Technology can now identify a patient’s unique genetic characteristics that will indicate whether they are likely to respond to the therapy. In this article, Dr James Harraway who is a Brisbane-based Genetic Pathologist at Sonic Genetics, explains what companion diagnostics are and how they support precision medicine.
If you work in the in vitro diagnostics (IVD), pharmaceutical or medical technology sector, it will have been difficult for you to avoid hearing the term ‘companion diagnostics’, an increasingly important area in the time of personalised medicine.
Not all humans’ genetic make-up is the same, and cancers arise through ‘somatic’ mutations (changes in the genetic make-up of the cancer cell). This means that people with the same cancer can have different genetic mutations causing their disease. These mutations can occur in patterns or ‘signatures’, sometimes called genetic scars. According to the Cancer Genome Atlas, for every cancer there are on average five genetic scars, which can be found in many possible different combinations.
Today, genetic technology allows healthcare professionals to pinpoint the right therapy for their patient. Several drugs have been developed and marketed with a companion diagnostic, a test to determine whether a patient has a biomarker that predicts a response to a drug. Such treatment is potentially more clinically and cost-effective, as the targeted therapy is prescribed to patients likely to respond. Without patients going through biomarker testing, clinicians cannot take advantage of precision medicine to its full potential.
Since the mapping of the human genome in 2003, it has been much easier for pharmaceutical companies to develop and manufacture drugs that are targeted to a specific biomarker that is the root cause of a disease.
Dr Harraway, who describes his responsibilities as ‘supervising testing for RNA and DNA changes which have medical significance’, remembers the concept of companion diagnostics for somatic (tumour) mutations being around since the early 2000s. The earliest example was assessing fusion of the BCR and ABL genes in chronic myelogenous leukaemia (CML) to confirm whether a patient should receive the cancer drug imatinib. Although the concept has been around for over 20 years, ‘IVD Companion Diagnostics’ were only formally included in the Therapeutic Goods (Medical Devices) Regulations 2002 from 1st February 2020 in Australia. A big part of Dr Harraway’s and his team’s workload is to run specific biomarker tests requested by specialists.
Some tests on tumour tissue for somatic mutations are pathologist determinable tests. This is when a pathologist starts by analysing a sample using microscopy, and decides that further genetic testing should be done to confirm a diagnosis or presence of a biomarker, and therefore a treatment decision. These pathologist determinable tests are funded by Medicare, and discussed at a multidisciplinary team meeting with the clinical team.
Determining genetic mutations in a tumour sample is only one of the many important responsibilities carried out by pathology laboratories relating to precision medicine. Pharmacogenetic testing is when the laboratory reviews whether the patient has inherited (‘germline’) changes in enzymes which process the drug that is going to be prescribed to them. This is important, as patients can respond badly to the wrong treatment, or the wrong dosages. However, genetics are not the only factor that influence drug metabolism, so they do not provide the complete picture.
“The genetics aren’t the only determinant of drug levels. There are other drugs that interact with the metabolising enzymes, there’s modifier genes, there’s other enzymatic pathways and so forth.”
Precision medicine is highly utilised in the oncology therapy area. Targeted cancer therapies against mutant cancer genes, such as tyrosine kinase inhibitors, are most effective and safe when prescribed to the right patients. This is not a one-size-fits-all approach, and this is where the biomarker test or companion diagnostic is critical.
“{The precision medicine} can be potentially harmful, and some people do less well if you give it to them. Companion diagnostics is refining who gets the treatment, people who are more likely to respond to that based on pharmacogenetics, or whose tumours are more likely to respond to that based on their specific somatic mutations.”
Targeted therapies can be effective, but if the drug is not suitable for the mutations in a tumour it may result in a worse prognosis than standard therapy. In addition, tumours that initially respond to a targeted therapy may develop new mutations which lead to resistance. Some of these new mutations can be detected by further laboratory tests.
The area of precision medicine and biomarkers is moving fast:
“We keep an eye on the literature and on international conferences, news feeds, and even social media like Twitter. There’s a lot of reading to do. Often by the time that Phase III clinical trials have been completed, {the drug and companion diagnostic} are often pretty well known in the field.”
Whilst Dr Harraway praises the progress made in Australia in this area, he notes that the time for new therapies and tests to obtain Federal government funding can be lengthy in some cases. The test must go through the Medical Services Advisory Committee (MSAC) and the drug through the Pharmaceutical Benefits Advisory Committee (PBAC) before both are reimbursed for patients. Whilst the Department of Health works hard to ensure both are recommended in a timely manner, this co-dependency can mean that the process can be protracted. A positive recommendation is required by both Committees before proceeding to simultaneous listing of the test on the MBS and the drug on the PBS.
Today, a tumour sample is typically assessed with separate tests on a one-by-one basis. Dr Harraway looks forward to when comprehensive genome profiling becomes more available in the near future.
“What we are moving towards is more comprehensive. Currently, we may test for one or two mutations or other biomarkers in a given tumour, to determine the usefulness of one type of therapy. So, you may do an EGFR test for a lung cancer, or a KRAS and NRAS test for a colorectal cancer, or a BRAF test for a melanoma. But testing uses up some of the tumour tissue each time you do it. And if there’s another biomarker which is useful, if you go one by one by one, it becomes inefficient and potentially you might not have enough material to for all of them.
“I think probably the way that things are moving, both overseas and in Australia, is towards more of what they call comprehensive genome profiling or CGP. CGPs are tests examining many genes at the same time, looking at different types of changes which can drive cancer: small mutations, fusions, rearrangements duplications, amplifications, deletions and so forth.
“And at the moment CGP is still quite expensive, as compared to looking at a single target, but the cost of doing that type of test is slowly coming down, at least in terms of the materials we use to run the tests in the laboratory. As you look at more genes and find more mutations, it can take longer to work out what the mutations mean and write a report, so there is an increased labour cost. However, this analysis is becoming easier over time, with more sophisticated computer programs and databases.”
As the Department of Health recommends more diagnostic test and targeted therapy combinations, Australian patients will have better access to state-of-the-art treatments for serious health conditions, giving them the opportunity for a better quality of life.
