Professor Martine Piccart is a past president of the European Organisation for Research and Treatment of Cancer, Chair of the Breast International Group (BIG) and head of medicine at the Jules Bordet cancer hospital in Brussels. She explains that cancer research needs to change so that cancer treatment can become truly personalised.
Personalised medicine is one of the objectives of the European Union’s Horizon 2020 funding programme and a high priority for oncology professionals: indeed, in oncology, many so-called ‘targeted therapies’ are designed to target very specific attributes of cancer and have a high cost, implying that prescribing the wrong treatment to the wrong patient at the wrong time can have very negative consequences for both patients and public health systems.
While personalised medicine (where treatment is adapted to the specific characteristics of each person’s cancer) is the dream of every oncologist and the legitimate expectation of every cancer patient, it can only materialise in the next decade if extensive collaborative research efforts are launched and accompanied by a revolution in the sociology of medical research. The latter implies moving away from small-scale research projects based on specific targets in cancer where data is often kept secret, and entering an era of ‘team science’ using automation equipment and broad data sharing.
There is indeed a huge gap between our rapidly growing knowledge about the complex molecular-biological landscape of cancer, and the extremely slow development of clinically useful indicators that can be used to target the disease. As a result, oncologists face serious challenges in daily clinical practice, including both the over- and under-treatment of patients and the prescription of ineffective therapies.
This remains true despite our living in the era of ‘targeted therapies’, given that the presence of the target in the tumour does not equal efficacy of the corresponding targeted drug. A relevant example here is the breast cancer drug Trastuzumab, which targets a specific protein at the cell surface and is prescribed to women whose cancer makes this protein in large quantities, both when cancer has spread around the body, and to prevent a relapse. While this agent is considered to be the ‘star’ of targeted drugs in view of its positive impact on breast cancer survival, oncologists know that roughly 50 % of all patients with cancer that makes the protein do not actually benefit from the drug.
‘Each patient is unique, and therefore each treatment plan must be unique.’
Professor Martine Piccart, head of medicine at the Jules Bordet cancer hospital, Brussels
The problem is that without proven ways of checking for drug resistance, we’re simply unable to identify those patients upfront. While ineffective therapy will be recognised in advanced disease after two or three months of exposure to the drug, this is not the case in early disease, where the ‘targeted drug’ is given for prolonged periods of time after surgery (12 months in the case of Trastuzumab) and in the absence of any sign of disease.
Greater progress in treatment tailoring has been made in colorectal and lung cancer than in breast cancer: the drug Cetuximab is known to be ineffective in the presence of some mutations and, therefore, its administration requires pre-testing for these. Similarly, the targeted drugs Gefitinib and Erlotinib are prescribed in non-small cell lung cancer only when specific mutations have been identified. In such cases, these drugs can be administered with an almost 70 % to 80 % chance of damaging the tumour.
The problems of potential over-treatment or under-treatment are particularly relevant to breast and colorectal cancers, for which preventative chemotherapy has been shown ‘on average’ to reduce the rates at which the cancer returns. But there is no ‘average’ patient in the clinic … !
Treatment needs to be unique
Each patient is unique, and therefore each treatment plan must be unique.
Our ability to identify the unique features of an individual patient’s cancer has been increasing dramatically. The last 15 years have witnessed the development and testing of different gene tests in breast cancer, several of which have shown robust abilities to predict the outcome of disease. In other words, they identify a subgroup of women with certain types of tumours who are very unlikely to experience a recurrence if treated with hormone therapy only. Two of these – Mammaprint and OncotypeDX – are undergoing prospective confirmation of their clinical efficacy in two large trials, MINDACT, backed by the European Organisation for Research and Treatment of Cancer, and TAILORx, backed by the US-based National Cancer Institute, which are expected to demonstrate that it is safe not to give chemotherapy in a subgroup of patients, with results expected in 2015 to 2016.
Similar attempts in other solid tumours have not taken place, illustrating the huge commitment that is needed to provide the highest level of evidence for new cancer indicators and, as a result, to improve treatment tailoring.
The search for gene tests that can specifically predict a patient’s response to cancer drugs has been far less successful, and it is losing ground in favour of next-generation DNA sequencing, also called molecular screening. The dramatic decrease in the cost of molecular screening renders it accessible to researchers, treating physicians, and wealthy patients. The hope here is to identify the actionable mutations within a tumour, in other words the ‘driver’ mutations for which targeted drugs exist and are expected to generate clinical benefit.
In this regard, Horizon 2020 could play a critical role in offering some coordinated actions in the DNA sequencing of malignant tumours: today’s efforts show huge fragmentation across the EU with only a few countries (France, the UK and the Netherlands) engaged, primarily in national sequencing programmes.
For Europe to remain competitive in this field and be able to enter efficient partnerships with the pharmaceutical industry – which is struggling with the rapidly increasing fragmentation of solid tumours – cross-border molecular screening programmes using robust technologies and mandating data sharing are vital to the personalised medicine initiative. Moreover, and more importantly, this step will be essential if we are to address existing inequalities in cancer care and cancer outcomes in the EU.
Academic researchers, in Europe and elsewhere, must start embracing complexity, since the likelihood that a single indicator of cancer will explain a cancer’s behaviour is extremely low: not only do tumours require in-depth characterisation, but their microenvironment and the genetic background of the individual patient needs to be considered as well. This multidimensional approach can also benefit from modern molecular imaging techniques, implying the need for much closer collaboration with imaging experts.
It is this kind of large, ambitious, multidimensional, collaborative research project that European cancer patients deserve and that, hopefully, will be granted in the EU Horizon 2020, if well designed and focused. These projects need a significant upgrade of bio-informatics tools and storage capacities, another area where Horizon 2020 could provide both a vision and data sharing platform. Needless to say, none of these dreams will be realised if the new EU regulation on data protection – soon to be finalised – will not carefully consider easy paths for researchers to access the huge amounts of valuable data that will accumulate in the genomic era of medicine.
Lastly, a clear and straightforward regulatory path will need to be created for new diagnostic tests. There is currently very little incentive for companies to invest in molecular diagnostics in the EU, and personalised oncology will remain an empty shell without a rigorous yet feasible methodology for obtaining regulatory approval of new, multiplex molecular tests.
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