Category Archives: news

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):

https://www.svt.se/nyheter/vetenskap/ny-metod-provas-mot-brostcancer-salva

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: https://openarchive.ki.se/xmlui/handle/10616/46178?_ga=2.116600580.308538842.1529001747-1483963573.1452614977

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:

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

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

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.

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.

Karma researchers use exome sequencing of plasma DNA for non-invasive monitoring of tumor burden

Non-invasive monitoring of tumor burden hold great promise for early detection of recurrent breast cancer. Karma researchers recently evaluated and improved exome sequencing to interrogate trace amounts of breast tumors in the plasma of breast cancer patients. “We are encourage by the results”, says Daniel Klevebring, lead author of the study. The researchers are now planning a larger study to investigate the use of exome sequencing of plasma in a primary setting.

Published in PlosOne, Aug 2014. Link to the published paper:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0104417

Karma validates volumetric breast density measurement tool

KARMA is the first study validating the performance of a volumetric breast density software (VolparaDensity) in a large-scale setting. Results of the study show that distributions of volumetric density are similar across different vendor platforms and that Volpara breast density is associated with established density determinants and breast cancer risk.

Link to published article:

Cancer Epidemiol Biomarkers Prev. 2014 Sep;23(9):1764-72. doi: 10.1158/1055-9965.EPI-13-1219. Epub 2014 Jul 10. Link to Pubmed: http://www.ncbi.nlm.nih.gov/pubmed/25012995

Karma plans a randomized clinical trial to investigate the effect of different doses of Tamoxifen through measuring the decrease of breast density in healthy women.

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.

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.

The clinical trial is in planning phase and will be launched during 2015

Breast cancer researcher connected to Karma wins L’Oreal women’s science fellowship

Dr Li Jingmei, 31, received this year’s UNESCO-L’Oreal International For Women In Science Fellowship, one of 15 women scientists around the world to do so. Li Jingmei currently work as postdoctoral research fellow at the Agency for Science, Technology and Research’s Genome Institute of Singapore, but have strong connections to Karolinska Institutet and the Karma-group

She will receive her award at a ceremony in Paris this month.

With her US$40,000 award, Dr Li will spend two years at Karolinska Institutet in Sweden, where she previously completed her doctorate in medical science.

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Dr Li Jingmei with mammogram images, which she studies to see how breast density predicts cancer risks. A young breast cancer researcher from Singapore will soon have the chance to continue her research on the data from the Karma cohort, thanks to a prestigious international science fellowship. — PHOTO:  L’OREAL SINGAPOR

Study shows mammographic density reduction as a prognostic marker of improved survival

Mammographic Density Reduction Is a Prognostic Marker of Response to Adjuvant Tamoxifen Therapy in Postmenopausal Patients With Breast Cancer

Tamoxifen treatment is associated with a reduction in mammographic density and an improved
survival. However, the extent to which change in mammographic density during adjuvant
tamoxifen therapy can be used to measure response to treatment is unknown.

Overall, 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up
mammogram were eligible for analysis. On the basis of treatment information abstracted from
medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic
density was measured by using an automated thresholding method and expressed as absolute
dense area. Change in mammographic density was calculated as percentage change from
baseline. Survival analysis was performed by using delayed-entry Cox proportional hazards
regression models, with death as a result of breast cancer as the end point. Analyses were
adjusted for a range of patient and tumor characteristics.

During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. Women treated with
tamoxifen who experienced a relative density reduction of more than 20% between baseline and
first follow-up mammogram had a reduced risk of death as a result of breast cancer of 50% (hazard
ratio, 0.50; 95% CI, 0.27 to 0.93) compared with women with stable mammographic density. In
the no-tamoxifen group, there was no statistically significant association between mammographic
density change and survival. The survival advantage was not observed when absolute dense areas
at baseline or follow-up were evaluated separately.

A decrease in mammographic density after breast cancer diagnosis appears to serve as a
prognostic marker for improved long-term survival in patients receiving adjuvant tamoxifen, and
these data should be externally validated.

Jingmei Li, Keith Humphreys, Louise Eriksson, Gustaf Edgren, Kamila Czene, and Per Hall

Click here for full article in Journal of Clinical Oncology

Unique study reveals genetic spelling mistakes that increase the risk of common cancers

[Press release, 27 March 2013] More than 80 genetic ’spelling mistakes’ that can increase the risk of breast, prostate and ovarian cancer have been found in a large, international research study within the framework of the EU Network COGS. For the first time, the researchers also have a relatively clear picture of the total number of genetic alterations that can be linked to these cancers. Ultimately the researchers hope to be able to calculate the individual risk of cancer, to better understand how these cancers develop and to be able to generate new treatments.

The main findings are published in five articles in a special issue on genetic risk factors for cancer in the prestigious scientific journal Nature Genetics. The articles originate from COGS (Collaborative Oncological Gene-environment Study), an EU-based consortium where more than 160 research groups from all over the world are included. In the five COGS studies 100,000 patients with breast, ovarian or prostate cancer and 100,000 healthy individuals from the general population were included.
http://www.nature.com/ng/journal/v45/n4/full/ng.2592.html?WT.ec_id=NG-201304 

Launching Karma Normal to study mammographic density in healthy women

In a substudy to Karma, scientists will study why it is more common among women with high mammographic density to develop breast cancer. The study will investigate breast tissue biopsies from women with low breast density and compare this with biopsies from women with dense breasts.

Karma Normal is a collaboration between researchers at the Karolinska Institute and physicians at the mammography clinic in Helsingborg Hospital. The study will invite randomly selected women in the Helsingborg area who already participates in Karma.

Medical doctors take biopsies from healthy breasts using the same procedures as in investigating a breast lump. The biopsies are analyzed with different methods which will present a picture of what the tissue looks like. The researchers will look into any cell composition that represents density and any composition that represents changes that would lead to a cancer later on in life.

The aim is to understand what gives rise to the density and what cell types and genes are influencing development of cancer, and hopefully to prevent breast cancer in the future.