How tamoxifen can induce uterine cancer

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 signalling pathway (PIK3) that is a well-known driver of uterine cancer development.

Tamoxifen is widely used in the adjuvant treatment of oestrogen receptor–positive breast cancer and is an important drug for premenopausal and postmenopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit, an adverse effect of tamoxifen is a 2–7-fold increased risk of uterine cancer after 2–5 years of treatment, with further increased risk after 10 years [1]. Dr Kirsten Kübler (Broad Institute, MA, USA) presented results of preclinical research aiming to clarify the mechanism by which tamoxifen increases the risk of uterine cancer and finding approaches to prevent tamoxifen-associated uterine cancer (TA-UC) [2].

Whole-exome sequencing was performed on 21 TA-UC samples obtained from the TAMARISK study [3]. 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-UCs of mutations in the phosphoinositol-3-kinase (PI3K) signalling 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 (P=0.003), and the gene PIK3R1 was mutated in none of the studied TA-UCs versus 31% of de novo uterine cancers (P=0.001).

Additional studies in in vivo mouse models demonstrated that tamoxifen activates the PI3K pathway and increases cell proliferation in normal mouse uterine tissue through paracrine and autocrine effects, both of which are abrogated by the PI3K inhibitor alpelisib. “This suggested that the tamoxifen-driven increase in PI3K pathway signalling 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.”

1. Davies C, et al. Lancet 2013;2381:805–816.
2. Kübler K, et al. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations. GS2-09, SABCS 2021 Virtual Meeting, 7–10 December.
3. Hoogendoorn WE, et al. Breast Cancer Research and Treatment. 2008;112;99–108.

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Posted on 31 January, 202231 January, 2022