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Women 50 Years Or Younger With Endometrial Cancer: The Argument for Universal Mismatch Repair Screening and Potential for Targeted Therapeutics

Ring, Kari L. MD*; Connor, Elizabeth V. MD; Atkins, Kristen A. MD; Ricketts, William PhD§; Kashlan, Basel MD§; Modesitt, Susan C. MD, FACOG, FACS

International Journal of Gynecological Cancer: June 2013 - Volume 23 - Issue 5 - p 853–860
doi: 10.1097/IGC.0b013e31828eed9c
Uterine Cancer

Objective To identify young patients with endometrial cancer with potential Lynch-related DNA mismatch repair (MMR) protein expression defects and stathmin (STMN1) expression (part of the phosphoinositol 3-kinase pathway) and to correlate clinical data.

Methods This retrospective study included women with endometrial cancer who were 50 years or younger at diagnosis. Clinical data were abstracted from chart review. Immunohistochemistry for MMR protein expression, STMN1, and pSTMN1 was performed and univariate analyses performed.

Results The mean age of 111 patients was 43 years, and the mean body mass index was 39.6 kg/m2. The majority of the endometrial cancers were endometrioid histology (87.4%), International Federation of Gynecology and Obstetrics stage I (73%) and grade 1 (58.6%). Loss of at least one MMR protein on immunohistochemistry was identified in 26% to 41% of patients depending on stringency. Women with loss of MMR protein expression were compared to women with intact tumor protein expression and were less likely to be stage I (58.6% vs 78.0%; P = 0.043), more likely to have grade 3 tumors (32.1% vs 13.9%; P = 0.034), had larger tumors (6.2 vs 3.7 cm; P < 0.001), had positive lymph nodes more often (24.1% vs 3.7%; P < 0.001), and more often reported a first-degree relative with colon cancer (17.2% vs 1.2%; P < 0.001). There were no significant differences in age, weight, body mass index, medical comorbidities, recurrence, or survival. Women with high STMN1 staining had significantly more grade 3 tumors (56.3% vs 15.8%; P = 0.001), more stage III/IV disease (37.5% vs 15.8%; P = 0.04), had higher mean percentage of myometrial invasion (38.9% vs 16.7%; P = 0.003), and more lymphovascular space invasion (43.8% vs 13.7%; P = 0.004).

Conclusions Clinical factors failed to differentiate between patients with intact or missing MMR protein expression, which supports universal screening for Lynch-associated protein defects in young women with endometrial cancer. Additionally, STMN1 staining may identify more aggressive tumors, which might benefit from more aggressive treatments or targeted treatment options.

*Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, TX; †Department of Obstetrics and Gynecology, Brown University, Providence, RI; ‡Department of Pathology, University of Virginia, Charlottesville, VA; §Ovagene Oncology Inc, CA; and ∥Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA.

Address correspondence and reprint requests to Susan C. Modesitt, MD, FACOG, FACS, Gynecologic Oncology Division, Obstetrics and Gynecology Department, Box 800712, University of Virginia Health System, Charlottesville, VA 22908-0712. E-mail:

This work was supported by a grant from the Emily Couric Clinical Cancer Center at the University of Virginia, and immunohistochemistry provided by Ovagene Oncology Inc.

William Ricketts, PhD, is a founder and Chief Scientific Officer of OvaGene Oncology. The remaining authors declare no conflict of interest.

Staining and reading of the de-identified slides was performed in the CLIA laboratory at OvaGene Oncology.

Received September 10, 2012

Accepted February 24, 2013

Copyright © 2013 by IGCS and ESGO