Clinical outcomes of patients with POLE mutated endometrioid endometrial cancer

Abstract

Objectives: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs).Methods: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins.Results: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%)Dr. Makker reports grants and personal fees from Esai; grants and personal fees from Merck; other from International PI 775-03/ E7080-G000-309; grants from Takeda (MSKCC PI C31004); personal fees from ArQule; grants and personal fees from Karyopharm; grants from AstraZeneca, grants from Lilly; personal fees from IBM Watson, outside the submitted work. Dr. Soslow reports personal fees from Ebix/Oakstone*; personal fees from Cambridge University Press**; personal fees from Springer Publishers**; personal fees from Roche***, outside the submitted work. (*Preparation of recorded lectures; **royalties; ***one lecture) Dr.

A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response

“…For example, in 1 single-institution study of n = 23 POLE endometrial cancers identified by cancer gene panel (MSK-IMPACT), 17% (4/23) were of advanced stage with extrauterine disease at the time of diagnosis, including 2 cases that were stage IV (distant metastasis). After a median follow-up of 30 months, 17% (4/23) of patients developed recurrences, of which 3 were distant metastases, including 2 brain metastases, and 1 patient died after 33 months (57). A separate large, multi-institutional study of POLE cancers by the NRG Oncology/Gynecologic Oncology Group found improved outcomes for the POLE group, but the differences were not statistically significant (58).…”

Risk Stratification of Endometrial Cancer Patients: FIGO Stage, Biomarkers and Molecular Classification

“…A recent meta-analysis described the histopathologic features and the prevalence of the ESMO risk category for each molecular subgroup and highlights that characteristics such as POLE mutation status and MMRd are more important than histologic features in prognostication [ 90 ]. However, 17% of POLE EC do recur after a median of 30 months follow-up [ 91 ]. The by far largest molecular group is the group of patients with NSMP tumours and almost half of the patients will be classified as such.…”

Complete Response to Pembrolizumab in Advanced Colon Cancer Harboring Somatic POLE F367S Mutation with Microsatellite Stability Status: A Case Study

“…The mutation of POLE exonuclease domain, detected in 6–12% of endometrial cancers, 5 , 6 1–2% of colorectal cancers, 7 , 8 and less than 1% in gastric, breast, and brain cancer, 9 , 10 has emerged as one of the most promising candidate biomarkers. POLE encodes the catalytic subunit of DNA polymerase epsilon, which replicates the leading DNA strand before cell division.…”