CANCER AND MONOCLONAL ANTIBODIES
Antibodies are a key component of the body’s immune defences. Each antibody comprises a constant region and a variable region. The variable region is responsible for the binding of the antibody to its target – this is illustrated in Figure1.
The normal function of antibodies is to bind to invading infectious organisms – viruses, bacteria, and so on. When exposed to a new infection, the body’s white blood cells identify it and select the cells (called lymphocytes) with the antibody-variable region best able to stick to and disable the invader. Production of the relevant cells is massively increased, followed by increased production of antibodies able to bind to the invader. Once bound, other immune cells identify the antibody-coated invaders and ingest them, using the antibody-constant region as a ‘hook’ for pulling them out of the circulation. The development of an immune system is one of the key evolutionary steps necessary for the existence of complex multicellular organisms. Those born with inherited defects in their immune systems struggle to survive childhood, underlining the importance of this function.
In the 1970s, technology was developed to exploit the ability of the immune system by manufacturing antibodies against ‘artificial’ targets such as cancer cells. These engineered targeted antibodies are called monoclonal antibodies – antibodies made by a single clone of cells – and can be made to stick to pretty much any chosen target. By picking targets on cancer cells, these natural molecules can be used both as an aid to imaging, by linkage to radioactive chemicals, or simply as treatments in their own right.
When they first appeared, it was thought that monoclonal antibodies would be the ‘magic bullet’ that would eradicate advanced cancer by being custom-made to order for each tumour. The reality sadly proved to be less dramatic, but 30 years on, monoclonal antibodies are now hitting the clinics in increasing numbers.
The best-known monoclonal antibody is probably trastuzumab, more often referred to by its trade name of Herceptin. The drug targets a protein on the surface of cancer cells known as HER2, part of a family of what are called growth factor receptors. These are best thought of as on/off switches regulated by circulating proteins (in this case called heregulin). Around one-third of breast cancers have an abnormal form of HER2 on the cell surface, essentially resulting in the switch being turned permanently ‘on’. Breast tumours that are HER2-positive grow faster and more aggressively than those that are HER2-negative. Targeting HER2 on the cell surface thus seemed a logical strategy and monoclonal antibodies a good way of going about it. Initial studies were carried out in women with HER2-positive tumours and confirmed that the approach worked, with the drug being licensed in 2002. Although results were positive, with shrinkage of tumours seen, they were not as dramatic as may have been hoped for. Nonetheless, further trials were deemed worthwhile, this time using Herceptin in conjunction with chemotherapy for advanced disease. These trials produced more striking results, with women receiving Herceptin surviving around 50% longer than those receiving just chemotherapy.
The next stage of development proved to be even more interesting. Having shown benefit in incurable disease, the next step was to test the drug in patients with earlier disease at a potentially curable stage, a strategy that had already proved successful with hormone therapy and chemotherapy. The Herceptin adjuvant trials were an oncological triumph, with a halving of the relapse risk and the possibility that some of the previously incurable women were actually cured. There was a catch, however. Most women with early HER2-positive breast cancer actually already had a good outlook just with surgery, radiotherapy, and chemotherapy. If a woman is already cured by these treatments, she clearly cannot benefit from any further treatment (and may indeed be harmed, as Herceptin carries a risk of heart disease).
Conversely, some women will still die despite all current therapies, and therefore they too will benefit relatively little. In between are the real winners, converted from those destined to relapse to those potentially cured. This means that in the adjuvant (preventative) setting, the number needed who must be treated to benefit one of the real winners is high, maybe as many as 20. As the cost of Herceptin is substantial (around £30,000 per year), the effective cost per woman saved can be estimated as around 20 × 30,000 = £600,000. Unsurprisingly, therefore, when the drug was licensed for adjuvant use, a further storm of controversy followed – how much is it reasonable to spend to save one life?