Wednesday, February 22, 2012

Made to Measure: Personalised cancer medicine

Doctors have long known that two patients with the same type of cancer may respond very differently to the same treatment; a person’s susceptibility to a disease as well as treatment success or resistance can vary from one person to another, even within family groups. But a greater understanding of our genetic information at the individual level is facilitating new approaches in the detection, treatment, and prevention of cancer and other diseases, which are more tailored to the needs of each patient.

The ‘one size fits all’ approach where a patient’s therapy was selected based on average results from randomised clinical trials is increasingly being replaced by targeted therapeutics and their related molecular diagnostics. The age of personalised medicine, first signalled in the 60s, is here and now and offering new hope for cancer patients.

The mapping of the human genome, completed in 2003, and recent advances in genome technologies have laid the groundwork for understanding the roles of genes in disease development. All diseases have a genetic component, whether inherited or resulting from the body's response to environmental stresses like viruses or toxins. Detecting these subtle mutations, or biomarkers, is a complex and ongoing challenge.

Most types of cancers are not single diseases. There can be over a dozen subtypes within a breast cancer diagnosis, for example. An ever-growing number of molecular diagnostic tests are becoming available commercially, aimed at identifying genetic mutations within a particular cancer that might be treatable with certain drugs. These gene tests can also detect errant genes in people at risk of developing certain cancers.

Using this genetic information to develop targeted cancer therapies is revolutionising how drugs are being designed and how patients are being treated.

“Put simply, personalised medicine is about making the treatment as individualised as the disease,” capsulates Dr David Gallagher, a medical oncologist and medical geneticist who returned to Ireland from the world-renowned Memorial Sloan-Kettering Cancer Centre in New York in 2010. He established the Cancer Genetics Clinic at the Mater Private Hospital, which opened in February 2011.

“Cancer genetics and personalised cancer medicine are closely related but not exactly the same thing. Personalised medicine is about individualising therapy for patients: taking a biopsy of a patient’s tumour and looking for molecular changes; genetic mutations and different expressions of proteins within the tumour that may allow you to select a tailored treatment for the individual based on the molecular makeup of their actual tumour.

“This is often what people are referring to when they talk about personalised medicine and it forms a major part of my daily work as a medical oncologist. Cancer genetics focuses largely on prevention; genetic testing for potential abnormalities before an individual gets cancer. If we find these genetic ‘red flags’ we can initiate a strategy of either early detection, which involve regular screening, or cancer prevention, which involves chemo prevention or surgical prevention.

“This personalised approach to cancer diagnosis and treatment is increasingly where medical oncology is trying to go and genetics is at the very centre of that. I dual trained as both a geneticist and an oncologist because that’s where I think the future of this field lies,” he tells Cancer Professional.

“In the oncology clinic, when a person is diagnosed with cancer, depending on their diagnosis there may or may not be a treatment that is available for their particular cancer subset. We can test for a protein marker or genetic marker that may influence their response to a drug, and if the individual has this biomarker they will go down one treatment paradigm, and if they don’t they may go down a different treatment route.”

The first step toward more individualised drug treatment for patients was taken over half a century ago with the identification of oestrogen receptors by Elwood Jensen at the University of Chicago in 1958. This discovery was followed by the introduction of the anti-oestrogen drug tamoxifen in the 1970s, which enabled a more individualised approach to the treatment of breast cancer patients.

About a decade later, researchers found that some women who had particularly fast-growing breast cancers expressed extra copies of a gene called HER-2 (Human Epidermal growth factor Receptor 2). The genes were producing many copies of a protein that appeared to be driving the growth of the cancer cells.

This discovery led to the development of another targeted therapy in the 1990s, the monoclonal antibody trastuzumab, which effectively latched onto the HER-2 proteins on the surface of a cancer cell and slowed or stopped cancer-cell growth in the 20% to 25% of breast cancer tumours that contained an amplified HER-2 gene.

Since then, numerous targeted anticancer therapies, covering a wide variety of targets in tumour tissue or the tumour's environment, have become the subject of extensive research and development activities worldwide. Clearly, pharmacogenomics is now a booming industry.

Already dozens of targeted agents have been approved for use in specific cancers including drugs that interfere with cell growth signalling (imatinib, gefitinib, etc) or tumour blood vessel development (bevacizumab, sunitinib, etc), as well as drugs that promote the specific death of cancer cells (bortezomib, pralatrexate, etc), stimulate the immune system to destroy specific cancer cells (rituximab, ipilimumab, etc) and deliver toxic molecules to cancer cells (brentuximab vedotin, ibritumomab tiuxetan, etc). 

Oncologists and their patients in Ireland are fortunate to have access to some of the most exciting, lead candidate drugs in cancer through participation in clinical trials directed by the All Ireland Cooperative Oncology Research Group (ICORG).

ICORG’s growing portfolio of member-generated clinical trials of some of top targeted agents from global market leaders, including the GlaxoSmithKline (GSK) B-RAF melanoma study. A total of 600 Irish patients were screened and 140 of these enrolled onto the trial last year. The drug is designed to attack a genetic mutation B-RAF that is found in half of patients with melanoma, and in other cancers such as colon and thyroid.

“In the lab the new treatment had yielded remarkable results, shrinking tumours and keeping them at bay. One Irish patient has also seen remarkable results that started within a week of taking the drug. On returning for the first scan six weeks after taking the drug there was a 50% reduction in the disease in his body and on recent scans there was a further 40% reduction and no new disease,” an ICORG spokesperson told Cancer Professional.

She also revealed that ICORG anticipates it will be working with between eight and ten of the most promising of the new targeted agents by the middle of 2012.

Another illustration of Ireland’s burgeoning leadership in this field is the recent announcement that St James’s Hospital is the leading European site in the crizotinib trial. This news is all the more exciting when examining early data for this drug. In the early phase studies more than 60% of lung cancer patients who received crizotinib were alive after two years, according to data released in June 2011.

“We are increasingly moving away from the ‘one size fits all’ approach to treating cancer, but it still how most patients are treated,” says Dr Gallagher. “However, every year this is changing, more and more. We are crossing the traditional tissue defined definition of cancer to a more molecular defined era of cancer, so breast cancers are being treated like stomach cancers because they have a similar molecular profile. That would never have happened in the past.”

Dr David Gallagher
He points out that even if targeted therapies are available, they cannot be delivered to "the right patient at the right time" without access to sophisticated diagnostic tools, making molecular diagnostics a key driver in personalised medicine.

Dr Gallagher remarks: “Molecular diagnostics is about analysing the tumour for different markers, whereby patients are ‘stratified’ into subgroups according to their biomarker profile and likely response to a specific treatment. Molecular tests are referred to as either predictive markers to guide treatment or prognostic markers that are used to inform prognosis after treatment.”

OncotypeDX, for example, is indicated for women for node negative, hormone receptor positive and HER 2 Neu negative invasive breast cancer, and provides a risk score that helps determine whether a woman should proceed with curative adjuvant chemotherapy in addition to hormone therapy.

The National Cancer Control Programme (NCCP) announced in October 2011 that breast cancer patients could now avail of the benefits of OncotypeDX in the public health service. The clinical data published for the use of this test has indicated that up to 30% of women who would otherwise have received chemotherapy will now be considered as low risk and as a result will be spared the toxicity and long term side effects of treatment. The NCCP expects around 300 women annually to undergo the test, with around 100 women subsequently excluding chemotherapy from their treatment plan.

For most drugs, such as tamoxifen and trastuzumab, the companion diagnostic tests are used to select the patients who are most likely to benefit from treatment; but such tests can also be used to predict toxicity. For example, irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype. Genetic polymorphism of the UGT1A1 gene is related to severe toxicity caused by the drug, such as leukopenia and diarrhoea. In order to identify the group of patients with aberration of the UGT1A1 gene who will need a reduced dose of irinotecan, a pharmacodiagnostic test was developed (Invader® UGT1A1 Molecular Assay). Another, similar genetic test to predict toxicity of 5-fluorouracil or capecitabine, and helps guide physician dosing decisions, was recently introduced (TheraGuide 5-FU).

Investigating mechanisms of sensitivity and resistance to new molecularly targeted cancer drugs is the principle aim of a recently established consortium of scientists, clinicians and industry partners in Ireland. Molecular Therapeutics for Cancer Ireland (MTCI) has already attracted huge investment, including a €6 million award by the EU to investigate possible treatments for difficult-to-treat types of breast cancer.

“At present, there is a lack of targeted therapies for two poor-prognosis subtypes of breast cancer namely ‘triple negative’ breast tumours and invasive lobular carcinomas of the breast,” says MTCI Investigator Professor William Gallagher, an Associate Professor of Cancer Biology in the UCD School of Biomolecular & Biomedical Science and a UCD Conway Institute, who is leading this research. “Together these subtypes make up almost 25% of all breast cancers. Our research will explore the role of kinases – the key regulators of cell function - in these types of breast cancer in order to develop therapeutic targets that may inhibit the rate of activation of kinases in cancer sufferers.”

Other national developments include the establishment of Ireland’s first Breast Cancer Tissue Bio Resource in 2010, which should enable speedier discoveries and ultimately more effective and personalised treatments for patients. In addition, a Germline DNA Bio Bank has just been set up at the Cancer Genetics Clinic in the Mater Private. The Clinic also expects to launch a new prostate cancer screening study in early 2012.

Although Irish efforts with regard to investigating and promoting more personalised cancer treatment is laudable, European health authorities see considerable scope for improvement throughout the EU. The Health Research Directorate of the European Commission organised a series of workshops on personalised medicine in 2010, culminating in a two-day conference in Brussels last year, where key opinion leaders addressed recent achievements in health related research leading to personalised medicine and identified priorities for future actions needed at the European level.

Arising from this, the European Commission is currently exploring whether a French cancer initiative could be applied in other EU countries. Under the French programme all cancer patients can be tested, free of charge, for the molecular characteristics of their particular tumours. Once tested, patients can be prescribed with the most appropriate medicine as soon as possible. This initiative is now in its sixth year.

Dr Fabien Calvo, Deputy Director-General and Director of Research at the French National Cancer Institute, explains: “The goal of the French programme is to offer each cancer patient access to a molecular test as soon as possible following the regulatory approval of a new targeted cancer therapy. For example, in 2008 the institute allocated €2.5 million for KRAS testing in colorectal cancer. This was not long after regulatory authorities approved cetuximab and panitumumab for patients with colorectal cancer with the non-mutated (wild-type) KRAS gene.

“Similarly in 2009, the institute allocated €1.7 million to the regions to test patients with activating mutations of the epidermal growth factor receptor (EGFR) in their tumours. This followed regulatory approval of gefitinib for metastatic non-small cell lung cancer in patients with activating mutations of EGFR.

“Although there is a cost to the government in offering these tests, there has also been a savings on the cost of medicines,” he stresses. Dr Calvo says that EGFR testing for patients with lung cancer has saved a massive €69 million for the health insurance system because only those patients who could benefit from gefitinib have received the treatment. 

Mr John Dalli, Commissioner for Health and Consumer Policy, European Commission, agrees that the high costs for personalised medicine should be offset by efficiency gains. He told the conference: “By offering personalised medicines to patients, healthcare providers can avoid trial and error and reduce adverse reactions. This offers the potential for major benefits to patients and to the healthcare system as a whole. At the moment, this potential is largely unexploited. Efforts by academia and industry need to be stepped up.”

The first article ever published that coined the term ‘personalised medicine’ (the Wall Street Journal/the Oncologist, 1999) predicted, “The race is on to come up with tailor-made drugs that will treat people based on their individual genetic makeup.” After many years of development, personalised health care is increasingly moving into clinical practice. Apple CEO Steve Jobs and maverick author Christopher Hitchens, who both recently succumbed to cancer, were among a select few patients to have their entire genomes sequenced in the hope of tailoring each man's cancer treatment to their specific genetic mutations within the cancer. Even still, the attempted treatments fell short of cures.

The era of personalised medicine is here, albeit in its infancy, and we have already seen the first important results. The promise of  “targeting drugs for each unique genetic profile” as outlined in the 1999 article is tantalisingly close but as of yet, far from being fulfilled.


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