Neratinib as adjuvant therapy in patients with HER2 positive breast cancer: expert opinion.

Neratinib is a tyrosine kinase receptor inhibitor used in the extended adjuvant therapy of early-stage breast cancer. After adjuvant trastuzumab therapy, neratinib reduces the risk of recurrence and, if taken within 1 year from trastuzumab, significantly improves the invasive disease-free survival of patients with early-stage human epidermal growth factor receptor-2 positive (HER2+) breast cancer with no increased risk of long-term toxicity. Diarrhea, the most common adverse event associated with neratinib use, deters some clinicians from prescribing this drug. However, neratinib-related toxicity is predictable, short-lived, mostly limited to the first month of treatment and can be managed with dose-escalation and prophylactic strategies. Thus, close surveillance and prompt management, relying on supportive care and administration schedule modification, allows discontinuation of treatment to be avoided.

Epigenetics: An opportunity to shape innate and adaptive immune responses.

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage-specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as 'trained immunity'. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.

Targeting Autophagy in Breast Cancer.

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

Correction to: The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis.

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The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis.

OBJECTIVE: To study the role of recombinant human LH supplementation in women with hypo-response to ovarian stimulation. METHODS: We performed a systematic review and meta-analysis of prospective clinical trials in which recombinant FSH monotherapy protocols were compared with LH-supplemented protocols in hypo-responders. A search was conducted of the Scopus, MEDLINE databases without time or language restrictions. Primary outcome was clinical pregnancy rate. RESULTS: Significantly higher clinical pregnancy rates (odds ratio: 2.03, P = 0.003), implantation rates (odds ratio: 2.62, P = 0.004) and number of oocytes retrieved (weight mean differences: 1.98, P = 0.03) were observed in hypo-responders supplemented with recombinant LH versus hypo-responders who underwent FSH monotherapy. No differences in terms of mature oocytes or miscarriage rates were found between the two groups. CONCLUSION: In conclusion, our analysis confirms that women with a hypo-response to exogenous gonadotropins might benefit from LH supplementation. However, more trials are required before a definitive conclusion can be drawn.

Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. METHODS: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. RESULTS: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, "significant nausea," and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). CONCLUSIONS: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

An Overview of the Roles of CDK4/6 Inhibitors in Metastatic Breast Cancer Elderly Patients.

Breast cancer is the most common type of cancer in women worldwide. Many studies indicate that breast cancer increases in elderly patients (≥70 years) and suggest that the higher cancer mortality in this population relative to that observed in younger women could be related to organ dysfunction, an advanced and delayed diagnosis, and other morbidities. Endocrine therapy (ET) represents the favorite treatment for patients affected by hormone receptor positive (HR+) metastatic breast cancer (MBC). Unfortunately, half of these patients are resistant to ET. In recent years, new therapeutic options, such as orally highly selective inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6), have been widely investigated in patients suffering from MBC with good outcomes. They are able to bypass resistance from hormonal therapy, by restoring hormone sensitivity and by delaying chemotherapeutic agent use. Thus, CDK4/6 inhibitors, combined with hormonal therapy, represent an alternative treatment for MBC. Unfortunately, the elderly population with MBC remains mostly excluded from clinical trials. Moreover, few data on the efficacy, safety, and short and longterm outcomes of therapies based on the combined treatment of ET and CDK4/6 inhibitors are available. This narrative review highlights the use of CDK 4/6 inhibitor-based therapy for MBC in elderly patients and suggests new therapeutic perspectives.

Effects on quality of life of weekly docetaxel-based chemotherapy in patients with locally advanced or metastatic breast cancer: results of a single-centre randomized phase 3 trial.

BACKGROUND: To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. METHODS: Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. RESULTS: From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. CONCLUSIONS: In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00540800.

Identification and Relative Quantification of hFSH Glycoforms in Women's Sera via MS-PRM-Based Approach.

Follicle-stimulating hormone (FSH) is a glycohormone synthesized by adenohypophysis, and it stimulates ovulation in women and spermatogenesis in men by binding to its receptor (FSHR). FSHR is involved in several mechanisms to transduce intracellular signals in response to the FSH stimulus. Exogenous FSH is currently used in the clinic for ovarian hyperstimulation during in vitro fertilization in women, and for treatment of infertility caused by gonadotropin deficiency in men. The glycosylation of FSH strongly affects the binding affinity to its receptor, hence significantly influencing the biological activity of the hormone. Therefore, the accurate measurement and characterization of serum hFSH glycoforms will contribute to elucidating the complex mechanism of action by which different glycoforms elicit distinct biological activity. Nowadays ELISA is the official method with which to monitor serum hFSH, but the test is unable to distinguish between the different FSH glycovariants and is therefore unsuitable to study the biological activity of this hormone. This study presents a preliminary alternative strategy for identifying and quantifying serum hFSH glycoforms based on immunopurification assay and mass spectrometry (MS), and parallel reaction monitoring (PRM) analysis. In this study, we provide an MS-PRM data acquisition method for hFSH glycopeptides identification with high specificity and their quantification by extracting the chromatographic traces of selected fragments of glycopeptides. Once set up for all its features, the proposed method could be transferred to the clinic to improve fertility treatments and follow-ups in men and women.

Sperm Oxidative Stress during In Vitro Manipulation and Its Effects on Sperm Function and Embryo Development.

Reactive oxygen species (ROS) generated at low levels during mitochondrial respiration have key roles in several signaling pathways. Oxidative stress (OS) arises when the generation of ROS exceeds the cell's antioxidant scavenging ability and leads to cell damage. Physiological ROS production in spermatozoa regulates essential functional characteristics such as motility, capacitation, acrosome reaction, hyperactivation, and sperm-oocyte fusion. OS can have detrimental effects on sperm function through lipid peroxidation, protein damage, and DNA strand breakage, which can eventually affect the fertility of an individual. Substantial evidence in the literature indicates that spermatozoa experiencing OS during in vitro manipulation procedures in human- and animal-assisted reproduction are increasingly associated with iatrogenic ROS production and eventual impairment of sperm function. Although a direct association between sperm OS and human assisted reproductive techniques (ART) outcomes after in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) is still a matter of debate, studies in animal models provide enough evidence on the adverse effects of sperm OS in vitro and defective fertilization and embryo development. This review summarized the literature on sperm OS in vitro, its effects on functional ability and embryo development, and the approaches that have been proposed to reduce iatrogenic sperm damage and altered embryonic development.

Distinct effects of epirubicin, cisplatin and cyclophosphamide on ovarian somatic cells of prepuberal ovaries.

In vitro culture models were used to characterize the effects of chemotherapeutic drugs and of LH on somatic cells from prepuberal mouse ovaries. All cell types (pre- and granulosa cells, pre-thecal and OSE cells) underwent apoptosis following Epirubicin (0.5µM) exposure for 24hrs (about 60%) and 48hrs (>80%). Cisplatin (10µM) and the Cyclophosphamide active metabolite, Phosphoramide Mustard (10µM), didn't cause apoptosis in 90% of pre-thecal and pre-granulosa cells up to 72hrs of exposure, although they suffered extensive DNA damage and cell cycle arrest, and acquired stress induced premature senescence (SIPS) features. Cultured granulosa cells didn't show evident DNA damage and remained viable without acquiring SIPS features; OSE cells were resistant to apoptosis and SIPS but not to DNA damage. These latter, like pre-thecal and pre-granulosa cells, were able of efficient DNA repair involving MLH1-dependent MMR pathways. SIPS features were also observed in ovary after in vivo treatment with Cisplatin. LH (200mIU/mL) didn't significantly influence apoptosis, SIPS and DNA damage but favoured DNA repair. These results show that somatic cells of prepuberal ovary response to drugs in different ways, either undergoing apoptosis or SIPS, either showing resistance to Cisplatin and Phosphoramide Mustard. Moreover, a new role of LH in promoting DNA repair was shown.

Correction: LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse.

Following publication of their article, the authors reported that the name of the fifth author had been formatted incorrectly in PubMed. Instead of "Rella FD" it should be "Di Rella F".

Metabolism and Autoimmune Responses: The microRNA Connection.

Distinct metabolic pathways are known to regulate growth, differentiation, survival, and activation of immune cells by providing energy and specific biosynthetic precursors. Compelling experimental evidence demonstrates that effector T cell functions are coupled with profound changes in cellular metabolism. Importantly, the effector T cell-dependent "anti-self" response characterizing the autoimmune diseases is accompanied by significant metabolic alterations. MicroRNAs (miRNAs), evolutionary conserved small non-coding RNA molecules that affect gene expression by binding to target messenger RNAs, are now known to regulate multiple functions of effector T cells, including the strength of their activation, thus contributing to immune homeostasis. In this review, we will examine the most recent studies that describe miRNA direct involvement in the metabolic reprogramming that marks effector T cell functions. In particular, we will focus on the work showing a connection between miRNA regulatory function and the molecular network dysregulation that leads to metabolic pathway derangement in autoimmunity. Finally, we will also speculate on the possibility that the interplay between miRNAs and metabolism in T cells may help identify novel miRNA-based therapeutic strategies to treat effector T cell immunometabolic alterations in pathological conditions such as autoimmunity and chronic inflammation.

Pharmacogenetics of FSH Action in the Female.

The purpose of a pharmacogenomic approach is to tailor treatment on the basis of an individual human genotype. This strategy is becoming increasingly common in medicine, and important results have been obtained in oncologic and antimicrobial therapies. The rapid technological developments and availability of innovative methodologies have revealed the existence of numerous genotypes that can influence the action of medications and give rise to the idea that a true "individualized" approach could become in the future a reality in clinical practice. Moreover, compared to the past, genotype analyses are now more easily available at accessible cost. Concerning human reproduction, there is ample evidence that several variants of gonadotropins and their receptors influence female reproductive health and ovarian response to exogenous gonadotropins. In more detail, variants in genes of follicle-stimulating hormone ß-chain (FSH-B) and its receptor (FSH-R) seem to be the most promising candidates for a pharmacogenomic approach to controlled ovarian stimulation in assisted reproductive technologies. In the present review, we summarize the evidence regarding FSH-B and FSH-R variants, with special reference to their impact on reproductive health and assisted reproductive technology treatments.

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin.

POSEIDON groups 1 and 2 patients respond poorly (<4 oocytes retrieved) or sub-optimally (4-9 oocytes retrieved) to gonadotropin stimulation despite the presence of adequate ovarian parameters, which negatively affect their cumulative chances of delivering a baby using Assisted Reproductive Technology. A polygenic trait involving gonadotropins and/or their receptors seems to be the primary pathophysiology mechanism explaining this phenomenon. The clinical management is mainly focused on maximizing oocyte yield as to increase the likelihood of having at least one euploid embryo for transfer. Indices such as FORT (follicle output rate) and FOI (follicle-to-oocyte index) may be used to determine if the ovarian reserve was properly explored during a previous ovarian stimulation. Testing for the presence of common polymorphisms affecting gonadotropins and/or their receptors can also be considered to identify patients at risk of hypo-response. An individualized estimation of the minimum number of oocytes needed to obtain at least one euploid embryo can assist counseling and treatment planning. Among currently existing pharmacological interventions, use of recombinant FSH in preference over urinary gonadotropin preparations, FSH dosage increase, and use of rLH supplementation may be considered -alone or combined- for optimally managing POSEIDON's groups 1 and 2 patients. However, given the recent introduction of the POSEIDON criteria, there is still a lack of studies examining the role of interventions specifically to patients classified as groups 1 and 2, thus making it an area for open research.

Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation.

The discovery of the transcription factor Forkhead box-p3 (Foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of T regulatory (Treg) cells, a cell population with a key immunoregulatory role. Work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of Foxp3 in Treg cells. The equilibrium between phenotypic plasticity and stability of Treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate Foxp3 expression. Recent reports have suggested that specific modifications of DNA and histones are required for the establishment of the chromatin structure in conventional CD4+ T (Tconv) cells for their future differentiation into the Treg cell lineage. In this review, we discuss the molecular events that control Foxp3 gene expression and address the associated alterations observed in human diseases. Also, we explore how Foxp3 influences the gene expression programs in Treg cells and how unique properties of Treg cell subsets are defined by other transcription factors.

Type 2 Diabetes: How Much of an Autoimmune Disease?

Type 2 diabetes (T2D) is characterized by a progressive status of chronic, low-grade inflammation (LGI) that accompanies the whole trajectory of the disease, from its inception to complication development. Accumulating evidence is disclosing a long list of possible "triggers" of inflammatory responses, many of which are promoted by unhealthy lifestyle choices and advanced age. Diabetic patients show an altered number and function of immune cells, of both innate and acquired immunity. Reactive autoantibodies against islet antigens can be detected in a subpopulation of patients, while emerging data are also suggesting an altered function of specific T lymphocyte populations, including T regulatory (Treg) cells. These observations led to the hypothesis that part of the inflammatory response mounting in T2D is attributable to an autoimmune phenomenon. Here, we review recent data supporting this framework, with a specific focus on both tissue resident and circulating Treg populations. We also propose that selective interception (or expansion) of T cell subsets could be an alternative avenue to dampen inappropriate inflammatory responses without compromising immune responses.

Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial.

AIM: The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours. PATIENTS AND METHODS: In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. RESULTS: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. CONCLUSION: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022).

Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial.

Within an ongoing multicentre phase 3 randomised trial (ELDA, cancertrials.gov ID: NCT00331097), early breast cancer patients, 65-79 years old, with average to high risk of recurrence, are randomly assigned to receive CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15), every 4 weeks. Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose. Before such change, 101 patients with a median age of 70 were randomly assigned CMF (53 patients) or docetaxel (48 patients). At least one grades 3-4 toxic event of any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel, respectively (p=0.0002). Grades 3-4 hematological events were observed in 37 (69.8%) vs. 4 (8.3%) cases (p<0.0001) and grades 3-4 non-hematological toxicity in 12 (22.6%) vs. 15 (31.2%) patients (p=0.11), with CMF and docetaxel, respectively. A higher incidence of anemia, neutropenia, thrombocytopenia and febrile neutropenia was reported with CMF. Constipation, mucositis, nausea and vomiting were more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver toxicity were more frequent with docetaxel. No significant interaction was found between the occurrence of severe toxicity and baseline variables, including creatinine clearance and geriatric activity scales. In conclusion, weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity.