Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives

Triple-negative breast cancer (TNBC) accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Despite an increasing understanding of the molecular heterogeneity of TNBC, clinical trials of targeted agents have thus far been disappointing; chemotherapy, in particular with anthracycline and taxanes, remains the backbone medical management for both early and metastatic TNBC. Nab-paclitaxel is a solvent-free, albumin-bound, nanoparticle formulation of paclitaxel and represents a novel formulation of an established, effective chemotherapeutic agent. Nab-paclitaxel has been specifically designed to overcome the limitations of conventional taxane formulations, including the barriers to effective drug delivery of highly lipophilic agents. It has shown significant efficacy and better tolerability than conventional taxanes in metastatic breast cancer and is approved for use in this setting. Increasing evidence suggests that nab-paclitaxel is effective in patients with more aggressive tumours, as seen in TNBC. Indeed, results of Phase II/III studies indicate that nab-paclitaxel may be effective as neoadjuvant treatment of TNBC. This article reviews the rationale and evidence supporting a role for nab-paclitaxel in the treatment of TNBC, including ongoing studies such as ADAPT-TN and tnAcity. In addition, the article reviews ongoing research into targeted therapies and immuno-oncology for the treatment of TNBC, and explores the potential role, current evidence and ongoing studies of nab-paclitaxel as the chemotherapy partner in combination with immunotherapy, where the unique properties of this taxane, including the lack of requirement for steroid pre-medication, may present an advantage

Reply to “Association of Serum Uric Acid Concentration With Metabolic Risk Factors in Patients With Type 2 Diabetes”

In our subsample of diabetic patients, serum UA was associated with other features of the metabolic syndrome and with signs of target organ damage in a similar way to that observed in the whole population of elderly, mostly obese, Neapolitan patients. However, on the basis of the different actions of UA described in the literature, it is theoretically conceivable that in select cases, as in the lean, male diabetics observed by Yanai and Hirowatari, UA might exert a protective role

Improving the Management of Breast Cancer

The clinical scenario for both early-stage breast cancer (EBC) and advanced breast cancer (ABC) is complex, multifaced and rapidly evolving. Overall, this work aimed at providing evidence to improve the management of EBC and ABC by: 1. Identifying or validating novel biomarkers predictive of response to treatments and novel pharmacological targets; 2. Improving treatment algorithms for hormone receptor positive/HER2-negative (HR+/HER2-neg.) ABC. With respect to the first objective, the focus was put on breast cancer molecular subtypes and the validation of their use in neoadjuvant setting in HER2-positive (+) tumors, so to predict pCR and support escalated or de-escalated therapeutic approaches. Furthermore, following the discovery of the efficacy of novel anti-HER2-directed ADC in HER2-neg. tumors presenting some level of expression of HER2 (i.e. HER2-low tumors), the first extensive molecular and clinicopathological characterization of this potentially novel subgroup of breast tumors was conducted. Finally, the mTOR inhibitor everolimus, in combination with exemestane is approved for pretreated HR+/HER2-neg. ABC. However, a number of very effective therapeutic alternatives has emerged during the last few years and the identification of biomarkers of response would be particularly useful to identify patients that might benefit most from this drug. With respect to the second aim, the focus was put on improving current treatment algorithms for advanced luminal tumors, due to the discrepancy observed between main international guidelines' recommendations and "real world" clinical practice. The studies conducted had the objective to provide a comprehensive assessment of the efficacy of current therapeutic options and novel pooled evidence to support current treatment guidelines and help clinician's with their therapeutic choices. All the thesis objectives were addressed in 5 different studies, now published in different peer-reviewed international journals. Overall, the articles that are part of this thesis provided evidence to: 1. Support the use of the PAM50 HER2-Enriched molecular subtype, if not in the clinical practice, at least in future clinical trials to assess neoadjuvant escalated or de-escalated therapeutic approaches in HER2+ tumors, irrespective of HR status; 2. Further explore circulating endothelial cells, neutrophil-to-lymphocyte ratio and lymphocytes subpopulations as biomarkers of response to select optimal candidates to everolimus in HR+ breast cancer patients; 3. Support main international treatment guidelines in recommending endocrine therapy + target therapy as the preferred 1st/2nd-line treatment of HR+/HER2-neg. postmenopausal metastatic breast tumors, especially CDK4/6-inhibitors-based regimens; 4. Support the use of CDK4/6-inhibitors-based regimens instead of single agent endocrine therapy, independently from age, menopausal status, endocrine sensitiveness and visceral involvement. Finally, we dissected for the first time the clinicopathological and molecular characteristics of HER2-low breast tumors and find out that this category do not show the features of an independent breast cancer subtype. However, the detection of HER2 low protein levels as well as the assessment of ERBB2 mRNA levels, might play an important role from a therapeutic perspective in the near future. Moreover, HR+/HER2-low showed distinct features from triple negative (TNBC)/HER2-low and HER2 0, as well as from HR+/HER2 0 tumors, while TNBC/HER2-low did not show substantial differences with TNBC/HER2 0

Health monitoring of electromechanical flight actuators via position-tracking predictive models

This article deals with the development and performance characterisation of model-based health monitoring algorithms for the detection of faults in an electromechanical actuator for unmanned aerial system flight controls. Two real-time executable position-tracking algorithms, based on predictors with different levels of complexity, are developed and compared in terms of false alarm rejection and fault detection capabilities, using a high-fidelity model of the actuator in which different types of faults are injected. The algorithms' performances are evaluated by simulating flight manoeuvres with the actuator in normal operation as well as with relevant faults (motor coil faults, motor magnet degradation, voltage supply decrease). The results demonstrate that an accurate position-tracking monitor allows to obtain a prompt fault detection and fail-safe mode engagement, while more detailed monitoring functions can be used for fault isolation only

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

Luminal-like HER2-negative stage IA breast cancer: A multicenter retrospective study on long-term outcome with propensity score analysis

The benefit of adding chemotherapy (CT) to adjuvant hormone therapy (HT) in stage IA luminal-like HER2-negative breast cancer (BC) is unclear. We retrospectively evaluated predictive factors and clinical outcome of 1,222 patients from 4 oncologic centers. Three hundred and eighty patients received CT and HT (CT-cohort) and 842 received HT alone (HT-cohort). Disease-free survival (DFS) and overall survival (OS) were evaluated with univariate and multivariate analyses. We also applied the propensity score methodology. Compared with the HT-cohort, patients in the CT-cohort were more likely to be younger, have larger tumors of a higher histological grade that were Ki67-positive, and lower estrogen and progesterone receptor expression. At univariate analysis, a higher histological grade and Ki67 were significantly associated to a lower DFS. At multivariable analysis, only histological grade was predictive of DFS. The CT-cohort had a worse outcome than the HT-cohort in terms of DFS and OS, but differences disappeared when matched according to propensity score. In summary, patients with stage IA luminal-like BC had an excellent prognosis, however relapse and mortality were higher in the CT-cohort than in the HT-cohort. Longer use of adjuvant HT or other therapeutic strategies may be needed to improve outcome

Demographic, tumor and clinical features of clinical trials versus clinical practice patients with HER2-positive early breast cancer: results of a prospective study

Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC

Clinical implications of the intrinsic molecular subtypes in hormone receptor-positive and HER2-negative metastatic breast cancer

Traditionally, the classification of breast cancer relies on the expression of immunohistochemical (IHC) biomarkers readily available in clinical practice. Using highly standardized and reproducible assays across patient cohorts, intrinsic molecular subtypes of breast cancer - also called 'intrinsic subtypes' (IS) - have been identified based on the expression of 50 genes. Although IHC-based subgroups and IS moderately correlate to each other, they are not superimposable. In fact, non-luminal biology has been detected in a substantial proportion (5-20%) of hormone receptor-positive (HoR+) tumors, has prognostic value, and identifies reduced and increased sensitivity to endocrine therapy and chemotherapy, respectively. During tumor progression, a shift toward a non-luminal estrogen-independent and more aggressive phenotype has been demonstrated. Intrinsic genomic instability and cell plasticity, alone or combined with external constraints deriving from treatment selective pressure or interplay with the tumor microenvironment, may represent the determinants of such biological diversity between primary and metastatic disease, and during metastatic tumor evolution. In this review, we describe the distribution and the clinical behavior of IS as the disease progresses, focusing on HoR+/HER2-negative advanced breast cancer. In addition, we provide an overview of the ongoing clinical trials aiming to validate the predictive and prognostic value of IS towards their incorporation into routine care

Combined effect of obesity and diabetes on early breast cancer outcome: A prospective observational study

Background: Previous studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients. Materials and Methods: Overall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi-square test and survival data by the log-rank test. Results: At diagnosis, obese and diabetic patients were more likely to be older (p < 0.0001) and post-menopausal (p < 0.0001) and to have a tumor larger than 2 cm (p < 0.0001) than patients in groups 1–3. At univariate analyses, obese and diabetic patients had a worse disease-free survival (p = 0.01) and overall survival (p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for diseasefree survival (hazard ratio=2.62, 95% CI 1.23–5.60) but not for overall survival. Conclusions: At diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cance