Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The ...identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 Del19 and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.
Gastric cancers have been historically classified based on histomorphologic features. The Cancer Genome Atlas network reported the comprehensive identification of genetic alterations associated with ...gastric cancer, identifying four distinct subtypes- Epstein-Barr virus (EBV)-positive, microsatellite-unstable/instability (MSI), genomically stable and chromosomal instability. In particular, EBV-positive and MSI gastric cancers seem responsive to novel immunotherapies drugs. The aim of this review is to describe MSI and EBV positive gastric cancer's subgroups and their relationship with novel immunotherapy.
Background: Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage ...irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy. Methods: We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group. Results: The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS (p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS (p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 95% CI 0.36–0.97, p = 0.037). Conclusions: This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients.
Systemic treatment of renal cancer (RCC) has undergone remarkable changes over the past 20 years with the introduction of immunotherapeutic agents targeting programmed cell death (PD-1)/programmed ...death-ligand 1 (PD-L1) axis, as a single-agent or combined with anti-CTLA-4 monoclonal antibodies (MoAbs) or a multi-target vascular endothelial growth factor-(VEGF) tyrosine kinase inhibitor (TKI). In this paper, we review the main evidence on the use of Immune Checkpoint Inhibitors (ICIs) for RCC treatment from the first demonstration of activity of a nivolumab single agent in a phase I trial to the novel combination strategies (anti-PD-1 plus anti-CTLA4 or anti-PD-1 plus TKI). In addition, we discuss the use of anti-PD-1/PD-L1 agents in patients with non-clear cells and rare histological subtype RCC. Then, we critically examine the current findings in biomarkers that have been proposed to be prognostic or predictive to the response of immunotherapy including immune gene expression signature, B7-H1 expression, PBRM1 loss of function, PD-L1 expression, frame shift indel count, mutations in bromodomain-containing genes in patients with MiT family translocation RCC (tRCC), high expression of the T-effector gene signature, and a high myeloid inflammation gene expression pattern. To date, a single biomarker as a predictor of response has not been established. Since the dynamic behavior of the immune response and the different impact of ICI treatment on patients with specific RCC subtypes, the integration of multiple biomarkers and further validation in clinical trials are needed.
Resectable gastric or gastroesophageal (G/GEJ) cancer is a heterogeneous disease with no defined molecularly based treatment strategy. Unfortunately, nearly half of patients experience disease ...recurrence despite standard treatments (neoadjuvant and/or adjuvant chemotherapy/chemoradiotherapy and surgery). In this review, we summarize the evidence of potential tailored approaches in perioperative treatment of G/GEJ cancer, with a special focus on patients with human epidermal growth factor receptor-2(HER2)-positive and microsatellite instability-high (MSI-H) tumors. In patients with resectable MSI-H G/GEJ adenocarcinoma, the ongoing INFINITY trial introduces the concept of non-operative management for patients with complete clinical-pathological-molecular response, and this could be a novel and potential practice changing strategy. Other pathways involving vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), claudin18 isoform 2 (CLDN18.2), and DNA damage repair proteins are also described, with limited evidence until now. Although tailored therapy appears to be a promising strategy for resectable G/GEJ cancer, there are several methodological issues to address: inadequate sample size for pivotal trials, underestimation of subgroup effects, and choice of primary endpoint (tumor-centered vs. patient-centered endpoints). A better optimization of G/GEJ cancer treatment allows maximizing patient outcomes. In the perioperative phase, although caution is mandatory, times are changing and tailored strategies could introduce new treatment concepts. Overall, MSI-H G/GEJ cancer patients possess the characteristics to be the subgroup that could receive the most benefit from a tailored approach.
BRAFV600-mutated colorectal cancer (CRC) accounts for 8% to 12% of all CRC diagnoses. These tumors are often associated with specific patient features, including right-sided primary tumor location, ...peritoneal and non-regional lymph node involvement, and poor prognosis. In approximately 30% of cases, a simultaneous mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype is identified. The prognostic impact of the BRAF mutation appears to be less marked in patients with MSI-H CRC than in patients with microsatellite stable (MSS) tumor. The treatment of BRAFV600-mutated CRC is still a challenge for the clinicians, mainly due to the poor survival outcomes obtained with traditional chemotherapy regimens.
In recent years, two novel treatment strategies have offered remarkable changes in the treatment of this specific patient subgroup. The first approach has included targeted therapies directed against BRAF and MEK, with support from the epidermal growth factor receptor (EGFR) blockade. The second approach has included immunotherapeutic agents that have been shown to be particularly promising for patients with simultaneous dMMR/MSI-H phenotype.
Here we review the clinical trials that specifically enrolled patients with BRAF-mutated CRC, from the phase I/II studies to the phase III trial BEACON CRC. We also examine the future directions towards a molecularly guided therapy for patients with BRAF-mutated CRC and the crucial role of a molecularly and clinically based algorithm in order to offer the best choice of treatment for these patients.
Objective
This study was performed to evaluate the prognostic meaning of volumetric and semi-quantitative parameters measured using 18FFDG PET/CT and somatostatin receptor (SSTR) imaging in patients ...with typical lung carcinoid (TC), and their relationship with proliferative index (Ki67).
Methods
We retrospectively reviewed 67 patients (38–94 years old, mean: 69.7) with diagnosis of TC who underwent 18FFDG PET/CT and/or SSTR scintigraphy/SPECT with 111InDTPA-Octreotide plus contrast-enhanced CT (CECT) at staging evaluation. All patients had Ki67 measured and a follow-up (FU) of at least 1 year. SSTR density (SSTRd) was calculated as the percentage difference of tumor/non-tumor ratio at 4 and 24 h post-injection. At PET/CT, metabolic activity was measured using SUVmax and SUVratio; volumetric parameters included MTV and TLG of the primary tumor, measured using the threshold SUV41%. ROC analysis, discriminant analysis and Kaplan–Meier curves (KM) were performed.
Results
11 patients died during FU. Disease stage (localized versus advanced), SUVratio, SUVmax, Ki67, MTV and TLG were significantly higher in non-survivors than in survivors. ROC curves resulted statistically significant for Ki67, SUVratio, SUVmax, MTV and TLG. On multivariate analysis, stage of disease and TLG were significant independent predictors of overall survival (OS). In KM curves, the combination of disease stage and TLG identified four groups with significantly different outcomes (
p
< 0.005). Metabolic activity (SUVmax and SUVratio) was confirmed as significant independent prognostic factor for OS also in patients with advanced disease, with the best AUC using SUVmax.
In patients with advanced and localized disease, SSTRd proved to be the best imaging prognostic factor for progression and for disease-free survival (DFS), respectively. In localized disease, SSTRd 31.5% identified two subgroups of patients with significant different DFS distribution and in advanced disease, a high cutoff value (58.5%) was a significant predictor of adverse prognosis.
Conclusion
Volumetric and semi-quantitative parameters measured using 18FFDG PET/CT and SSTR imaging combined with Ki67 may provide a reference for prognosis evaluation of patients with TC, to better stratify risk groups with the goal of developing individualized therapeutic strategies.
The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, ...and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.
Background Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) ...adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. Methods RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. Results Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. Conclusions These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets. Keywords: FLOT, Perioperative chemotherapy, Gastric cancer, Gastro-oesophageal junction adenocarcinoma, pCR, MSI
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
hERG1 potassium channels are widely expressed in human cancers of different origins, where they affect several key aspects of cellular behaviour. The present study was designed to evaluate the ...expression and clinical relevance of hERG1 protein in cancer tissues from patients suffering from neuroendocrine tumours (NETs) of ileal (iNETs) and pancreatic (pNETs) origin, with available clinicopathological history and follow-up. The study was carried out by immunohistochemistry with an anti-hERG1 monoclonal antibody. In a subset of samples, a different antibody directed against the hERG1/β1 integrin complex was also used. The analysis showed for the first time that hERG1 is expressed in human NETs originating from either the ileum or the pancreas. hERG1 turned out to have a prognostic value in NETs, showing (i) a statistically significant positive impact on OS of patients affected by ileal NETs, regardless the TNM stage; (ii) a statistically significant positive impact on OS of patients affected by aggressive (TNM stage IV) disease, either ileal or pancreatic; (iii) a trend to a negative impact on OS of patients affected by less aggressive (TNM stage I-III) disease, either ileal or pancreatic. Moreover, in order to evaluate whether ERG1 was functionally expressed in a cellular model of pNET, the INS1E rat insulinoma cell line was used, and it emerged that blocking ERG1 with a specific inhibitor of the channel (E4031) turned out in a significant reduction in cell proliferation.
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