Study: Tamoxifen May Boost PI3K Signaling to Increase Uterine Cancer Risk in Patients with Breast Cancer

Uterine cancers that developed in patients treated with tamoxifen (Soltamox) had fewer phosphinositol-3-kinase (P13K) pathway mutations and may have been driven by tamoxifen-induced P13K pathway activation, according to a presentation from the San Antonio Breast Cancer Symposium 2021.

Tamoxifen is given to many patients—specifically premenopausal patients—with breast cancers that express the estrogen receptor, which drives breast tumor growth. Further, it blocks estrogen receptor activity in the breast, but it can activate the estrogen receptor in other tissues, such as the uterus, which can lead to a rare adverse effect 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 the 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.”

Kirsten Kübler, MD, PhD, and colleagues performed whole-exome sequencing on 21 TA-UC samples from the TAMARISK study to further evaluate the occurrence of secondary cancers in tamoxifen-treated patients. The results were compared to de novo uterine cancers, which are cancers that are not associated with tamoxifen use. The researchers found that most genomic alterations occurred at similar rates between TA-UC and de novo uterine cancers, according to the study.

The significant exception was a significantly decreased frequency of mutations in the PI3K signaling pathway in patients with TA-UCs. Additionally, 2 essential components of the P13K 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 not mutated in any of the studied TA-UCs versus 31% of de novo uterine cancers.

The findings were confirmed using droplet digital PCR to interrogate PIK3CA hotspot mutations in 40 other independent samples from TAMARISK and comparing the data with a group of de novo uterine cancers from AACR Project Genie. The researchers found a decreased incidence of PIK3CA mutations in the TA-UC samples (7.5% versus 21%).

To continuing investigating the mechanism of decreased PI3K pathway mutations in TA-UCs, the research team evaluated uterine tissue from tamoxifen-treated mice, in which they discovered that tamoxifen increased the expression of Ki67. Additionally, the team sequenced RNA from the uterine tissue and tainted for phosphorylated proteins in the PI3K pathway, such as IGF1R, AKT, and S6, which indicates pathway activation, according to the study.

In an attempt to diminish the tamoxifen-driven increase in PI3K pathway activity in mice, the team found that co-treatment diminished the increases in Ki67 staining and 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 press release.

She noted that long-term data from the IBIS-1 study showed that the excess risk of uterine cancer was confined to the duration of treatment. Jeselsohn added that the TA-UC finding may depend on the non-mutant activation of a pathway as part of the multi-step process of tumor development.

The study limitations include a relatively small number of available patient samples, because TA-UC is not a common disease, and the samples being from formalin-fixed paraffin-embedded tissue, which led to new challenges related to genomic characterization, according to the study.

REFERENCE

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