PI3K Inhibitors May Help Prevent Tamoxifen-Associated Uterine Cancer in Patients With Breast Cancer


Uterine cancers that developed in patients with breast cancer treated with tamoxifen had fewer phosphoinositol-3-kinase (PI3K) pathway mutations and may have been driven by tamoxifen-induced PI3K pathway activation, according to a study presented at the San Antonio Breast Cancer Symposium. This increase in PI3K pathway activation was mitigated by treatment with the PI3K inhibitor alpelisib in preclinical studies, according to the study authors.

Tamoxifen is given to many patients with breast cancers that express the estrogen receptor, especially premenopausal patients. The drug blocks estrogen receptor activity in the breast, but can also activate estrogen receptors in other tissues, including the uterus. This can lead to the uncommon adverse event known as tamoxifen-associated uterine cancer (TA-UC).

“We want to make sure people understand that tamoxifen is safe to use, and tamoxifen-associated uterine cancer is infrequent,” said study author Rinath Jeselsohn, MD, an assistant professor of medicine and medical oncology at Dana-Farber Cancer Institute and Harvard Medical School, in a press release. “We wanted to understand the mechanisms behind this uncommon event to potentially help patients who are at an increased risk of uterine cancer due to other additional risk factors.”

To better understand the mutational landscape of TA-UC, investigators performed whole-exome sequencing on 21 TA-UC samples from the TAMARISK study, which evaluated the occurrence of secondary cancers in tamoxifen-treated patients. These results were then compared with novo uterine cancers—cancers that were not associated with tamoxifen use—from The Cancer Genome Atlas.

The investigators found that most genomic alterations occurred at similar rates between TA-UC and de novo uterine cancers, with the exception of a significant decrease in PI3K mutations in patients with TA-UCs. The gene PIK3CA was mutated in 14% of TA-UCs compared to 48% of de novo uterine cancers, and the gene PIK3R1 was mutated in none of the studied TA-UCs versus 31% of de novo uterine cancers. A mouse model study revealed a significant increase in PI3K pathway activation among tamoxifen-treated mice, as compared with mice treated vehicle control, according to the study authors.

The researchers attempted to mitigate the increase in PI3K pathway activity through the use of the PI3K inhibitor alpelisibin conjunction with tamoxifen. According to the study data, co-treatment decreased the markers of PI3K signaling.

“For women taking tamoxifen for breast cancer, there may be a possibility of using a PI3K inhibitor for those who are at an increased risk of uterine cancer, as a prevention strategy,” Jeselsohn said in the release.


Tamoxifen may boost PI3K signaling to increase uterine cancer risk in patients with breast cancer [news release]. SABCS; December 7, 2021. Accessed December 14, 2021. https://aacr.ent.box.com/s/fdpqv25i37rpc4ztbve0vtyx71od4wdb

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