In 1999, I was fortunate to be one of the first to witness dramatic tumour regression in patients with non-small cell lung cancer (NSCLC) following treatment targeted at the epidermal growth factor receptor (EGFR). It was a watershed moment for precision medicine when we and other groups showed that patients with such tumours invariably had an activating mutation in the drug’s target, EGFR, and that these patients achieved much better outcomes than those with tumours without the mutation treated similarly.
Precision medicine had been gradually gaining momentum as we considered how to select a patient’s cancer treatment according to the characteristics of their tumour, and not just on the basis of where the tumour started. We’d already seen some less refined efforts and successes with precision medicine, such as HER2 testing in breast cancer. But, for me, it was the profound effects we saw in the most common form of lung cancer that indicated the true potential of precision medicine and what it could mean for researchers and clinicians – and, most of all, for patients.
The EGFR story was a catalyst for the rapid advances that we have subsequently seen in precision medicine. While it took eight years to develop and market a suitable EGFR diagnostic so that patients with NSCLC could be routinely tested for mutations, it took just three years for a test for anaplastic lymphoma kinase (ALK) to advance from lab to clinic.
Today, we can look for hundreds of thousands of genomic alterations across hundreds of genes at the same time, and thousands of targeted drugs are being studied. Alongside the advances in lung cancer we are seeing rapid developments in the use of BRCA1/2 testing to indicate likely response to poly ADP ribose polymerase (PARP) inhibitors in ovarian and breast cancers, and possibly to other tumour types in the longer term. In addition, biomarkers such as programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are being used increasingly to identify patients most suitable for checkpoint inhibitors.
Collaboration and information sharing is key
Our experience with EGFR gave credence to the concept of true translational research. The barriers between preclinical and clinical research are being broken down, so there is more rapid exchange of ideas and knowledge. We are also seeing more emphasis on a ‘pre-competition phase’ of research when there is greater collaboration between investigators, both in academia and industry, for example in making genomic profiling results or certain clinical information more widely available, in a compliant way, to other researchers. Sharing this type of pre-competitive infrastructure enables us to speed up drug discovery and more quickly separate promising leads from likely failures.
In immunotherapy, an initiative involving several biopharmas to develop standardised immunohistochemistry scoring for identifying suitable patients for checkpoint inhibitors recently resulted in an important consensus published jointly by all the relevant companies and the Food and Drug Administration (FDA).
Here at Foundation Medicine, we see the benefits of collaborating with AstraZeneca on a daily basis – working in parallel to turn disease biomarkers into companion diagnostics for a new generation of targeted therapies.
‘Doing far more with far less’ is the over-riding theme of the technological advances that are helping us move ahead with precision medicine, whether we are dealing with tissue, blood or other samples. Developments in hybrid capture-based next generation sequencing (NGS), the ability to separate RNA from paraffin-embedded tissue samples, and the growing use of circulating tumour DNA (ctDNA) are enabling us to improve the way we characterise genomic mutations in our patients and speed up development of targeted drugs.
Clustered regularly interspaced short palindromic repeats (CRISPR) is arousing huge interest because it offers fast, simple very precise genome editing. Its potential in preclinical drug discovery is already becoming apparent and clinicians in China and the USA have recently described active and planned clinical studies using CRISPR as a therapeutic intervention in patients with cancer.
Spreading the word and improving access
As precision medicine becomes reality for patients with a growing range of tumour types, education is a major priority. Many clinicians know about gene mutations, such as in EGFR and ALK, and some check patient samples for them. But few are aware that tests are already available for mutations in over 300 cancer-related genes. They may also question the value of broad based profiling if there are no drugs to treat many identifiable mutations or patients live hundreds of miles from centres where they could gain access to pipeline medicines through clinical trials.
To address these challenges, companies such as AstraZeneca and Foundation Medicine are working to speed up clinical trials and bring them closer to patients so they can benefit from advances in precision medicines as quickly and safely as possible.
As well as educating clinicians about the potential of precision medicine, we must also talk honestly with patients. We should explain the spectrum of potential outcomes – the best, the worst and the likely – before asking for their consent, just as we would with surgery or chemotherapy. Patient advocacy groups are engaging in various ways and we are starting to see initiatives to raise awareness about the value of broad genomic profiling.
Clearly there is a lot of interest in the potential of precision medicine in immunotherapy, including personalised cancer vaccines. There is also the continuing challenge, at a population level, of being able to explain why one patient responds well to a treatment while another doesn’t.
A decade or so ago, who would have guessed that patients with tumours as hard to treat as lung cancer and malignant melanoma would be first to benefit from our early advances in precision medicine? Looking ahead, I wouldn’t be surprised if we started to see real progress for pancreatic and colon cancers.
As a scientific community, we are now galvanised towards making progress in precision medicine through our collaborations and partnerships. I can’t set a date but I think that, within the next five to 10 years, precision medicine will enable us to refine our therapies to achieve better outcomes across a broad range of cancers and, no doubt, for patients with cardiovascular, respiratory and many other diseases too.
Precision medicine at AstraZeneca
Precision medicine is transforming the way we use and develop medicines, and at AstraZeneca we are at the forefront of this transformation. Working with partners like Foundation Medicine, we are pushing the boundaries of science to deliver the next wave of innovative, life-changing medicines. Learn more.