All posts by mattiashammarstrom

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

KARISMA results: Low dose of tamoxifen have a potential treatment effect

The results from the 6-armed RCT trial KARISMA show that 2.5 mg of tamoxifen has the potential to be as effective in reducing incidence and recurrence of breast cancer as the established 20 mg dose. 

Mammographic density change is a proxy for tamoxifen therapy response. We tested if lower doses of tamoxifen were non-inferior to reduce mammographic density and associated with fewer symptoms.

In all 1440 women, aged 40 to 74 years, participating in the Swedish mammography screening program were included in the six-months double-blind six-arm randomized placebo-controlled KARISMA phase II trial and randomized to either placebo, 1, 2.5, 5, 10 and 20 mg of tamoxifen.

The participants had non-inferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group. The reduction was confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.

In conclusion,  premenopausal women showed non-inferior magnitude of breast density decrease at 2.5 mg of tamoxifen and experienced fewer side effects compared to the standard dose of 20 mg.

Future studies should test if 2.5 mg of tamoxifen reduces the risk of primary breast cancer.

Eriksson, et al J Clin Oncol. 2021 Mar 18:JCO2002598. doi: 10.1200/JCO.20.02598.


A thesis based on the Karma Cohort and focusing on breast cancer risk prediction and prevention was defended 15 January, 2021

The thesis included a paper describing a unique tool, STRATUS, for measuring mammographic density regardless of type of image and vendor. This tool and additional mammographic features was used for generating a risk prediction tool and described below, published 20-09-08 (please see below). The thesis also described the Karisma trial where lower doses of tamoxifen were tested. In short, 1,440 women were randomised to placebo, 1, 2.5, 5, 10 and 20 mg and it turned out that 2.5 mg could be equally affective as 20 mg of tamoxifen but come with a 50% reduction in side effects (paper accepted for publication J Clin Oncology). Lastly, modelling the impact of a tamoxifen induced density decrease showed that the mammographic sensitivity would increase enabling even earlier detection of breast cancers and thereby a reduction in interval cancers by 24%.

A clinical model for identifying the short-term risk of breast cancer. Eriksson et al. Breast Cancer Reesearch, 2017. DOI: 10.1186/s13058-017-0820-y

Use of Low-Dose Tamoxifen to Increase Mammographic Screening Sensitivity in Premenopausal Women. Eriksson et al. Cancer. 2021. DOI: 10.3390/cancers13020302

Use of Low-Dose Tamoxifen to Increase Mammographic Screening Sensitivity in Premenopausal Women. Eriksson et al. Cancer. DOI: 10.3390/cancers13020302

A thesis based on the Karma Cohort and focusing on mammographic features was defended 11 December, 2020

Shadi Azam has published three papers (see links below) and have one paper in manuscript. Shadi has over the last years worked hard trying to understand the factors behind two mammographic “features” and how these features influence the risk of breast cancer. The features are mammographic density change and breast microcalcifications. None of them are currently particularly well covered in the scientific literature. 

Surprisingly few of the established risk factors for breast cancer influences mammographic density change and the change does not seem to influence subsequent risk of breast cancer. Most factors influencing the risk of breast cancers do not seem to influence the risk of microcalcifications in the same direction. On the other hand, microcalcifications seem to be as a strong risk factor for breast cancer as mammographic density in postmenopausal women. 

Determinants of Mammographic Density Change. Azam et al. 2019. JNCI Cancer Spectr. DOI: 10.1093/jncics/pkz004

Mammographic Density Change and Risk of Breast Cancer. Azam et al. Journal of the National Cancer Institute. DOI: 10.1093/jnci/djz149

Predictors of mammographic microcalcifications. Azam et al. Int J Cancer. 2021. DOI: 10.1002/ijc.33302

A short term risk model identifies women that will be diagnosed with breast cancer

Using the prospective screening Karma cohort, an image-based breast cancer 2-year risk model was developed using mammographic features (density, masses, microcalcifications) identified using artificial intelligence. The model could be extended by including a polygenic risk score with 313 single nucleotide polymorphisms. The area under the receiver operating characteristic curve (AUC) for the image-based model was 0.73 (95% confidence interval [CI]: 0.71, 0.74) and for the genetic extended model was 0.77 (95% CI: 0.75, 0.79). There was a relative 9-fold difference in risk between women at high risk (8% of the population) and those at general risk. High-risk women were more likely to be diagnosed with stage II cancers and with tumours 20 mm or larger and were less likely to have stage I and estrogen receptor-positive tumours.

Identification of Women at High Risk of Breast Cancer Who Need Supplemental Screening. Eriksson et al. Radiology, 2020. DOI: 10.1148/radiol.2020201620

Change in mammographic density do not seem to influence the risk of breast cancer

The association between annual mammographic density change and breast cancer risk was evaluated using the Karma Cohort (N = 43 810). Density was measured using the STRATUS method and relative mammographic density change was categorized as decreased (>10% decrease per year), stable (no change), or increased (>10% increase per year). Cox proportional hazards regression was used to estimate the association.

In all, 563 women were diagnosed with breast cancer but no significant association between mammographic density change and breast cancer was seen. Adding baseline mammographic density did not influence the results.

Mammographic Density Change and Risk of Breast Cancer. Azam et al. Journal of the National Cancer Institute. DOI: 10.1093/jnci/djz149