Biomarkers of Prognosis and Efficacy of Anti-angiogenic Therapy in Metastatic Clear Cell Renal Cancer

D’Aniello, Carmine; Berretta, Massimiliano; Cavaliere, Carla; Rossetti, Sabrina; Facchini, Gaetano; Iovane, Gelsomina; Mollo, Giovanna; Capasso, Mariagrazia; Pepa, Chiara Della; Pesce, Liuska; D'Errico, D; Buonerba, Carlo; Lorenzo, Giuseppe Di; Pisconti, Salvatore; Vita, Ferdinando De

doi:10.3389/fonc.2019.01400

Cited by 42 publications

(42 citation statements)

References 158 publications

(108 reference statements)

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“…Angiogenesis plays a key role in RCC tumorigenesis and progression, directing the immune system through the abnormal formation of tumor vessels and the promotion of an immunosuppressive tumor microenvironment. Therefore, antiangiogenic treatments remain a valid therapeutic option in selected patients, since they modulate immune responses [10,21,22]. This activity is essential to enhancing the performance of immunotherapy agents, which have shown promising treatment outcomes also for advanced RCC [23].…”

Section: Discussionmentioning

confidence: 99%

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Zizzari

Napoletano

Filippo

et al. 2020

Cancers

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With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR–TKIs), the survival of patients with advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFNγ, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence.

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Section: Discussionmentioning

confidence: 99%

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Zizzari

Napoletano

Filippo

et al. 2020

Cancers

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“…Molecular markers can be classified according to their physiological location into tissue and soluble factors [43]. Among the above-mentioned traditional histological features, carbonic anhydrase IX (CaIX) [44], CXCR4 [45], HIF-1α and HIF-2α [46], have been reported to predict response to sorafenib or sunitinib as well as improved PFS despite no consistent impact on OS is reported. Furthermore, PD-L1 expression is associated with poor clinical outcome [47], without a predictive role of response to cabozantinib and axitinib plus anti-PD1/PD-L1 [4,[48][49][50][51].…”

Section: From the Cytogenetics To The Mutational Landscape Of Rccmentioning

confidence: 99%

“…The assessment of the soluble factors evaluation has also been extensively investigated in the prognostic stratification attempts, uncovering VEGF/VEGFR, LDH, IL-6, IL-8, osteopontin (OPN), HGF and TIMP1 to be significant drivers of patient's prognosis and response to therapy [52][53][54][55]. Remarkably, nucleotide polymorphisms (SNPs) of IL-8, HIF-1α and VEGF axis deemed significantly impacting the therapeutic outcome; however, no validation has been achieved in statistically powered clinical studies [46,56].…”

Section: From the Cytogenetics To The Mutational Landscape Of Rccmentioning

confidence: 99%

“…Proteomics-based subtyping of ccRCC, either according to Brannon et al (two clusters, ccA and ccB) [65], Chen et al (three clusters, CC-e.1, CC-e.2, CC-e.3) [66], or KIRC analysis (four clusters m1-m4) [67] consistently deconvolute the biologic taxonomy of disease phenotype. Moreover, the combination of the singular subtypes can dissect three different clinical behaviors: 1) good prognosis group (cluster ccA, CC-e.2, and m1), involved chromatin modifier genes mutations, such as PBRM1; 2) poor prognosis group (cluster ccB, CC-e.3, m3), associated with higher expression of CDKN2A and hypoxia-related genes, chromatin remodeling genes mutation including SETD2 or BAP1, PI3K/AKT/mTOR pathway genes mutations, epithelial-mesenchymal transition, hypermethylation, and a metabolic shift with higher glutathione and dipeptide levels; 3) intermediate prognosis group (cluster 3, CC-e.1, m2, and m4) associated with BAP1 mutations and base-excision repair [46]. Additionally, data obtained from 942 surgical series pinpoint a molecular signature consisting of 16 genes that could predict post-surgery relapse and could be translated into clinical trials [68].…”

Section: Molecular Classificationmentioning

confidence: 99%

“…(Figure 2 Due to the dynamic plethora of therapeutic options available to date, it is critical to identify criteria driving personalized approaches. Indeed, real-life clinical practice faces the significant challenge of patient selection by tailoring a TKI-vs. ICI-based and mono-vs. combination-therapeutic strategy [46,97]. Currently, besides the obvious impact of clinical individual risk profiling and comorbidities potentially influencing the safety issues, the single decision-making tool is represented by the risk stratification considered by the regulatory agencies.…”

Section: Therapeutic Window Driven By Angiogenesis and The Immune Sysmentioning

confidence: 99%

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Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

Argentiero

Solimando

Krebs

et al. 2020

Preprint

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Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintained and reinforced their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

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External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations

Maffezzoli,

Santoni,

Mazzaschi

et al. 2024

Clin Exp Metastasis

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Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients’ counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47–0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39–0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.

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Biomarkers of Prognosis and Efficacy of Anti-angiogenic Therapy in Metastatic Clear Cell Renal Cancer

Cited by 42 publications

References 158 publications

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations

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