Highlights
- •Patients with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4.
- •When grouped by molecular subtype, there was a significant difference between groups.
- •Using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts.
- •The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments.
- •These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.
Abstract
Background
Homologous recombination deficiency (HRD) score is related to chemotherapy response
in some cancers, but its role in endometrial cancer in not known. We determined frequency
and clinical significance of alterations in the HR pathway in endometrial cancer.
Methods
253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts
(discovery and replication) were tested for HRD score using the Myriad HRD assay,
microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation
sequencing assay. HRD scores were also generated on endometrial cancer cell lines
and in vivo response to olaparib was assessed.
Results
ROC curves were employed to determine optimal cutoffs of HRD in relation to survival
impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the
discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended
toward worse survival as compared to those with HRD score < 4. Both cohorts were further
separated into four groups according to molecular subtypes (TMB positive; MSI positive;
HRD positive; all others). When grouped by molecular subtype, there was a significant
difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib
in in vitro and in vivo experiments.
Conclusions
High HRD score was associated with worse DFS in our patient cohort. These findings
suggest that HRD score may have clinical utility in patients with advanced or recurrent
endometrial cancer.
Keywords
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Article info
Publication history
Published online: February 06, 2021
Accepted:
December 9,
2020
Received:
August 1,
2020
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
