Background:

Breast cancer is the leading cause of cancer-related mortality in women world-wide. Research has been conducted to reduce breast cancer mortality mainly through better diagnostic tools, screening programs and targeted therapy. A measure to prevent the onset of the disease in high-risk women is to use selective estrogen receptor modulators, such as tamoxifen. The drug is, however, associated with many side effects, reducing life quality, adherence and uptake. We therefore seek to understand the effects of tamoxifen on a systemic level.

Methods:

We explored the response associated with tamoxifen use using 176 samples from the KARISMA phase II low-dose tamoxifen trial. The levels of > 2000 circulating proteins were measured using the Olink Explore 3k platform in age and BMI-matched women taking placebo (N=44) and 20 mg tamoxifen (N=44). The protein levels were measured at baseline and at 6 months in both treatment arms to study differential protein response by using a linear model adjusted for age and BMI at baseline.

Results:

Comparing the protein levels between treatment arms at baseline showed no proteins exhibiting significant differences (FDR > 0.05), and levels in the placebo group remained stable over 6 months. Contrasting the changes in protein levels between the treatment arms over the 6-month administration period revealed wide-spread changes in the proteome, summing to 193 (~10%) of the measured proteins showing statistically significant differences in protein level (FDR < 0.05). The protein response was spread across the different functional categories, showing a systemic effect associated with the intake of tamoxifen.

Conclusions:

This pilot study shows that intake of tamoxifen is linked to strong and wide-spread changes in the circulating proteome, warranting continued investigations into the functional pathways of treatment response. Future endeavours should focus on replication with more samples from different treatment arms, use of orthogonal technologies to confirm and expand our insights, study of metabolites of tamoxifen, and consider menopause status when interpreting the effects on breast cancer biology.