The role of epithelial-to-mesenchymal plasticity in ovarian cancer progression and therapy resistance

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance

The addition of bevacizumab to standard chemotherapy in breast cancer : which patient benefits the most?

Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor, is an effective and well-tolerated treatment option for patients with breast cancer. Bevacizumab has demonstrated a gain in progression-free survival and a trend towards an overall survival benefit in various subgroups of breast cancer. Given the lack of a predictive biomarker, we performed a literature search with regard to efficacy and tolerability of bevacizumab in different subgroups of breast cancer patients and in different settings. In the metastatic setting, the efficacy of bevacizumab has been most extensively studied and demonstrated in patients with triple-negative breast cancer, the most difficult-to-treat population among patients with advanced disease and also the group with the biggest need for new treatment options. Overall, bevacizumab is well tolerated with very few serious adverse events. Bevacizumab is also an active and feasible treatment option for patients above 70 years of age

The nocebo effect and tobacco control : first, do no harm?

Since tobacco remains a leading cause of global morbidity and mortality, emphasis needs to be given to preventive approaches to tobacco consumption. Environmental and policy strategies with fear appeals are important contributors to reductions in smoking prevalence. Fear appeals are persuasive messages-often using graphic and emotionally evocative imagery and language-that attempt to scare their audiences into tobacco cessation. While the intentions of fear appeals are benign, their effects are not necessarily so; here, we argue that some fear appeals carry a significant risk of backfiring by eliciting nocebo effects among its viewers. In this context, it is important to recognize that there is currently no justification for disregarding potential nocebo effects. Therefore, we should improve our understanding of nocebo effects in the field of preventive medicine, as well as the impact of strategies aimed at mitigating their negative health effects

Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study

Seguretat; Càncer d'ovariSeguridad; Cáncer de ovarioSafety; Ovarian cancerPURPOSE Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population

Heterogeneous response of chemotherapy-related cognitive decline in patients with breast cancer : a prospective study

Objective: A significant proportion of adjuvant-treated breast cancer patients experience cognitive decline, challenging the person's ability to return to normal activities after treatment. However, not every patient experiences cognitive problems, and even in patients with impairments, determining clinically important cognitive decline remains challenging. Our objective was to explore differences in neuropsychological performance following adjuvant chemotherapy (CT) in patients with breast cancer. Method: We conducted a prospective observational study in an Oncology Breast Clinic and assessed neuropsychological performance before and after adjuvant CT and in non-CT-treated women with breast cancer and healthy controls (HCs). Standardised between-group differences and regression-based change scores were calculated. Results: CT-treated patients (n= 66) performed significantly different from non-CT-treated patients (n= 39) and HCs (n= 56). There was a significant effect on verbal fluency (p= .0013). CT performed significantly worse than non-CT and HC [effect size (ES) = .89,p< .001 and ES = .61,p <= .001, respectively] and from HCs with regard to proactive interference (ES = .62,p <= .001). Regression-based scores revealed more severe cognitive decline in the CT-treated group [24.24% (16/66)] than in the non-CT-treated group [15.20% (6/39)] and HC group [7.14% (4/56)]. Patients who underwent CT and showed cognitive decline were less educated and older, with significantly lower baseline scores. Conclusions: CT-treated patients showed more vulnerability on cognitive control and monitoring than non-CT-treated breast cancer patients and HCs. Older patients with less education and lower baseline cognitive performance represent a group at risk for cognitive decline following CT. Identification of patients at risk for decline could improve targeted support and rehabilitation

Treatment algorithm in patients with ovarian cancer

Most ovarian cancer patients are diagnosed only at advanced stages when survival outcomes are worse, and when therapeutic decisions might prove challenging. The fundamental treatment for women with ovarian cancer includes debulking surgery whenever possible and appropriate systemic therapy (chemotherapy, targeted and antiangiogenic agents). In the last few years, knowledge about histological and molecular characteristics of ovarian cancer subtypes and stages has increased considerably. This has enabled the development and improvement of several options for the diagnosis and treatment of ovarian cancer in a patient-tailored approach. Accordingly, therapeutic decisions are guided by the characteristics of the patient and the tumour, especially the molecular features of the cancer subtype and disease stage. Particularly relevant are the advances in early genetic testing of germline and somatic mutations involved in DNA repair, and the clinical development of targeted agents. In order to implement the best individual medical strategies, in this article, we present an algorithm of treatment options, including recently developed targeted agents, for primary and recurrent ovarian cancer patients in Belgium

Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer

Purpose The subcutaneous (SC) administration of trastuzumab is highly preferred by patients. At home, administration of trastuzumab SC might further improve patient benefit. The aims of the BELIS study are to evaluate the safety and tolerability of trastuzumab SC when administered at home by a healthcare professional (HCP) and to evaluate patient-reported outcomes for treatment experience of at home cancer therapy. Methods This open-label phase IIIb study enrolled HER2-positive early breast cancer patients in Belgium and Israel who completed the first six cycles of trastuzumab IV (neo)adjuvant therapy. The study consisted of three consecutive treatment periods: three cycles of trastuzumab IV and SC each at the hospital and six cycles of trastuzumab SC at home. Results Between November 2013 and December 2014, 23 centres enrolled 102 patients in the intent-to-treat population of which 101 patients entered the safety population. No new safety signals were detected with as expected, more mild administration site events with trastuzumab SC when compared to IV treatment. All patients agreed that they had benefit from at home administration to a large (18/81; 22%) or very large (63/81; 78%) extent. All HCPs (21/21) agreed that SC is the quickest method from start of preparation to finish of administration and that less resource use is needed. Conclusion The results of the BELIS study support that trastuzumab SC can be safely administered at home by a HCP and all patients considered this setting as beneficial. HCPs consider the SC formulation as the quickest method to administer trastuzumab

Adipose tissue in breast cancer : not an idle bystander but an active participant in breast cancer progression

Background: Adipose tissue is a dynamic organ that secretes a plethora of molecules called adipokines. In breast cancer we find a unique situation were genetically changed cells (the cancer cells) are in close contact with adipocytes. Moreover, obesity is a known negative prognostic marker for postmenopausal breast cancer patients. We hypothesize that adipocyte-derived factors influence breast cancer progression. Materials and methods: Adipose tissue was collected from breast cancer patients undergoing a mastectomy. After macroscopic removal of blood vessels and connective tissue, the adipose tissue was carefully cut into 2-3mm3 pieces and were incubated in specific adipose-tissue culture medium. After 24h, the medium was collected and the quality was checked by determining the concentration of total proteins, leptin, adiponectin, TNFalpha and triglycerides. This conditioned medium of adipose tissue (CM AT) was used for in vitro experimentation with MCF-7 breast cancer cells. Results: Effect of AT on morphology and aggregation: when MCF-7 cells are grown in a culture flask, they tend to form round compact islands. Under influence of CM AT, the islands form sharp edges, the cells in an island can be counted individually and they show scattering. Importantly, despite the major changes in cellular morphology, CM AT removal rescued the compact island formation of MCF-7 cells. In the slow aggregation assay, cells treated with CM AT (and a subtherapeutic concentration of a neutralizing E-cadherin antibody) lost the ability to form compact aggregates. Furthermore, MCF-7 spheroids placed inside adipose tissue showed massive reorganization into an irregularly shaped mass. Effect of AT on proliferation: starting from an equal number of cells and counting them every 2 days, it became clear that MCF-7 cells with CM AT had a higher rate of proliferation than MCF-7 cells in control medium. This stimulation of proliferation was confirmed by cell cycle analysis which revealed a doubling of cells in the G2/M phase, and western blot which showed an upregulation of cyclin A and cyclin E, both positive regulators of the cell cycle. Effect of AT on invasion: a 24h collagen type I invasion assay revealed invasive characteristics of MCF-7 cells treated with CM AT while MCF-7 cells in control conditions are round and non-invasive. In contrast, a transwell collagen test over 14 days was not able to show MCF-7 cells invading the collagen gel under influence of CM AT. However, the growth pattern of MCF-7 cells on the collagen gel was clearly disorganised when compared with the control situation. Conclusion: These findings suggest that adipose tissue-derived factors exert a dramatic selective force on patterning, invasion and growth of MCF-7 breast cancer cells. Unraveling the mechanism behind these observations may provide vital information regarding the link between obesity and poor prognosis in postmenopausal breast cancer