Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: Protocol detailing observations in a whole of population cohort

Background: The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2- targeted therapies in Australia. Methods/design: Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2- targeted therapies to undertake this research. Ethics and dissemination: Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these treatments

Treatment switching in cancer trials: Issues and proposals

Objectives: Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs. Methods: Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement. Results: Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges. Conclusions: The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders

Trastuzumab and metastatic breast cancer: Trastuzumab use in Australia - Monitoring the effect of an expensive medicine access program

Purpose: Data from clinical trials are used for drug registration; however, many cancer medicines are ultimately used off-label. This study examines the extent to which the clinical practice use of trastuzumab for the treatment of metastatic breast cancer differs from its use under trial conditions. Methods: This study involved all women (N = 1,469) with metastatic breast cancer who received trastuzumab in Australia between December 2001 and March 2005. Given that Australia operates a universal health care system, administrative databases could be examined to determine the duration of therapy, rate of off-label use, compliance with cardiac monitoring, and the extent of drug wastage (volume and cost). Results: A total of 433 enrollees (29.5%) received trastuzumab as monotherapy and 1,036 enrollees (70.5%) received the drug in combination with chemotherapy. A total of 321 women (22%) received off-label trastuzumab. The median duration of trastuzumab therapy was longer than that on trial: 5.6 v 3.1 months for enrollees receiving monotherapy and 12.5 v 6.9 months for concomitant chemotherapy. Only 47 (3%) of enrollees received cardiac monitoring before and during trastuzumab therapy. We estimated 24% of trastuzumab dispensed was discarded, at a cost of $21.1 million Australian. Alternative administration schedules and the addition of another vial size potentially reduce wastage to 6% of volume dispensed. Conclusion: Debates about the use of expensive cancer medicines should consider postmarketing assessments as well as trial experience. The longer duration of trastuzumab use in clinical practice and the high rates of off-label use provide incentive for new clinical trials. Strategies to improve cardiac monitoring and to minimize drug wastage are issues that require immediate attention

Association of ten gastrointestinal and other medical conditions with positivity to faecal occult blood testing in routine screening:a large prospective study of women in England

Background: In 2006, the Bowel Cancer Screening Programme (BCSP) in England began offering biennial faecal occult blood testing (FOBt) at ages 60-69 years. Although FOBt is aimed at detecting colorectal neoplasms, other conditions can affect the result. In a large UK prospective study, we examined associations, both before and after screening, between FOBt-positivity and 10 conditions that are often associated with gastrointestinal bleeding. Methods: By electronically linking BCSP and Million Women Study records, we identified 604,495 women without prior colorectal cancer who participated in their first routine FOBt screening between 2006 and 2012. Regression models, using linked national hospital admission records, yielded adjusted relative risks (RRs) in FOBt-positive versus FOBt-negative women for colorectal cancer, adenoma, diverticular disease, inflammatory bowel disease, haemorrhoids, upper gastrointestinal cancer, oesophagitis, peptic ulcer, anaemia and other haematological disorders. Findings: RRs in FOBt-positive versus FOBt-negative women were 201.3 for colorectal cancer and 197.9 for adenoma within 12 months after screening and 3.5 and 4.9, respectively, 12-24 months after screening; pand#60;0.001 for all RRs. Within 12 months after screening, the RR for inflammatory bowel disease was 26.3, and ranged from 2 to 5 for upper gastrointestinal or haematological disorders. The RRs of being diagnosed with any of the 8 conditions other than colorectal neoplasms before screening and in the 12-24 months after screening, were 1.81 and 1.92, respectively. Conclusions: While fOBt-positivity is associated with a substantially increased risk of colorectal neoplasms after screening, eight other gastrointestinal and haematological conditions are associated with FOBt-positivity, both before and after screening

Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression

© 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc. Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A > G and c.-7C > T) within the MLH1 5â²untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expr ession and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A > G and c.-7C > T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5â²UTR in the pathogenesis of Lynch syndrome.Link_to_subscribed_fulltex

Identification of 5 novel genes methylated in breast and other epithelial cancers

<p>Abstract</p> <p>Background</p> <p>There are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer.</p> <p>Results</p> <p>Using this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; <it>EMILIN2, SALL1</it>, <it>DBC1</it>, <it>FBLN2 </it>and <it>CIDE-A</it>. Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of <it>EMILIN2 </it>was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers.</p> <p>Conclusion</p> <p>The combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy.</p