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 1960s, 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 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. A growing number of molecular diagnostic tests are becoming available, aimed at identifying genetic mutations within a particular cancer that might be treatable with certain drugs. These tests can also detect errant genes in people at risk of developing certain cancers. Using this information to develop targeted cancer therapies is revolutionising how drugs are being designed and how patients are being treated.

Getting personal

“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 make-up 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 involves 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 Scope.

“In the 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.”

First steps

The first step towards 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 20-25% of breast cancer tumours that contained an amplified HER-2 gene. 

Since then, numerous targeted anti-cancer 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). 

Clinical trials in Ireland

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 Scope. She also revealed that ICORG anticipates it will be working with between eight and 10 of the most exciting of the new targeted agents by the middle of 2012.

Another illustration of Ireland’s burgeoning leadership in this field was 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.

The molecular era

“We are increasingly moving away from the ‘one size fits all’ approach to treating cancer, but it’s still how most patients are treated,” remarks 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.”

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 to 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 have 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 help 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 E6 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 Prof William Gallagher, an associate professor of cancer biology in the UCD School of Biomolecular and Biomedical Science and 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 been set up at the Cancer Genetics Clinic in the Mater Private. 

Work in progress

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 is tantalisingly close but, as of yet, far from being fulfilled.