Dual drug targeting to kill colon cancers.

INTRODUCTION: Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair-wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. OBJECTIVES: To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. METHODS: The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro-cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. RESULTS: Colon cancer cells in non-adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro-apoptotic Bcl-2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. CONCLUSION: By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro-survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro-survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations.

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial.

INTRODUCTION: Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC. METHODS: Patients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria. RESULTS: 27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to gBRCA status and type of response. CONCLUSIONS: Early-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.

BACKGROUND: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. DISCUSSION: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. CONCLUSIONS: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.

Expression patterns and clinical significance of the potential cancer stem cell markers OCT4 and NANOG in colorectal cancer patients.

Colorectal cancer (CRC) is one of the most important malignancies and causes of cancer-related deaths worldwide. Cancer stem cell markers identification could be helpful to acquire important prognostic information and develop new treatment regimens. This study aimed to evaluate the expression of OCT4 and NANOG in CRC patients and their clinical significance.Totally 359 CRC samples were stained for OCT4 and NANOG expression using tissue microarray. The correlation between their expression and clinical and pathological features was explored.The majority of CRC cases showed low-level expression of OCT4 (80%) and NANOG (75%). Lower expression of OCT4 was more often detected in CRC cases with no vascular involvement (P = .01). Also, a trend found between low level of OCT4 expression and absence of distant metastasis or lymph node involvement (P = .07 and P = .09, respectively). Surprisingly, a significant positive correlation was observed between NANOG expression and cellular differentiation (P = .05). Our combined analysis demonstrated that OCT4 low/NANOG low phenotype has frequently seen in colorectal cancer cases with no vascular invasion (P = .05).Our observations indicated that higher expression of OCT4 and NANOG can confer malignant and aggressive behavior to CRC. Evaluation of the co-expression of these cancer stem cell markers can serve a new diagnostic and prognostic approach in CRC patients. These findings also suggested that simultaneous expression of OCT4 and NANOG can be considered as a therapeutic marker for targeted therapy of CRC, especially in advanced stages.

Immune system and angiogenesis-related potential surrogate biomarkers of response to everolimus-based treatment in hormone receptor-positive breast cancer: an exploratory study.

PURPOSE: mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity. METHODS: We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study. RESULTS: The circulating levels of CD3+/CD8+, CD3+/CD4+, and overall T lymphocytes were higher in responders versus non-responders at baseline (p = 0.017, p < 0.001, p = 0.034) and after treatment (p = 0.01, p = 0.003, p = 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (p < 0.001). Patients with low NLR (≤ 4.4) showed a better progression-free survival compared to patients with high NLR (> 4.4) (p = 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after. CONCLUSIONS: Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.

Association between neutropenia and response to ramucirumab and paclitaxel in patients with metastatic gastric cancer.

The aim of this study was to evaluate if the occurrence of neutropenia is correlated with response to ramucirumab plus paclitaxel for metastatic gastric cancer. This is a retrospective study of patients treated with ramucirumab plus paclitaxel. Fifty-three patients were evaluated. Among these, 10 patients (26.5%) developed grade ≥3 neutropenia. Patients with grade ≥3 neutropenia reported a progression-free survival of 6.6 months (95% confidence interval 3.3-8.4) and overall survival of 11 months (95% confidence interval 5.9-13.1) vs. 4.4 months (95% confidence interval 3.9-5.2) and 8.7 months (95% confidence interval 7.8-10.1) respectively in patients' group with lower grade events. Our analysis seems to suggest that the occurrence of neutropenia predicts response to treatment with ramucirumab and paclitaxel.

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis.

Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.

Corticosteroid switch after progression on abiraterone acetate plus prednisone.

INTRODUCTION: Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone. MATERIALS AND METHODS: The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option. RESULTS: A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223. CONCLUSION: Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone.

Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

BACKGROUND: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. METHODS: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. RESULTS: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36-0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72-0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57-0.74; p < 0.001) in patients with PD-L1 positive tumours. CONCLUSIONS: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

Is there still a place for vinorelbine in advanced metastatic castration resistant prostate cancer?

The aim of this paper was to evaluate the activity and tolerability of oral vinorelbine in patients with advanced castration resistant prostate cancer (CRPC) who progressed after a minimum of three lines including: abiraterone acetate, docetaxel, cabazitaxel, and enzalutamide.Treatment consisted of weekly oral vinorelbine 60 mg/m. Chemotherapy was administered until disease progression or unacceptable toxicity.Twenty-six patients received vinorelbine: their median age was 74 years (range 58-84 years). Twenty-four (92.3%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in 2 patients (7.7%). Among the subjects who were symptomatic at baseline, pain was reduced in 3 patients (13.6%) with a significant decrease in analgesic use. Median progression-free survival was 9 weeks (95% CI: 7 to 11) and median overall survival was 17 weeks (95% CI: 12 to 22). Treatment was well tolerated, and no grade 4 toxicities were observed.Our findings do not suggest the use of oral vinorelbine on a weekly schedule, in CRPC heavily pre-treated.

Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer.

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in recent decades, improving the life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the Cyclin dependent kinase inhibitors family INK4 that specifically inhibit CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years, the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in other BC subtypes. In HER2-positive BC, a combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, the efficacy of CDK4/6 inhibitors has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions for ongoing clinical trials and predictive biomarkers will be further debated.

Influence of Age and the Gleason Score in the Choice of Novel Hormonal Therapies Before and After Chemotherapy.

BACKGROUND: Novel hormonal therapies (NHTs) have enriched the therapeutic armamentarium available for patients with castration-resistant prostate cancer. However, there is a need for clinical indicators able to drive treatment decisions and timing. The aim of this report is to perform a pooled analysis based on all available literature focused on prediction of efficacy and survival in patients treated with NHTs before and postchemotherapy. METHODS: After reviewing the studies included in this work, the efficacy and the survival of NHTs according to age and Gleason score (GS) was focused. RESULTS: A total of eight studies were included in the analysis. With regard to age, the survival hazard ratio shows a better outcome, for both elderly and young patients, in postchemotherapy studies. With regard to progression-free survival, the subgroup analysis of pre- and postchemotherapy studies demonstrates the effect of NHTs on the reduction of risk of progression is greater in prechemotherapy studies irrespective of age. With regard to GS, NHTs show higher efficacy when administered postchemotherapy in patients with GS <8, whereas in patients with GS ≥8 NHTs are more effective in the prechemotherapy setting. CONCLUSION: Given the limitations of a meta-analysis of data from the literature, the results show that progression-free survival is always higher when NHTs are administered prechemotherapy in comparison with postchemotherapy. This benefit, however, translates in a reduction of risk of death only in patients with GS ≥8. In the other patients, the risk of death decreases when NHTs are administered postchemotherapy.

Association between ramucirumab-related hypertension and response to treatment in patients with metastatic gastric cancer.

PURPOSE: Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway, such as ramucirumab. The aim of this study was to retrospectively evaluate if occurrence of HTN is correlated with response to second line treatment with ramucirumab+paclitaxel for metastatic gastric cancer. METHODS: Treatment consisted of ramucirumab 8 mg/kg intravenously (iv) on days 1 and 15, plus paclitaxel 80 mg/m2 iv on days 1, 8, and 15 of a 28-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Thirty-four patients were retrospectively evaluated. Among these, 6 (17.6%) developed grade 3 ramucirumab-induced HTN. These patients had a better outcome than those with lesser grades events, with a progression-free survival (PFS) of 7.8 months (95% CI 4.4-not reached) versus 4.2 months (95% CI 3.1-5.2) (p=0.001). overall survival (OS) was 11.9 months (95% CI 9.3-not reached) in the grade 3 HTN group, versus 7.2 months (95% CI 5.9-10.1). CONCLUSIONS: Despite the small number of patients and the retrospective nature of the data, our analysis showed that occurrence of ramucirumab-related HTN, in particular G3 HTN, predicts response to treatment with ramucirumab+paclitaxel in patients with metastatic gastric cancer.

Lenvatinib for the treatment of renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for 2-3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC. AREAS COVERED: Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma. EXPERT OPINION: Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.

Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- 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.

Benefit of the addition of hormone therapy to neoadjuvant anthracycline-based chemotherapy for breast cancer: comparison of predicted and observed pCR.

INTRODUCTION: Neoadjuvant hormonal therapy is generally considered a valid option for hormone receptor positive breast cancer (BC) patients who are unfit for chemotherapy or surgery. AIMS: Whilst numerous studies analyzed efficacy of neoadjuvant chemotherapy (CT) or endocrine therapy (HT) alone in hormone receptor positive patients, there is a lack of research looking at the usefulness of a preoperative combinatorial approach of CT and HT in this patient subgroup. METHODS: Using a predictive model previously described in the literature, developed to analyze the probability of benefit from preoperative chemotherapy, we were able to compare pathological complete response (pCR) rates expected with the use of CT alone with the pCR rates reported in a population of 192 patients treated with the combination of tamoxifen plus anthracycline-based CT at Cremona Hospital between 2003 and 2006. RESULTS: Even with a relatively small patient population, this approach provided insightful information for the selection of hormone receptor positive BC patients most likely to benefit from the use of preoperative HT and CT in combination. Whilst no statistically significant benefit was obtained with the addition of tamoxifen to neoadjuvant chemotherapy in the entire population, or in any of the molecular stratification subgroups, the analysis of the calibration curve showed that a combinatorial approach may improve pCR in patients with luminal B tumors. More specific trials should be designed to confirm our initial results. CONCLUSION: To the best of our knowledge, this is the first report investigating the efficacy of the combination of CT and HT in the neoadjuvant treatment of hormone receptor positive BC.

Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer.

PURPOSE: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer. PATIENTS AND METHODS: One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization. RESULTS: VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival. CONCLUSION: Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline-based treatment outcome.

Could gonadotropin-releasing hormone analogs be helpful in the treatment of triple-negative breast cancer?

AIM: Treatment of triple-negative breast cancer (TNBC) imposes great challenges, due to a lack of molecular targets. While use of gonadotropin-releasing hormone (GnRH) analogs has been validated in ER-positive breast cancer, this option has not been investigated in TNBC, even though a significant portion of these tumors upregulate GnRH receptors. We performed a meta-analysis of the literature to evaluate the effect of GnRH analogs in TNBC. METHODS: Four studies were included in this study. RESULTS: We detected a non-significant improvement in overall survival with GnRH analogs, while progression-free survival was unchanged. DISCUSSION: The majority of the trials evaluated in this analysis were designed to test efficacy of GnRH analogs in preventing premature ovarian failure. This may represent a limitation of our study as these trials were not specifically designed to detect differences in survival outcome measures. CONCLUSION: Our results suggest that GnRH analogs may be useful as a targeted therapy in TNBC. Randomized prospective clinical trials are needed to investigate this hypothesis in the clinic.

Advances in systemic therapy for malignant mesothelioma: future perspectives.

Malignant mesothelioma is a rare and aggressive form of cancer affecting the mesothelium. This mainly occupational disease is becoming more common in those countries where asbestos has been used for industrial applications. Notwithstanding the progress made in the field, patients do not survive more than 12 months on average with standard treatment. With the advent of next generation sequencing, it is now possible to study the mutational landscape of each tumor with the aim of identifying the genetic aberrations driving tumorigenesis. This review encompasses the latest research in the field, with particular attention to new chemotherapy combinatorial regimens, molecular targets and immunotherapies, providing a comprehensive picture of the current and future treatment options for malignant mesothelioma patients.

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®) 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: 1.0-15.9; 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.