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 in January 2015 and updated in February 2017
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. By the time they are diagnosed, around 25% of patients with CRC have disease that has clearly spread to other parts of the body (i.e. become metastatic). 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 the disease within 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.
Patients are also benefiting from earlier diagnosis, when surgery is more likely to achieve a cure, and from new techniques that can destroy some tumour metastases. Advances in our ability to detect sites of disease through better imaging are also making an important contribution.
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 molecule drugs 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 there is also an abnormality in the molecule responsible for downstream intracellular signalling (RAS), cetuximab and panitumumab are ineffective. Indeed, if given in conjunction with a particular form of chemotherapy containing the drug oxaliplatin, 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. But this technique is not in routine use.
Although the position is not yet clear, tumours with mutation of a gene coding for another downstream signalling molecule, called BRAF, may also be less responsive to anti-EGFR agents. Around 8-12% of colorectal cancers have BRAF mutations. Along with RAS testing, it may be helpful to know if individual patients’ tumours have BRAF mutations.
In patients with tumours that are not suited to treatment with drugs directed at EGFR, another class of biological agents may be recommended. These are drugs that target a different growth factor -- Vascular Endothelial Growth Factor (VEGF). As its name suggests, this factor promotes the growth of blood vessels, including those that supply blood to the tumour. Preventing this can cause the tumour to shrink. The most widely used anti-VEGF drug is the antibody bevacizumab. Other possibilities include aflibercept and ramucirumab.
The advantage of using drugs that target VEGF is that the need for blood vessels is common to all colorectal tumours, so the presence or absence of specific mutations in the cancer cell (such as those of RAS and BRAF) do not have to be taken into account. On the other hand, a drug like bevacizumab carries a risk of potentially severe side effects, notably bleeding, and so may not be suited to all patients.
These examples illustrate 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.
Abnormal mechanisms of cell repair
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, i.e. treatment designed to reduce the risk that metastatic disease will develop following removal of the primary tumour. Testing for MSI in the individual patient – to establish whether CRC risk may be inherited – is valuable in deciding whether genetic counselling of other family members is needed. It may also help in personalising treatment with an entirely new class of drugs called immune checkpoint inhibitors. These agents, which are proving valuable in a range of tumour types, have been described as “taking the brakes off” the immune system, allowing our own bodies to more effectively counter the cancer.
Treating patients with few metastases
In certain cases of advanced CRC, metastases are confined to a few secondary cancers in the liver. In such patients, surgical removal of the secondaries – if their size and location permit an operation – can lead to long-term survival, even cure. When surgery is not feasible initially, giving a combination of chemotherapy drugs (often accompanied by a biological agent) can sometimes make an operation possible by shrinking the tumours. This is termed “conversion therapy”.
For patients with few metastases – in the liver or other sites such as the lung – it may also be possible to use a range of non-surgical techniques to destroy the secondary tumours. There are now many tools in the box. These techniques include destruction (termed ablation) using radiotherapy, or the localised application of extreme heat or cold, or cutting off the blood supply to the cancer by blocking the artery that feeds it – a procedure called embolisation.
The best approach to use will depend on the individual circumstances of the patient, including their ability to withstand surgery, and the characteristics of their metastases – particularly where they are in the body and how large they have grown.
Personalised care in an increasingly complex world
The wealth of advances being made – and the many implications they have for the care of individual patients – are reflected in the latest ESMO CRC treatment guidelines. They include recommendations for the initial treatment of metastatic CRC and options that are available for second- and third-line treatment that may be needed if the cancer fails to respond to first-line drugs or if it starts to grow again after a period of disease control.
All of these decisions will be made taking into account the specific circumstances of each patient.
An implication of this complexity is that the best and most personalised care now depends on being treated at highly specialised cancer centres. In these hospitals, a range of experts from different fields (surgery, radiotherapy, medical oncology, nursing, pathology, imaging....) co-operate in multi-disciplinary teams to determine the most appropriate treatments to offer at every stage of the disease.