Advances in Women's Health

Endometrial cancer accounts for more than 90 percent of uterine cancer cases. According to the American Cancer Society, it is the most common cancer of the female reproductive organs, and nearly 66,000 new cases of endometrial and uterine sarcomas combined are expected to be diagnosed in 2022. Despite these statistics, the clinical approach to endometrial cancer relies on a model developed over 30 years ago that defines two subtypes of endometrial cancer: type I low grade with endometrioid histology, hormone receptor positive, and a good prognosis, and type II high grade with non-endometrioid histology, often hormone receptor negative, and a poor prognosis.

Low-grade, low-stage endometrial cancer is generally treated surgically and carries a five-year survival rate of 95 percent. However, for those patients who have a recurrence, the prognosis is poor and there are limited treatment options. The fundamental cause as to why certain tumors recur despite a lack of histologic or clinical evidence indicating aggressive behavior is not yet understood. Additionally, there is little available information on predictive markers or mutation profiles associated with recurrence.

Dr. Eloise Chapman-Davis

Dr. Kevin Holcomb

The developing era of molecular and genomic tumor characterization holds promise for defining prognostic subtypes of endometrial cancer more accurately. Eloise Chapman-Davis, MD, and Kevin Holcomb, MD, gynecologic oncologists at NewYork-Presbyterian/Weill Cornell Medical Center, joined with colleagues in Pathology and Laboratory Medicine and the Englander Institute for Precision Medicine at Weill Cornell Medicine to identify the molecular profiles of the primary carcinomas and genomic differences between primary tumors and subsequent recurrences. Establishing the factors that influence low-grade, low-stage endometrial cancer (LGLS EC) to act more aggressively will help clinicians determine the need for adjuvant therapy or a more extensive initial intervention.

In their study, 12 cases of LGLS EC were identified in the surgical pathology archives of Weill Cornell Medicine, including 4 cases with recurrence and 8 controls without recurrence. Tissue specimens were evaluated via whole-exome sequencing. The resulting data support that a subset of LGLS EC may be genetically predisposed to recurrence.

The results of the study published in the September 6, 2021, online issue of the International Journal of Gynecological Pathology included:

• 2 of 3 recurrent cases gained a mutation associated with genetic instability (TP53 and POLE) and 1 case acquired a mutation in DDR2 kinase, a potential therapeutic target
• All recurrent cases showed PIK3CA mutation, while only 3 of 8 controls did
• LGLS EC with recurrence showed higher MSIsensor scores compared with those without recurrence (MSIsensor is microsatellite instability detection using paired tumor-normal sequence data)
• The level of copy number gains in LGLS EC with recurrence was larger than those without recurrence
• Recurrent cases showed higher tumor mutation burden than non-recurrent cases, with one exception

The Weill Cornell Medicine team noted, “As molecular testing continues to become more commonplace in practice, it is imperative that we continue to seek out molecular identifiers for patients who are at risk for recurrence, as there is untapped potential to preemptively identify patients who are at risk for recurrent and typically untreatable disease. Although this is a small WES-based and targeted sequencing study, it supports that molecular differences may define cases of LGLS EC that recur and those that do not.”