Low doses of the investigational medicinal product endoxifen reduce breast density to the same extent as the standard treatment tamoxifen, but without causing such troublesome side effects. This is shown by a new study from Karolinska Institutet published in the Journal of the National Cancer Institute. The results may have implications for future preventive treatment of breast cancer.

Tamoxifen is a well-established drug that has been used for more than 40 years to reduce the risk of recurrence in patients with breast cancer. The drug is also approved for prevention of breast cancer in women at increased risk.

However, the side effects of tamoxifen are a major problem. Many women experience menopausal-like symptoms, such as hot flushes, which means that many do not complete the treatment.

Endoxifen is the most active metabolite formed when tamoxifen is broken down in the body. The new study investigated whether endoxifen in tablet form could provide the same biological impact and a more predictable effect than tamoxifen.

A total of 240 healthy, premenopausal women were randomised to receive a placebo or 1 or 2 mg of endoxifen daily for six months. The researchers then measured mammographic breast density. High mammographic density can contribute to an increased risk of breast cancer but a reduction during treatment can be a good measure of therapeutic outcome.

”Both 1 and 2 milligrams of endoxifen resulted in a clear reduction in breast density compared with the placebo,” says Mattias Hammarström, co-author and PhD candidate at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.

The results show that 1 mg of endoxifen reduced breast density by an average of 19 per cent and 2 mg by 26 per cent. Data from a previous study show that 20 mg of tamoxifen reduces density by approximately 18.5 per cent. The effect of low-dose endoxifen thus corresponded to that seen with tamoxifen.

Participants who received 2 mg of endoxifen reported a greater worsening of hot flushes and night sweats compared with the lower-dose group, whilst the 1 mg group had a safety profile similar to that of the placebo with respect to serious side effects and biomarkers.
”Our results suggest that a lower dose may be sufficient to affect breast density, whilst also appearing to be better tolerated,” says Mattias Hammarström.

The study is a so-called proof-of-concept trial, meaning it is designed to demonstrate that a treatment produces the expected biological effect before larger and longer trials are conducted. However, the study cannot show whether endoxifen reduces the risk of breast cancer or recurrence.
The study is funded by Atossa Therapeutics. Several researchers report links to the company. See the study for more information.

Publication
”Endoxifen for mammographic density reduction – results from the karisma endoxifen trial”, Per Hall, Mattias Hammarström, Jenny Bergqvist, Kamila Czene, Mikael Eriksson, Marike Gabrielson, José Tapia, Steven Quay, Stephen Nash, Magnus Bäcklund, Journal of the National Cancer Institute, online xx 2026, doi: 10.1093/jnci/djag087

After piloting for feasibly in 2024, the SMART trial (Stockholm MAmmography Risk stratified Trial) is now in full recruitment mode. Including two main hospitals, Södersjukhuset and Capio St Göran, in the Stockholm area, covering ≈ 70% of all women included in the mammography screening program in Stockholm. SMART will recruit a total of 46 000 women.

The overarching aim of SMART is to compare the effectiveness of current screening practice with screening based on the individual risk of breast cancer.

In SMART women who recently had a normal mammogram will be randomised to either an intervention or control arm. Women randomised to the intervention arm will have their 2-year breast cancer risk assessed upfront. This is done via an AI (artificial intelligence) derived analysis of the mammograms. Women scored with an increased 2-year risk will be offered a contrast enhanced mammography (CEM) within 2 months of baseline mammogram and an additional mammography 12 months after baseline mammography. It is anticipated that a little less than 20% of all women will be considered at elevated risk. The control group will consist of women randomised identified as having the same increased 2-year risk of breast cancer.

The possible benefits of individualised screening will be contrasted to the possible harms defined as unnecessary recalls, biopsies and induced anxiety and worry.

SMART (Stockholm MAmmography Risk stratified Trial) is a phase 2 study conducted at the mammography unit at Södersjukhuset (Stockholm South General Hospital), Sweden. The purpose of the study is to test if individualized, risk-based breast cancer screening is superior to current practice in Sweden. In SMART we will test if an individualized, imaging-based AI screening model is a more effective way of detect women with the highest risk of developing breast cancer in the next two years. The SMART study is expected to enroll 70,000 women who will join following their regularly scheduled bi-annual mammogram. The SMART study starts to enroll participant during 2024.

The researchers in SMART now have the pleasure to announce that the US based company, Atossa Therapeutics inc, a clinical-stage biopharmaceutical company is going to support the study.

Please read Atossa Therapeutics press release about why they think SMART is an important study to support. Link to press release

In an exploratory analysis of the KARISMA trial, we took advantage of the full 48-item KARISMA symptom questionnaire to describe the complete side effect spectra at different doses of tamoxifen in healthy women.

We found that symptoms and adherence are influenced by menopausal status. Premenopausal women on 20 mg standard dose decreased in weight and waist circumference as well as in breast sensitivity. In addition, postmenopausal women reported higher symptom severity across all doses and discontinuation rate was two-fold compared to premenopausal women.

We identified five symptoms which constitute the greatest magnitude of severity change after 20 mg tamoxifen exposure, independent of menopausal status: hot flashes, night sweats, cold sweats, vaginal discharge and muscle cramps. Interestingly, we did not find any increase in severity scores in ten pre-defined psychological symptoms.

When comparing the top5 symptoms in premenopausal women randomized to low-dose (2.5, 5 mg) versus high-dose (10, 20 mg), the mean change was 34% lower in the low-dose group. No dose dependent difference was seen in postmenopausal women.

Our findings give new insights which may influence future dosing strategies of tamoxifen in both the adjuvant and preventive settings.

Hammarström, et al. Br J Cancer. 2023 May 6. DOI: 10.1038/s41416-023-02293-z