D. J. Kerr

The TERT variant rs2736100 is associated with colorectal cancer risk

Background:Polymorphic variation at the 5p15.33 (TERT–CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined.Methods:We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail.Results:rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10−4). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10−5; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified.Conclusion:The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT–CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk.

Implications of polygenic risk for personalised colorectal cancer screening

BACKGROUND We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.

Variation in the availability of cancer drug generics in the United States of America

While most of the attention and spending in the oncology community in the United States has been focused on the remarkable scientific inventions of the newer targeted drugs, the shortage of the older essential cancer drugs that are off patent, mostly generics and injectables, has a threatening impact on the health of cancer patients, the execution of clinical trials and the identification of newer drugs and thus impacts upon the burden of costs and pressures on the health system in the United States. It is a part of the problem of the scarcity of generics across all medical specialties, but its oncology is particularly vulnerable. The problem in The United States has been increasing since the beginning of the 21st century until the 2011; since then there has been some improvement in 2012 and the first two quarters of 2013. In the second quarter of 2012, there were 211 active shortages, down from 246 reports of active shortages in the same quarter of 2011. The Food and Drug Administration (FDA) officials ascribe the improvement to efforts that the agency made after President Obama issued an executive order in 2012 that impel the FDA to obtain early reports from companies about potential shortages. The drivers of the shortages are multi-factorial. But are largely economic and are due to the lack of incentives to produce generics. There are efforts from the US government, politicians and the medical, pharmacy and oncology communities. However, the problem is still serious. There is a general agreement that efforts so far have not been adequate, and that there is a need for addressing effectively the fundamentals and the underlying causes. There is a lot that could be done in the United States and across the world to improve the accessibility of economically sustainable better value cancer drugs regardless of whether they are brand or generics and aiming at a win-win outcome for all stakeholders.

What is the role and impact of molecular markers on treatment decisions in the adjuvant setting of colorectal cancer

Despite curative surgery for localized disease, approximately 40% of colorectal cancer patients will eventually relapse. In patients with stage III disease, adjuvant chemotherapy has been shown to lead to definite improvements in survival. The situation for those with stage II disease is more uncertain, with up to 80% thought to be cured by surgery alone. Therefore, there exists a need to identify, pre-treatment, those

Cancer in Africa: supporting advocates to stop the runaway train

Until very recently, international health bodies such as the World Health Organisation (WHO) concentrated their efforts on the prevention of contagious disease, while chronic noncontagious conditions such as cancer, cardiovascular disease, diabetes, and respiratory diseases have been side-lined. Yet cancer accounts for almost 13% of all deaths worldwide, more than those caused by human immunodeficiency virus/ acquired immunodeficiency syndrome, tuberculosis, and malaria combined, and the largest mortality burden occurs in lowand middle-income countries (IARC globocan). Even among oncologists, cancer may not be the first disease that comes to mind when thinking about the major causes of morbidity and mortality in Africa. However, it is responsible for over 715 000[1] deaths per year on that continent, and WHO has recently estimated that by 2020 there will be a million new cancer cases a year in sub-Saharan Africa alone [2]. This is a huge social and economic burden in a part of the world that has very little in the way of facilities for cancer patients, let alone the provision of the effective screening and public education programmes that could aid in cancer prevention and control. It would be easy to be pessimistic and say that the parlous political and economic state of so many African nations means that there is little that can be done about this situation. But we only have to look at the stunning success of advocacy campaigns in high-income countries to see that big changes can be brought about via relatively simple means—organised public pressure delivering the right messages to the right people. In some African countries, advocacy campaigns have already been successful in improving cancer health education and hence prevention, and in the provision of hitherto unavailable facilities for cancer patients and their doctors. This is why four organisations—the Africa Oxford Cancer Foundation (AfrOx), the African Organisation for Research and Training in Cancer (AORTIC), the European Society for Medical Oncology (ESMO), and the Union for International Cancer Control (UICC)—have launched a ‘toolkit’ to provide an advocacy roadmap so that many more individuals and organisations can become involved in cancer advocacy in Africa. The Non-Communicable Disease (NCD) Alliance has identified five priority actions to provide an effective response to the preventable morbidity and mortality of NCDs, including cancer [3]. These are leadership, prevention, treatment, international co-operation, and monitoring and accountability. They also call for the delivery of five priority interventions— tobacco control, salt reduction, improved diets and physical activity, a reduction in high levels of alcohol intake, and essential drugs and technologies. These interventions are not just important for their health effects, but they were also chosen because of their cost-effectiveness and low cost of implementation. They are also politically feasible to a large extent in almost every country in the world. If implemented globally, it is estimated that they would reduce NCD death rates by 2% across the world and avoid tens of millions of premature deaths in this decade alone. The WHO has called for just such a reduction [4]. While these five interventions can help with cancer control in the future, it is important to support those already suffering from chronic diseases in countries where healthcare systems are under-resourced. A particular problem of these diseases is that they require care to be given over long periods, often over the whole lifetime of the patient. This requires a completely different organisation, both from the point of view of the healthcare provider and from the patient, than that which is required for acute interventions. Well-organised, effective primary care is essential, but how often is this available in low-income countries? This is where advocacy comes in; in addition to planning and implementing prevention programmes to change risky health behaviours, for example, community action can also appeal for primary healthcare programmes that correspond to the needs of those with chronic diseases. Many of the interventions mentioned in the toolkit are not complicated, expensive, or high-tech. In order to undertake them, all that is needed are motivated people who have done their research in order to get the right message to the right place. For example, some African advocates have worked with the media to bring about changes in national cancer policy, and developed public information campaigns on nutrition or childhood cancers. Yet others have lobbied governments for national cancer registries, or for palliative care programmes—particularly important in countries where early detection is rare and the chances of curative treatment severely restricted. When Kenya was slow to ratify the Framework Convention on Tobacco Control, one of the members of the African Tobacco Control Consortium (ATCC) knew who to talk to in order to get things moving and the convention ratified within days. Following ratification, the next step was to pass legislation, so the ATCC set out to identify those members of parliament (MPs) most likely to vote for it. When they found that the taxation of tobacco was not included in the legislation because it was the responsibility of the Finance Ministry, they prepared an economic case for the introduction of a 10% tobacco tax. ed ito ria l editorial Annals of Oncology 24: 855–856, 2013 doi:10.1093/annonc/mdt062

Better value cancer care for the 21st century

editorial Better value cancer care for the 21st century The last two decades have seen steady improvements in the quality of cancer care. We have embraced multidisciplinary team working, site specialised by focussing expertise on specific cancer subtypes, increased the power, reliability and quality of the clinical trials which underpin our evidence base, and taken this forward into the production of practical management guidelines. The EuroCare studies, published in this Journal [1], have shown a trend of increasing survival, which has been attributed to earlier detection and better treatment. There is wide variation in outcomes when we compare international mortality figures but no clear explanation to account for this disparity, although there have been speculative claims correlating survival with access to new drugs and radiotherapy equipment, or the number of oncologists, or the overall cancer spend [2]. It has been estimated that if we could improve UKs cancer survival figures to those of European leaders, say Sweden, thousands of lives would be saved every year—quite a prize for any health economy. There is no doubt that the challenges facing the cancer community reflect a subset of the major problems that afflict general Health Services in all of Europes nation states:-Unwarranted variation in quality and patient experience-Patient harm even when quality is high-Waste, namely the consumption of resources that do not add value for patients-Inequities and inequalities in care-Inadequate focus on prevention Furthermore, every major European cancer service has to face the additional critical challenges of rising demand and increasing need, which must be met within significant financial constraints. It is clear that these problems cannot be solved solely by further scientific advances or by spending more and more money, even if that were an option. We estimate that the total cancer spend across Europes population of 850 million citizens is of the order of 75 billion Euros. These problems cannot be solved by reorganising the bureaucracy of health care, which usually achieves superficial change rather than transformation. We believe that these challenges can be solved by intelligent and committed clinical leadership which takes account not only of the individual patient whom we review in the clinic but also of the wider population of patients whom we serve within our community. What is needed is revolution, not reorganisation, in the way that people who manage health services think, make decisions and act. In UK, the current Health Reform Bill has two …