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  • 555 Association between molecular heterogeneity and prognosis in non-P53 metastatic endometrial carcinoma: ancillary analysis of the UTOLA phase II GINECO trial

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03. Endometrial cancer
555 Association between molecular heterogeneity and prognosis in non-P53 metastatic endometrial carcinoma: ancillary analysis of the UTOLA phase II GINECO trial
  1. Guillaume Beinse1,
  2. Karen Leroy2,
  3. Pierre-Alexandre Just3,
  4. Corinne Jeanne4,
  5. Alexandra Leary5,
  6. Benoit You6,
  7. Laurence Gladieff7,
  8. Manuel Rodrigues8,
  9. Olivier Tredan9,
  10. Sophie Abadie-Lacourtoisie10,
  11. Leïla Bengrine Lefevre11,
  12. Pierre-Emmanuel Brache4,
  13. Coriolan Lebreton12,
  14. Elsa Kalbacher13,
  15. Pierre Fournel14,
  16. Cyril Foa15,
  17. Rémy Largillier16,
  18. Florence Joly4,
  19. Jérôme Alexandre17 and
  20. Dominique Vaur4
  1. 1Hôpital Cochin, Institut du cancer Paris CARPEM, Paris, France, GINEGEPS, Paris, France
  2. 2Department of genomic medicine for tumours and cancers, Hôpital Européen Georges Pompidou, Paris, France
  3. 3AP-HM, Hôpital de la Timone, service d’anatomie pathologique, Marseille, France
  4. 4Centre François Baclesse, Caen, France
  5. 5Cancer Medicine department, Institut de Cancérologie Gustave Roussy, Villejuif, France
  6. 6Centre Hospitalier Lyon-Sud, Lyon, France
  7. 7Institut Claudius Regaud - IUCT Oncopole, Toulouse, France
  8. 8Department of Medical Oncology, INSERM U830, Institut Curie, Paris, France
  9. 9Centre Léon Bérard, Lyon, France
  10. 10Department of Oncology, Institut de Cancérologie de l’Ouest, Site Paul Papin, Angers, France
  11. 11Department of Oncology, Centre Georges François Leclerc, Dijon, France
  12. 12Institut Bergonié, Bordeaux, France
  13. 13Department of Oncology, CHU Jean Minjoz, Besançon, France
  14. 14CHU de Saint-Etienne, Saint-Etienne, France
  15. 15Department of Medical Oncology, Hôpital Saint-Joseph, Marseille, France
  16. 16Centre Azuréen de Cancérologie, Mougins, France
  17. 17Université de Paris Cité, Hôpital Cochin, Paris, France

Abstract

Introduction/Background The UTOLA study, comparing maintenance olaparib vs placebo in advanced/metastatic endometrial cancer (EC), did not find progression-free-survival (PFS) difference. Subgroup analysis suggests some efficacy of olaparib in HRD positive tumor (Joly et al ESMO 2023). Here, we explored the molecular heterogeneity and prognosis of non-p53 tumors.

Methodology Tumors from patients included in UTOLA (NCT03745950) with prospective targeted next-generation sequencing (NGS) were included in this analysis. NGS data were centrally analyzed (127 genes, targeting 667,5Kb, including POLE (exo-nuclease domain, EDM), TP53, PIK3CA, PIK3R1, PTEN, and CTNNB1). Tumors were categorized following ESMO-ESTRO-ESP guidelines: POLE-EDM-mutated, mismatch repair-deficient (dMMR), p53-abnormal (p53abn) (abnormal immunohistochemistry expression or TP53 mutation), and tumors with no specific molecular profile (NSMP). Non-p53 molecular subgroups were further categorized based on a-priori hypotheses: mutational burden (TMB-high>27 mut/Mb (2.5 standard deviation within p53abn group)) for dMMR tumors, and PTEN/PIK3R1-wild-type status (Momeni-Boroujeni, 2022) and KRAS/CTNNB1 mutations for NSMP tumors. Genomic instability was assessed by the GIScar score (Leman, 2023). The reference group for PFS analyses was the p53abn.

Results Excluding one POLE tumor, 136 patients were categorized as follows: dMMR (N=19), among which 9 (50%) had low TMB (more frequently of histological high-grade, p<0.05); NSMP (N=38), among which 12 (31%) were categorized PTEN/PIK3R1-wild-type tumors (all randomized to olaparib), and 18 (47%) KRAS/CTNNB1-mutated; and p53 (N=79). PTEN/PIK3R1-wild-type tumors had higher numbers of large genomic events (GIScar score). Molecular group (NSMP/dMMR/p53abn) was not associated with PFS. Prognosis of KRAS/CTNNB1-driven NSMP and high-TMB dMMR tumors were similar to p53abn tumors (median PFS 5–7 months) while patients with PTEN/PIK3R1-wild-type NSMP (15 months) and with low-TMB dMMR tumors (15 months) experienced better outcomes.

Conclusion Our results suggest that the mutational heterogeneity of advanced/metastatic EC within molecular subgroup is associated with patient prognosis. Further studies on subclassification of NSMP and dMMR tumors should be encouraged for future clinical trials.

Disclosures The UTOLA trial was funded by ASTRAZENECA.

https://doi.org/10.1136/ijgc-2024-ESGO.351

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