By Melissa Moffitt, MD

Gynecologic Oncologist, Assistant Professor, Department of OB/GYN, Oregon Health & Science University, Portland

Dr. Moffitt reports no financial releationships relevant to this field of study.

SYNOPSIS: In this retrospective cohort study, researchers studied the prognosis and outcomes for young women with endometrial cancer and compared them according to tumor molecular classification.

SOURCE: Britton H, Huang L, Lum A, et al. Molecular classification defines outcomes and opportunities in young women with endometrial cancer. Gynecol Oncol 2019;153:487-495.

Britton et al1 identified a cohort of 257 patients who were diagnosed with endometrial cancer before the age of 50 and for whom they had corresponding clinical and outcomes data. Half of these women were nulliparous at diagnosis, and 28% were younger than 40 years of age. Many of these patients had been categorized previously into three groups according to identified risk factors: high estrogen exposure, Lynch syndrome-like family history, or no identifiable risk.2

The researchers performed immunohistochemistry staining on the endometrial biopsy and/or hysterectomy specimens for p53 and for two mismatch repair (MMR) genes, PMS2 and MSH6. DNA extraction and polymerase chain reaction (PCR) testing for POLE mutations were performed. Cases were categorized first by their MMR gene status. Next, those who did not have MMR deficiency were subdivided by POLE status. Lastly, those with MMR genes intact and no POLE mutations were stratified by p53 status. Univariable survival analysis was performed for the molecularly categorized subtypes and the risk-factor categorized subtypes, including overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). The univariable survival analysis of the molecularly categorized subtypes had many statistically significant clinical associations, including age at diagnosis, body mass index, stage, grade, histology, adjuvant treatment, and risk factor categorization.

Kaplan-Meier curves showed that molecular subtypes were associated with OS and DSS. Those with p53 mutations had the shortest OS and DSS; those with MMR deficiencies also had shorter OS and DSS. Those with POLE mutations showed the best OS and DSS, while those with intact p53 staining had outcomes nearly as good as those with POLE mutations. Multivariable survival analysis, correcting for characteristics such as age, body mass index, grade and adjuvant treatments, showed that molecular subtypes continued to be associated with OS and DSS. The risk factor subgroups were not associated with survival parameters.

COMMENTARY

For many years, endometrial cancer has been categorized by histology and for endometrioid carcinomas, by grade. The low-grade endometrioid adenocarcinomas that arise out of atypical endometrial hyperplasia due to excess unopposed estrogen have been termed Type 1.3 That was to contrast them from the obviously more aggressive subtypes that arise from atrophic endometrium, without signs of excess estrogen, such as serous carcinomas, which thus were termed Type 2. This way of categorizing endometrial cancer was simple, but was not very meaningful clinically.

In 2013, The Cancer Genome Atlas4 (TCGA) molecularly analyzed 373 endometrial cancers and found four molecular subtypes: copy number high (serous-like); copy number low (endometrioid-like); POLE (ultramutated); and micro-satellite instability (hypermutated). These subgroups were found to be associated with clinical outcomes. The technology used by TCGA is used in research currently, but cost limits its clinical use. In 2015, Talhouk et al5 published a Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), an algorithm for pathologists to identify the four TCGA subtypes. The ProMisE algorithm is what was used by Britton et al in this study on young women.

Endometrial cancer is one of the few malignancies with increasing incidence and mortality in the United States, thought to be subsequent to the increasing rate of obesity. Although the median age of diagnosis for endometrial cancer is 63 years, more than 20% of women diagnosed with endometrial cancer are premenopausal. Young women diagnosed with endometrial cancer often seek to maintain their fertility. Only those with low-grade endometrioid adenocarcinoma, who are clinically Stage I and have imaging suggestive of minimal invasion, are appropriate candidates. Even in this optimized cohort of patients, the usual fertility-sparing treatment with progestins is effective only three-quarters of the time.6

In this article, the authors give us a potential tool to better assess candidates for fertility-sparing treatment: We can add molecular subtyping using the ProMisE algorithm on the endometrial sample as was done in this study. Those found to have p53 mutations and MMR deficiencies (who have worse outcomes), can be counseled to see a reproductive endocrinologist and infertility specialist for egg preservation before starting standard cancer treatments. Alternatively, patients found to have POLE mutations, or those with intact MMR and p53 expression, can be counseled regarding their expected excellent outcomes, and encouraged to pursue fertility- or ovarian-conserving therapy.

Given the growing accumulation of information correlating these TCGA subgroups to outcomes, some version of this ProMiseE algorithm will be widely adapted soon by most gynecologic pathologists and performed on routine endometrial biopsy and hysterectomy specimens. Like gynecologic oncologists, gynecologists familiar with these tests and their meaning will be grateful to know, immediately upon receipt of pathology results, how to counsel their patients more accurately on outcomes and prognosis.

REFERENCES

  1. Britton H, Huang L, Lum A, et al. Molecular classification defines outcomes and opportunities in young women with endometrial cancer. Gynecol Oncol 2019;153:487-495.
  2. Burleigh A, Talhouk A, Gilks CB, McAlpine JN. Clinical and pathological characterization of endometrial cancer in young women: Identification of a cohort without classical risk factors. Gynecol Oncol 2015;138:141-146.
  3. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983;15:10-17.
  4. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67-73.
  5. Talhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 2015;113:299-310.
  6. Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: A systematic review and metaanalysis. Am J Obstet Gynecol 2012;207:266.