Category Archives: news

SMART supported by Atossa Therapeutics Inc

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

KARISMA results: Side effects of low-dose tamoxifen

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

Karma CREME results: Topical endoxifen lowered breast density, but came with unacceptable skin toxicity. 

In the 3-armed double-blinded randomized clinical trial Karma CREME we found that a daily local application on the breast skin with a lotion, containing the tamoxifen metabolite Z-endoxifen, can lower the mammographic breast density already after a few weeks of use.

Ninety women, 30 in each dose arm, were randomized to placebo, 10 and 20 mg of topical endoxifen for 6 months. They were instructed to apply the lotion every morning on the skin on both breasts. Mammographic density and symptoms were measured at baseline and study exit.

After 3-4 weeks of participation in Karma CREME many women started to notice skin rashes on their breasts, some with itching. Women who tried to continue experienced worsening of the skin reaction, with spreading of rashes outside the breast area. After contact with the study staff these participants were advised to immediately stop using the application. They were called in for physical examination, blood sampling and a follow-up mammogram.

After unblinding it was obvious that the skin toxicity was related to topical endoxifen and not only to the lotion: Only 2 of the 30 women in the lower dose (10 mg) completed the 6 months of treatment, none of the 30 women in the higher dose (20 mg). Of the participants in the placebo group 23 of the 30 women completed the 6 months. The mean time to study exit was 1.6, 2.5 and 4.9 months in the 20 mg, 10 mg and placebo group, respectively.

Despite the high discontinuation rate, driven by skin rashes, we found a significant mammographic density decrease, a dose dependent increase in plasma concentration of Z-endoxifen with no systemic side effects. Thus, topical application of tamoxifen metabolites has a potential to decrease breast cancer incidence without major systemic side effects. However, endoxifen is not suitable for daily topical administration.

In previous pilot studies with topical endoxifen, the exposure had been limited to single doses.

Karma CREME gave us insights on the challenges with finding an acceptable dose regimen for topical applications. This lead to a changed focus and planning of a study with per oral endoxifen (KARISMA Endoxifen).

Bäcklund M, et al. Topical Endoxifen for Mammographic Density Reduction-A Randomized Controlled Trial. Oncologist. 2022 May 23:oyac102. doi: 10.1093/oncolo/oyac102.


CYP2D6 genotype predicts tamoxifen discontinuation and drug response in the KARISMA trial

In an analysis of the KARISMA trial investigating tamoxifen response by CYP2D6 metabolizer status we found that discontinuation was higher in poor CYP2D6 metabolizers compared to less efficient metabolizers.

One in three ultrarapid CYP2D6 metabolizers discontinued tamoxifen therapy within 1 month, which is substantially higher than in poor metabolizers.

In addition we demonstrated that poor CYP2D6 metabolizers experienced no mammographic density reduction whereas ultrarapid CYP2D6 metabolizers experienced statistically significant mammographic density reduction, higher endoxifen level and more side-effects.

He, et al Ann Oncol. 2021 Oct;32(10):1286-1293. doi: 10.1016

Karma starts new clinical trial on contrast enhanced mammography

Karma Kontrast is a randomised clinical trial conducted at the mammography unit at Södersjukhuset (Stockholm South General Hospital), Sweden, in collaboration with researchers at Karolinska institutet. The trial will study if contrast enhanced mammography can be used to improve mammography screening. Karma Kontrast is anticipated to go on until January 2022 and will enrol 420 participants. 

Due to the pandemic situation enrolment is postponed.

Read more about the trial here (in Swedish only). 

Karisma 2 Biopsy study on low-dose tamoxifen

Analyses are ongoing in the Karisma 2 Biopsy study. Karisma 2 Biopsy is a nested cohort within the Karisma 2 clinical trial on low-dose tamoxifen, conducted during 2017-2019 in Sweden. In all, 96 participants donated breast biopsied before and after treatment with tamoxifen or placebo. Analyses are ongoing and results are expected after the summer. 

Karisma 2 clinical trial on low-dose tamoxifen is completed

We have now completed the Karisma 2 randomised clinical trial on low-dose tamoxifen. In all, 1,440 women were included in the Swedish two-centre study, at Södersjukhuset in Stockholm and at Unilabs in Lund. 

The results are being analysed and the first paper is expected to be published after the summer 2020. 

Karisma-2 is a dose optimisation study using tamoxifen for preventive use. Women were randomised to five arms of tamoxifen or placebo and were treated for six months. 

Papers on Mammographic Density Change and breast cancer

Doctoral student Shadi Azam has recently published two papers investigating mammographic density change using the KARMA cohort. 

In a first paper studying the determinants of change, Azam and colleagues conclude that most risk factors for breast cancer are associated with baseline mammographic density. In contrast, only age, BMI and physical activity are determinants of mammographic density change. 

In a second paper, Azam et al. suggest that, although mammographic density is a strong risk factor for breast cancer, mammographic density change does not influence breast cancer risk. Furthermore, density change does not seem to influence the association between baseline mammographic density and breast cancer risk. 

The papers can be found at: 

Determinants of Mammographic Density Change.

Azam S, Sjölander A, Eriksson M, Gabrielson M, Czene K, Hall P.

JNCI Cancer Spectr. 2019 Feb 4;3(1):pkz004. doi: 10.1093/jncics/pkz004. eCollection 2019 Mar.

Mammographic Density Change and Risk of Breast Cancer.

Azam S, Eriksson M, Sjölander A, Hellgren R, Gabrielson M, Czene K, Hall P

J Natl Cancer Inst. 2019 Jul 12. pii: djz149. doi: 10.1093/jnci/djz149. 

Inclusion to Karisma-2 now completed

We have now completed the inclusion of 1,440 women in the Karisma-2 double-blinded clinical trial at the breast centre at Södersjukhuset in Stockholm and at Unilabs in Lund. 

Karisma-2 is adose optimisation study using tamoxifen for preventive use.Women were randomised to five arms of tamoxifen or placebo and are treated for six months. 

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.

Preliminary results are expected in late autumn 2019. 

Karma participants answer questionnaire about breast cancer risk communication

Around 62,000 Karma participants have recently received emails regarding strategies for breast cancer risk communication. The Karma group aim to collect questionnaire data from the Karma participants on whether they want to know about their individual risk of breast cancer, and if so, how and by whom the risk should be communicated to the women. 

– The Karma project is currently developing a model for individual risk prediction, says Professor Per Hall, PI of the Karma study. 

– But before we test such a model in real life and in the clinics, we need to have a better understanding of how women perceive risk, and how we best can communicate about risk in a screening setting. What do screening women consider as gains and losses by changing the screening routine, and are the women interested in participating in preventive strategies such as physical activity and dietary consultation, says Per Hall. 

The risk communication questionnaire in an international collaboration between researchers in Sweden, the UK and the Netherlands. 

– Sweden has always been in the frontline regarding breast cancer screening therefore it is only logical that we are now taking the next step, says Per Hall. 

– I am convinced that we will be the first in the world to implement individualised and risk based breast cancer screening.

Swedish media covers Karma CREME-1 study start

Earlier this month the Swedish national television (SVT) visited the Karma study center and met with professor Per Hall, principal investigator of Karma CREME-1 and other personal at the center.

Lisa Frimoding, the first included participant in Karma CREME-1 was interviewed and said – “I think it is important to participate in these types of studies, it may truly help those that are affected. And I might be affected in the future, or my daughter, or mother, or sister”.

“Today we are quite good at predicting which women have a high risk of developing breast cancer, based on breast density, family history, and lifestyle factors. If this crème is working, those women willing to have their individual risk assessed should also be offered medications to reduce the risk of developing breast caner”, says Per Hall.

The complete story can be found here (in Swedish only):

Karma clinical trial on topical endoxifen soon opens for inclusion

The Swedish Medical Products Agency (MPA) has approved a Phase 2 study of topical endoxifen for preventive treatment of women with mammographic breast density. The study, called Karma CREME-1, will be conducted at Stockholm South General Hospital in Sweden and will be led by principal investigator and Karma cohort initiator Dr. Per Hall, MD, Ph.D., Head of the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet. The topical endoxifen is developed by Atossa Genetics Inc. The study will open for inclusion by the end of June 2018.

Thesis on aggressive breast cancer based on the Karma study published

On the 23rd of February, Dr Johanna Holm defended her thesis entitled “Aggressive breast cancer: epidemiological studies addressing disease heterogeneity”, partly based on Karma samples. In her thesis, Dr. Holm was seeking to increase our understanding of aggressive breast cancer, and how risk factors may be related to it. Her work highlight that interval breast cancers in women with low mammographic density have the most aggressive phenotype, and also suggest disparate genetic backgrounds of screen-detected breast cancers and interval breast cancer. She also show that women at high risk of breast cancer based on genetic and lifestyle factors were significantly more likely to be diagnosed with breast cancer with a favourable prognosis. Her work emphasises that breast cancer subtypes have different aetiologies and highlight the need to identify risk factors separately for distinct breast cancer subtypes and ages of onset.

Link to Dr. Holms thesis:

Karma cohort part of novel discoveries of new genetic breast cancer risk variants

As part of international research consortium including Karma samples, 72 new gene variants that predispose to breast cancer have been identified through an analysis of genetic data from more than 275,000 women, whereof 146,000 with breast cancer. Many of the genes lie in regulatory, rather than coding regions, and some are specific for oestrogen receptor negative breast cancer. “These findings add significantly to our understanding of the inherited basis of breast cancer,” commented Doug Easton, Ph.D., from the University of Cambridge, U.K., one of the lead investigators for the OncoArray consortium, to GEN News. The consortium includes more than 550 researchers at 300 research facilities across the globe.

The OncoArray consortium’s results are published in Nature and in Nature Genetics.

Links to articles in Nature and in Nature Genetics:

The first Karma based model for predicting risk of breast cancer has been published

One of the key aims of the Karma Project is to identify the women that eventually will be diagnosed with breast cancer. In collaboration with the Swedish mammography screening program we identified increased levels of mammographic density, microcalcifications and suspicious lumps in the breast as key factors for breast cancer risk. We created a risk model to identify the women who are at high risk after a negative mammography to develop breast cancer until the next mammography visit. In the paper (Eriksson et al, 2017) we show that the high-risk women had a nearly 9-fold increased risk of breast cancer compared to the low risk women. In the full model, also accounting for age of the woman, body-mass-index, use of hormonal replacement therapy, and family history of breast cancer, we identified a small proportion of women who had a very high risk for breast cancer within two years after a regular mammography visit.

The paper was published in Breast Cancer Research, March 2017.

Eriksson M, Czene K, Pawitan Y, Leifland K, Darabi H, Hall P. A clinical model for identifying the short-term risk of breast cancer. Breast Cancer Res. 2017 Mar 14;19(1):29. doi: 10.1186/s13058-017-0820-y. PMID: 28288659

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.