Post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific survival: a nested case-control study in a breast cancer cohort from the UK Clinical Practice Research Datalink

INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients.

METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis).

RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy.

CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.

Human papilloma viruses (HPVs) no co-existence in breast cancer and cervical cells in the same patient

High-risk HPVs were detected in both breast cancer tissues and cervical cells from 56 breast cancer patients. The results suggested that HPV infection did not coexist in breast and cervical tissues. HPV infection of the breast cancer tissue is more likely to happen in patients without cervical infection.

KIF2A silencing inhibits the proliferation and migration of breast cancer cells and correlates with unfavorable prognosis in breast cancer

Background: Kinesin family member 2a (KIF2A), a type of motor protein found in eukaryotic cells, is associated with development and progression of various human cancers. The role of KIF2A during breast cancer tumorigenesis and progression was studied.

Methods: Immunohistochemical staining, real time RT-PCR and western blot were used to examine the expression of KIF2A in cancer tissues and adjacent normal tissues from breast cancer patients. Patients' survival in relation to KIF2A expression was estimated using the Kaplan-Meier survival and multivariate analysis. Breast cancer cell line, MDA-MB-231 was used to study the proliferation, migration and invasion of cells following KIF2A-siRNA transfection.

Results: The expression of KIF2A in cancer tissues was higher than that in normal adjacent tissues from the same patient (P <0.05). KIF2A expression in cancer tissue with lymph node metastasis and HER2 positive cancer were higher than that in cancer tissue without (P <0.05). A negative correlation was found between KIF2A expression levels in breast cancer and the survival time of breast cancer patients (P <0.05). In addition, multivariate analysis indicated that KIF2A was an independent prognostic for outcome in breast cancer (OR: 16.55, 95% CI: 2.216-123.631, P = 0.006). The proliferation, migration and invasion of cancer cells in vitro were suppressed by KIF2A gene silencing (P <0.05).

Conclusions: KIF2A may play an important role in breast cancer progression and is potentially a novel predictive and prognostic marker for breast cancer.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment

This is the protocol for a review and there is no abstract. The objectives are as follows:

The primary objective of this review is to evaluate the effects of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments). Patients who have received treatments such as cranial radiation for central nervous system tumours or metastases are not the focus of this review and will be excluded.

A second objective is to evaluate the effectiveness of non-pharmacological interventions for improving non-cognitive outcomes e.g. quality of life among this population.

Thirdly, we will extract and analyse data regarding the duration of intervention effects.

Fourthly, we will examine each study to identify safety as an outcome and incorporate information on intervention safety where possible. Evidence for the review will be based on data from randomised trials.

The need for qualitative methodologies in cancer cachexia research

Background: Cancer cachexia is not well understood or managed in clinical practice (Delmore 2000; Poole and Froggatt 2002). Whilst a dedicated effort has been made towards understanding the biological processes of the syndrome, little attention has been paid to its multidimensional impact. This is despite previous qualitative research, enriching our understanding of the holistic impact of the syndrome which traditional quantitative methods could not have uncovered (Reid 2007).

Aim: The aim of this study is to determine the adequacy of the existing clinical knowledge base of cancer cachexia management.

Methods: A systematic critical review of the literature on cancer cachexia was undertaken.

Results: There is a need to develop protocols for care delivery, which move beyond a purely biological approach to care towards a more holistic approach. This can only be achieved by gaining the perspectives of those who are involved in care delivery to advanced cancer patients with cachexia and their families using qualitative methodologies.

Conclusions: Cancer cachexia is a complex, challenging syndrome, which must be understood from a holistic bio-psychosocial model of care in order to meet the multidimensional needs of this client population. The perspectives of those involved in care delivery is required in order to contribute to a knowledge base which will inform the development of interventions directed at empowering patients and their families to understand cancer cachexia and recognise it as part of the disease process.

Who accesses complementary therapies and why?: An evaluation of a cancer care service

Introduction

Advances in cancer diagnosis and treatment have resulted in longer survival, meaning patients are living with a chronic-type condition. Therefore the needs of such patients have changed placing greater emphasis on survivorship, such as impact on quality of life and sleep patterns. Evidence suggests complementary therapies positively impact not only on the cancer patient's quality of life but also on family members and friends.

Methodology

This service evaluation examines self-reported benefits following a course of complementary therapy offered by a local cancer charity.

Results

Analysis of self-reported sleep scores and perceived quality of life experiences confirmed a number of trends relating to the demographics of people accessing the complementary therapy service.

Conclusion

Results suggest the complementary therapies provided by Action Cancer significantly improved clients' quality of life. Based on these findings the authors make a number of recommendations in relation to the use of complementary therapies by cancer patients.

The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink

PURPOSE: Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.

METHODS: Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.

RESULTS: Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.

CONCLUSIONS: There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

A role of autophagy in PTP4A3-driven cancer progression

Autophagy, a "self-eating" cellular process, has dual roles in promoting and suppressing tumor growth, depending on cellular context. PTP4A3/PRL-3, a plasma membrane and endosomal phosphatase, promotes multiple oncogenic processes including cell proliferation, invasion, and cancer metastasis. In this study, we demonstrate that PTP4A3 accumulates in autophagosomes upon inhibition of autophagic degradation. Expression of PTP4A3 enhances PIK3C3-BECN1-dependent autophagosome formation and accelerates LC3-I to LC3-II conversion in an ATG5-dependent manner. PTP4A3 overexpression also enhances the degradation of SQSTM1, a key autophagy substrate. These functions of PTP4A3 are dependent on its catalytic activity and prenylation-dependent membrane association. These results suggest that PTP4A3 functions to promote canonical autophagy flux. Unexpectedly, following autophagy activation, PTP4A3 serves as a novel autophagic substrate, thereby establishing a negative feedback-loop that may be required to fine-tune autophagy activity. Functionally, PTP4A3 utilizes the autophagy pathway to promote cell growth, concomitant with the activation of AKT. Clinically, from the largest ovarian cancer data set (GSE 9899, n = 285) available in GEO, high levels of expression of both PTP4A3 and autophagy genes significantly predict poor prognosis of ovarian cancer patients. These studies reveal a critical role of autophagy in PTP4A3-driven cancer progression, suggesting that autophagy could be a potential Achilles heel to block PTP4A3-mediated tumor progression in stratified patients with high expression of both PTP4A3 and autophagy genes.

Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study

Background: Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population based cohort of lung cancer patients.
Methods: Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by statin use before and after diagnosis and to adjust these HRs for potential confounders.
Results: In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR=0.89, 95% CI 0.78, 1.02; P=0.09). Associations were more marked after 12 prescriptions (adjusted HR=0.81, 95% CI 0.67, 0.98; P=0.03) and when lipophilic statins were investigated (adjusted HR=0.81, 95% CI 0.70, 0.94; P=0.01) but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.83, 0.93; P<0.001).
Conclusions: There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality.
 Impact: These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients.

Prognostic significance of minichromosome maintenance proteins in breast cancer

A role for the minichromosome maintenance (MCM) proteins in cancer initiation and progression is slowly emerging. Functioning as a complex to ensure a single chromosomal replication per cell cycle, the six family members have been implicated in several neoplastic disease states, including breast cancer. Our study aim to investigate the prognostic significance of these proteins in breast cancer. We studied the expression of MCMs in various datasets and the associations of the expression with clinicopathological parameters. When considered alone, high level MCM4 overexpression was only weakly associated with shorter survival in the combined breast cancer patient cohort (n = 1441, Hazard Ratio = 1.31; 95% Confidence Interval = 1.11-1.55; p = 0.001). On the other hand, when we studied all six components of the MCM complex, we found that overexpression of all MCMs was strongly associated with shorter survival in the same cohort (n = 1441, Hazard Ratio = 1.75; 95% Confidence Interval = 1.31-2.34; p <0.001), suggesting these MCM proteins may cooperate to promote breast cancer progression. Indeed, their expressions were significantly correlated with each other in these cohorts. In addition, we found that increasing number of overexpressed MCMs was associated with negative ER status as well as treatment response. Together, our findings are reproducible in seven independent breast cancer cohorts, with 1441 patients, and suggest that MCM profiling could potentially be used to predict response to treatment and prognosis in breast cancer patients.

“A quiet still voice that just touches”: music’s relevance for adults living with life-threatening cancer diagnoses.

Purpose
Music has historically aided health and loss-adaptation, however, cancer patients’ experience of music for self-care is not well understood. This study examines adult cancer patients’ views about music’s role before and after diagnosis.
Methods
Constructivist approach, with grounded theory informed design using convenience, snowball and theoretical sampling. Patients from Australian metropolitan cancer and hospice settings completed demographic questionnaires and participated in semi-structured interviews. Qualitative inter-rater reliability was applied.
Results
Fifty-two patients reported comparable time spent experiencing music pre-post diagnosis. Music may remain incidental; however, many patients adapt music usage to ameliorate cancer’s aversive effects. Patients often draw from their musical lives and explore unfamiliar music to: remain connected with pre-illness identities; strengthen capacity for enduring treatment, ongoing survival (even when knowing “you’re going to die”), or facing death; reframe upended worlds; and live enriched lives. Patients can ascribe human or physical properties to music when describing its transformative effects. Familiar lyrics maybe reinterpreted, and patients’ intensified emotional reactions to music can reflect their threatened mortality. Sometimes music becomes inaccessible, elusive, and/or intensifies distress and is avoided. Families’, friends’ and professionals’ recognition of patients’ altered musical lives and music-based suggestions can extend patients’ use of music for self-care.
Conclusion
Health professionals can support patients by inquiring about their music behaviours and recognising that altered music usage may signify vulnerability. Although commonly recommended, hospital concerts and music broadcasts need sensitive delivery. Patients’ preferred music should be available in diagnostic, treatment and palliative settings because it can promote endurance and life enrichment.

Validation of the completeness and accuracy of the Northern Ireland Cancer Registry

Background: It has been suggested that inaccuracies in cancer registries are distorting UK survival statistics. This study compared the Northern Ireland Cancer Registry (NICR) database of living patients, with independent data held by Northern Ireland's General Practitioners (GPs) to compare and validate the recorded diagnoses and dates held by the registry. 

Methods: All 387 GP practice managers were invited to participate. 100 practices (25.84%) responded. Comparisons were made for 17,102 patients, equivalent to 29.08% of the living patients (58,798) extracted from the NICR between 1993 and 2010. 

Results: There were no significant differences (p > 0.05) between the responding and nonresponding GP patient profiles for age, marital status or deprivation score. However, the responding GPs included more female patients (p = 0.02). NICR data accuracy was high, 0.08% of GP cancer patients (n = 15) were not included in registry records and 0.02% (n = 2) had a diagnosis date which varied more than 2 weeks from GP records (3 weeks and 5 months). The NICR had recorded two different tumour types and three different tumour statuses (benign vs. malignant) to the GPs. 

Conclusion: This comparison demonstrates a high level of accuracy within the NICR and that the survival statistics based on this data can be relied upon.

HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF-Mutant Colorectal Cancer by Downregulation of c-FLIPL

Purpose: Activating mutations in the BRAF oncogene are found in 8% to 15% of colorectal cancer patients and have been associated with poor survival. In contrast with BRAF-mutant (MT) melanoma, inhibition of the MAPK pathway is ineffective in the majority of BRAFMT colorectal cancer patients. Therefore, identification of novel therapies for BRAFMT colorectal cancer is urgently needed.

Experimental Design: BRAFMT and wild-type (WT) colorectal cancer models were assessed in vitro and in vivo. Small-molecule inhibitors of MEK1/2, MET, and HDAC were used, overexpression and siRNA approaches were applied, and cell death was assessed by flow cytometry, Western blotting, cell viability, and caspase activity assays.

Results: Increased c-MET-STAT3 signaling was identified as a novel adaptive resistance mechanism to MEK inhibitors (MEKi) in BRAFMT colorectal cancer models in vitro and in vivo. Moreover, MEKi treatment resulted in acute increases in transcription of the endogenous caspase-8 inhibitor c-FLIPL in BRAFMT cells, but not in BRAFWT cells, and inhibition of STAT3 activity abrogated MEKi-induced c-FLIPL expression. In addition, treatment with c-FLIP–specific siRNA or HDAC inhibitors abrogated MEKi-induced upregulation of c-FLIPL expression and resulted in significant increases in MEKi-induced cell death in BRAFMT colorectal cancer cells. Notably, combined HDAC inhibitor/MEKi treatment resulted in dramatically attenuated tumor growth in BRAFMT xenografts.

Conclusions: Our findings indicate that c-MET/STAT3-dependent upregulation of c-FLIPL expression is an important escape mechanism following MEKi treatment in BRAFMT colorectal cancer. Thus, combinations of MEKi with inhibitors of c-MET or c-FLIP (e.g., HDAC inhibitors) could be potential novel treatment strategies for BRAFMT colorectal cancer.

Guidance on the management of diarrhoea during cancer chemotherapy

Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. Previous management guidelines were based on poor evidence and neglect physiological causes of chemotherapy-induced diarrhoea. In the absence of level 1 evidence from randomised controlled trials, we developed practical guidance for clinicians based on a literature review by a multidisciplinary team of clinical oncologists, dietitians, gastroenterologists, medical oncologists, nurses, pharmacist, and a surgeon. Education of patients and their carers about the risks associated with, and management of, chemotherapy-induced diarrhoea is the foundation for optimum treatment of toxic effects. Adequate—and, if necessary, repeated—assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. In view of the burden of chemotherapy-induced diarrhoea, appropriate multidisciplinary research to assess meaningful endpoints is urgently required.

Post-diagnostic oral bisphosphonate use and colorectal cancer mortality: a population-based cohort study within the UK Clinical Practice Research Datalink

Background:We conducted the first study to investigate post-diagnostic oral bisphosphonates use and colorectal cancer-specific mortality.

Methods:Colorectal cancer patients were identified from the National Cancer Data Repository (1998–2007) and linked to the UK Clinical Practice Research Datalink, providing prescription records, and Office of National Statistics mortality data. Time-dependent Cox regression models investigated colorectal cancer-specific mortality in post-diagnostic bisphosphonate users.

Results:Overall, in 4791 colorectal cancer patients, there was no evidence of an association between bisphosphonate use and colorectal cancer-specific mortality (adjusted hazard ratio=1.11; 95% confidence interval 0.80, 1.54) or with drug frequency or type.

Conclusions:In this novel population-based cohort study, post-diagnostic bisphosphonate use was not associated with longer rates of colorectal cancer survival.