Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib.

Autor:	Kwan TT; Clovis Oncology Inc, Boulder, Colorado., Oza AM; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Tinker AV; BC Cancer-Vancouver, Vancouver, British Columbia, Canada., Ray-Coquard I; Groupe d'Investigateurs Nationaux pour les Etudes des Cancers de l'Ovaire, Lyon, France.; Medical Oncology Department, Centre Léon Bérard, Lyon, France.; Centre Léon Bérard, University Claude Bernard, Lyon, France., Oaknin A; Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain., Aghajanian C; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Lorusso D; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; Now with Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Scientific Directorate, Rome, Italy., Colombo N; Gynecologic Cancer Medical Treatments, European Institute of Oncology IRCCS, Milan, Italy.; Obstetrics and Gynaecology, University of Milan-Bicocca, Milan, Italy., Dean A; Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia., Weberpals J; Division of Gynecologic Oncology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., Severson E; Pathology and Diagnostic Medicine, Foundation Medicine, Cambridge, Massachusetts., Vo LT; Clovis Oncology Inc, Boulder, Colorado., Goble S; Clovis Oncology Inc, Boulder, Colorado., Maloney L; Clovis Oncology Inc, Boulder, Colorado., Harding T; Clovis Oncology Inc, Boulder, Colorado., Kaufmann SH; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Ledermann JA; Department of Oncology, UCL Cancer Institute, University College London, London, UK., Coleman RL; Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, The University of Texas, Houston.; Now with US Oncology Research, The Woodlands, Texas., McNeish IA; Department of Surgery and Cancer, Imperial College London, London, UK., Lin KK; Clovis Oncology Inc, Boulder, Colorado., Swisher EM; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle.
Jazyk:	angličtina
Zdroj:	JAMA oncology [JAMA Oncol] 2021 Dec 01; Vol. 7 (12), pp. 1772-1781.
DOI:	10.1001/jamaoncol.2021.4664
Abstrakt:	Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors. Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment. Design, Setting, and Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment. Main Outcomes and Measures: Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates. Results: Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs. Conclusions and Relevance: The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.
Databáze:	MEDLINE
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