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

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Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma

Malignant Mesothelioma (MM) is a rare and aggressive form of tumour that affects the lining of the internal organs for which current treatments have not been proven to be very effective. P16(INK4A) tumour suppressor encoding CDKN2A gene is often downregulated in MM. This protein is a cyclin dependent kinase 4 and 6 inhibitor, that normally phosphorylates RB1, which has to be un-phosphorylated in order to block cell-cycle at G1 in normal cells. Adding CDK inhibitor molecules to MM in pre-clinical studies has been proven to restore the normal function of p16(INK4A), blocking thereby MM cell cycle at G1. Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

5noBACKGROUND: Several randomized phase III trials in neuroendocrine tumors (NETs) showed the clinical role of new targeted agents and their impact on tumor response and outcome of whose patients affected by advanced NET. In this study, we summarize the available clinical data related to clinical efficacy of targeted therapies in the treatment of advanced NETs. METHODS: A meta-analysis of randomized studies in accordance with the PRISMA guidelines was performed after searching the databases of PubMed, the Cochrane Library, and the ASCO University Meeting for relevant publications. RESULTS: One thousand 9 hundred and 8 cases were included in the meta-analysis; among these, 1012 were in the experimental arm and 896 were in the control arm. The pooled analysis of the use of target agents in NETs revealed significantly increased of progression free survival compared to control group (hazard ratio = 0.59, 95% CI:0.42-0.84; P = 0.003). Subgroup analysis of patients according to tumor site showed a difference in favor of pancreatic neuroendocrine tumors. Moreover, targeted therapies improved the overall survival (hazard ratio = 0.79, 95%CI: 0.63-0.98; P = 0.03), and response rate (hazard ratio = 3.33, 95% CI 2.02-5.49; P < 0.00001) in all types of NETs. CONCLUSION: Our analysis supports the routine use of targeted agents for treatment of neuroendocrine tumors with particular regards to the pancreatic neuroendocrine tumorspartially_openembargoed_20171001Roviello, Giandomenico; Zanotti, Laura; Venturini, Sergio; Bottini, Alberto; Generali, DanieleRoviello, Giandomenico; Zanotti, Laura; Venturini, Sergio; Bottini, Alberto; Generali, Daniel

Abemaciclib: A CDK4/6 inhibitor for the treatment of HR+/HEeR2- advanced breast cancer

Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials

Therapeutic resistance and optimal drug sequencing in HER2-positive metastatic breast cancer: unmet needs and future perspectives

In the last couple of decades substantial therapeutic improvements deeply influenced the treatment of HER2-positive metastatic breast cancer. The most impactful advancements were obtained especially in the first-line setting, with the trastuzumab/pertuzumab anti-HER2 double blockade, and in the second line, with the advent of the potent antibody-drug conjugate trastuzumab deruxtecan. Nevertheless, a careful observation of the patterns of early-progression and long-term effects on overall survival of the most novel agents and combinations, highlights the challenges represented by the emergence of therapeutic resistance and optimal drug sequencing. The integration of sequence studies, tumor-related biomarker development/implementation and understanding of primary mechanisms of resistance to novel anti-HER2 agents, will be the way to move forward to effectively tackle these novel unmet needs

Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition

Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15-40% increase in in vitro trastuzumab-mediated ADCC; antibodies blocking the NKG2D receptor significantly reduced this enhancement. NKG2D receptor expression was increased by docetaxel treatment in circulating and splenic NK cells from mice xenografted with tumor cells, an increase related to expansion of the CD11b+Ly6G+ cell population. Accordingly, NK cells derived from HER2+ BC patients after treatment with taxane-containing therapy expressed higher levels of NKG2D receptor than before treatment. Moreover, plasma obtained from these patients recapitulated the modulation of NKG2D on healthy donors' NK cells, improving their trastuzumab-mediated activity in vitro. This enhancement occurred mainly using plasma from patients with low NKG2D basal expression. Our results indicate that taxanes increase tumor susceptibility to ADCC by acting on tumor and NK cells, and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect, especially in patients with low basal immune effector cytotoxic activit

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

Efficacy and safety of T-DM1 in the 'common-practice' of HER2+ advanced breast cancer setting: a multicenter study

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this 'field-practice' study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively.In conclusion, in this 'real-word' study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatini

Influence of Prior Tyrosine Kinase Inhibitor on Survival for Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab or Cabozantinib: Data from a Literature-based Meta-analysis

The aim of this letter is to focus on the survival of patients treated with nivolumab and cabozantinib according to prior first-line TKI. We used data from CheckMate 025 and METEOR for a subsequent subgroup analysi

Current Trends in Liquid Biopsy Tracking Resistance in Molecular Breast Cancer-Targeted Therapies

Breast cancer (BC) is the most commonly occurring type of cancer in women, being a major cancer-related cause of mortality worldwide. With the advancement in current therapeutic options, including hormone therapy and targeted therapies, there is a need for more accurate and less invasive options to monitor cancer progression in patients. Liquid biopsy has evolved rapidly, being able to detect small quantities of nucleic acids or cell-free DNA in the blood of BC patients. This method addresses three major issues of needle biopsy: firstly, it is more permissive by being less invasive and does not require needling the organs; secondly, it covers for the heterogeneous nature of the tumor of origin, which could lead to an otherwise inaccurate representation of the cancer-driving mutations; thirdly, it better represents the type of tumor that the primary tumor is going to evolve into before it starts to metastasize. This current review will address the current advancements in liquid biopsy in the context of BC, highlighting the pros and challenges