Personalised Medicine at a Glance: Colorectal Cancer
For patients, policy makers and other non-medical professionals
This text was prepared by ESMO for the European Alliance for Personalised Medicine – January 2015
In Europe each year, there are almost half a million new cases of colorectal cancer (CRC), and CRC is responsible for over 200,000 deaths. Around 25% of patients with CRC have disease that has spread to other parts of the body (i.e. become metastatic) by the time they are diagnosed. In a further 50%, the cancer – even though apparently confined to the colon at diagnosis – will eventually appear in other organs despite attempts at curative therapy.
Yet, even with these discouraging aspects, approaching 60% of patients diagnosed with CRC will not die from it over the following five years. The range of drugs available to treat metastatic CRC is rapidly expanding and, in this area of cancer as in others, major advances are being made in our ability to assign specific treatments to subgroups of patients who are most likely to benefit.
Abnormal growth signalling
Cells divide in response to signals from growth factors that interact (like a key in a lock) with receptors on the cell surface. If there is too much of a particular growth factor, or if there are too many receptors, or if receptors are abnormally sensitive, inappropriate growth signals are sent from the cell surface to its nucleus, and the cell divides when it should not.
This uncontrolled cell division is the essence of cancer. And the essence of novel, biologically-targeted anti-cancer drugs is to block abnormal growth signalling. One way of doing this is to use small molecules that enter the cell and prevent transmission of the growth signal from the activated receptor to the nucleus. Another is to use a drug to block the receptor and so stop its activation by a growth factor. Typically, these receptor-blocking drugs are large molecules based on our immune system and called monoclonal antibodies.
Video resource: How personalised medicine will affect colorectal cancer patients
Molecular testing and targeted therapies
The discovery that abnormalities in the epidermal growth factor receptor (EGFR) contribute to the development and growth of CRC was the starting point for personalised treatment based on the molecular characteristics of an individual colon tumour. Also crucial was the availability of drugs that could block the receptor. The anti-EGFR monoclonal antibodies cetuximab and panitumumab are the two most important examples.
Many colorectal cancers have EGFR abnormalities. But not all such tumours respond to drugs directed against the faulty receptor. If one of the molecules responsible for downstream intracellular signalling (KRAS, or Kirsten Rat Sarcoma-2 virus oncogene) is also mutated, cetuximab and panitumumab are ineffective. When given in conjunction with a particular form of chemotherapy, they may even worsen outcome.
It is therefore important to find out the RAS status of each tumour and to exclude the 30-50% of CRC patients who have such mutations from anti-EGFR treatment. A further difficulty is that tumour cells may develop RAS mutations in the course of treatment, even if they are not present at the outset. This can lead to the development of resistance to anti-EGFR agents. To avoid the need for patients to have a second tumour biopsy, it may be possible to detect development of RAS resistance mutations by analysis of tumour DNA circulating in the patient’s blood.
Although the position is not yet entirely clear, tumours with mutation of a gene coding for another downstream signalling molecule, called BRAF, may also be unresponsive to anti-EGFR agents. Around 5-10% of colorectal cancers have BRAF mutations.
This example illustrates the potential but also the complexity of personalising anticancer therapy based on biomarkers. Even when a relevant molecular abnormality is identified, the subgroup of tumours which are positive on this test needs to be further dissected to establish which cancers among them are sensitive and which resistant to targeted drugs. And to truly personalise therapy for metastatic CRC, we may have to look not for the presence or absence of one, two or even three markers but at a tumour gene signature which is almost unique.
In certain cases of advanced CRC, metastases are confined to the liver. In such patients, surgical removal of the secondary cancers – if their size and location permit an operation – can lead to long-term survival. Even when surgery is initially impractical, giving a combination of chemotherapy drugs (often accompanied by a biological agent) can sometimes make an operation feasible. The surgical approach to CRC must therefore also be personalised.
The majority of colorectal cancers occur independently of family history. But there are hereditary forms of the disease, as in the 3-5% of CRCs caused by Lynch syndrome. These cancers are linked to specific defects (termed “microsatellite instability”, or MSI) in the cellular mechanisms that control repair of DNA. People with a family history suggesting a high risk of hereditary CRC should be regularly screened.
MSI is not confined to hereditary CRC and is found in around 15% of colon tumours. Such cancers do not respond as well as non-MSI cancers to standard regimens used in chemotherapy. So there is a case for taking the presence of MSI into account, especially when considering whether or not a patient should have “adjuvant” chemotherapy, ie treatment designed to reduce the risk that metastatic disease will develop following removal of the primary tumour.