Tumor Mutational Burden Guides Therapy in a Treatment Refractory <i>POLE-</i>Mutant Uterine Carcinosarcoma

Bhangoo, Munveer S.; Boasberg, Peter D.; Mehta, Pareen; Elvin, Julia A.; Ali, Siraj M.; Wu, Winnie; Klempner, Samuel J.

doi:10.1634/theoncologist.2017-0342

Cited by 40 publications

(30 citation statements)

References 39 publications

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“…Genomic analyses have shown that particular mutational signatures can contribute to high TMB independently from MSI status. These include BRCA1/2 (breast cancer genes 1 and 2) and APOBEC deficiency, neoantigen load, ultraviolet rays exposure and mutations affecting TP53 and polymerase e (POLE) (supplementary Figure S2, available at Annals of Oncology online) [7,59,70,[90][91][92][93][94][95].…”

Section: Annals Of Oncologymentioning

confidence: 99%

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

et al. 2019

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Background: Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. Methods: To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. Results: The MSI-related definitions, for which a consensus framework was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. Conclusions: This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.

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Section: Annals Of Oncologymentioning

confidence: 99%

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

et al. 2019

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“…34,35 Furthermore, it has also been reported that POLEmutant endometrial and colorectal tumors had a high somatic mutation burden, elevated expression of immune checkpoint genes and increased lymphocytic infiltration, [36][37][38][39][40][41][42][43] and therefore immune checkpoint inhibitors was recommended for treating cancers with POLE-mutations. 41,44 Similar recommendation was also demonstrated in mismatch repair (MMR) deficient cancers regardless of the cancers' tissue of origin. 45 In this phase II clinical trial, clinical benefit was observed in 53% patients, half of whom also carried germline mutations in MMR genes.…”

Section: Discussionmentioning

confidence: 59%

“…Our finding is consistent with recent findings that POLE mutations can contribute to susceptibility to a broad cancer spectrum including OC . Furthermore, it has also been reported that POLE ‐mutant endometrial and colorectal tumors had a high somatic mutation burden, elevated expression of immune checkpoint genes and increased lymphocytic infiltration, and therefore immune checkpoint inhibitors was recommended for treating cancers with POLE ‐mutations . Similar recommendation was also demonstrated in mismatch repair (MMR) deficient cancers regardless of the cancers’ tissue of origin .…”

Section: Discussionmentioning

confidence: 75%

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Zhu

Zhang

Chen

et al. 2019

Intl Journal of Cancer

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Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two‐stage design to identify new OC predisposition genes. We first carried out a large germline whole‐exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case–control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.

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“…This point may suggest the beneficial effect of PD-L1 blockade in cases with UCS. Recently the first case was reported as anti PDL-1 (pembrolizumab) response in DNA polymerase epsilon (POLE)mutant UCS [27]. Due to the atypical pathogenesis and poor prognosis despite conventional adjuvant chemotherapies, it is imperative to try to better understand the molecular pathogenesis of UCS and to find targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression in uterine carcinosarcoma

Güleç

Bağır

Paydaş

et al. 2020

European Journal of Obstetrics & Gynecology and Reproductiv

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Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma

Cited by 40 publications

References 39 publications

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Prognostic significance of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression in uterine carcinosarcoma

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