Drug Given for Breast Cancer Increases Uterine Cancer Risk

Uterine cancers developed in patients treated with tamoxifen had fewer PI3K pathway mutations and may have instead been driven by tamoxifen-induced PI3K pathway activation, according to a study presented at the San Antonio Breast Cancer Symposium.

Tamoxifen is a drug given to breast cancer patients, which blocks estrogen receptor activity to stop the tumor growth in the breast.

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‘Tamoxifen-associated uterine cancer risk in patients with breast cancer may be concurrently treated with PI3K pathway inhibitors.’

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At the same time, it can also activate the estrogen receptor in other tissues, such as the uterus. This can lead to an uncommon side 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.

Cancer treatments that increase the risk for secondary tumors typically do so by creating and/or selecting for mutations that cause uncontrolled growth in other tissues.

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To define the mutational landscape of TA-UC, researchers performed whole-exome sequencing on 21 TA-UC samples from the study which evaluated the occurrence of secondary cancers in tamoxifen-treated patients.

They compared the results with cancers that were not associated with tamoxifen use and found that most genomic alterations occurred at similar rates between TA-UC and de novo uterine cancers.

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The key exception was a significantly decreased frequency of mutations in the phosphoinositol-3-kinase (PI3K) signaling pathway, a well-known driver of uterine cancer development in patients with TA-UCs.

The gene PIK3CA was mutated in 14 percent of TA-UCs versus 48 percent of de novo uterine cancers, and the gene PIK3R1 was mutated in none of the studied TA-UCs versus 31 percent of de novo uterine cancers.

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Researchers verified these findings by using droplet digital PCR to interrogate PIK3CA hotspot mutations in 40 other independent samples and found a decreased incidence of PIK3CA mutations in the TA-UC samples—7.5 percent versus 21 percent.

To investigate the mechanisms of decreased PI3K pathway mutations in TA-UCs, researchers examined uterine tissue from tamoxifen-treated mice. They found that tamoxifen increased the expression of Ki67, a marker of cell proliferation.

They also sequenced RNA from the uterine tissue and stained for phosphorylated proteins in the PI3K pathway – such as IGF1R, AKT, and S6 – which indicates pathway activation.

These data revealed a significant increase in PI3K pathway activation among tamoxifen-treated mice, as compared with mice-treated vehicle control.

The long-term data from the study also showed that the excess risk of uterine cancer was confined to the duration of treatment and this finding may be a part of the multi-step process of tumor development.

Limitations of this study include a relatively small number of available patient samples since TA-UC is not a common disease, as well as the fact that samples were from formalin-fixed paraffin-embedded tissue, which introduces challenges related to genomic characterization.

Source-Medindia