The most comprehensive characterization of the molecular alterations in endometrial cancer to date has been completed, promising to allow more precise diagnosis in women and, ultimately, individualized treatment.

“This integrated genomic and proteomic analysis of 373 endometrial cancers provides insights into disease biology and diagnostic classification that could have immediate therapeutic application,” investigators from The Cancer Genome Atlas (TCGA) Research Network wrote in Nature on May 2nd, 2013. For example, “endometrial cancer has more frequent mutations in the PI(3)K/AKT pathway than any other tumor type studied by The Cancer Genome Atlas so far.”1

More importantly, the study found that “uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas,” pointing to a future in which underlying genetics, rather than tumor type, will be the treatment target. Surprisingly, they also found many shared characteristics between endometrioid tumors and colorectal tumors, both of which demonstrate a high frequency of microsatellite instability (MSI).

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“The molecular landscape of endometrial cancer as of 2013 has been defined,” Douglas A. Levine, MD, head of the Gynecology Research Laboratory at Memorial Sloan-Kettering Cancer Center, New York, and a co-leader in the study, told “These findings will lead to improved diagnostic approaches for pathologists and better decision-making tools for clinicians to determine which patients need additional treatment after surgery and which patients can be spared unnecessary toxicity.”

Among women in the United States, endometrial cancer is the fourth most common malignancy. In 2013, an estimated 49,500 new cases will be diagnosed and 8,200 women will die.2 “The main reason more endometrial cancer research has not been done to date is that endometrial cancer has less than half the incident cases compared to the big four tumors—breast, prostate, lung, and colon,” Dr. Levine said. “Furthermore, endometrial cancer as a whole is a fairly curable disease, providing more reason why this molecular stratification can be clinically useful.”

For the study reported in Nature, more than 100 investigators collected tumor samples and corresponding germline DNA from 373 patients; these included 307 patients with endometrioid tumors and 66 patients with serous tumors (n=53) or mixed histology (n=13). “Comprehensive molecular analyses were performed at independent centers using six genomic or proteomic platforms,” the investigators reported.

Classifying Endometrial Tumors

Based on integrated data, their analysis identified four novel genomic-based subtypes of endometrial cancer, POLE ultramutated, MSI hypermutated, copy-number low, and copy-number high. The POLE subtype was found in approximately 10% of endometrioid tumors, according to the Nature article. Each was named for one of its notable characteristics, summarized in Table 1.

Table 1. Endometrial Cancer Genomic-based Subtypes1

Subtypes Characteristics
POLE ultramutated ŸŸ-Unusually high mutation rates and hotspot mutations in the POLE gene
MSI hypermutated -Exhibits a high mutation rate, as well as few copy-number alterations
-No mutations in the POLE gene
Copy-number low -Shows the greatest microsatellite stability
-Has high frequency of mutations in CTNNB1, a gene critical for maintaining linings of organs such as the endometrium
Copy-number high -Displays alterations and a mutation landscape characteristic of serous tumors, but included some endometrioid samples 

To date, endometrioid cancers have been broadly classified as type I or II. Type I tumors are linked to estrogen excess, obesity, hormone-receptor positivity, and a favorable prognosis compared with type II, which are primarily serous tumors more common in older nonobese women and have a worse outcome, the TCGA Research Network investigators noted. Patients with “early-stage endometrioid cancers are often treated with adjuvant radiotherapy, whereas serous tumors are treated with chemotherapy, similar to advanced-stage cancers of either histological subtype,” they added. “Therefore, proper subtype classification is crucial for selecting appropriate adjuvant therapy.”