Would the combination of everolimus with endocrine-therapy help in FGFR2 positive serous endometrial cancer?

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Circulating tumor cells correlate with patterns of recurrence in patients with hormone-sensitive prostate cancer

The aim of this study was to evaluate the correlation between circulating tumor cells (CTCs) and patterns of recurrence in patients with hormone-sensitive prostate cancer. The study involved patients with histologically confirmed, advanced prostatic adenocarcinoma, who were tested for CTCs (Veridex\uae) when they developed recurrence after radical prostatectomy or external beam radiation between 2008 and 2014. Forty-two prostate cancer patients were evaluated. CTCs were detected in 14 out of 42 (33.3%) patients (Group A), while the remaining 28 (66.7%) showed undetectable levels of CTCs (Group B). The mean prostate-specific antigen value was higher in Group A in comparison to Group B (6.2 vs 3.3 ng/dL) (P=0.48). Presence of bone metastases alone or along with nodal metastases was more common in Group A (57.1%) in comparison to Group B (25%) (P=0.04). In a univariate analysis, the presence of CTCs at diagnosis correlated with the development of bone recurrence (OR: 4; 95% CI: 1.0\u201315.9; P=0.05). Even if the study enrolled only a small number of patients, the detection of CTCs in the blood appears to correlate with the pattern of progression in patients with hormone-sensitive prostate cancer, suggesting a possible role in anticipating recurrence at the bone in men with higher tumor load. Further prospective studies are warranted in this setting

A Case–Control Study by ddPCR of ALU 260/111 and LINE-1 266/97 Copy Number Ratio in Circulating Cell-Free DNA in Plasma Revealed LINE-1 266/97 as a Potential Biomarker for Early Breast Cancer Detection

Background: In Western countries, breast cancer (BC) is the most common cancer in women. Early detection has a positive impact on survival, quality of life, and public health costs. Mammography screening programs have increased early detection rates, but new approaches to more personalized surveillance could further improve diagnosis. Circulating cell-free DNA (cfDNA) in blood could provide a potential tool for early diagnosis by analyzing cfDNA quantity, circulating tumor DNA mutations, or cfDNA integrity (cfDI). Methods: Plasma was obtained from the blood of 106 breast cancer patients (cases) and 103 healthy women (controls). Digital droplet PCR was used for the determination of ALU 260/111 bp and LINE-1 266/97 bp copy number ratio and cfDI. cfDNA abundance was calculated using copies of the EEF1A2 gene. The accuracy of biomarker discrimination was analyzed with receiver operating characteristic curve (ROC). Sensitivity analyses were performed to account for age as a potential confounder. Results: Cases had significantly lower ALU 260/111 or LINE-1 266/97 copy number ratios (median; ALU 260/111 = 0.08, LINE-1 266/97 = 0.20), compared with control (median; ALU 260/111 = 0.10, LINE-1 266/97 = 0.28) (p < 0.001). ROC analysis showed that copy number ratio discriminated cases from controls (area under the curve, AUC = 0.69, 95% CI: 0.62–0.76 for ALU and 0.80, 95% CI: 0.73–0.86 for LINE-1). ROC from cfDI confirmed the better diagnostic performance of LINE-1 compared with ALU. Conclusions: Analysis of LINE-1 266/97 copy number ratio or cfDI by ddPCR appears to be a useful noninvasive test that could aid in early BC detection. Further studies in a large cohort are needed to validate the biomarker

Determination of plasmatic microRNA levels by ddPCR as peripheral biomarkers for IDH-wild type glioblastomas: a pilot study

BACKGROUND: Glioblastoma (GBM) is the most frequent malignant brain tumour in adults with a dismal prognosis. Peripheral biomarkers may be useful and effective in managing patients affected by GBM. The aim of our study was to analyse the plasmatic levels of three miRNAs as possible GBM-specific biomarkers. We focused on miR-21-5p – an onco-miR overexpressed in blood, tumour tissue and cell cultures derived from patients affected by GBM – miR-23b-3p – overexpressed in GBM, especially under hypoxic conditions – and miR-34a-5p – a tumour suppressor miR downregulated in tumour tissue and serum of patients with GBM. MATERIALS AND METHODS: Eight patients presenting with firstly-diagnosed IDH-wild type GBM and 10 age- and gender-matched healthy volunteers (hV) have been enrolled in the study. Peripheral blood samples were collected at diagnosis and one month after surgery. Total RNA was isolated from plasma by means of miRNeasy Serum/Plasma Kit (Qiagen), according to the manufacturer’s instructions. Digital droplet PCR (ddPCR) was performed for each miRNA according to the QX200 EvaGreen ddPCR protocol. RESULTS: The circulating concentrations of miR-21-5p were in mean 24.00 (28.44) and 72.40 (147.88) copies/L in patients with GBM at diagnosis and one month after surgery (p=0.38), respectively, compared with 98.74 copies/L ( 123.60) quantified in hV (p=0.09; p=0.69). The mean peripheral levels of miR-23b-3p were 0.49 copies/L (0.49) at diagnosis and 3.02 copies/L (6.88) one month after surgery (p=0.32) in patients with GBM, and 2.56 copies/L (5.57) in hV (p=0.31; p=0.88). Analysing plasmatic expression of miR-34a-5p, 1.11 (1.55) and 1.85 copies/L (1.87) were measured on average at diagnosis and one month after surgery in patients with GBM (p=0.41), while 0.73 copies/L (0.85) in hV (p=0.52; p=0.11). CONCLUSIONS: We preliminarily reported higher concentrations of circulating miR-21-5p, miR-23b-3p and miR-34a-5p in plasma of patients affected by IDH-wild type GBM one month after surgery compared to the levels at diagnosis

Apatinib for the treatment of gastric cancer

Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models. AREAS COVERED: Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer. Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cance

Low-Dose Oral Ethinylestradiol With Concomitant Low-Dose Acetylsalicylic Acid for Advanced Castrate-Resistant Prostate Cancer

BACKGROUND: The aim of the present study was to evaluate the activity and tolerability of low-dose oral ethinylestradiol (EE) and luteinizing hormone-releasing hormone analogue with concomitant low-dose acetylsalicylic acid (ASA) as a thromboprophylactic agent for advanced castrate-resistant prostate cancer (CRPC). PATIENTS AND METHODS: The patients received an EE dose of 150 \u3bcg daily (50 \u3bcg 3 times daily) and an ASA dose of 100 mg once daily. The primary endpoint was the prostate-specific antigen response. RESULTS: A total of 32 patients were enrolled. A PSA response was observed in 19 patients (59.3%; 95% confidence interval [CI], 41%-76%). The median progression-free survival was 9.4 months (95% CI, 6.5-14.1 months). The treatment was generally well tolerated and no grade 3-4 toxicity was observed. Only 1 patient interrupted EE because of a cardiac event and 1 patient experienced grade 2 nausea and vomiting. No major bleeding occurred. CONCLUSION: Low-dose EE with concomitant low-dose ASA is safe, showing potential activity in patients with advanced CRPC, and should be investigated furthe

Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts

A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanconi anemia, homologous recombination, base excision repair, mismatch repair and translesion repair pathways and the methylation patterns of some of these genes. We also investigated the correlation with the response to platinum-based therapy. The mRNA levels of the selected genes were evaluated by Real Time-PCR (RT-PCR) with ad hoc validated primers and gene promoter methylation by pyrosequencing. All the DNA repair genes were variably expressed in all 42 PDX samples analyzed, with no particular histotype-specific pattern of expression. In high-grade serous/endometrioid PDXs, the CDK12 mRNA expression levels positively correlated with the expression of TP53BP1, PALB2, XPF and POLB. High-grade serous/endometrioid PDXs with TP53 mutations had significantly higher levels of POLQ, FANCD2, RAD51 and POLB than high-grade TP53 wild type PDXs. The mRNA levels of CDK12, PALB2 and XPF inversely associated with the in vivo DDP antitumor activity; higher CDK12 mRNA levels were associated with a higher recurrence rate in ovarian patients with low residual tumor. These data support the important role of CDK12 in the response to a platinum based therapy in ovarian patients

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5\u2009ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with 65 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P\u2009<\u20090.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p\u2009<\u20090.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P\u2009<\u20090.0001), HER2-positive (36.7 months vs. 20.4 months, P\u2009<\u20090.0001), and triple negative (23.8 months vs. 9.0 months, P\u2009<\u20090.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials

Human Herpesvirus-8 Infection Leads to Expansion of the Preimmune/Natural Effector B Cell Compartment

BACKGROUND: Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS) and of some lymphoproliferative disorders of B cells. Most malignancies develop after long-lasting viral dormancy, and a preventing role for both humoral and cellular immune control is suggested by the high frequency of these pathologies in immunosuppressed patients. B cells, macrophages and dendritic cells of peripheral lymphoid organs and blood represent the major reservoir of HHV-8. Due to the dual role of B cells in HHV-8 infection, both as virus reservoir and as agents of humoral immune control, we analyzed the subset distribution and the functional state of peripheral blood B cells in HHV-8-infected individuals with and without cKS. METHODOLOGY/PRINCIPAL FINDINGS: Circulating B cells and their subsets were analyzed by 6-color flow cytometry in the following groups: 1- patients HHV-8 positive with classic KS (cKS) (n = 47); 2- subjects HHV-8 positive and cKS negative (HSP) (n = 10); 3- healthy controls, HHV-8 negative and cKS negative (HC) (n = 43). The number of B cells belonging to the preimmune/natural effector compartment, including transitional, pre-naïve, naïve and MZ-like subsets, was significantly higher among HHV-8 positive subjects, with or without cKS, while was comparable to healthy controls in the antigen-experienced T-cell dependent compartment. The increased number of preimmune/natural effector B cells was associated with increased resistance to spontaneous apoptosis, while it did not correlate with HHV-8 viral load. CONCLUSIONS/SIGNIFICANCE: Our results indicate that long-lasting HHV-8 infection promotes an imbalance in peripheral B cell subsets, perturbing the equilibrium between earlier and later steps of maturation and activation processes. This observation may broaden our understanding of the complex interplay between viral and immune factors leading HHV-8-infected individuals to develop HHV-8-associated malignancies

Diagnostic tests based on gene expression profile in breast cancer: from background to clinical use

Breast cancer is a complex disease with heterogeneous presentation and clinical course. The last decade has witnessed the development, commercialization, and increasing use of multigene assays, designed to support physicians and patients in clinical decision making in early-stage breast cancer. These include Oncotype DX\uae, MammaPrint\uae, and Prosigna\u2122 assays. The assays differ in the technological platforms used for assessment of gene expression, in the number of genes and in the specific genes that are being tested, in the patient populations used for their development and validation, and in their clinical utility. This review focuses on these three commercialized assays, their development, validation, and clinical utility. The review also addresses ongoing prospective trials investigating these assays and health-economic considerations relating to their us