Highlights • Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. • The AR and PI3K/Akt/mTOR ...signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. • Germline mutations in DNA repair genes (BRCA2, BRCA1, MSH2, HOXB13) have been related to an increased risk of developing PCa. • The PI3K/Akt pathway is the second most commonly genomic aberration hyperactivated in advanced PCa, after AR alterations.
Highlights • We examine the recent findings on the mechanisms of drug resistance in bladder cancer. • We report the methods employed in the assessment of these markers. • We highlight the potential ...strategies to overcome such resistance.
Background
Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are ...available regarding the efficacy of cabozantinib following immunotherapy.
Objective
To describe the outcome of cabozantinib in patients previously treated with immunotherapy.
Patients and methods
Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.
Results
Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (
p
< 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3–14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up.
Conclusions
Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.
In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint ...inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this setting. The complement system (CS) plays a central role in promoting the growth and progression of mRCC. In particular, mRCC has been defined as an "aggressive complement tumor", which encompasses a group of malignancies with poor prognosie and highly expressed complement components. Several preclinical and retrospective studies have demonstrated the negative prognostic role of the complement in mRCC; however, there is little evidence on its possible role as a predictor of the response to ICIs. The purpose of this review is to explore more deeply the physio-pathological role of the complement in the development of RCC and its possible future use in clinical practice as a prognostic and predictive factor.
Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical ...trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the usefulness of immunotherapy due to the activation of several escape mechanisms. Indeed, the tumor microenvironment has an almost full immunosuppressive profile, creating an obstacle to therapeutic treatment. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) governs a plethora of cellular processes, including maintenance of genomic stability, cell survival/apoptosis, migration, and metabolism. The repertoire of PTEN functions has recently been expanded to include regulation of the tumor microenvironment and immune system, leading to a drastic reevaluation of the canonical paradigm of PTEN action with new potential implications for immunotherapy-based approaches. Understanding the implication of PTEN in cancer immunoediting and immune evasion is crucial to develop new cancer intervention strategies. Recent evidence has shown a double context-dependent role of PTEN in anticancer immunity. Here we summarize the current knowledge of PTEN’s role at a crossroads between tumor and immune compartments, highlighting the most recent findings that are likely to change future clinical practice.
We investigated the frequency of detection and the prognostic and predictive significance of circulating tumor cells (CTCs) in patients with recurrent/metastatic (R/M) head and neck carcinoma (HNC) ...before starting systemic therapy.
Using the CellSearch technology, CTCs were assessed prospectively in peripheral blood of 53 R/M-HNC patients. We performed spiking experiments to test the diagnostic performance of the CellSearch platform in identifying squamous carcinoma cells.
CTCs were identified in 14 (26%) and 22 (41%) patients at baseline and at any time point, respectively. In univariate analysis ≥2 CTCs had a poorer prognostic role than 0-1 CTC. In multivariate analysis, the presence of one CTC or more was associated with a poor prognosis both in terms of progression-free survival (PFS) Hazard Ratio (HR): 3.068, 95% confidence interval (CI): 1.53-6.13, p 0.002 and overall survival (OS) HR: 3.0, 95% CI: 1.48-6.0, p 0.002. A disease control after systemic therapy was obtained in 8% of CTC-positive patients as opposed to 45% in CTC-negative ones (p 0.03). The epidermal growth factor receptor (EGFR) expression was identified in 45% of CTC-positive patients.
In conclusion, CTCs are detected in one out of three patients with RM-HNC. CTC detection is a strong prognostic parameter and may be predictive of treatment efficacy. The frequency of EGFR expression in CTCs seems to be lower than that expected in the primary tumor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To the Editor:
Sweeney et al. (Aug. 20 issue)
1
report a marked survival advantage with concomitant docetaxel and androgen-deprivation therapy (ADT), as compared with ADT alone, in patients with ...hormone-sensitive metastatic prostate cancer. However, it would be interesting to compare the experimental group with the subgroup of the control group that received subsequent docetaxel after the development of castration resistance to clarify the effect of timing on patient outcomes. In addition, the survival benefit was more pronounced in high-risk patients, with an extraordinary hazard ratio of 0.61. This underlines the need for more accurate models integrating data on disease volume . . .
Highlights • Prostate cancer is an androgen-dependent tumor, relying on the androgen receptor (AR). • Translational research focuses on the identification of biomarkers predictive of treatment ...response. • Recent advances highlighted the role of androgen receptor splice variants (AR-Vs), mainly AR-V7, as potential prognostic and predictive biomarkers. • ARv-V7 seems to be a prognostic marker of aggressive cancer behavior, being associated with shorter survival in CRPC patients. • AR-V7 seems to be involved in limiting the efficacy of androgen deprivation therapies, in mediating resistance to enzalutamide and abiraterone, and in influencing the prostate cancer sensibility to anti-microtubules chemotherapeutics.
The therapeutic sc"enario of metastatic renal cell cancer (mRCC) has noticeably increased, ranging from the most studied molecular target therapies to those most recently introduced, up to immune ...checkpoint inhibitors (ICIs). The most recent clinical trials with an ICI-based combination of molecular targeted agents and ICI show how, by restoring an efficient immune response against cancer cells and by establishing an immunological memory, it is possible to obtain not only a better radiological response but also a longer progression-free and overall survival. However, the role of tyrosine kinase inhibitors (TKIs) remains of fundamental importance, especially in patients who, for clinical characteristics, tumor burden and comorbidity, could have greater benefit from the use of TKIs in monotherapy rather than in combination with other therapies. However, to use these novel options in the best possible way, knowledge is required not only of the data from the large clinical trials but also of the biological mechanisms, molecular pathways, immunological mechanisms, and methodological issues related to both new response criteria and endpoints. In this complex scenario, we review the latest results of the latest clinical trials and provide guidance for overcoming the barriers to decision-making to offer a practical approach to the management of mRCC in daily clinical practice. Moreover, based on recent literature, we discuss the most innovative combination strategies that would allow us to achieve the best clinical therapeutic results.
Cancer-related pain, usually associated with bone metastases, is a frequent and debilitating morbidity in patients with prostate cancer. To date there are only limited data regarding the prognostic ...role of pain in men with metastatic castration-sensitive prostate cancer (mCSPC). The objective of our analysis was to assess if the presence of pain can be considered an independent prognostic factor in mCSPC patients.
A retrospective analysis was performed on patients with mCSPC referring to six oncology centers in Italy. Clinical and pathological features were recorded. Patients were considered to have pain if this was reported within the patient's file or in case of a chronic analgesic therapy was found among the concomitant medications. Survivals were estimated by the Kaplan-Meier method, and compared across groups using the log-rank test. Cox proportional hazard models, stratified according to the baseline characteristics, were used to estimate hazard ratios for overall survival (OS). All the variables were significant if p < 0.05.
Data about pain were available for 365 cases and pain was present in 34.8% of patients. Pain was mainly associated with high value of prostate-specific antigen, metastatic bone extension regardless of the site, and lymph node involvement. mCSPC patients with pain had in most of the cases high-volume or Hr disease, and significant shorter OS (27.0 vs. 58.2 months, p < 0.001) and PFS (10.1 vs. 17.4 months, p < 0.001) compared to those without pain. The negative impact of pain on OS remained significant even if adjusted for CHAARTED or LATITUDE classification, and other significant baseline prognostic factors.
This analysis supports the poor prognostic role of cancer-related pain in the setting of mCSPC patients. A prospective validation is required.
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