Gene Signature May Predict Response to Tamoxifen

Roxanne Nelson

July 17, 2014

A gene signature that appears to be specific for predicting response to tamoxifen in patients with estrogen-receptor (ER)-positive breast cancer has been identified, although the results are preliminary.

The work centers on the USP9X gene, which loses function in breast cancer cells, resulting in tamoxifen resistance. The research was published in the July 15 issue of Cancer Research.

Tamoxifen, which acts as an antagonist at the estrogen receptor, is widely used in the treatment of ER-positive breast cancer.

However, about one-third of patients "experience a relapse after adjuvant treatment with tamoxifen. Median overall survival in these patients, even with further treatment, is around 30 to 45 months," explained lead investigator René Bernards, PhD, professor and head of the division of molecular carcinogenesis at the Netherlands Cancer Institute in Amsterdam.

"It has been very difficult to identify patients whose tumors lack a proper response to tamoxifen," Dr. Bernards said in a statement. "We used an innovative approach to identify genes that help foretell whether a patient will respond to tamoxifen, and we showed that this gene signature performed well in 2 large patient groups."

The team is currently validating the results using data and tumor material from a prospective randomized controlled trial, and hopes to have this work completed by the end of 2014.

"For this test to gain clinical validity, we need to perform an analysis of a randomized clinical trial in which breast cancer patients are treated with tamoxifen or placebo," he told Medscape Medical News. "These studies were done 30 years ago, but tissue is still available for some of them."

"If this is successful, clinical implementation is a logical next step," Dr. Bernards said.

Large-scale Genetic Screen

To address whether the loss of function of certain genes is involved in tamoxifen resistance, Dr. Bernards and his colleagues performed a large-scale loss-of-function genetic screen to identify candidate resistance genes.

They conducted a short hairpin (sh)RNA screen on the hormone-dependent human luminal breast cancer cell line ZR-75-1 to identify genes "in which knockdown could induce tamoxifen resistance." shRNA is an RNA sequence with a tight hairpin turn that can be used to silence target gene expression through RNA interference.

By evaluating the shRNAs that survive after treatment with tamoxifen, the investigators were able to identify USP9X.

USP9X affects the stability and activity of numerous regulatory proteins that influence cell survival. Previous research has suggested a "prosurvival" role for USP9X in several hematologic cancers — including B-cell and mantle cell lymphomas, chronic myeloid leukemia, and multiple myeloma — through the stabilization of MCL1.

In addition, USP9X can act as a tumor suppressor (particularly in pancreatic cancer) and plays a role in cell death induced by oxidative stress through apoptosis signal-regulating kinase 1.

The investigators also identified genes that were altered during treatment with tamoxifen in the absence of USP9X. Using this gene signature, they were able to determine which patients with ER-positive breast cancer would experience a poor outcome after adjuvant treatment with tamoxifen.

Specific for Endocrine Therapy

They tested the signature in 2 cohorts of patients with ER-positive breast cancer (primarily postmenopausal) not receiving adjuvant endocrine treatment. The gene-expression signature was specific in its lack of correlation with survival in patients who did not receive endocrine therapy, the investigators report.

Most of the patients identified as responsive with the USP9X signature were of the luminal A subtype, whereas patients identified as resistant were more often of the luminal B subtype.

However, approximately 30% of luminal B tumors were classified as tamoxifen-sensitive and approximately 30% of luminal A tumors were classified as tamoxifen-resistant, which suggests that the gene signature can be used to identify subgroups of luminal A and luminal B tumors most likely to benefit from adjuvant tamoxifen treatment, the investigators note.

This study was funded by grants from the Dutch Cancer Society. The authors have disclosed no relevant financial relationships.

Cancer Res. 2014;74:3810-3820. Abstract

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