The antigenic link between thyroid autoimmunity and breast cancer

The association between breast cancer and benign thyroid disorders, in particular thyroid autoimmunity, has been debated for decades. Autoantibodies to thyroid peroxidase, the hallmark of thyroid autoimmunity, have a higher prevalence among patients with breast cancer compared with the general population. Furthermore a correlation between their positivity and a better prognosis of breast cancer was found in several independent small-scale studies, even if such observation was not confirmed in a subsequent retrospective study conducted on the largest patient cohort to date. The thyroid and mammary glands present several biological similarities, therefore the hypothesis of an immune response to shared thyroid/breast antigens could in part explain the association between thyroid autoimmunity and breast cancer. The sodium iodide symporter is expressed in both glands, however it seems unlikely to be the key common antigen, considering that autoantibodies targeting it are rare. Instead thyroid peroxidase, one of the major thyroid autoantigens, is also expressed in breast tissue and therefore represents the main antigenic link between thyroid autoimmunity and breast cancer. Furthermore lactoperoxidase, an enzyme of the same family that shares structural similarities with thyroid peroxidase, is expressed in neoplastic breast cells and is responsible for the cross-reactivity with some autoantibodies to thyroid peroxidase. Novel strategies for the diagnosis and treatment of breast cancer might take advantage of the antigenic link between thyroid and breast tissues

3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response

The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity

Soluble interleukin-6 receptor mediated fatigue highlights immunological heterogeneity of patients with early breast cancer who undergo radiation therapy

Purpose This study aimed to explore the associations between dose-volume parameters of localized breast irradiation, longitudinal interleukin-6 soluble receptor (sIL-6R), and leukocyte counts as markers of an immune-mediated response and fatigue as a centrally-driven behavior. Methods and Materials This prospective cohort study recruited 100 women who were diagnosed with stage 0-IIIa breast cancer, prescribed 40 Gy in 15 fractions over 3 weeks adjuvant radiation therapy, and had no prior or concurrent chemotherapy. Dose-volume parameters were derived from treatment plans and related to serum sIL-6R concentrations, leukocyte counts, and a validated measure of self-reported fatigue at baseline, after 10 and 15 fractions, and 4 weeks after radiation therapy. Results sIL-6R concertation was significantly higher in patients with a total volume of tissue irradiated within the 50% isodose >2040 cm3 (P = .003). When controlling for body mass index, this result only remained significant after treatment. The volume of liver irradiated within the 10% isodose correlated with the sIL-6R concentration during and after radiation therapy (ρ = .3-.4; P = .03-.007). The 38% of the cohort that was classified as fatigued had a higher mean sIL-6sR concentration at all observation points, but the differences were only statistically significant during radiation therapy: Mean (standard deviation [SD]) after 15 fractions for fatigued patients was 47.6 ng/dL (11.2 SD) versus 41.6 ng/dL (11.4 SD) for nonfatigued patients (P = .01). Cohort leukocyte counts and leukocyte subsets decreased consistently from baseline and the values for the fatigued group were 4% lower at baseline and between 7% and 9% lower during and after treatment compared with those of the nonfatigued group but the differences were not statistically significant. Conclusions This is the first study to show that localized irradiation induces increased systemic sIL-6R during treatment in participants who reported elevated levels of fatigue before, during, and after treatment. This behavioral response appears to reflect a variation in innate host immunity, which then mediates the cellular and/or psychological stress of radiation therapy

PELP-1 regulates adverse responses to endocrine therapy in Estrogen Receptor (ER) positive breast cancer

Introduction: Endocrine therapy has played an important role in the management of ER positive breast cancer over recent decades. Despite this, not all patients respond equally to endocrine intervention, which can lead to resistance, associated disease relapse and progression. Previous reports suggest that endocrine agents themselves may induce an invasive phenotype in ER positive breast cancers with low/aberrant expression of E-cadherin. Here we investigate this phenomenon further and provide data supporting a role for the ER co-receptor, PELP-1, in mediating an adverse response to endocrine agents. Materials and Methods: The effects of tamoxifen, fulvestrant and estrogen withdrawal (as a model for aromatase inhibitor therapy) on the invasive and migratory capacity of endocrine-sensitive MCF-7 and T47D cells, in the presence or absence of functional E-cadherin and/or PELP-1 (using siRNA knockdown), was assessed via Matrigel invasion and Boyden chamber migration assays. The effects of these endocrine therapies alongside E-cadherin/PELP-1 modulation on cell proliferation were further assessed by MTT assay. Western blotting using phospho-specific antibodies was performed to investigate signalling pathway changes associated with endocrine-induced changes in invasion and migration. Results: Both tamoxifen and fulvestrant induced a pro-invasive and pro-migratory phenotype in ER positive breast cancer cells displaying a high basal expression of PELP-1, which was augmented in the context of poor cell-cell contact. This process occurred in a Src-dependent manner with Src inhibition reversing endocrine induced invasion/migration. While this adverse response was observed using both tamoxifen and fulvestrant therapy, it was not observed under conditions of estrogen withdrawal. Conclusions: Our data confirms previous reports that anti-estrogens induce an adverse cell phenotype in ER+ breast cancer, particularly in the absence of homotypic cell contact. These results implicate E-cadherin and PELP-1 as potential biomarkers when deciding upon optimum adjuvant endocrine therapy, whereby tumours with high PELP-1/low E-cadherin expression may benefit from estrogen withdrawal therapy via aromatase inhibition, as opposed to ER modulation/antagonism

Overexpression of specific CD44 isoforms is associated with aggressive cell features in acquired endocrine resistance

While endocrine therapy is the mainstay of ER+ breast cancer, the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance that is associated with disease relapse and poor prognosis. Our previous studies revealed that acquired resistance is accompanied by a gain in cellular invasion and migration and also that CD44 family proteins are overexpressed in the resistant phenotype. Given the association of CD44 with tumor progression, we hypothesized that its overexpression may act to promote the aggressive behavior of endocrine-resistant breast cancers. Here, we have investigated further the role of two specific CD44 isoforms, CD44v3 and CD44v6, in the endocrine-resistant phenotype. Our data revealed that overexpression of CD44v6, but not CD44v3, in endocrine-sensitive MCF-7 cells resulted in a gain in EGFR signaling, enhanced their endogenous invasive capacity, and attenuated their response to endocrine treatment. Suppression of CD44v6 in endocrine-resistant cell models was associated with a reduction in their invasive capacity. Our data suggest that upregulation of CD44v6 in acquired resistant breast cancer may contribute to a gain in the aggressive phenotype of these cells and loss of endocrine response through transactivation of the EGFR pathway. Future therapeutic targeting of CD44v6 may prove to be an effective strategy alongside EGFR-targeted agents in delaying/preventing acquired resistance in breast cancer

QUALZICE: A QUALitative exploration of the experiences of the participants from the ZICE clinical trial (metastatic breast cancer) receiving intravenous or oral bisphosphonates

BACKGROUND: This qualitative sub-study aimed to explore the experiences of participants on the National Cancer Research Institute ZICE clinical trial, a randomised trial assessing two types of bisphosphonate treatment in breast cancer patients with bone metastases. Participants in the clinical trial were randomly allocated to receive either zoledronate, delivered by an intravenous (IV) infusion at clinic, or oral ibandronate, taken at home.METHODS: Qualitative research interviews were conducted with participant groups organised by treatment and location. Interviews covered experiences and understanding of bisphosphonate treatment, the experience of the delivery mechanisms (IV or oral), side effects and benefits, and quality of life issues. The analytic framework was interpretative phenomenological analysis.RESULTS: This paper reports on one of four superordinate themes: participants' experience of the ZICE trial, which explores the participants' experiences with clinical trial-related processes. Results show that participants were generally satisfied with their randomised treatment, although most participants had an initial preference for oral bisphosphonates. Some difficulties were reported from participants for both interventions: needle phobia, poor veins, difficulty with swallowing and gastric side effects, but pain control was improved with both modes of delivery. However, the infused bisphosphonate was reported to lose effectiveness after three weeks for some participants, whereas the oral bisphosphonate was reported to give consistent pain control. Geographical location and distance to travel made little difference to convenience of access to clinic as the reported lengths of travel time were similar due to traffic congestion in the urban areas. Most participants understood the trial processes, such as randomisation, and information about bisphosphonates but some participants showed little understanding of certain aspects of the trial. Some participants reported difficulties in accessing dental treatment due to their dentist's perceptions of bisphosphonate treatment.CONCLUSIONS: In trials of medicinal products, especially when testing for non-inferiority, participants' preferences and idiosyncrasies in relation to treatments should not be assumed. This study has shown that in a trial context, participants' views can usefully add to the main trial outcomes and they should be taken into account when prescribing in the real world.TRIAL REGISTRATION: ISRCTN13914201. Main ZICE MREC: 05/MRE09/57. CRUK E/04/022.</p

Mesenchymal chondrosarcoma of the maxilla

We report, to our knowledge, the 10th recorded case of mesenchymal chondrosarcoma (MC) occurring in the maxilla. Our case is the youngest person reported with a tumour in this location. The prognosis for cure is poor with a high incidence of local recurrence as well as metastases. Treatment is based on radical surgery. Radiotherapy and chemotherapy have a adjuvant role but additional experience with this tumour is required to define the most efficacious treatment

The use of randomisation-based efficacy estimators in non-inferiority trials

Background In a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. However, PP analysis relies on the often implausible assumption of no confounders. Randomisation-based efficacy estimators (RBEEs) allow for treatment non-adherence while maintaining a comparison of randomised groups. Fischer et al. have developed an approach for estimating RBEEs in randomised trials with two active treatments, a common feature of NI trials. The aim of this paper was to demonstrate the use of RBEEs in NI trials using this approach, and to appraise the feasibility of these estimators as the primary analysis in NI trials. Methods Two NI trials were used. One comparing two different dosing regimens for the maintenance of remission in people with ulcerative colitis (CODA), and the other comparing an orally administered treatment to an intravenously administered treatment in preventing skeletal-related events in patients with bone metastases from breast cancer (ZICE). Variables that predicted adherence in each of the trial arms, and were also independent of outcome, were sought in each of the studies. Structural mean models (SMMs) were fitted that conditioned on these variables, and the point estimates and confidence intervals compared to that found in the corresponding ITT and PP analyses. Results In the CODA study, no variables were found that differentially predicted treatment adherence while remaining independent of outcome. The SMM, using standard methodology, moved the point estimate closer to 0 (no difference between arms) compared to the ITT and PP analyses, but the confidence interval was still within the NI margin, indicating that the conclusions drawn would remain the same. In the ZICE study, cognitive functioning as measured by the corresponding domain of the QLQ-C30, and use of chemotherapy at baseline were both differentially associated with adherence while remaining independent of outcome. However, while the SMM again moved the point estimate closer to 0, the confidence interval was wide, overlapping with any NI margin that could be justified. Conclusion Deriving RBEEs in NI trials with two active treatments can provide a randomisation-respecting estimate of treatment efficacy that accounts for treatment adherence, is straightforward to implement, but requires thorough planning during the design stage of the study to ensure that strong baseline predictors of treatment are captured. Extension of the approach to handle nonlinear outcome variables is also required. Trial registration The CODA study: ClinicalTrials.gov, identifier: NCT00708656. Registered on 8 April 2008. The ZICE study trial: ClinicalTrials.gov, identifier: NCT00326820. Registered on 16 May 2006

Modified Needleman-Wunsch algorithm for clinical pathway clustering

Clinical pathways are used to guide clinicians to provide a standardised delivery of care. Because of their standardisation, the aim of clinical pathways is to reduce variation in both care process and patient outcomes. When learning clinical pathways from data through data mining, it is common practice to represent each patient pathway as a string corresponding to their movements through activities. Clustering techniques are popular methods for pathway mining, and therefore this paper focuses on distance metrics applied to string data for k-medoids clustering. The two main aims are to firstly, develop a technique that seamlessly integrates expert information with data and secondly, to develop a string distance metric for the purpose of process data. The overall goal was to allow for more meaningful clustering results to be found by adding context into the string similarity calculation. Eight common distance metrics and their applicability are discussed. These distance metrics prove to give an arbitrary distance, without consideration for context, and each produce different results. As a result, this paper describes the development of a new distance metric, the modified Needleman–Wunsch algorithm, that allows for expert interaction with the calculation by assigning groupings and rankings to activities, which provide context to the strings. This algorithm has been developed in partnership with UK’s National Health Service (NHS) with the focus on a lung cancer pathway, however the handling of the data and algorithm allows for application to any disease type. This method is contained within Sim.Pro.Flow, a publicly available decision support tool