The focus of Professor Downward’s laboratory is unravelling the molecular mechanisms by which dominant oncogenes, such as RAS and EGFR (epidermal growth factor receptor), drive tumour formation, growth and spread. This has led to the identification of numerous molecular targets for pharmacological intervention, several of which can now be blocked with clinically approved drugs, including inhibitors of MEK, RAF, EGFR and mTOR, with many other targeted agents in advanced stages of clinical trials.
Despite these huge advances, it is still the case that the benefits of these targeted treatments are either temporary (in the case of EGFR-mutant cancers) or marginal (in the case of RAS-mutant cancers), at least in part because of heterogeneity of tumours upon presentation and the rapid development of drug resistance.
In common solid tumours where RAS or EGFR mutations are frequent, for example lung, pancreas, colon and melanoma, early surgical intervention is by far the most effective therapeutic approach available at present. Even in extremely poor-prognosis cancers such as lung (20% KRAS mutation and 15% EGFR mutation) and pancreas (90% KRAS mutation), surgery at the earliest stages of the disease is often curative. For example, surgery will cure about 50% of patients with stage I non-small cell lung cancer, mostly without additional chemotherapy. By contrast, overall five-year survival for all patients with lung cancer is just 9% in the UK. In pancreatic cancer, which has the worst prognosis of the common cancers, surgery has the capacity to cure as many of 40% of patients with localised disease. Five-year survival overall for pancreatic cancer is less than 4% in the UK.
The most important limitation to the use of curative surgery is the fact that patients present with cancers that have already spread beyond their primary site. Even if surgery is able to remove the primary tumour entirely, metastasis may have occurred, leading to the development of multiple secondary lesions that cannot all be removed surgically. Improved ability to detect cancers at a very early stage would allow greater use of surgery and might hold out the promise of greatly enhanced cure rates.
While advances in early detection of cancer are occurring on many fronts, including imaging and the investigation of a wide range of biomarkers, some of the most exciting developments in recent years have come from the ability to analyse tumour-derived DNA in circulating blood, either as circulating free tumour DNA fragments, or in circulating tumour cells (CTCs). The study of CTCs holds immense promise for improving our understanding of cancer biology, but the relative difficulty of handling and isolating CTCs compared with the ease of handling free DNA in the cell-free component of blood makes the analysis of circulating free tumour DNA especially attractive as an approach to the early detection of cancer.
One of the interests of the Lung Cancer Group at the ICR is the development of improved detection of lung and other cancers at an early stage where they can still be cured surgically, in particular through the identification of circulating tumour DNA in the blood.