Comprehensive immunomolecular profiling of endometrial carcinoma: A tertiary retrospective study

Victoor, Jasper; Borght, Sara Vander; Spans, Lien; Lehnert, Stefan; Brems, Hilde; Laenen, Annouschka; Vergote, Ignace; Gorp, Toon Van; Nieuwenhuysen, Els Van; Han, Sileny; Timmerman, S.; Rompuy, Anne‐Sophie Van; Bempt, Isabelle Vanden

doi:10.1016/j.ygyno.2021.06.030

Cited by 10 publications

(2 citation statements)

References 37 publications

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“…Regarding genomic profiling, our data further confirm the high frequency of ARID1A mutation in endometrial carcinoma, detected in 41.6% of patients in our series versus 40% in the literature 24. Evidence also suggests that this aberrant gene expression is mutually exclusive with TP53 ,24 25 which our observation confirmed, as no ARID1A mutations were detected in the high-copy number subgroup. Furthermore, our analysis matches the finding of approximately 20% of endometrial carcinoma tumors presenting a BRCA alteration (22% from our data) 26…”

Section: Discussionsupporting

confidence: 88%

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience

Salutari

Ghizzoni

Carbone

et al. 2023

International Journal of Gynecological Cancer

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ObjectiveNext-generation sequencing (NGS) analysis has become an essential tool for endometrial carcinoma management. Moreover, molecular-driven therapies play an increasingly remarkable role in the era of precision oncology. This study aims to determine the clinical relevance of NGS testing in endometrial carcinoma management by analyzing the clinical benefit of NGS-driven targeted therapies.MethodsA single-center retrospective study was conducted on 25 endometrial carcinoma patients who underwent Foundation Medicine CDx assay at Fondazione Policlinico Universitario Agostino Gemelli, IRCCS (Rome, Italy). Tumor samples were analyzed by Foundation One CDx. A descriptive analysis of tumor genome profiles was performed. Assessment of clinical benefit according to RECIST 1.1 criteria was analyzed for patients who received a tailored treatment according to actionable targets identified by NGS testing.ResultsOut of 25 endometrial carcinoma patients, 11 received targeted therapy. One patient was excluded from the clinical benefit assessment because of COVID-19-related death 1 month after starting the treatment. Eight of the remaining 10 patients benefited from targeted therapies, with an overall clinical benefit rate of 80%. A targeted agent belonging to the PI3K pathway was given to seven patients, with evidence of three partial responses (42.9%), three stable diseases (42.9%), and one progressive disease (14.2%) according to RECIST 1.1 criteria. One complete response (33.3%), one stable disease (33.3%), and one progressive disease (33.3%) were observed in the three patients treated with poly(ADP-ribose) polymerase (PARP) inhibitors according to their homologous recombination deficiency (HRD) status.ConclusionThis study highlights the importance of characterizing the mutation profile of patient tumors through NGS. Our findings suggest a clinical benefit of using NGS-driven targeted therapies in endometrial carcinoma patients. However, this personalized approach could benefit the health system in terms of cost-effectiveness by reducing the costs of inappropriate, ineffective, and often expensive treatments.

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Section: Discussionsupporting

confidence: 88%

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience

Salutari

Ghizzoni

Carbone

et al. 2023

International Journal of Gynecological Cancer

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“…The prognostic effect of TILs has been widely discussed as pro ( 49 , 51 , 52 ), and contra ( 7 , 8 , 40 ). Since there is a positive correlation between POLE mutated tumors and a higher CD8 + intra-tumoral immune infiltrate ( 5 – 8 , 14 , 44 – 46 ), it would be logical that their prognostic significance might be dependent on case numbers of POLE mutated ECs. This has recently been shown by a meta-analysis of almost two thousand EC cases ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Spatial distribution of CD3- and CD8-positive lymphocytes as pretest for POLE wild-type in molecular subgroups of endometrial carcinoma

et al. 2023

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IntroductionOver the years, the molecular classification of endometrial carcinoma has evolved significantly. Both POLEmut and MMRdef cases share tumor biological similarities like high tumor mutational burden and induce strong lymphatic reactions. While therefore use case scenarios for pretesting with tumor-infiltrating lymphocytes to replace molecular analysis did not show promising results, such testing may be warranted in cases where an inverse prediction, such as that of POLEwt, is being considered. For that reason we used a spatial digital pathology method to quantitatively examine CD3+ and CD8+ immune infiltrates in comparison to conventional histopathological parameters, prognostics and as potential pretest before molecular analysis.MethodsWe applied a four-color multiplex immunofluorescence assay for pan-cytokeratin, CD3, CD8, and DAPI on 252 endometrial carcinomas as testing and compared it to further 213 cases as validation cohort from a similar multiplexing assay. We quantitatively assessed immune infiltrates in microscopic distances within the carcinoma, in a close distance of 50 microns, and in more distant areas.ResultsRegarding prognostics, high CD3+ and CD8+ densities in intra-tumoral and close subregions pointed toward a favorable outcome. However, TCGA subtyping outperforms prognostication of CD3 and CD8 based parameters. Different CD3+ and CD8+ densities were significantly associated with the TCGA subgroups, but not consistently for histopathological parameter. In the testing cohort, intra-tumoral densities of less than 50 intra-tumoral CD8+ cells/mm2 were the most suitable parameter to assume a POLEwt, irrespective of an MMRdef, NSMP or p53abn background. An application to the validation cohort corroborates these findings with an overall sensitivity of 95.5%.DiscussionMolecular confirmation of POLEmut cases remains the gold standard. Even if CD3+ and CD8+ cell densities appeared less prognostic than TCGA, low intra-tumoral CD8+ values predict a POLE wild-type at substantial percentage rates, but not vice versa. This inverse correlation might be useful to increase pretest probabilities in consecutive POLE testing. Molecular subtyping is currently not conducted in one-third of cases deemed low-risk based on conventional clinical and histopathological parameters. However, this percentage could potentially be increased to two-thirds by excluding sequencing of predicted POLE wild-type cases, which could be determined through precise quantification of intra-tumoral CD8+ cells.

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Association of mismatch repair deficiency in endometrial cancer with 18F-FDG PET/CT and clinicopathological features and their prognostic value

Sun,

Yao,

Zeng

et al. 2023

Ann Nucl Med

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Comprehensive immunomolecular profiling of endometrial carcinoma: A tertiary retrospective study

Cited by 10 publications

References 37 publications

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience

Spatial distribution of CD3- and CD8-positive lymphocytes as pretest for POLE wild-type in molecular subgroups of endometrial carcinoma

Association of mismatch repair deficiency in endometrial cancer with 18F-FDG PET/CT and clinicopathological features and their prognostic value

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