Diane Libert

Folate receptor alpha ( FRα / FOLR1 ) and HER2 immunohistochemical staining in high‐grade endometrial carcinoma with aberrant p53 expression

Aims Mirvetuximab soravtansine is an anti‐FOLR1 (folate receptor 1/alpha) antibody–drug conjugate with a companion diagnostic immunohistochemical (IHC) biomarker for platinum‐resistant ovarian, fallopian tube and primary peritoneal carcinoma. Its effectiveness has sparked interest in FOLR1 expression in endometrial carcinoma. We evaluate the relationship of FOLR1 and HER2‐IHC expression in high‐grade p53‐aberrantly expressed endometrial carcinomas, as overexpression of both is associated with high‐grade histologic features and aggressiveness. Methods and results Carcinomas were scored for HER2‐IHC by both gastric and endometrial serous criteria and FOLR1‐IHC by Ventana package insert on tissue microarray cores. Intratumoral heterogeneity was quantified for HER2 and FOLR1 expression across multiple cores from the same tumour. A total of 291 cores (226 endometrial serous, 47 high‐grade endometrioid and 18 high‐grade Müllerian carcinoma, nos) were collected from 66 cases (discrete accession dates) from 62 patients. When stratified by two‐category HER2‐IHC status (0/1+ vs. 2+/3+, either criteria), significantly more HER2 2+/3+ cores (16/133, 12%) were FOLR1‐positive by a ≥75% cut‐off than HER2 0/1+ specimens (8/158, 5%, P  = 0.031). Results were similar by a ≥25% cut‐off (49/133, 37% vs. 38/158, 24%; P  = 0.018). More cases with high HER2‐IHC heterogeneity (2–3‐pt difference) also demonstrated FOLR1‐IHC heterogeneity (≥50% score difference between cores from the same case) than cases with no or low (1‐pt) HER2‐IHC heterogeneity, though most cases did not show high HER2 or FOLR1 intratumoral heterogeneity (16.7%–18.2% 2–3‐pt difference and 12.1% ≥50% score difference). Conclusions A positive correlation between HER2 and FOLR1 overexpression may be seen in high‐grade endometrial carcinomas with aberrant p53 expression, which may extend to intratumoral heterogeneity of biomarker expression.

Prognostic performance of FIGO 2023 endometrial carcinoma staging: a comparison to FIGO 2009 staging in the setting of known and unknown molecular classification

AimsThe 2023 FIGO staging criteria for endometrial cancer (EC) introduced marked changes from the 2009 version. The full implication of these changes for patient diagnosis and treatment is unknown. We evaluate the differences in staging and prognostication between the two systems, with and without inclusion of molecular classification.Methods and resultsWe assigned (1) FIGO 2009, (2) 2023 molecular‐agnostic and (3) 2023 molecular‐informed stages to 404 fully staged and molecularly classified patients with EC. Disease‐specific and progression/relapse‐free survival were analysed via the Kaplan–Meier method and compared with log‐rank testing; 118 of 252 (47%) FIGO 2009 stage I patients were upstaged based on histopathological findings alone. Stage I/II subgroup survival distribution analysis showed a worse prognosis in FIGO 2023 IIB and IIC patients. In the molecular‐informed FIGO 2023 system, three of 15 (20%) POLE‐mutated stage I/II cases were downstaged from FIGO 2009 and eight (53%) were downstaged from molecular‐agnostic FIGO 2023. Fifty‐one of 60 (85%) p53‐abnormal tumours were upstaged from the FIGO 2009, whereas 13 of 60 (22%) were upstaged from the 2023 molecular‐agnostic stage. Molecular classification improved prognostic stratification for both 2009 and 2023 FIGO systems.ConclusionsDownstaging based on POLE mutation more accurately represents patient outcomes. However, in the absence of known POLE status, applying molecular‐agnostic FIGO 2023 criteria for stage I/II disease should be conducted with caution. For aggressive histotypes, additionally reporting FIGO 2009 stage should be considered. Upstaging based on substantial lymphovascular space invasion, aggressive histotype with any myometrial invasion and abnormal p53 improves prognostic discernment. Further subdivisions within stage I/II provide minimal additional prognostic information.