Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These ...alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.
Purpose
Combining CDK4/6 inhibitors and endocrine therapy (ET) improved outcomes for the treatment of metastatic HR+/HER2− breast cancers. Here, we performed a meta-analysis of randomized clinical ...trials (RCTs) to better define the benefit and the risk of CDK4/6 inhibitors plus ET for endocrine-sensitive or endocrine-resistant population in metastatic HR+/HER2− breast cancer.
Method
A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 June 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS), as well as odds ratios (ORs) for objective response rates, ≥ G3–G4 adverse events (AEs), and G3–G4 neutropenia were calculated for each trial. A meta-analysis was carried out using the random-effects model.
Results
Eight RCTs were eligible including 4578 breast cancer patients. Adding CDK4/6 inhibitors to ET in endocrine-sensitive (HR 0.55, 95% CI 0.50–0.62) or endocrine-resistant setting (HR 0.51, 95% CI 0.43–0.61) significantly improved the PFS of metastatic HR+/HER2− breast cancers regardless of menopausal status and site of metastasis. Moreover, CDK4/6 inhibitors plus ET meaningfully improved objective response rate in endocrine-sensitive (ORs 0.62, 95% CI 0.52–0.73) or endocrine-resistant setting (ORs 0.33, 95% CI 0.24–0.47). The use of these drugs was characterized by a significant increase of G3–G4 AEs (OR 10.88, 95% CI 6.53–18.14).
Conclusion
Emerging data provide a new standard treatment for advanced HR+/HER2− breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs.
The novel coronavirus disease 2019 (COVID-19) shows a wide spectrum of clinical presentations, severity, and fatality rates. The reason older patients and males show increased risk of severe disease ...and death remains uncertain. Sex hormones, such as estradiol, progesterone, and testosterone, might be implicated in the age-dependent and sex-specific severity of COVID-19. High testosterone levels could upregulate transmembrane serine protease 2 (TMPRSS2), facilitating the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells via angiotensin-converting enzyme 2 (ACE2). Data from patients with prostate cancer treated with androgen-deprivation therapy seem to confirm this hypothesis. Clinical studies on TMPRSS2 inhibitors, such as camostat, nafamostat, and bromhexine, are ongoing. Antiandrogens, such as bicalutamide and enzalutamide, are also under investigation. Conversely, other studies suggest that the immune modulating properties of androgens could protect from the unfavorable cytokine storm, and that low testosterone levels might be associated with a worse prognosis in patients with COVID-19. Some evidence also supports the notion that estrogens and progesterone might exert a protective effect on females, through direct antiviral activity or immune-mediated mechanisms, thus explaining the higher COVID-19 severity in post-menopausal women. In this perspective, we discuss the available evidence on sex hormones and hormone therapy in patients infected with SARS-CoV-2, and we highlight the possible implications for cancer patients, who can receive hormonal therapies during their treatment plans.
Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal ...disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.
The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) ...is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient’s risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers.
The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone ...acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177–PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN).
Nonmetastatic castration-resistant prostate cancer (nmCRPC) represents a condition in which patients with prostate cancer show biochemical progression during treatment with androgen-deprivation ...therapy (ADT) without signs of radiographic progression according to conventional imaging. The SPARTAN, ARAMIS and PROSPER trials showed that apalutamide, darolutamide and enzalutamide, respectively, prolong metastasis-free survival (MFS) and overall survival (OS) of nmCRPC patients with a short PSA doubling time, and these antiandrogens have been recently introduced in clinical practice as a new standard of care. No direct comparison of these three agents has been conducted to support treatment choice. In addition, a significant proportion of nmCRPC on conventional imaging is classified as metastatic with new imaging modalities such as the prostate-specific membrane antigen positron emission tomography (PSMA-PET). Some experts posit that these "new metastatic" patients should be treated as mCRPC, resizing the impact of nmCRPC trials, whereas other authors suggest that they should be treated as nmCRPC patients, based on the design of pivotal trials. This review discusses the most convincing evidence regarding the use of novel antiandrogens in patients with nmCRPC and the implications of novel imaging techniques for treatment selection.
Background:
In recent years, new therapeutic combinations based on immunotherapy provided significant benefits as a first-line treatment for patients with advanced renal cell carcinoma (mRCC).
...Objective:
This work aims to address the lack of head-to-head comparisons and the uncertainty of the benefit from immunotherapy-based combinations in all the International Metastatic RCC Database Consortium (IMDC) subgroups.
Design, setting, and participants:
A systematic review and a network meta-analysis were performed. Overall survival (OS) in the intention-to-treat (ITT) population was the primary endpoint. OS according to IMDC subgroups (favorable, intermediate, poor), PD-L1 expression, and grade ⩾3 adverse events (AEs) were secondary endpoints. A SUCRA analysis was performed.
Results and limitations:
Six randomized phase III trials with 5121 patients were included. There was a high likelihood (82%) that nivolumab-cabozantinib was the preferred treatment in OS. The benefit of ICI-based combinations over sunitinib was unclear in the favorable-risk subgroup. Nivolumab-ipilimumab had the best risk/benefit ratio among all the ICI-based combinations. The limitations were the lack of individual patient data; the heterogeneity of patients’ characteristics, trial designs, and follow-up times; and a limited number of studies for indirect comparisons.
Conclusions:
A customized approach for the first-line treatment of patients with mRCC should consider the risk/benefit profile of each treatment option, especially considering the likeliness of long-term survival finally reached in this setting.
Abstract
Emerging evidence highlights the potential prognostic relevance of circulating lipids in metastatic castration-resistant prostate cancer (mCRPC), with a proposed 3-lipid signature. This ...study aims to analyze the lipidomic profiles of individuals with mCRPC to identify lipid species that could serve as predictive indicators of prognosis and therapeutic response. Plasma samples were collected from mCRPC patients initiating first-line treatment (1 L) (n = 29) and those previously treated with at least two lines of therapy (> 2 L) (n = 19), including an androgen-receptor signaling inhibitor and a taxane. Employing an untargeted lipidomic approach, lipids were extracted from the plasma samples and subjected to analysis. A comprehensive identification and quantification of 789 plasma lipids was achieved. Notably, 75 species displayed significant dysregulation in > 2 L patients in comparison to the 1 L group. Among these, 63 species exhibited elevated levels, while 12 were reduced. Patients included in > 2 L cohort showed elevated levels of acylcarnitines (CAR), diacylglycerols (DG), phosphatidylethanolamines (PE), triacylglycerols (TG), and ceramides (Cer). Notably, some upregulated lipids, including CAR 14:0, CAR 24:1, Cer d18:1/16:0, Cer d18:1/18:0 (C18 Cer), Cer d18:2/18:0, Cer d18:1/24:1, and Cer d20:1/24:1, showed significant associations with overall survival (OS) in univariate models. Specifically, increased levels of C18 Cer remained significantly associated with poorer OS in the multivariate model, even after adjusting for treatment line and PSA levels (Hazard Ratio: 3.59 95% Confidence Interval 1.51–8.52, p = 0.004). Employing quantitative mass spectrometry, our findings underscore the independent prognostic significance of C18 Cer in individuals with mCRPC. This discovery opens avenues for further studies within this field.
The COVID-19 outbreak rapidly became a public health emergency affecting particularly the frail category as cancer patients. This led oncologists to radical changes in patient management, facing the ...unprecedent issue whether treatments in oncology could be postponed without compromising their efficacy.
To discuss legal implications in oncology practice during the COVID-19 pandemic.
Treatment delay is not always feasible in oncology where the timing often plays a key role and may impact significantly in prognosis. During the COVID-19 pandemic, the oncologists were found between the anvil and the hammer, on the one hand the need to treat cancer patients aiming to improve clinical benefits, and on the other hand the goal to reduce the risk of COVID-19 infection avoiding or delaying immunosuppressive treatments and hospital exposure. Therefore, two rising scenarios with possible implications in both criminal and civil law are emerging. Firstly, oncologists may be "accused" of having delayed or omitted the diagnosis and/or treatments with consequent worsening of patients' outcome. Secondly, oncologists can be blamed for having exposed patients to hospital environment considered at risk for COVID-19 transmission.
During the COVID-19 pandemic, clinical decision making should be well-balanced through a careful examination between clinical performance status, age, comorbidities, aim of the treatment, and the potential risk of COVID-19 infection in order to avoid the risk of suboptimal cancer care with potential legal repercussion. Moreover, all cases should be discussed in the oncology team or in the tumor board in order to share the best strategy to adopt case by case.
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