Dataset Information

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients.

ABSTRACT: Fibroblast growth factor receptor (FGFR) genomic alterations (GAs) represent an actionable target, key to the pathogenesis of some urothelial cancers (UCs). Though FGFR GAs are common in noninvasive UC, little is known about their role in the metastatic(m) setting and response to therapy. This study aimed to assess the impact of FGFR alterations on sensitivity to systemic treatments and survival and to validate Bajorin's and Bellmunt's prognostic scores in mUC patients according to their FGFR status. We retrospectively analyzed data from 98 patients with tumor-sequenced UC who received treatment between January 2010 and December 2020. Up to 77 developed metastatic disease and were deemed the study population. Twenty-six showed FGFR GAs. A trend toward a better response to cisplatin and checkpoint inhibitors was suggested favoring FGFR GA tumors. FGFR GA patients who received an FGFR inhibitor as first-line had poorer responses compared with other options (20% vs. 68.4%, p = 0.0065). Median PFS was 6 vs. 5 months in the FGFR GA vs. FGFR WT cohort (p = 0.71). Median OS was significantly worse in the FGFR GA vs. FGFR WT cohort (16.2 vs. 31.9 months, p = 0.045). Multivariate analyses deemed FGFR GAs as a factor independently associated with the outcome (HR 2.59 (95% CI 1.21-5.55)). Bajorin's model correctly predicted clinical outcomes in the whole study population but not in FGFR GA cases. FGFR GAs are a relevant biomarker in mUC that could condition the response to systemic therapy. New prognostic models, including this molecular determination, should be designed and validated.

SUBMITTER: Sevillano Fernandez E

PROVIDER: S-EPMC9369263 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients.

Sevillano Fernández Elena E Madurga de Lacalle Rodrigo R Rodriguez Moreno Juan Francisco JF Barquín García Arantzazu A Yagüe Fernández Mónica M Navarro Alcaraz Paloma P Barba Llacer María M Quiralte Pulido Miguel M García-Donás Jiménez Jesús J

Journal of clinical medicine 20220801 15

Fibroblast growth factor receptor (FGFR) genomic alterations (GAs) represent an actionable target, key to the pathogenesis of some urothelial cancers (UCs). Though FGFR GAs are common in noninvasive UC, little is known about their role in the metastatic(m) setting and response to therapy. This study aimed to assess the impact of FGFR alterations on sensitivity to systemic treatments and survival and to validate Bajorin's and Bellmunt's prognostic scores in mUC patients according to their FGFR st ...[more]

PMID: 35956100

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Project description:BackgroundDNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear.Materials and methodsWe retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI.ResultsDDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003).ConclusionsGenomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression.Implications for practiceSomatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

Project description:BackgroundExisting data on metastatic upper tract urothelial carcinoma (mUTUC) are limited. In this study, we investigated the prognostic value of site-specific metastases in patients with mUTUC and its association with survival outcomes.MethodsWe retrospectively collected data from the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2016. Kaplan-Meier analysis with a log-rank test was used for survival comparisons. Multivariate Cox regression was employed to predict overall survival (OS) and cancer-specific survival (CSS).Results633 patients were selected in this study cohort. The median follow-up was 6 months (IQR 2-13) and a total of 584 (92.3%) deaths were recorded. Within the population presenting with a single metastatic organ site, the most common metastatic sites were distant lymph nodes, accounting for 36%, followed by lung, bone and liver metastases, accounting for 26%, 22.8% and 16.2%, respectively. In patients with a single metastatic organ site, the Kaplan-Meier curves showed significantly worse OS for patients with liver metastases vs. patients presenting with metastases in a distant lymph node (p < 0.001), bone (p = 0.023) or lung (p = 0.026). When analyzing CSS, statistically significant differences were detectable only between patients presenting with liver metastases vs. distant lymph node metastases (p < 0.001). Multivariate analyses showed that the presence of liver (OS: HR = 1.732, 95% CI = 1.234-2.430, p < 0.001; CSS: HR = 1.531, 95% CI = 1.062-2.207, p = 0.022) or multiple metastatic organ sites (OS: HR = 1.425, 95% CI = 1.159-1.753, p < 0.001; CSS: HR = 1.417, 95% CI = 1.141-1.760, p = 0.002) was an independent predictor of poor survival. Additionally, survival benefits were found in patients undergoing radical nephroureterectomy (RNU) (OS: HR = 0.675, 95% CI = 0.514-0.886, p = 0.005; CSS: HR = 0.671, 95% CI = 0.505-0.891, p = 0.006) and chemotherapy (CHT) (OS: HR = 0.405, 95% CI = 0.313-0.523, p < 0.001; CSS: HR = 0.435, 95% CI = 0.333-0.570, p < 0.001).ConclusionsA distant lymph node was the most common site of single-organ metastases for mUTUC. Patients with liver metastases and patients with multiple organ metastases exhibited worse survival outcomes. Lastly, CHT administration and RNU were revealed to be predictors of better survival outcomes in the mUTUC cohort.

Project description:IntroductionThe homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations.MethodsWe conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival.Results151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations.ConclusionHRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.

Dataset Information

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients.

Publications

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients.

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