Despite advances in screening and therapeutics cancer continues to be one of the major causes of morbidity and mortality worldwide. The molecular profile of tumor is routinely assessed by surgical or ...bioptic samples, however, genotyping of tissue has inherent limitations: it represents a single snapshot in time and it is subjected to spatial selection bias owing to tumor heterogeneity. Liquid biopsy has emerged as a novel, non-invasive opportunity of detecting and monitoring cancer in several body fluids instead of tumor tissue. Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), RNA (mRNA and microRNA), microvesicles, including exosomes and tumor “educated platelets” were recently identified as a source of genomic information in cancer patients which could reflect all subclones present in primary and metastatic lesions allowing sequential monitoring of disease evolution. In this review, we summarize the currently available information concerning liquid biopsy in breast cancer, colon cancer, lung cancer and melanoma. These promising issues still need to be standardized and harmonized across laboratories, before fully adopting liquid biopsy approaches into clinical practice.
Clinical efficacy of intravitreal anti-VEGF drugs has been widely demonstrated in several angiogenesis-driven eye diseases including diabetic macular edema and the neovascular form of age-related ...macular degeneration. Pegaptanib, ranibizumab, and aflibercept have been approved for use in the eye, whereas bevacizumab is widely used by ophthalmologists to treat patients "off-label". These drugs are active in the nanomolar to picomolar range; however, caution is required when establishing the rank order of affinity and potency due to in vitro inter-experimental variation. Despite the small doses used for eye diseases and the intravitreal route of administration may limit systemic side effects, these drugs can penetrate into blood circulation and alter systemic VEGF with unknown clinical consequences, particularly in vulnerable groups of patients. Clinical pharmacokinetics of ocular anti-VEGF agents should therefore be taken into account when choosing the right drug for the individual patient. The gaps in current understanding that leave open important questions are as follows: (i) uncertainty about which drug should be given first, (ii) how long these drugs can be used safely, and (iii) the choice of the best pharmacological strategy after first-line treatment failure. The current review article, based on the information published in peer-reviewed published papers relevant to anti-VEGF treatments and available on the PubMed database, describes in detail the clinical pharmacology of this class of drugs to provide a sound pharmacological basis for their proper use in ophthalmology clinical practice.
During lung carcinogenesis, different epigenetic changes occur and, among these, DNA methylation aberrations play a critical role, representing an appealing biomarker for cancer screening. In this ...Cancer issue, Zhao et al. systematically assessed the associations of genetically predicted DNA methylation CpGs with non–small cell lung cancer risk.
Epidermal Growth Factor Receptor (EGFR) enacts major roles in the maintenance of epithelial tissues. However, when EGFR signaling is altered, it becomes the grand orchestrator of epithelial ...transformation, and hence one of the most world-wide studied tyrosine kinase receptors involved in neoplasia, in several tissues. In the last decades, EGFR-targeted therapies shaped the new era of precision-oncology. Despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us. Studies investigating the function of this protein in solid malignancies have revealed numerous ways how tumor cells dysregulate EGFR function. Starting from preclinical models (cell lines, organoids, murine models) and validating in clinical specimens, EGFR-related oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread enriching the therapeutic portfolios, were identified. Focusing on non-small cell lung cancer (NSCLC), where EGFR mutations are major players in the adenocarcinoma subtype, we will go over the most relevant discoveries that led us to understand EGFR and beyond, and highlight how they revolutionized cancer treatment by expanding the therapeutic arsenal at our disposal.
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•Lenvatinib is the first therapeutic option in patients with radioiodine-refractory differentiated thyroid cancer.•Common adverse drug reactions can be managed by monitoring of ...patients, drug dose adaptation and/or specific therapy.•No dose adjustment needed for mild-to-moderate hepatic/renal failure.•No significant interaction with food or CYP3A4 inducers/inhibitors.•Avoid combinations with clearly established QT prolongation agents or use drugs with no torsadogenic potential.
Lenvatinib is a non-selective tyrosine kinase inhibitor (TKI) with high in vitro potency against vascular endothelial growth factor receptors. Although this drug is used to treat several cancer types, it is the most effective TKI used in patients with thyroid cancer. Lenvatinib is well tolerated and the most common adverse drug reactions can be adequately managed by dose adjustment. Particularly, blood pressure and cardiac function monitoring, as well as antihypertensive treatment optimization, may be required in patients treated with lenvatinib. Dose reduction should be taken into account in patients with body weight <60 kg or severe hepatic failure. No significant change in lenvatinib pharmacokinetics has been observed with other patient-related factors and very few data are available on lenvatinib pharmacogenetics. Lenvatinib can be administered orally regardless of food and no clinically relevant drug-drug interactions have been reported.
Anti-PD1 and anti-PD-L1 agents may have intrinsic and clinically relevant differences in the treatment of non-small cell lung cancer (NSCLC) patients. By reviewing currently available indirect ...evidence on these agents for NSCLC treatment, highlighting possible inter- and intra-class dissimilarities, anti-PD1 agents showed a higher response rate and a better outcome when combined with chemotherapy for the first-line treatment of patients with squamous and PD-L1 low advanced NSCLC, as compared to anti-PD-L1 agents. Conversely, anti-PD-L1 agents were responsible for less severe adverse events (AEs), particularly, immunerelated AEs. These differences could be explained by their different specific properties. Considering possible differences between anti-PD1 and anti-PD-L1 agents could be clinically relevant for treatment tailoring and inspiring new investigational approaches.
Background
It is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and ...IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLC patients.
Methods
Patients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision
®
V3.0 platform.
Results
Thirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached
p
= 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (
p
= 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached,
p
= 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well.
Conclusions
A combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.
Abstract Background The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration-resistant prostate cancer (CRPC). Due to limitations of the methods ...available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice. Objective To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA. Design, setting, and participants Plasma samples were collected from 36 CRPC patients before they began second-line hormonal treatment. Exosomes were isolated and RNA extracted for analysis of AR-V7 by ddPCR. Outcome measurements and statistical analysis The absolute target gene concentration as copies per milliliter (copies/ml) was determined by ddPCR. Statistical analyses were performed with SPSS software (IBM Corp., Armonk, NY, USA). Results and limitations A total of 26 patients received abiraterone and 10 enzalutamide; 39% of patients were found to be AR-V7 positive (AR-V7+ ). Median progression-free survival was significantly longer in AR-V7 negative (AR-V7− ) versus AR-V7+ patients (20 vs 3 mo; p < 0.001). Overall survival was significantly shorter in AR-V7+ participants at baseline compared with AR-V7− participants (8 mo vs not reached; p < 0.001). Conclusions This study demonstrates that plasma-derived exosomal RNA is a reliable source of AR-V7 that can be detected sensitively by ddPCR assay. We also showed that resistance to hormonal therapy may be predicted by AR-V7, making it a clinically relevant biomarker. Patient summary We report a first study on a method for androgen receptor splice variant 7 (AR-V7) detection in RNA extracted from cancer cell vesicles released in blood. Results confirmed the role of AR-V7 as a predictive biomarker of resistance to hormonal therapy. Our assay showed that vesicles are a reliable source of AR-V7 RNA and that the method is fast, highly sensitive, and affordable.
Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant ...predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.
Aims
Low‐grade myofibroblastic sarcoma (LGMS) is a rarely metastasizing myofibroblastic tumour mostly affecting extremities and the head and neck of adults. Histologically, it shows long infiltrative ...fascicles of spindle cells with moderate nuclear atypia. By immunohistochemistry, it stains positive for smooth muscle actin (SMA) and sometimes for desmin. To date, no recurrent genetic abnormalities have been described. Ubiquitin‐specific peptidase 6 (USP6) gene rearrangement is typically found in some benign bone and soft‐tissue tumours including nodular fasciitis (NF), among others. Nevertheless, rare cases of USP6‐rearranged tumours resembling NF with atypical features have been reported.
Methods and Results
One index case of LGMS of the deltoid in a 56‐year‐old man presented the THBS2::USP6 translocation by RNA sequencing (Archer FusionPlex Sarcoma v2 panel). Further screening of 11 cases of LGMS using fluorescent in situ hybridization (FISH) analysis with a USP6 break‐apart probe identified two additional cases. These cases were investigated with RNA‐sequencing, and a RRBP1::USP6 translocation was detected in one. The other case was not assessable because of low‐quality RNA. Noteworthy, rearranged LGMSs presented distinctive features including variable multinodular/plexiform architecture, prominent vasculature with occasional wall thickening, scattered osteoclast‐like multinucleated giant cells, and peripheral lymphoid aggregates.
Conclusion
Our findings support the notion that among soft‐tissue neoplasms with fibroblastic/myofibroblastic phenotype, USP6 rearrangement is not limited to benign tumours, and warrants further investigation of genetic changes in myofibroblastic sarcomas.
We present the clinicopathologic and immunohistochemical features of three cases of myofibroblastic sarcoma harbouring a USP6 gene rearrangement. These cases showed distinctive histologic features in comparison with other myofibroblastic sarcomas, including variable multinodular/plexiform architecture, prominent vasculature with occasional wall thickening, scattered osteoclast‐like multinucleated giant cells, and peripheral lymphoid aggregates.
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