TY - JOUR
T1 - Clinical Behavior and Molecular Landscape of Stage I p53-abnormal Low-Grade Endometrioid Endometrial Carcinomas
AU - Jamieson, Amy
AU - Vermij, Lisa
AU - Kramer, Claire J H
AU - Jobsen, Jan J
AU - Jürgenliemk-Schulz, Ina
AU - Lutgens, Ludy
AU - Mens, Jan Willem
AU - Haverkort, Marie A D
AU - Slot, Annerie
AU - Nout, Remi A
AU - Oosting, Jan
AU - Carlson, Joseph
AU - Howitt, Brooke E
AU - Ip, Philip P C
AU - Lax, Sigurd F
AU - McCluggage, W Glenn
AU - Singh, Naveena
AU - McAlpine, Jessica N
AU - Creutzberg, Carien L
AU - Horeweg, Nanda
AU - Gilks, C Blake
AU - Bosse, Tjalling
PY - 2023/12
Y1 - 2023/12
N2 - PURPOSE: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathological and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. EXPERIMENTAL DESIGN: Previously diagnosed stage I p53abn EC (POLE-wildtype, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53-status. Immunohistochemical profiling, next generation sequencing and shallow whole genome sequencing was performed. Kaplan-Meier's method was used for survival analysis. RESULTS: We identified 55 stage I p53abn low-grade EEC among 3387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The immunohistochemical and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. CONCLUSIONS: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.
AB - PURPOSE: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathological and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. EXPERIMENTAL DESIGN: Previously diagnosed stage I p53abn EC (POLE-wildtype, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53-status. Immunohistochemical profiling, next generation sequencing and shallow whole genome sequencing was performed. Kaplan-Meier's method was used for survival analysis. RESULTS: We identified 55 stage I p53abn low-grade EEC among 3387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The immunohistochemical and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. CONCLUSIONS: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.
U2 - 10.1158/1078-0432.CCR-23-1397
DO - 10.1158/1078-0432.CCR-23-1397
M3 - Article
SN - 1078-0432
VL - 29
SP - 4949
EP - 4957
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -