Tamoxifen-induced PI3 kinase pathway activation may increase uterine cancer risk
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Patients with breast cancer who developed tamoxifen-associated uterine cancer had fewer phosphatidylinositol 3-kinase pathway mutations than those with de novo cases, according to results presented at San Antonio Breast Cancer Symposium.
This finding suggests these cancers may have been driven by tamoxifen-induced activation of the phosphatidylinositol 3-kinase (PI3K) pathway, researchers concluded.
“We identified a novel mechanism of drug-related tumorigenesis in which a drug is activating a signaling pathway and replacing a driver mutation,” Rinath Jeselsohn, MD, assistant professor of medicine and medical oncology at Dana-Farber Cancer Institute and Harvard Medical School, told Healio. “These results indicate that tamoxifen does not directly induce mutations in the uterus.”
Treatment with the PI3 kinase inhibitor alpelisib (Piqray, Novartis) mitigated this increased pathway activation, researchers found.
Many patients — particularly premenopausal women — with ER-positive breast cancers receive tamoxifen.
The agent blocks ER receptor activity in the breast; however, it can activate the ER receptor in other tissues, including the uterus.
“Tamoxifen is the first drug of targeted treatment in cancer and remains an important endocrine treatment in breast cancer,” Jeselsohn said. “One drawback of tamoxifen is that it is associated with ... a 2-7-fold increased risk [for uterine cancers], although, overall, the risk [for] uterine cancer with tamoxifen treatment is low.
“In this study, we sought to gain insights into the mechanisms of tamoxifen-associated uterine cancer, as this is not well-understood, with the aim to identify potential therapeutic approaches to prevent tamoxifen-associated uterine cancers in high-risk patients,” Jeselsohn added. “Other drug-related cancers — also not highly frequent, such as chemotherapy-related cancers — are associated with drug-induced mutagenesis. Based on this, we wanted to investigate if tamoxifen acts in a similar manner and induces genomic changes.”
Jeselsohn and colleagues — including Kirsten Kübler, MD, PhD, and Gad Getz, PhD — performed whole-exome sequencing on 21 tamoxifen-associated uterine cancer samples to define their mutational landscape. Researchers compared their findings with samples of de novo uterine cancer from The Cancer Genome Atlas.
Results showed the majority of genomic alterations occurred at similar rates in the tamoxifen-associated and de novo cancers.
However, the analysis revealed one important exception: Researchers observed significantly reduced frequency of mutations in the PI3K signaling pathway — an established driver of uterine cancer — among patients with tamoxifen-associated cancers.
Results showed fewer PIK3CA mutations (14% vs. 48%) and PIK3R1 mutations (0% vs. 31%) of the tamoxifen-associated cancer samples.
Jeselsohn and colleagues aimed to confirm these results by using droplet digital polymerase chain reaction to assess PIK3CA hotspot mutations in 40 additional samples of tamoxifen-associated uterine cancer and comparing them with data from de novo uterine cancers included in AACR Project GENIE. Once again, they identified reduced frequency of PIK3CA mutations in the tamoxifen-associated uterine cancer samples vs. de novo uterine cancer samples (7.5% vs. 21%).
Researchers then examined uterine tissue of tamoxifen-treated mice to evaluate the mechanisms of reduced PI3K pathway mutations in tamoxifen-associated uterine cancers. They determined tamoxifen heightened expression of Ki67, a nuclear protein associated with cellular proliferation.
Jeselsohn and colleagues also sequenced RNA from the uterine tissue and stained for phosphorylated proteins in the PI3K pathway, an indication of pathway activation. They observed a significant increase in PI3K pathway activation among tamoxifen-treated mice vs. controls.
The findings suggest the tamoxifen-driven increase in PI3K pathway signaling may essentially replace PIK3CA or PIK3R1 mutations to stimulate development of uterine cancer, researchers concluded.
“Our finding that tamoxifen-associated uterine cancers had a lower frequency of PIK3CA and PIK3R1 mutations was unexpected and surprising,” Jeselsohn told Healio. “To our knowledge, a decrease in the prevalence of a mutation has not been associated with drug-related cancer and we are not aware of drugs taking the role of a driver event.”
The results suggested increased uterine cancer risk likely is mostly confined to the duration of the treatment when tamoxifen is activating the PI3K pathway, Jeselsohn said.
“This could reassure patients and is in line with clinical data from the IBIS-1 clinical trial, in which the increased risk of uterine cancer was confined to the duration of treatment,” Jeselsohn said.
Researchers subsequently treated mice with alpelisib in combination with tamoxifen to try to mitigate the increased PI3K pathway activity driven by tamoxifen. Results showed alpelisib can block the activation of the PI3K pathway induced by tamoxifen and reduce associated cell proliferation, according to researchers.
“These results suggest that alpelisib treatment could prevent the development of tamoxifen-associated uterine cancers,” Jeselsohn said. “Further investigation of such an approach could be relevant to patients that have multiple risk factors for the development of uterine cancer and are taking tamoxifen for breast cancer.”
Researchers acknowledged study limitations, including the small number of available patient samples and the fact samples came from formalin-fixed paraffin-embedded tissue, which creates challenges with genomic characterization.
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Kubler K, et al. Abstract GS2-09. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
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