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

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

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

Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: Where we are now and where we are going

AbstractNear 75% of all breast cancers (BC) express estrogen receptors (ER) and/or progesterone receptors (PgR), while up to 20% of BC show an overexpression/amplification of Human Epidermal Growth Factor Receptor 2 (HER2). Around 50% of all HER2-overexpressing BC show the coexistence of both HER2 overexpression/amplification and ER and/or PgR overexpression. Numerous in vitro and in vivo studies suggest the existence of a cross-talk between their downstream pathways, which seem to affect the natural history, response to therapy and outcome of patients affected by this subset of BC. Meta-analyses or subgroup analysis of numerous neo-/adjuvant trials demonstrated significant clinical implications deriving from ER/HER2 co-existence, consisting in a different pattern of relapse and dissimilar outcome in response to anti-HER2 therapy. However, only two randomized trials in early disease and three in advanced disease specifically addressed the issue whether a combined approach with both hormonal and anti-HER2 therapy would have a better therapeutic impact in this subset of BC compared to the lone anti-HER2 or hormonal therapies (HT). None of these trials demonstrated improvements in overall survival, even though several efficacy end-points such as progression free survival, in advanced setting, or pCR rates in neoadjuvant setting, often favored the combined hormonal and anti-HER2 therapeutic approach. In the next few years, a certain number of ongoing randomized trials, both in neoadjuvant and advanced setting, will evaluate the efficacy of new anti-HER2 drugs, T-DM1 and pertuzumab, in combination with HT, helping to improve the therapeutic strategy for this specific subtype of breast tumors

Multiple Bayesian network meta-analyses to establish therapeutic algorithms for metastatic triple negative breast cancer

Immunotherapy; PARP inhibitors; PembrolizumabImmunoteràpia; Inhibidors de PARP; PembrolizumabInmunoterapia; Inhibidores de PARP; PembrolizumabMetastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS)

Anthracyclines Strike Back: Rediscovering Non-Pegylated Liposomal Doxorubicin in Current Therapeutic Scenarios of Breast Cancer

Antraciclines; Càncer de mama; Receptor hormonalAntraciclinas; Cáncer de mama; Receptor hormonalAnthracyclines; Breast cancer; Hormone receptorAnthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.This study was supported by Mednote, spin-off—University of Trieste, within the Mozart Program

Unexpected ovarian activity in premenopausal breast cancer survivors treated with exemestane and GnRH analogues

n/

Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer

Background: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. Methods: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. Results: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. Conclusions: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC