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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e21144-e21144
    Abstract: e21144 Background: Immune Checkpoint Inhibitors (ICIs) changed the algorithm of treatment for Non-Small Cell Lung Cancer (NSCLC). Consequently, an increased incidence of specific immune-related adverse events (irAEs) were reported, although a clear relationship between toxicity and response to ICIs was not identified. To date no strong predictive factor of response to ICIs are univocally recognized in NSCLC. Methods: This is an observational, retro-prospective, monocentric study aimed to evaluate, in patients (pts) with NSCLC treated with ICIs, the predictive impact of selected blood biomarkers and the occurrence of irAEs on survival. Differential cells count, and specifically the Absolute Eosinophil Count (AEC, N°/μL), were registered at baseline to evaluate their impact on response to ICIs. Patients were divided in two groups: those with high AEC ( 〉 190/µL, group A), and those with low basal AEC ( 〈 190/µL, group B). Results: We enrolled 48 pts, median age was 70 years. All pts were treated with an ICI as single-agent: 5 (10%) with Nivolumab (N), 37 (77%) with Pembrolizumab (P), and 5 pts received Atezolizumab (A). Thirty-seven pts were treated in first-line setting, 9 pts in second-line, and 2 pts in successive lines. Of total, 63% pts (30/48) developed at least one irAE: an endocrine event occurred in 11 pts (23%), gastrointestinal toxicity in 10 pts (21%), dermatological events in 19 pts (40%), while a pulmonary irAE in 6 pts (13%). Progression free survival (PFS) was higher in group A than in group B (16 vs 9.5, p = 0.041) with a trend for a superior median Overall Survival (mOS) (median not reached vs 23 months, p = 0.07, respectively). At a median follow-up of 18 months (mos), pts who developed at least one irAE had a significant benefit in PFS (15mos vs 8mos, p = 0.027), reporting a trend for better PFS for pts with endocrine toxicities (p = 0.057) and GI- toxicities (p = 0.051) vs no toxicities. Pulmonary irAEs are significantly related to a better PFS: median not reached vs 12 mos, p = 0.025. Conclusions: In this real-life experience we observed that baseline AEC values correlates with PFS in pts with NSCLC treated with ICIs. Additional analyses are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Moreover, our study underlines that the development of toxicities, in particular pulmonary ones, could be considered as a predictive indicator of response to ICIs in NSCLC. With all the limitations of being a small analysis, our real-life experience is innovative and explored prospectively the potential role of differential cell count and irAEs as predictive biomarkers of survival in NSCLC patients treated with ICIs.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 3
    In: Pharmacology & Therapeutics, Elsevier BV, Vol. 237 ( 2022-09), p. 108170-
    Type of Medium: Online Resource
    ISSN: 0163-7258
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1500663-3
    SSG: 15,3
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e16314-e16314
    Abstract: e16314 Background: Pancreatic adenocarcinoma (PC) is one of the big killers with a 5-year disease-free survival (DFS) rate of 19-26% after resection despite adjuvant treatments. KRAS mutations have been reported in approximately 90% of PC cases and, beyond KRAS activation by gene mutations, several miRNAs directly targeting KRAS have been reported to be simultaneously downregulated, strengthening the already activated RAS signaling. In addition, the interplay between miRNAs and RAS includes downstream miRNA effectors whose role needs to be elucidated. The aim of this study was to evaluate the expression of candidate miRNAs strictly related to KRAS expression in order to elucidate the prognostic value. Methods: In this single-center observational prospective study we included patients with pathologically confirmed PC, who underwent radical surgery and were referred to the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy), between 2015 and 2022. Total RNA was extracted from FFPE sections, retro-transcribed and the resulting cDNA was then used for qPCR analysis. Results: Among 44 patients included in the study, 34.1% were male and 65.9% female (median age 75 years). The majority of cases had the primary tumor located at the head of the pancreas (65.9%) and the pathological stage was pT1-2 in 45.5%, pT3 in 54.5%, pN0 in 22.7%, pN+ in 77.3%. Overall, 63.6% of patients received adjuvant chemotherapy and 69.0% experienced disease recurrence. Twenty-three specimens were adequate for miRNA analysis. A different expression of the three target miRNAs between PC and healthy tissue was observed: miR-155 was overexpressed and miR-206 downregulated in PC, while miR-143 had a similar expression in both tissues. miR-143 overexpression was associated with nodal involvement (pN+) at the pathological examination (p = 0.029). Among clinicopathological features, pN+ was associated with shorter DFS (p = 0.009) and overall survival (OS) (p = 0.021) compared to pN0. A trend toward inferior DFS was observed for higher expression of miR-206 (p = 0.095) and miR-143 (p = 0.092). Among patients receiving a first-line treatment for advanced disease, miR-155 was overexpressed in responders vs non-responders (p = 0.048). Conclusions: miRNA expression is involved in tumorigenesis and metastatic spread in PC. A comprehensive analysis of the miRNA-RAS interplay deserves to be further investigated as a predictor of clinical outcome, especially for miR-143 overexpression which was associated with lymphatic spread and, consequently, poor prognosis.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-11-29)
    Abstract: About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs. Methods Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA. Results Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases. Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031). Conclusions Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2649216-7
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