Cancer Biomarkers: Powering Precision Medicine
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Researchers are developing biomarker tests to detect cancer early, monitor therapeutic efficacy and predict outcomes – making diagnosis and treatment more precise.
“A biomarker is generally something that you can measure in a patient that will give you information,” explains Karen Swales, Senior Scientific Officer in the Pharmacodynamics Biomarker Group at The Institute of Cancer Research, London, UK. “But the outcome will depend on the specific type of biomarker.”
Diagnostic biomarkers can detect and identify cancer or its relapse, prognostic biomarkers give an early indication of the severity of the disease, and predictive biomarkers can help doctors to select what therapies might work best for a patient. During clinical trials, pharmacodynamic biomarkers can offer an early insight into the effects of an experimental drug on the body.
As cancer is a genetic disease that is driven by alterations in the genome, there has been considerable attention to the genetic analysis of tumors. But researchers are also developing biomarker tests to measure different molecular changes – and using samples that are easier to collect from patients, such as blood or hair.
Stratifying patients using genetic biomarkers
The ever-increasing catalog of genetic changes involved in cancer development is fueling a new generation of targeted drugs that are designed to address specific weaknesses in tumor cells. But these drugs will only work in a subset of patients – creating a demand for genetic stratification.
For example, molecular testing for a specific mutation in the BRAF gene in metastatic melanomas is used to identify people who may benefit from BRAF inhibitors - or KRAS mutation testing in metastatic colorectal tumors before prescribing epidermal growth factor receptor (EGFR) blockers.
“We are seeing an increasing need to measure more and more of these DNA-based alterations,” says Edwin Cuppen, Scientific Director of the Hartwig Medical Foundation, The Netherlands.
As more targeted drugs continue to reach the market, each with its own paired biomarker-based test to identify a specific subset of patients, this is creating a new challenge for clinicians. Due to an ever-increasing complexity, some researchers are highlighting the need to switch from individual tests to more comprehensive genomic tumor profiling.
The rapid evolution of next-generation sequencing technologies is enabling this shift. Many large-scale tumor genomic sequencing programs, such as the 100,000 Genomes Project, are focusing on the analysis of primary tumors. But one large recent study carried out whole-genome sequencing of metastatic tumors.
“We found that 62% of metastatic tumors had genetic biomarkers that may be used to stratify patients towards therapies that have either been approved or are in clinical trials,” says Cuppen.
Although the specific treatment was not always registered for the patient’s indication, in a follow-up pilot study, 34% of patients had a clinical response after being prescribed the suggested off-label therapy.
“This might be a very useful approach, if it’s properly documented,” says Cuppen.
Biomarkers are accelerating clinical trials
Pharmacodynamic biomarkers, which measure whether a drug is biologically available and is hitting its desired target, can help inform the best dosage and schedules for an experimental drug - or enable go/no-go decisions on whether it should be progressed further.
“We can tell doctors when they’ve reached a dose that’s actually switching off the target, which gives them the chance to reduce toxicity without affecting the impact of the drug on the cancer,” explains Swales.
Testing samples at various time points can also enable clinicians to optimize drug scheduling.
“For example, we were able to feedback during a Phase I trial of a novel PI3K inhibitor that giving the drug only once a day wasn’t inhibiting the target for long enough,” says Swales. “So the company switched to twice-daily dosing to take forward into Phase II.”
Traditionally, Phase I trials involve giving different patients increasing doses of a drug, but pharmacodynamic biomarkers provide the opportunity for innovative strategies that can help speed up the process.
“We’ve been involved in a trial that used intra-patient dose escalation, which proved very successful,” says Swales.
Developing robust biomarker assays
Identifying the best pharmacodynamic biomarkers and developing the most suitable assays requires a good understanding of pathways that the drug is designed to target.
“Many drugs target overactive proteins that help a tumor to grow and spread,” explains Swales. “So, we will often need to design an assay to see whether it is successfully switching off that protein – and how long for.”
Many researchers use immunoassays, which can accurately detect and quantify the protein of interest – even when it is present only at extremely low levels. But a major challenge with many of these techniques is the requirement for two highly specific antibodies.
“But often that’s just not possible with novel biomarkers,” says Swales. “There may not be good antibodies available and we need to develop the assays too quickly to allow us to generate a custom antibody.”
To help overcome this challenge, the team is using a new capillary-based immunoassay known as Wes.
“It’s a bit like Western blotting but the gel is instead done inside a glass capillary,” explains Swales. “As well as requiring only one antibody, it’s also much quicker and you need much smaller volumes, which is really important with clinical samples.
Samples that are less invasive to collect
The gold standard for pharmacodynamic biomarkers involves the testing of tumor biopsies. But these can be difficult to collect, particularly for cancers that lie deep inside the body that can only be reached using an invasive surgical procedure.
“You usually only get pre- and post-dose tumor sample – so you’ve only really got one shot at predicting the right time for when to take it,” says Swales.
Researchers are aiming to develop assays that can measure relevant biomarkers in samples that are more easily accessible, opening more opportunities for serial collection.
“For example, we’ve worked a lot with platelets, which are good for looking at changes in certain phosphoproteins,” says Swales. “And we’ve also developed assays on plucked eyebrow hairs, which patients are usually happy for us to collect regularly.”
But as some targets are only expressed in tumors, developing sensitive molecular assays that require tiny sample volumes can be beneficial.
“We’re working on a clinical trial where we are using a novel molecular assay to measure RNA biomarkers, which was not only appropriate for that drug target but means we can get a lot more data from a tumor sample than we might otherwise,” says Swales.
Benefits for patients
Cancer biomarkers are already starting to transform patient diagnosis and treatment – but this is only the beginning of precision medicine.
While tests for DNA-based tumor biomarkers are already helping doctors to select drugs for individual patients, whole-genome sequencing is set to take this to a new level of sophistication.
“We believe that every cancer patient should have the opportunity to have a high-resolution image of their tumor DNA to catalog all treatment options that are available,” says Cuppen.
And researchers are using biomarkers to speed up drug development, which should lead to effective new therapies reaching cancer patients faster.
“Knowing that a drug that you’ve worked on is helping patients live longer is an amazing thing to be able to contribute to,” says Swales.