In a new thesis, Mattias Hammarström studied whether lower doses of tamoxifen and also its active metabolite endoxifen for direct administration, as a preventive medication could reduce side effects while still affecting breast tissue in healthy women. The findings suggest that lower doses of tamoxifen and a low dose of endoxifen may offer a better balance between biological effects and side effects, potentially contributing to more individualised approaches to breast cancer prevention.
Breast cancer is the most common cancer among women worldwide. Although treatments have improved, preventing breast cancer remains an important goal. Some women may benefit from preventive medication, but for healthy women, the potential benefits must be balanced against side effects. Tamoxifen has been used to treat breast cancer for decades and can also reduce the risk of developing the disease. Endoxifen is considered one of the most active metabolites of tamoxifen and has not yet been evaluated as a new drug for breast cancer prevention. Tamoxifen and its metabolites block the effects of the hormone estrogen in breast tissue and thereby inhibit estrogen-driven cancer growth. However, side effects such as hot flashes and night sweats can discourage women from taking preventive treatment.
Mattias Hammarström is project manager In the KARMA programme and PhD student at the Department of Medical Epidemiology and Biostatistics , Karolinska Institutet, and his thesis includes four studies, based on two randomised, placebo-controlled clinical trials, the KARISMA trials, in healthy women treated for six months.
What have you done in your studies?
“We investigated different doses of tamoxifen and endoxifen and examined side effects, treatment adherence and changes in mammographic breast density. We used breast density as a measure of treatment response. Some previous studies indicate a lower breast cancer risk if density declines during treatment, although it does not prove that a treatment prevents breast cancer.”
What are the most important results in your thesis?
“Lower doses of tamoxifen were associated with less severe side effects, particularly among women who had not reached menopause. In these women, low levels of endoxifen in the blood were also associated with similar reductions in breast density, seen in the standard 20 mg dose of tamoxifen. My studies also showed that side effects can influence whether women continue taking preventive medication. We found that early worsening of symptoms such as hot flashes was associated with subsequent non-adherence of tamoxifen. When endoxifen was given directly, both 1 mg and 2 mg reduced breast density compared with placebo. Women receiving 1 mg reported a similar symptom profile to those receiving placebo, while 2 mg was associated with more hot flashes and night sweats. Together, the findings support further research into lower-dose tamoxifen and low-dose endoxifen as possible ways to achieve a better acceptance and uptake in primary breast cancer prevention in women with a high risk of breast cancer.”
Why did you become interested in this topic?
“Our research group has been working for more than 15 years to reduce the burden of breast cancer through prevention. Initially, I worked as a clinical trial manager, coordinating the practical aspects of our studies, including staff, study protocols, monitoring and trial operations. Later, I had the the opportunity to become more involved in the scientific work through PhD studies. I share the vision of our entire research group: if we can prevent breast cancer before it develops, we can reduce both the suffering experienced by individuals and the costs to society. However, our goal should not be to offer preventive treatment to as many women as possible, but to identify those most likely to benefit, while carefully balancing the potential benefits and harms for each individual.”
What do you think should be done in future health care and research?
“The most important next step is to investigate whether lower doses of tamoxifen and oral endoxifen can also reduce breast cancer incidence. Our studies used mammographic breast density as a biomarker of treatment response. Although reductions in breast density are associated with lower breast cancer risk, we cannot conclude that the reductions observed in our studies translate into fewer breast cancers. Therefore, larger studies with long-term follow-up are needed to establish their preventive effectiveness.”
Doctoral thesis
Mattias Hammarström, November 2026.
Facts about doctoral theses
A doctoral thesis is the final written product of a postgraduate education, which in Sweden corresponds to four years of full-time studies. It varies between different disciplines how a doctoral thesis is structured. In the field of medicine, the doctoral student usually collects three to five scientific articles and presents them together with a thesis summary or overview, a so-called ‘kappa’ (literally meaning overcoat in Swedish).
After the doctoral student has passed the public defence of the thesis, he or she receives a doctoral degree (also called a PhD), which is the highest possible educational degree in Sweden. Karolinska Institutet has approximately 2,000 active doctoral students and each year approximately 350 doctoral theses are published at our university.
