Clinical significance of homologous recombination deficiency score testing in endometrial Cancer

Siedel, Jean; Ring, Kari L.; Hu, Wei; Dood, Robert; Wang, Ying; Baggerly, Keith A.; Darcy, Kathleen M.; Conrads, Thomas P.; Gallagher, Shannon; Tshiaba, Placede; Neff, Chris; Timms, Kirsten M.; Mangala, Selanere L.; Westin, Shannon N.; Broaddus, Russell R.; López-Berestein, Gabriel; Lu, Karen H.; Coleman, Robert L.; Maxwell, G. Larry; Sood, Anil K.

doi:10.1016/j.ygyno.2020.12.010

Cited by 25 publications

(17 citation statements)

References 22 publications

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“…HRD was observed in six out of 12 p53 abn tumours, but in none of the 11 NSMP/MMRd/ POLE mut tumours. In another study, high HRD score was associated with worse disease-free survival in endometrial carcinoma 55. These findings support prospective trials investigating PARP inhibitors to target HRD in endometrial cancer.…”

Section: Treatment Responsesupporting

confidence: 54%

Molecular classification of endometrial carcinoma: a clinically oriented review

2022

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The Cancer Genome Atlas research network performed a genome-wide analysis of endometrial carcinomas in 2013 and classified tumours into four distinct subgroups: polymerase-ϵ ultramutated, microsatellite unstable hypermutated, copy-number low and copy-number high. These molecular alterations are mostly mutually exclusive as only about 3% of tumours exhibit more than one molecular signature. Apart from the polymerase-ϵ ultramutated subgroup, molecular classification can be reproduced by using surrogate markers. This has facilitated the implementation of molecular diagnostics into routine patient care. Molecular subgroups are associated with different prognoses; thus, improved risk assessment is their most obvious clinical application. However, based on their unique molecular architectures, molecular subgroups should not be regarded simply as risk groups but rather as distinct diseases. This has prompted us and others to examine the role of molecular subgroups in modifying the prognostic effect of traditional risk factors, including clinical factors, uterine factors and tissue biomarkers, and in predicting the response to adjuvant therapies. In the following review, we summarise the current knowledge of molecularly classified endometrial carcinoma and present, based on our own experience, a proposal for implementing molecular classification into daily practice in pathology laboratories.

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Section: Treatment Responsesupporting

confidence: 54%

Molecular classification of endometrial carcinoma: a clinically oriented review

2022

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“…EC has been proved to be a homologous recombination‐deficient tumor. However, there is limited knowledge about the clinical significance of HR deficiency in EC 32 …”

Section: Discussionmentioning

confidence: 99%

“…However, there is limited knowledge about the clinical significance of HR deficiency in EC. 32 To obtain more convincing experimental results, our research team will further study the correlation between PARP inhibitors and HR defects in EC.…”

Section: Discussionmentioning

confidence: 99%

Blocking PARP activity with the inhibitor veliparib enhances radiotherapy sensitivity in endometrial carcinoma

Wang

Xing

Lin

et al. 2022

Clinical Laboratory Analysis

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Objective Our study aimed to investigate the potential clinical utility of a poly(ADP‐ribose) polymerase (PARP) inhibitor, veliparib (ABT‐888), as a radiosensitizer in the medication of endometrial carcinoma (EC). Methods Human Ishikawa endometrial adenocarcinoma cells were treated with veliparib, radiotherapy (RT), or combination treatment. The viabilities, radiosensitivity enhancement ratio (sensitizer enhancement ratio (SER), and apoptosis of Ishikawa cells were, respectively, evaluated by Cell Counting Kit‐8 (CCK‐8), colony formation experiment, and flow cytometry. The tumor growth was assessed by xenograft mice models. Western blot assay investigated the expression of DNA damage and apoptosis‐related proteins in vivo and in vitro. Results Cell Counting Kit‐8 revealed that the 10% inhibition concentration (IC10) and 50% inhibition concentration (IC50) values of veliparib‐treated Ishikawa cells were 1.7 and 133.5 µM, respectively. The SER of veliparib combined with RT was 1.229 in vitro. Flow cytometry analysis results indicated that the apoptosis rate of the veliparib + RT group was markedly higher than that of the RT group in vitro (p < 0.05). Furthermore, in vivo data revealed that veliparib + RT treatment significantly decreased tumor growth compared with single treatments of veliparib or RT and with the control group (p < 0.05). Then western blot confirmed the levels of anti‐phospho‐histone (γH2AX), caspase‐3, and B‐cell lymphoma 2 (Bcl‐2) associated protein X (Bax) were significantly higher in the veliparib + RT group, while the level of Bcl‐2 was lower compared with that of the RT group (p < 0.05), both in vivo and in vitro. Conclusion Our results indicate that veliparib in combination with RT markedly improved the therapeutic efficiency in human endometrial carcinoma.

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“… 50 Siedel et al used the Myriad HRD assay on two EC cohorts and found a cut-off HRD score ⩾4 was associated with worse survival, and the median HRD scores for endometrioid EC, mixed serous and endometrioid EC, and serous EC were 3, 15.5 and 28.5 respectively. 51 The worse survival outcomes for high HRD score EC differs from HGSOC and basal-like breast cancer, where HRD high tumours show improved outcomes in both tumour types. This same group also determined the HRD scores of 12 EC cell lines.…”

Section: P53abn Endometrial Cancermentioning

confidence: 98%

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

2021

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Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

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Clinical significance of homologous recombination deficiency score testing in endometrial Cancer

Cited by 25 publications

References 22 publications

Molecular classification of endometrial carcinoma: a clinically oriented review

Molecular classification of endometrial carcinoma: a clinically oriented review

Blocking PARP activity with the inhibitor veliparib enhances radiotherapy sensitivity in endometrial carcinoma

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

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