The 4 different molecular subtypes of endometrial clear cell carcinoma (CCC) were associated with differences in prognosis, with 1 subtype — p53 wild-type (wt)/no specific molecular profile (NSMP) — identified as a distinct subset of endometrial cancer, according to results of a study published in Gynecologic Oncology.

CCC occurs in less than 6% of endometrial carcinoma cases, but is considered a type II endometrial cancer because of its aggressive disease course — it commonly results in extrauterine spread, which carries a poor prognosis.

“More recently, mutational diversity within CCCs has been appreciated,” the authors wrote, which has resulted in the questioning of the current strategy to manage CCCs based on the prototypical type II tumor, serous carcinoma.

The aim of this study was to characterize CCCs according to 4 molecular subtypes identified by the Cancer Genome Atlas’s validated ProMisE classifier.

The study evaluated 52 CCC tumors and categorized them using the ProMisE classifier as either 1) POLE mutations, 2) DNA mismatch repair deficiency (dMMR), 3) p53wt/NSMP, or 4) p53 abnormal, including complete loss or overexpression of p53. PD-L1 positivity and the tumor immune landscape were also analyzed. The clinicopathologic characteristics was evaluated for the molecular subtypes.

In this cohort, the majority of cases were classified as p53wt at 53.8%, followed by 34.6% that were p53 abnormal, 9.6% that were dMMR, and 1.9% that had POLE mutations. Age differed significantly between the subtypes (P =.001), with a mean of 72.2 in the p53wt group, 67.5 in the p53 abnormal group, 49.3 in the dMMR group, and 42.1 in the POLE mutation group. Body mass index, disease stage, myometrial invasion, nodal status, and use or type of adjuvant treatment did not differ between the subtypes.

Of the tumors evaluable for estrogen receptor (ER) staining, 87.2% were negative. In the p53wt/NSMP subtype, 84.6% of tumors were ER-negative. However, there was no association between ER positivity and molecular subgroup. L1CAM overexpression was present in 60.4% of CCC tumors, with the highest proportion of positive tumors in the p53 abnormal group at 68.8% and the p53wt/NSMP group at 65.4%. Similar to ER expression, there as no significant association between molecular subtype and L1CAM expression.

Progression-free survival was significantly different between the subtypes (log rank P =.0238). Worse PFS was associated with p53 abnormal, followed by p53wt, and POLE mutations or dMMR. This trend was similar for overall survival and disease-specific survival, but they were not significant.

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Together with the differences in age, the authors stated that these data support “molecular subtype as being more important than histotype in these tumors.”

High levels of tumor-infiltrating lymphocytes and high density of CD3 and CD8 were both associated with improved overall survival, disease-specific survival, and PFS.

The authors concluded that “these data strongly support considering p53wt/NSMP CCC to be a distinct category” within CCC.

Reference

Kim SR, Cloutier BT, Leung S, et al. Molecular subtypes of clear cell carcinoma of the endometrium: Opportunities for prognostic and predictive stratification [published online April 21, 2020]. Gynecologic Oncol. doi: 10.1016/j.ygyno.2020.04.043