The Karma research group at Karolinska Institutet is creating the world’s best-characterized breast cancer cohort. The aim is to reduce the mortality and incidence in breast cancer through translational research focusing on breast cancer prevention.

Karma researcher identifies discontinuation of adjuvant hormone therapy as a major problem in breast cancer care

That adjuvant hormone therapy lowers the risk of breast cancer recurrence by approximately 40 per cent and breast cancer specific mortality with approximately 30 per cent has been shown in numerous studies. Proportion of women that stop taking their medication ranges from 20-70 per cent but few studies have addressed predictors of discontinuation of adjuvant hormone therapy.

In a study published in June 2015 (Wei He, Fang Fang, Catherine Varnum, Per Hall, Mikael Eriksson, Kamila Czene, Journal of Clinical Oncology) it was found that women at higher risk of discontinuation were more likely to have a family history of ovarian cancer, to be younger than 40 years or older than 65 years, and to use analgesics and hypnotics /sedatives. These results are most clinically relevant since doctors can use the results to identify factors that predict which patients will stop using adjuvant hormone therapy.

The research on discontinuation is continuing with a focus on breast cancer patients that after discontinuation later takes up therapy. To restart therapy is to the benefit of patients but the prognosis does not reach that of those patients that sticks to therapy. However, it is significantly better than for those who stops altogether. The paper is accepted for publication in Journal of the National Cancer Institute.

The second phase of Karisma is about to start

One of the focuses of Karma is to reduce the number of women diagnosed with breast cancer. There are several ways of decreasing the risk of breast cancer. Interventions range from increased physical activity to prophylactic mastectomy (surgically removing the breasts). The Karma Intervention Trial, Karisma, aims at identifying the optimal preventive dose of the anti-hormonal drug tamoxifen.

Tamoxifen is used by breast cancer patients to lower the risk of a breast cancer recurrence. It has been shown that perfectly healthy women lower their risk of breast cancer by 50% if they use tamoxifen. However, tamoxifen is not used for prevention due severe side effects.

It is not obvious that the same dose should be used for prevention as the dose given to breast cancer patients. We are therefore testing if lower doses of tamoxifen have the same therapeutic effect as clinically accepted 20 mg.

Identifying women at increased risk of interval cancers

Using data from the Karma Cohort, Mikael Eriksson, Karolinska Institutet, has developed a risk prediction tool that identifies women at very high of developing an interval cancer. Interval cancers are breast cancers diagnosed in the interval between two scheduled mammography screens. Interval cancers are considered to particularly aggressive cancers but are quite heterogeneous in their clinical behavior.

A tool that identifies women at high risk of interval cancers has the potential to improve mammography screening programs through selection of women that are in need of additional examination and not just a mammogram.

A manuscript has been submitted to Breast Cancer Research.

First thesis based on the Karma Study published

On the 15th of January, Dr Thang Thrinh, Karolinska Institutet, defended his thesis entitled ”Determinants of breast cancer risk; focusing on mammographic density”. Thang’s thesis deals with how physical activity, alcohol consumption and cigarette smoking affect the risk of breast cancer through their influence on mammographic density.

Mammographic density is defined as the radiographically dense tissue, consisting of glandular and connective tissues, appearing bright on a mammogram, whilst non-dense, fatty tissue appears dark on a mammogram. The more bright the mammogram, the more glandular cells and the higher the risk of developing breast cancer. See images below (left: non-dense breast, right: highly dense breast).

Women who participated in the Karma study answered a large number of questions related to lifestyle when they entered the study. Participants were invited to the study when they performed the biannual mammography screening. Dr Thang wanted to find out if women who, for example, drank more wine had more dense breasts than women who totally abstained from alcohol.

In short, the conclusions that could be drawn from this thesis was:

Women who were physically active had a lower mammographic density, which most certainly reduces the risk of breast cancer. The more vigorous the physical activity, the lower the breast density. We also wanted to find out if women with an increased risk of breast cancer needed to do harder physical exercise than women with a lower risk. Background risk of breast cancer was estimated using the Tyrer – Cuzick score. Our findings suggested that women with a higher background risk of breast cancer needs to be more physically active, to reduce breast density, than women with lesser background risk.

Regarding alcohol consumption the findings are quite the opposite. The more alcohol a woman drinks, the higher the breast density and the higher the risk of breast cancer. However, it seems that daily consumption of wine has to exceed 1 glass wine/day to influence breast density. Similar to the findings of physical activity, background risk of breast cancer influenced how alcohol affects mammographic density. If you have a high risk of breast cancer you should be careful with alcohol.

Finally dr Thang studied change in mammographic breast density among cigarette smoking women. Surprisingly enough, in women who smoke the density is lower than in non-smoking women, despite the fact that smoking is known to increase the risk of breast cancer. Thang explained the effect of cigarette smoking on breast density as tobacco having an ”anti-hormonal” effect (which lowers the density) but that tobacco contains so many other toxic / carcinogenic substances that increase the risk of breast cancer so the overall effect is an increased risk of breast cancer.

Professor Per Hall, dr Thang’s supervisor, comments on the results: ”The findings are exciting and show that in the future, when we are able to predict a woman’s individual risk of breast cancer, lifestyle related advise can be given in preventive breast cancer care. As a matter of fact, already today, we can advise women who wish to reduce their risk of breast cancer to be physically active, drink moderately and not to smoke.

Karma launch Karisma, a randomized clinical trial, to identify an optimal Tamoxifen dose for reducing risk of breast cancer.

Tamoxifen has been used for several years as adjuvant therapy for women diagnosed with breast cancer. Tamoxifen was introduced already in the 1970s and reduces the risk of breast cancer recurrence with approximately 30%. Recent studies also indicate that use of Tamoxifen as primary prevention for healthy women at high risk reduce breast cancer incidence.

Despite the remarkable risk reduction in preventive studies, primary preventive strategies are scarcely part of clinical routine. There are several possible reasons for the reluctance. The major one being that the side effects of these therapies are not trivial. Serious side effects could only be acceptable for those that benefit from therapy, that is, there is a need of identifying women at high risk.

Also, there is not a consensus on dose needed in the preventive setting. So far only full therapeutic dose has been tested and no attempts have been made to determine if lower doses prevent women from being diagnosed with breast cancer.

As a first step toward a larger prospective study the Karma group are now planning to launch a randomized, double-blind, placebo controlled trial to investigate the mammographic density reduction at different doses of Tamoxifen.

Our aim is to identify an optimal Tamoxifen dose for reducing risk of breast cancer. Mammographic density reduction will be used as a proxy for therapy response and thereby indirectly incidence.

A pilot study started march 2015 and is ongoing. A roll-out of a full scale trial is planned to be be launched during 2016.