Genetic 'Hotspot' Found in High-Risk Endometrial Cancer

Janis C. Kelly

September 11, 2014

Most endometrial carcinomas (70% to 80%) are type I endometrioid endometrial carcinomas (EECs) with a good prognosis, but a subset of younger patients have more aggressive, hard-to-treat tumors with worse outcomes.

Now a  team of researchers from the University of Texas MD Anderson Cancer Center in Houston may have found a clue that could eventually help clinicians select patients likely to benefit from earlier aggressive treatment.

The team identified a set of mutations in EEC that might help serve as a biomarker of poor-prognosis disease.

Their study will be published in the September issue of Journal of the National Cancer Institute.

Mutations in exon 3 of the CTNNB1 gene are associated with worse outcomes for women with otherwise typical low-grade, early-stage EEC.

The research also provides evidence that obesity is not the only major risk factor for more aggressive disease, the authors point out.

Obesity-Related Estrogen Not the Only Driver

The new findings should be incorporated into medical education, suggested senior author Russell R. Broaddus, MD, PhD, professor of pathology at MD Anderson, told Medscape Medical News.

"We are classically taught that young, obese women with EEC have tumors that are driven by estrogen-induced signaling pathways. Our data demonstrate that this is not entirely true. The EEC subset with CTNNB1 mutations have significantly lower estrogen receptor (ER) and progesterone receptor (PR) levels than the other subset with mainly low-grade, low-stage EEC."

EEC is not a singular disease, he also suggested. "We were surprised at the molecular heterogeneity of EEC. We were also very surprised to find that the subset of patients marked by CTNNB1 mutation is significantly younger and more obese than other EEC patients," said Dr Broaddus.

Dr. Broaddus and colleagues first used archival material from 271 EEC cases in The Cancer Genome Atlas to search for molecular fingerprints that might be associated with some of the varied clinical outcomes. The researchers then used an independent sample cohort of 184 EEC cases diagnosed at MD Anderson from 1998 to 2009 to validate the proposed marker.

The CTNNB1 gene is normally involved in the creation and maintenance of epithelial cells. Mutations in CTNNB1 could be grouped into 4 transcriptome subtypes of EEC with distinct clinicopathologic characteristics and mutations.

Cluster I consisted of low-grade (1 and 2) and low-stage (I and II) tumors that were more likely to have microsatellite instability, as well as higher ER and PR expression.

Cluster II tumors were also low-grade and low-stage, but patients were younger and had worse overall survival   and a trend toward worse progression-free survival than those with cluster I after adjustment for grade, stage, and age.

Patients in clusters III and IV were more likely to have advanced (grade 3, stage III or IV) tumors.

The cluster II tumors had significantly more CTNNB1 gene mutations (P < .001) than tumors in the other subtypes, and most of these mutations were missense mutations in exon 3. The authors also found that CTNNB1 mutations at exon 3 were consistently correlated with younger patients, but mutations outside exon 3 were not.

"Although associated with younger age, patients in Cluster II experienced poorer overall survival compared to those in Cluster I…which we hypothesize is a consequence of upregulated Wnt/β-catenin signaling in Cluster II," the authors wrote. The Wnt/β-catenin pathway is important in carcinogenesis and tumor progression, and higher expression of Wnt downstream targets (which include CTNNB1) has been associated with decreased overall survival, according to the authors.

Marker Might Help Clinicians

"Clinically, we have known for a long time that there is a subset of EEC patients who will recur after primary surgery and ultimately succumb to this recurrence," said Dr. Broaddus.

The new findings are boon to clinicians, he suggested.

"In the past, we had no way of identifying up-front who these patients are. The finding that CTNNB1 mutation is associated with poor outcome in this group of patients now gives clinicians a tool that can be used to identify these patients at the time of diagnosis. Since the CTNNB1 mutation is in a hot-spot, sequencing to detect these mutations is relatively straightforward and can be done in the clinical molecular diagnostics laboratory," Dr. Broaddus said.

Dr. Broaddus explained that once a patient with low-grade, low-stage EEC is identified as having the CTNNB1 mutation, gynecologic oncologists might contemplate providing these patients with more aggressive therapy beyond hysterectomy.

"What that specific aggressive therapy should be is currently not known but should be the focus of prospective clinical trials," he also said.

"Tactics in addition to the usual hysterectomy could include a more aggressive surgical approach to include extensive lymphadenectomy; postoperative pelvic radiation treatment; postoperative adjuvant chemotherapy; or postoperative targeted therapy using a PI3K/AKT/mTOR inhibitor, since this signalling pathway is activated in the vast majority of endometrial cancers, including EEC with CTNNB1 mutation," Dr. Broaddus said.

A key unanswered question is whether the best predictor of outcome in EEC patients is the CTNNB1 mutation itself or levels of expression of genes known to be activated by the mutation.

"CTNNB1 mutation analysis is the more attractive option clinically, as this is a more straight-forward test, but we need to advocate for prospective clinical trials to evaluate this prognostic tool," Dr. Broaddus said.

Several drugs that target tumors with CTNNB1 mutations are in phase 1/2 clinical trials.

The study was funded by a Career Development Award from MD Anderson Gynecologic SPORE in Uterine Cancers, the Genome Data Analysis Centers from the National Institutes of Health, and the National Foundation for Cancer Research. The authors have disclosed no relevant financial relationships.

J Natl Cancer Inst. 2014;106. Abstract

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