Long-term use of tamoxifen is associated with an increased risk for the development of uterine cancer. New research shows that tamoxifen directly activates a signaling pathway (PIK3) that is a well-known driver of uterine cancer development.
Tamoxifen is widely used in the adjuvant treatment of ER-positive breast cancer and is an important drug for pre-menopausal and post-menopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit in improving relapse-free and overall survival in these patients, an adverse effect of tamoxifen is a 2- to 7-fold increased risk of uterine cancer after 2–5 years of treatment, with further increased risk after 10 years [1]. To date, the mechanism of tamoxifen-driven tumorigenesis is not well understood, and preventive approaches are lacking. Dr. Kirsten Kübler (Berlin Institute of Health, Germany) presented results of pre-clinical research aiming to clarify the mechanism by which tamoxifen increases the risk of uterine cancer and find approaches to prevent tamoxifen-associated uterine cancer (TA-UC) [2]. Whole-exome sequencing was performed on 21 TA-UC samples obtained from the ‘Tamoxifen Associated Malignancies: Aspects of Risk’ (TAMARISK) study. These data were compared with molecular data from 544 de novo uterine cancers, cancers that were not associated with tamoxifen use. Most genomic alterations occurred at similar rates between TA-UC and de novo uterine cancers. The key exception was a significantly decreased frequency in patients with TA-UC of mutations in the phosphoinositol-3-kinase (PI3K) signaling pathway, a well-known driver of uterine cancer development. Two essential components of the PI3K pathway were affected: the gene PIK3CA was mutated in 14% of TA-UCs versus 48% of de novo uterine cancers, and the gene PIK3R1 was mutated in none of the studied TA-UC versus 31% of de novo uterine cancers. Additional studies in vivo mouse models demonstrated that tamoxifen activated the PI3K pathway and increased cell proliferation in normal mouse uterine tissue through paracrine and autocrine effects, both of which were abrogated by the PI3K inhibitor alpelisib. “This suggested that the tamoxifen-driven increase in PI3K pathway signaling may, in effect, substitute for a PIK3CA or PIK3R1 mutation to stimulate uterine cancer development,” explained Dr. Kübler. “Furthermore, the ability of a PI3K inhibitor to reduce cell proliferation in our mouse model raises the possibility that downregulating the PI3K pathway may prevent or significantly reduce TA-UC development, offering a potential future therapeutic and prevention strategy for specific high-risk patients undergoing tamoxifen therapy.”
- Davies C, et al. Lancet 2013;2381:805-816
- Kübler K, et al. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations. SABCS 2021 Virtual Meeting, abstract GS2-09
- Hoogendoorn WE, et al. Breast Cancer Research and Treatment. 2008;112;99–108.
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