'utilizzo della frazione tumorale, calcolata dal DNA circolante libero, quale indice prognostico per pazienti affette da carcinoma ovarico epiteliale sieroso di alto grado. Metodi: Lo scopo principale della ricerca era individuare fattori clinici e biologici che potessero, al momento della diagnosi, stratificare le diverse prospettive di progressione libera da malattia (PFS) e sopravvivenza complessiva (OS) nei pazienti con carcinoma ovarico epiteliale (EOC) di stadio III/IV. Sono stati inclusi 172 pazienti su un totale di 398 partecipanti nello studio clinico. Erano disponibili campioni di plasma raccolti dopo l'intervento chirurgico di riduzione del volume e prima dell'avvio del trattamento iniziale a base di platino. Il DNA circolante libero (cfDNA) è stato estratto dal plasma utilizzando il sistema Maxwell RSC di Promega, le librerie genomiche complete (HyperPlus, Roche) sono state preparate e sequenziate. L'algoritmo IchorCNA è stato impiegato per determinare la percentuale di frazione tumorale (TF). Risultati: La frazione tumorale è stata calcolata per le 172 pazienti in diversi time point e successivamente è stata esaminata la sua correlazione con la sopravvivenza libera da progressione (PFS) e la sopravvivenza complessiva (OS) tramite analisi univariata, che ha rivelato risultati statisticamente significativi. In seguito, sono state condotte analisi multivariate per esplorare le correlazioni con altre variabili, dimostrando correlazioni significative con la presenza di malattia residua e l'istologia del tumore. Le stesse analisi sono state eseguite utilizzando un valore "cut-off" per la frazione tumorale, trasformandola in una variabile dicotomica. È stato così possibile confermare le correlazioni precedenti e confrontare il suo valore prognostico con quello di CA125, comunemente utilizzato come gold standard, mediante analisi univariata e multivariata. Conclusioni: L’analisi retrospettiva, condotta nell'ambito dello studio clinico MITO-16A/MaNGO-OV2A, dimostra per la prima volta che la frazione tumorale (TF) dopo l'intervento chirurgico è un marker prognostico negli stadi avanzati del carcinoma ovarico epiteliale sieroso di alto grado (HGS-EOC). In particolare, è stato dimostrato che, utilizzando la sequenza completa del genoma somatico (sWGS), è possibile predire in modo migliore rispetto ai parametri convenzionali considerati attualmente (la malattia residua, l'intervallo libero dal platino e il CA125) la risposta alla chemioterapia di prima linea e il rischio di ricaduta dei pazienti.
“Il DNA tumorale circolante quale fattore prognostico indipendente della sopravvivenza delle pazienti affette da tumore ovarico sieroso ad alto grado: l’esperienza del MITO-16a/MaNGO-OV2a clinical trial”
RIVA, FEDERICA
2022/2023
Abstract
Thesis Objective: The objective of this study is to evaluate the use of circulating tumor DNA fraction, calculated from free circulating DNA, as a prognostic indicator for patients with high-grade serous epithelial ovarian carcinoma. Methods:The primary aim of the study was to identify clinical and biological factors capable of stratifying the varying perspectives of progression-free survival (PFS) and overall survival (OS) at the time of diagnosis in patients with stage III/IV epithelial ovarian carcinoma (EOC). A total of 172 patients out of 398 participants in the clinical trial were included in the analysis. Plasma samples collected after debulking surgery and before the initiation of frontline platinum-based treatment were available for analysis. Circulating free DNA (cfDNA) was extracted from plasma using the Maxwell RSC system from Promega, and whole-genome libraries (HyperPlus, Roche) were prepared and sequenced. The IchorCNA algorithm was utilized to determine the percentage of tumor fraction (TF) Results: The tumor fraction was calculated for the 172 patients at various time points, and its correlation with progression-free survival (PFS) and overall survival (OS) was subsequently examined through univariate analysis, revealing statistically significant results. Following this, multivariate analyses were conducted to explore correlations with other variables, demonstrating significant associations with residual disease presence and tumor histology. The same analyses were performed using a "cut-off" value for the tumor fraction, transforming it into a dichotomous variable. This enabled confirmation of previous correlations and comparison of its prognostic value with that of CA125, commonly used as the gold standard, through univariate and multivariate analyses. Conclusions: The retrospective analysis, conducted within the MITO-16A/MaNGO-OV2A clinical trial, demonstrates for the first time that tumor fraction (TF) after surgical intervention is a prognostic marker in advanced stages of high-grade serous epithelial ovarian carcinoma (HGS-EOC). In particular, it has been shown that, using whole-genome somatic sequencing (sWGS), it is possible to predict better than currently considered conventional parameters (residual disease, platinum-free interval, and CA125) the response to frontline chemotherapy and the risk of relapse in patientsÈ consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/17376