Sarcomas developed in patients with Lynch Syndrome are enriched in pleomorphic soft-tissue sarcomas and are sensitive to immunotherapy

F Poumeaud; T Valentin; N Fares; B Segier; S Watson; B Verret; C Tlemsani; N Penel; S Lejeune; N Firmin; A Sabouret; J-C Thery; S Bonvalot; E Cottereau; E Cauchin; A Lancon; S Nambot; H Zattara; M Coudert; E Fourme; C Nogues; D Tougeron; F Prieur; M-A Collonge-Rame; C Denis; P Laurent-Puig; S Chieze-Valero; H Dreyfus; M Jaffrelot; P Vande Perre; P Rochaix; A Gomez-Mascard; P Rochefort; S Campoy; F Chibon; C Lasset; J Selves; R Guimbaud

doi:10.1016/j.ejca.2024.115196

Sarcomas developed in patients with Lynch Syndrome are enriched in pleomorphic soft-tissue sarcomas and are sensitive to immunotherapy

Eur J Cancer. 2024 Dec 21:216:115196. doi: 10.1016/j.ejca.2024.115196. Online ahead of print.

Authors

F Poumeaud¹, T Valentin², N Fares³, B Segier⁴, S Watson⁵, B Verret⁶, C Tlemsani⁷, N Penel⁸, S Lejeune⁹, N Firmin¹⁰, A Sabouret⁵, J-C Thery¹¹, S Bonvalot⁴, E Cottereau¹², E Cauchin¹³, A Lancon¹⁴, S Nambot¹⁴, H Zattara¹⁵, M Coudert¹³, E Fourme⁴, C Nogues¹⁶, D Tougeron¹⁷, F Prieur¹⁸, M-A Collonge-Rame¹⁹, C Denis²⁰, P Laurent-Puig⁶, S Chieze-Valero²¹, H Dreyfus²², M Jaffrelot²³, P Vande Perre²⁴, P Rochaix²⁵, A Gomez-Mascard²⁵, P Rochefort²⁶, S Campoy²⁶, F Chibon²⁵, C Lasset²⁶, J Selves²⁵, R Guimbaud²⁷

Affiliations

¹ Department of Medical Oncology, Oncopole Claudius Regaud, Toulouse, France; Department of Digestive Medical Oncology, Toulouse University Hospital, Toulouse, France; Toulouse Cancer Research Centre, Toulouse, France.
² Department of Medical Oncology, Oncopole Claudius Regaud, Toulouse, France; Toulouse Cancer Research Centre, Toulouse, France.
³ Department of Digestive Medical Oncology, Toulouse University Hospital, Toulouse, France; Toulouse Cancer Research Centre, Toulouse, France.
⁴ Biostatistics & Health Date Science Unit, Oncopole Claudius Regaud IUCT-O, Toulouse, France.
⁵ Department of Medical Oncology, Institut Curie, Paris, France.
⁶ Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
⁷ Department of Medical Oncology, APHP, Paris, France.
⁸ Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
⁹ Department of Oncogenetics, Lille University Hospital, Lille, France.
¹⁰ Department of Medical Oncology, Institut du Cancer de Montpellier, Montpellier, France.
¹¹ Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.
¹² Department of Oncogenetics, Tours University Hospital, Tours, France.
¹³ Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.
¹⁴ Department of Oncogenetics, Centre Georges François Leclerc, Dijon, France.
¹⁵ Department of Oncogenetics, Marseille University Hospital, Marseille, France.
¹⁶ Department of Oncogenetics, Institut Paoli Calmettes, Marseille, France.
¹⁷ Department of Medical Oncology, Poitiers University Hospital, Poitiers, France.
¹⁸ Department of Oncogenetics, Saint Etienne University Hospital, Saint Etienne, France.
¹⁹ Department of Oncogenetics, Besançon University Hospital, Besançon, France.
²⁰ Department of Oncogenetics, Strasbourg University Hospital, Strasbourg, France.
²¹ Department of Oncogenetics, Niort Hospital Centre, Niort, France.
²² Department of Medical Oncology, Institut Sainte Catherine, Avignon, France.
²³ Department of Digestive Medical Oncology, Toulouse University Hospital, Toulouse, France; Department of Oncogenetics, Oncopole Claudius Regaud, Toulouse, France.
²⁴ Department of Oncogenetics, Oncopole Claudius Regaud, Toulouse, France.
²⁵ Toulouse Cancer Research Centre, Toulouse, France; Department of Pathology, Toulouse University Hospital, Toulouse, France.
²⁶ Department of Oncogenetics, Centre Léon Bérard, Lyon, France; Groupe Génétique et Cancer, Unicancer, France.
²⁷ Department of Digestive Medical Oncology, Toulouse University Hospital, Toulouse, France; Toulouse Cancer Research Centre, Toulouse, France; Department of Oncogenetics, Oncopole Claudius Regaud, Toulouse, France; Groupe Génétique et Cancer, Unicancer, France. Electronic address: [email protected].

PMID: 39742560
DOI: 10.1016/j.ejca.2024.115196

Abstract

Background: Sarcomas do not belong to the Lynch Syndrome (LS)-tumour spectrum. A growing body literature has reported sarcomas in patients with LS. Clinical and tumour characteristics of these patients remain unknown.

Patients and methods: We set up the first national retrospective study, SarcLynch, describing the pathological and clinical characteristics of sarcomas developed in patients with LS. Patients were identified from two national networks and included from 23 centres in France.

Results: Eighty-one patients participated in the SarcLynch study. Sixty-seven (83 %) tumours were soft-tissue sarcomas (STS) and 14 (17 %) bone sarcomas. Among STS, 59 (88 %) showed a pleomorphic component, with undifferentiated pleomorphic sarcoma (UPS) (36 %) and pleomorphic rhabdomyosarcoma (pRMS) (21 %) being the most represented subtypes. Sarcoma was the first neoplastic event in 32 patients (40 %). Thirty-two patients (40 %) were carriers of MSH2 germline pathogenic variants. Among patients who underwent an assessment of deficient mismatch repair (dMMR) by immunohistochemistry and/or molecular biology status, 75 % were dMMR by immunohistochemistry and 45 % were microsatellite instability high (MSI-H). Eight patients received immune checkpoint inhibitors and 4 (50 %) exhibited an objective response with 3 complete radiological response including 1 patient with pathological complete response. Duration of response ranged from 6 to 20 months.

Conclusions: SarcLynch, the largest multicentric series describing sarcomas developed in patients with LS, revealed an enrichment in patients with pleomorphic sarcomas - especially UPS and pRMS. This finding strongly supports screening for MMR status evaluation in these rare histotypes both for oncogenetic screening and therapeutic interest. Considering an objective response rate of 50 %, access to immunotherapy should be considered in these tumours.

Keywords: Deficient mismatch repair; Immune checkpoint inhibitors; Lynch Syndrome; MSH2; Microsatellite instability; Pleomorphic rhabdomyosarcomas.