Tanya T Kwan1, Amit M Oza2, Anna V Tinker3, Isabelle Ray-Coquard4,5,6, Ana Oaknin7, Carol Aghajanian8, Domenica Lorusso9,10, Nicoletta Colombo11,12, Andrew Dean13, Johanne Weberpals14, Eric Severson15, Lan-Thanh Vo1, Sandra Goble1, Lara Maloney1, Thomas Harding1, Scott H Kaufmann16, Jonathan A Ledermann17, Robert L Coleman18,19, Iain A McNeish20, Kevin K Lin1, Elizabeth M Swisher21. 1. Clovis Oncology Inc, Boulder, Colorado. 2. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. 3. BC Cancer-Vancouver, Vancouver, British Columbia, Canada. 4. Groupe d'Investigateurs Nationaux pour les Etudes des Cancers de l'Ovaire, Lyon, France. 5. Medical Oncology Department, Centre Léon Bérard, Lyon, France. 6. Centre Léon Bérard, University Claude Bernard, Lyon, France. 7. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 8. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 9. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 10. Now with Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Scientific Directorate, Rome, Italy. 11. Gynecologic Cancer Medical Treatments, European Institute of Oncology IRCCS, Milan, Italy. 12. Obstetrics and Gynaecology, University of Milan-Bicocca, Milan, Italy. 13. Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia. 14. Division of Gynecologic Oncology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 15. Pathology and Diagnostic Medicine, Foundation Medicine, Cambridge, Massachusetts. 16. Department of Oncology, Mayo Clinic, Rochester, Minnesota. 17. Department of Oncology, UCL Cancer Institute, University College London, London, UK. 18. Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, The University of Texas, Houston. 19. Now with US Oncology Research, The Woodlands, Texas. 20. Department of Surgery and Cancer, Imperial College London, London, UK. 21. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle.
Abstract
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.
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.
Authors: Amer M Zeidan; Jan Philipp Bewersdorf; Rena Buckstein; Mikkael A Sekeres; David P Steensma; Uwe Platzbecker; Sanam Loghavi; Jacqueline Boultwood; Rafael Bejar; John M Bennett; Uma Borate; Andrew M Brunner; Hetty Carraway; Jane E Churpek; Naval G Daver; Matteo Della Porta; Amy E DeZern; Fabio Efficace; Pierre Fenaux; Maria E Figueroa; Peter Greenberg; Elizabeth A Griffiths; Stephanie Halene; Robert P Hasserjian; Christopher S Hourigan; Nina Kim; Tae Kon Kim; Rami S Komrokji; Vijay Kutchroo; Alan F List; Richard F Little; Ravi Majeti; Aziz Nazha; Stephen D Nimer; Olatoyosi Odenike; Eric Padron; Mrinal M Patnaik; Gail J Roboz; David A Sallman; Guillermo Sanz; Maximilian Stahl; Daniel T Starczynowski; Justin Taylor; Zhuoer Xie; Mina Xu; Michael R Savona; Andrew H Wei; Omar Abdel-Wahab; Valeria Santini Journal: Leukemia Date: 2022-10-20 Impact factor: 12.883
Authors: Chenjie Zeng; Lisa A Bastarache; Ran Tao; Eric Venner; Scott Hebbring; Justin D Andujar; Sarah T Bland; David R Crosslin; Siddharth Pratap; Ayorinde Cooley; Jennifer A Pacheco; Kurt D Christensen; Emma Perez; Carrie L Blout Zawatsky; Leora Witkowski; Hana Zouk; Chunhua Weng; Kathleen A Leppig; Patrick M A Sleiman; Hakon Hakonarson; Marc S Williams; Yuan Luo; Gail P Jarvik; Robert C Green; Wendy K Chung; Ali G Gharavi; Niall J Lennon; Heidi L Rehm; Richard A Gibbs; Josh F Peterson; Dan M Roden; Georgia L Wiesner; Joshua C Denny Journal: JAMA Oncol Date: 2022-06-01 Impact factor: 33.006