Individually tailored treatment to reduce mortality

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Increased knowledge about the risk factors for breast cancer has made it possible to identify women who run the highest risk of being affected. Scientists are now working towards turning theory into practice - large-scale preventative initiatives and more individually tailored treatment are to reduce mortality from the disease dramatically.

One in eight women in Sweden will receive a diagnosis of breast cancer - it is the most common form of cancer among women. The prognosis for such patients has improved significantly during the past 30 years, but the number of women affected has increased during this period. This means that breast cancer causes as many deaths today as it did 30 years ago, despite intense research and advances in the care available. This can be compared with the case of cardiovascular disease, where mortality has been halved during the same period.

Bild på Per Hall

"This is an ongoing epidemic, and we should not accept it. We have not made the same progress in cancer as we have in cardiovascular disease, but I am convinced that we will", says Per Hall, Professor in Radiation Epidemiology at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.

A new research project

Per Hall and Professor Jonas Bergh are leading a new research project, known as the "Märit and Hans Rausing's Breast Cancer Initiative". The project has been made possible by a large donation from the Rausing family, and its overall aim is to reduce in the long term the number of newly diagnosed breast cancer cases by 40-50%. New methods to reduce the risk of women being affected by breast cancer will be developed within the framework of this project. The project also involves a major investment to develop improved diagnostic methods and treatment, so that those who are affected obtain the best possible care. The successful campaign against cardio-vascular disease will function as a model for the project. This campaign discovered a number of important risk factors at an early phase (blood lipid levels, high blood pressure, smoking, etc.) and made it possible to identify individuals at risk at an early stage and provide preventative treatment.

Around 10 factors are known to influence the risk of being affected by breast cancer. Most are related in one way or another to levels of the female sex hormones progesterone and oestrogen, both of which stimulate cell growth and may, under certain circumstance, increase the risk of cancer. In addition, 18 genetic alterations that increase the risk of breast cancer have been identified; the reasons for this are in many cases more or less unknown. All women over 40 years of age are currently offered mammography screening, which seeks to detect early tumours.

The new project is to investigate the prospects of expanding the Swedish screening programme, so that it identifies not only early cases of cancer but also healthy women who run a much higher risk of subsequently developing cancer. The first phase of the project will involve inviting all women undergoing mammograms in Stockholm to take part in the project. Those who agree to take part will provide a blood sample for genetic analysis and will reply to a web-based questionnaire concerning lifestyle.

"After we have collected and analysed the information, we will be able to distinguish between women who run a low risk and women who run a high risk. Those at low risk are spared unnecessary worry, and may not need to return for any further investigations. Preventative measures can be provided for those at high risk and we hope in this way to prevent breast cancer in many women who would otherwise develop the disease", says Per Hall.

Breast density

One factor that may have major significance in the assessment is the difference between breast densities. This can be easily determined from the mammograms, but is not currently used as a prognostic factor. Scientists know, however, that women with very dense tissue in the breasts, and low levels of fat, run a risk of being affected by breast cancer that is approximately six times higher than that of women with low density. But they do not know what the dense regions of the breast consist of, nor do they know why the density influences the risk of cancer.

Bild på Arne ÖstmanArne Östman, Professor in Molecular Oncology at the Department of Oncology-Pathology, is one of the scientists at Karolinska Institutet who are examining the role of breast density. He is leader of the STARGET research network, in which cancer researchers are studying two cell types that have previously been considered to be of limited significance for cancer: pericytes, which are found in blood vessels, and fibroblasts, which are a form of connective tissue cell.

"It may be the case that it is not only the glandular tissue in the breast that contributes to the development of cancer, as has been assumed. The connective tissue between the glands may play a role. We are planning to test this hypothesis by characterising the glandular tissue and connective tissue in women with different breast densities", says Arne Östman.

A genetic test in addition to the measurement of breast density may give valuable information, but this part of the project lies in the future.

"The first step is to identify more genes. The risk-associated genes that we have identified account for only a few percent of breast cancer cases", says Per Hall. He is coordinating a research project together with scientists at Cambridge University in which 55 international research groups are together looking for genetic alterations that are coupled with breast cancer. The scientists agree that the most effective way of reducing mortality from breast cancer is to prevent the disease. The only question is: how to proceed?

"The fact that it is difficult to influence the risk factors for breast cancer is a difficult dilemma. It is not possible to change either the density of your breasts or the composition of your genes, and it is difficult to convince a woman to start a family early by arguing that this will reduce the risk of breast cancer", says Per Hall.

Preventative medicines

Preventative medicines will almost certainly be more important in combating breast cancer than changes in lifestyle, although there are no good preventative medicines available. While it is true that one drug that is used in the treatment of breast cancer, the hormone inhibitor tamoxifen, reduces the risk of the disease by approximately 40%, even in healthy women, this drug is not given to healthy women since the adverse effects are considered to be too severe. It remains to be seen whether this assessment will be maintained if scientists are able to identify a fraction of the population who run a very high risk, which may be as high as 50%, of developing breast cancer and who would benefit from this treatment.

Women who are affected by breast cancer generally undergo surgery, followed by radiation therapy of the breast and chemotherapy. The purpose of the chemotherapy is to prevent recurrence, which often means spread of the cancer in the body and a dramatically poorer prognosis. Taking preventative medicines has not always been a part of the treatment of breast cancer, and its introduction led to a major fall in the risk of recurrence.

Tailored treatment

Bild på Jonas BerghHowever, it is still difficult for doctors to know in any individual case what type of preventative treatment will be most effective. The choice of treatment is based on, among other things, a number of properties of the breast cancer tumours that can be analysed, such as size, spread, hormone sensitivity, rate of growth and alterations in a gene known as HER-2/neu.

"This gives some idea of the prognosis, but it is a poor basis for knowing which treatment is going to work best. Some women who should have a good prognosis suffer recurrence, while others with a poor prognosis remain unexpectedly healthy. Thus there is a great deal of interest in finding better ways of giving the right treatment to the right person", says Jonas Bergh, Professor in Oncology at the Department of Oncology-Pathology

Jonas Bergh's research group has specialised in the clinical testing of new cancer drugs, the development of diagnostic methods, and the development of treatments. One aspect of the group's work is the analysis of breast cancer markers, seeking gene alterations and molecular markers that can be used to improve diagnosis. The aim is to produce a larger set of prognostic factors that can form the basis for assessing prognosis and determining treatment. The tumours have been collected at the Karolinska Institutet biobank, to which blood and tumour tissue from patients who want to contribute to research is continuously being added. The diagnostic techniques currently available allow doctors to differentiate between 4-5 main types of breast cancer tumour, and they can then choose between around 20 different drugs. Jonas Bergh believes that considerably more drugs will be available in the future, specially designed to optimise the treatment result for various subgroups of patients.

"We hope that the pharmaceutical industry will develop new medicines that can be used to prevent breast cancer in healthy women who are known to run a high risk. Unfortunately, there is little research under way in this field at the moment", says Jonas Bergh.

Long-term side effects

As the probability of surviving breast cancer has increased, the long-term side effects of radiation therapy and chemotherapy have become an ever-greater problem, something that Per Hall has shown in several studies. Radiation therapy of left-side breast cancer increases the risk of myocardial infarction, while leukaemia is more common in women who have undergone chemotherapy. Research is under way to find out whether reducing the radiation dose can reduce the harmful effects, which may arise several decades after the original treatment.

Both Per Hall and Jonas Bergh emphasise that the situation for breast cancer patients is much better in Sweden than it is in many other countries. There are many reasons for this, including a good national collaboration between scientists and decision-makers. Sweden has been the first country in the world to introduce several important measures, such as mammography and various new treatments.

"If you are going to be affected by breast cancer anywhere, then you should do it in Sweden," says Per Hall, "the prognosis for breast cancer patients here is among the best in the world."

Risk factors

The factors that influence the risk of developing breast cancer are nearly all related, directly or indirectly, to the levels of female sex hormones. The exception to this is previous exposure to radiation.

Strong influence

  • Age
  • Carrying the gene BRCA1 or BRCA2
  • High density of breast tissue

Medium influence

  • Family history of breast cancer
  • Early exposure to radiation
  • Use of hormone substitute therapy

Weak influence

  • High age at first pregnancy
  • Low age at first menstruation
  • High alcohol consumption
  • High BMI after menopause

Text: Ola Danielsson. Published in the magazine "Medicinsk Vetenskap", no 2 2010.

Tumour Biology