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
Even in tumours that arise in the same organ, there are many different subtypes. Thanks to advances in molecular medicine, we are increasingly able to distinguish between them. Care of women with breast cancer is being improved by tailoring treatment to the molecular characteristics of individual tumours, as well as to the size and spread of the cancer and the patient’s menopausal status.
Personalisation starts with screening
Around 3.8 million women in Europe have breast cancer. The number of cases is rising because of earlier detection through mammography and because the population is ageing. Breast cancer is the leading cause of cancer deaths among European women. Even so, the chances that an individual woman with breast cancer will die of the disease is falling. This is partly due to the fact that cancers are identified at an earlier and more curable stage, and partly due to advances in treatment.
The personalisation of breast cancer care is a major factor in improving outcomes. This approach starts with screening. Women from families with a history of breast cancer are at higher risk of developing the disease themselves. This is particularly so if women carry the BRCA1 or BRCA2 gene mutation which means that cells do not repair DNA as effectively as normal. Women with a family history of breast (and ovarian) cancer can be tested for BRCA mutations and need to have more frequent screening. The use of magnetic resonance imaging (MRI) adds to the value of mammography in detecting breast tumours at an early stage.
Video resource: How personalised medicine will affect breast cancer patients
Tailoring breast cancer treatment
If a tumour is found, the tailoring of care to a woman’s particular circumstances moves to the next stage. Among the critical factors that determine the nature of treatment are the type of cell that has become malignant and the size of the tumour and its grade, i.e. the extent to which the cells differ from normal when viewed under a microscope. But perhaps of greatest importance is whether or not the cancer has spread within the breast or to lymph nodes in the armpit or to nodes and organs elsewhere in the body. Spread to sites in the body that are distant from the primary tumour is termed metastasis (and the secondary cancers are called metastases).
Although chemotherapy is sometimes given to shrink otherwise inoperable tumours, initial treatment for most women with breast cancer is surgery. Where possible, the tumour and a surrounding margin of tissue will be removed while healthy breast tissue is conserved, i.e. by a lumpectomy operation rather than mastectomy.
Existing or potential spread of the cancer within and close to the breast can be managed by radiotherapy. But if there are metastases elsewhere in the body, systemic cytotoxic chemotherapy is frequently required. This form of therapy kills rapidly dividing cells. But it does not distinguish between cells that are proliferating quickly because they are cancerous and healthy cells in the bone marrow and gastrointestinal tract that divide rapidly as part of their normal function. Increased risk of infection, and nausea and vomiting are frequent side-effects. If cytotoxic chemotherapy can safely be avoided in some patients, they can be spared these toxicities.
Treatment based on the molecular characteristics of breast cancer
Increasingly, the molecular characteristics of the individual patient’s tumour are being taken into account when deciding on treatment. To truly match therapy to the patient, we need to identify the biological factors that drive tumour growth in specific cases.
Because breast tissue is designed to respond to hormonal changes in the woman’s body, many – but not all – breast tumours express oestrogen receptors and grow in response to their activation. Around thirty years ago, doctors showed that the growth of breast tumours that are oestrogen receptor positive (ER+) could be prevented or delayed by using anti-oestrogen drugs such as tamoxifen and the aromatase inhibitors. These were the first targeted drugs in breast cancer; indeed, they were probably the first targeted drugs in any area of cancer medicine.
In some women with hormone-receptor positive cancers, hormone therapy – also called endocrine therapy – is sufficient on its own to minimise the chances that the tumour will recur following an operation to remove all detectable tumour. In other women, hormonal agents are used together with cytotoxic drugs or other targeted therapies.
A notable example (in women with advanced breast cancer) is the use of hormone therapy in combination with a new kind of agent – palbociclib. Proteins called cyclin-dependent kinases (CDKs) promote the proliferation of tumour cells. Inhibiting the activity of CDKs 4 and 6 – which is achieved by giving palbociclib – delays breast cancer progression more than hormone treatment alone.
Non-hormonal drivers of tumour growth have also been identified. A particularly aggressive subtype of breast cancer has a gene abnormality that causes tumour cells to over-express the human epidermal growth factor receptor HER2. Once this became clear, pharmacologists developed antibodies that would block the receptor. Trastuzumab was the first such agent, and this has now been followed by pertuzumab and TDM-1. Scientists also developed small molecule drugs that act within the cell to block downstream growth signalling caused by receptor activation. Lapatinib is an important example.
In women with HER2-positive breast cancer who have had surgery to remove all that can be found of the tumour, therapy using anti-HER2 drugs – along with standard treatment – roughly halves the risk that the cancer will recur. If the cancer does return, anti-HER2 drugs can again be used.
But it is important to understand that even if the HER2 target is present on the tumour cells, there is no guarantee that an anti-HER2 drug will benefit a specific patient. We urgently need biomarkers that predict the sensitivity or resistance of individual tumours to drugs directed against the HER2 receptor. The same is true with drugs that target the oestrogen receptor.
As well as the molecular characteristics mentioned above, other markers may help distinguish between more and less aggressive breast cancers, and so in the personalising of treatment according to individual risk. Ki67, a marker that shows the speed of cancer cell proliferation, is an example. The predictive value of other markers is being investigated and we hope that their combined use will enable us to obtain a “genetic fingerprint” for a specific tumour, allowing therapy to be fine-tuned to the individual patient.
There are already statistical tools that combine the clinical and molecular characteristics of cancers to predict risk of recurrence following surgery. These can be used to guide treatment in individual patients.
Though their use holds great promise, the multiplicity of potential molecular markers is daunting. A further layer of complexity arises from the fact that the mechanisms responsible for tumour growth can change with time even within a particular patient. So a cancer that is HER2 positive when the primary tumour is first discovered may have become HER2 negative if the cancer returns. Repeated evaluation of the tumour may be required if we are to achieve the ultimate aim of personalised medicine, i.e. ensuring that the right drug is given to the right patient at the right time.
Taking all factors into account
So far, we have talked mostly about the characteristics of an individual patient’s tumour. Of course, we must also take into account the characteristics of the individual patient.
All effective treatments have side-effects, and patients differ in the risks that these pose. One important consideration is whether someone has diseases other than cancer – such as heart and blood pressure problems or diabetes – that may make them more susceptible to the toxicities associated with anti-cancer drugs. Another important factor is previous treatment.
A woman who has had certain drugs after breast surgery, to improve her chances of staying free of cancer, may have an unacceptable risk of side-effects if the same drugs are used again. Damage to the heart, for example, can be cumulative. Fortunately, there are classes of drug that are equally effective against the cancer while being less toxic to the heart.
It is also possible to reduce side-effects in patients at particular risk by choosing anticancer drugs that are a little less effective – but substantially less toxic – or by giving drugs at lower doses and more frequently.
Probably the most important consideration of all when personalising breast cancer care is to take the patient’s individual preferences into account. What does the patient most want from treatment? Is it – above all else – to improve the chances of cure, or to extend survival, or perhaps (in an elderly patient, for example) to maintain independence and quality of life?
There is much still to be achieved in the struggle against breast cancer, but women today have an unparalleled range of options when considering their aims in having treatment, and how best to achieve them.