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 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). 

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. 

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. 

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. 

The last participants have now ended their participation in Karma Crème-1 and the study is officially closed. Analyses are on-going and we are expecting to publish the results during the autumn 2019.

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. 

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.

On the 23^rd 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: https://openarchive.ki.se/xmlui/handle/10616/46178?_ga=2.116600580.308538842.1529001747-1483963573.1452614977

The Karisma 2 trial on dose optimisation of tamoxifen for preventive use has now reached 800 participants in Lund and in Stockholm and has thereby reached the halfway through milestone. Karisma 2 in expected to close the inclusion by December 2018.

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:

https://www.nature.com/articles/nature24284

https://www.nature.com/articles/ng.3785

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