Complete remission with olaparib in BRIP1-mutated metastatic high-grade pleomorphic sarcoma: case study and literature review – an example of a genomic profiling-based tumor treatment, in a cancer type with high unmet clinical need
DOI:
https://doi.org/10.2340/1651-226X.2025.43374Keywords:
Poly(ADP-ribose) Polymerase Inhibitors, BRIP1 protein, human, Sarcoma, Recombinational DNA Repair, Remission Induction, High-Throughput Nucleotide Sequencing, Precision MedicineAbstract
Background and purpose: Patients with high-grade metastatic sarcoma have a poor prognosis and limited treatment options, mostly involving chemotherapy with palliative intent. In the past years, next
generation sequencing has proven its benefit in cancer diagnostics and prediction of treatment response to targeted therapy.
Patient/material and methods: We present a case of response and long-term complete remission under treatment with the poly(ADP-ribose) polymerase inhibitor (PARP-inhibitor) olaparib in a patient with metastatic high-grade pleomorphic sarcoma, with an next generation sequencing detected BRIP1-mutation. Additionally, a literature search regarding the pathophysiology of BRIP1-mutations and the role of PARP-inhibitors in BRIP1-mutated cancer was conducted.
Results: A 67-year-old female patient was diagnosed with a high-grade intra-abdominal pleomorphic sarcoma, which was surgically resected. One year later, metastatic lesions in the right lung were observed. Genomic profiling identified a BRIP1-mutation. Based on this finding, the patient was included in the PRECISION-2 olaparib study, which evaluates the efficacy of olaparib in advanced cancers of any type harboring mutations in a homologous recombination gene. Within 2 months of olaparib treatment, regression of the pulmonary metastases was observed with ongoing complete remission for currently 36 months. A review of the available literature highlights the importance of BRIP1 in the homologous recombination repair pathway and its role as a cancer susceptibility gene. Studies in BRIP1-mutated breast cancer, ovarian cancer, and prostate cancer suggest a clinical benefit of PARP-inhibitor use.
Interpretation: We here describe the first case of a metastatic BRIP1-mutated sarcoma, undergoing a complete radiologic response to olaparib treatment. We highlight an underexplored role of homologous recombination deficiency in non-traditional cancer types and postulate a tumor-agnostic approach to the use of PARP-inhibitors in BRIP1-mutated tumors.
Downloads
References
Carbone F, Pizzolorusso A, Di Lorenzo G, Di Marzo M, Cannella L, Barretta ML, et al. Multidisciplinary management of retroperitoneal sarcoma: diagnosis, prognostic factors and treatment. Cancers (Basel). 2021;13:4016.
https://doi.org/10.3390/cancers13164016 DOI: https://doi.org/10.3390/cancers13164016
Gronchi A, Miah AB, Dei Tos AP, Abecassis N, Bajpai J, Bauer S, et al. Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32:1348–65.
https://doi.org/10.1016/j.annonc.2021.07.006 DOI: https://doi.org/10.1016/j.annonc.2021.07.006
Graves L, Jeck WR, Grilley-Olson JE. A league of its own? Established and emerging therapies in undifferentiated pleomorphic sarcoma. Curr Treat Options Oncol. 2023;24:212–28.
https://doi.org/10.1007/s11864-023-01054-7 DOI: https://doi.org/10.1007/s11864-023-01054-7
Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC). Eur Heart J Cardiovasc Imaging. 2022;23:e333–465.
van Houdt WJ, Zaidi S, Messiou C, Thway K, Strauss DC, Jones RL. Treatment of retroperitoneal sarcoma: current standards and new developments. Curr Opin Oncol. 2017;29:260–7.
https://doi.org/10.1097/CCO.0000000000000377 DOI: https://doi.org/10.1097/CCO.0000000000000377
Ferrario T, Karakousis CP. Retroperitoneal sarcomas: grade and survival. Arch Surg. 2003;138:248–51.
https://doi.org/10.1001/archsurg.138.3.248 DOI: https://doi.org/10.1001/archsurg.138.3.248
Abdelfatah E, Guzzetta AA, Nagarajan N, Wolfgang CL, Pawlik TM, Choti MA, et al. Long‐term outcomes in treatment of retroperitoneal sarcomas: a 15 year single‐institution evaluation of prognostic features. J Surg Oncol. 2016;114:56–64.
https://doi.org/10.1002/jso.24256 DOI: https://doi.org/10.1002/jso.24256
Dangoor A, Seddon B, Gerrand C, Grimer R, Whelan J, Judson I. UK guidelines for the management of soft tissue sarcomas. Clin Sarcoma Res. 2016;6:1–26.
https://doi.org/10.1186/s13569-016-0060-4 DOI: https://doi.org/10.1186/s13569-016-0060-4
Maes B, Dedeurwaerdere F, Vanden Bempt I, Van Huysse J, Rottey S, Vermeij J, et al. Comprehensive genomic profiling for precision oncology: the Belgian approach for Local Laboratory Extensive Tumour Testing study (BALLETT). European Congress of Pathology. European Congress of Pathology (Dublin, du 10/09/2023 au 13/09/2023).
Thouvenin J, Van Marcke C, Decoster L, Raicevic G, Punie K, Vandenbulcke M, et al. PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment. ESMO Open. 2022;7:100524.
https://doi.org/10.1016/j.esmoop.2022.100524 DOI: https://doi.org/10.1016/j.esmoop.2022.100524
Joris S. Efficacy of olaparib in advanced cancers occurring in patients with germline mutations or somatic tumor mutations in homologous recombination genes (1-2018 BSMO [Accessed 2025-08-27]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT03967938?term=HRD+olaparib&cntry=BE&draw=2&rank=1
Stewart MD, Merino Vega D, Arend RC, Baden JF, Barbash O, Beaubier N, et al. Homologous recombination deficiency: concepts, definitions, and assays. Oncologist. 2022;27:167–74.
https://doi.org/10.1093/oncolo/oyab053 DOI: https://doi.org/10.1093/oncolo/oyab053
Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2012;12:68–78.
https://doi.org/10.1038/nrc3181 DOI: https://doi.org/10.1038/nrc3181
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science (1979). 1990;250:1684–9.
https://doi.org/10.1126/science.2270482 DOI: https://doi.org/10.1126/science.2270482
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–92.
https://doi.org/10.1038/378789a0 DOI: https://doi.org/10.1038/378789a0
Sokolova A, Johnstone KJ, McCart Reed AE, Simpson PT, Lakhani SR. Hereditary breast cancer: syndromes, tumour pathology and molecular testing. Histopathology. 2023;82:70–82.
https://doi.org/10.1111/his.14808 DOI: https://doi.org/10.1111/his.14808
Cantor SB, Guillemette S. Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. Fut Oncol. 2011;7:253–61.
https://doi.org/10.2217/fon.10.191 DOI: https://doi.org/10.2217/fon.10.191
Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001;105:149–60.
https://doi.org/10.1016/S0092-8674(01)00304-X DOI: https://doi.org/10.1016/S0092-8674(01)00304-X
Paluch-Shimon S, Cardoso F, Sessa C, Balmaña J, Cardoso MJ, Gilbert F, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. 2016;27:v103–10.
https://doi.org/10.1093/annonc/mdw327 DOI: https://doi.org/10.1093/annonc/mdw327
European Medicines Agency. Lynparza EMA authorisation 2024 [Internet]. [cited 2024 Jan 15]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza
European Medicines Agency. Zejula EMA authorisation 2024 [Internet]. [cited 2024 Jan 15]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/zejula
European Medicines Agency. Talzenna EMA authorisation 2021 [Internet]. [cited 2024 Jan 15]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/talzenna
European Medicines Agency. Rubraca EMA authorisation 2023 [Internet]. [cited 2024 Jan 15]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/rubraca
Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33:304.
https://doi.org/10.1200/JCO.2014.57.1414 DOI: https://doi.org/10.1200/JCO.2014.57.1414
Weber-Lassalle N, Hauke J, Ramser J, Richters L, Groß E, Blümcke B, et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res. 2018;20:7.
https://doi.org/10.1186/s13058-018-0935-9 DOI: https://doi.org/10.1186/s13058-018-0935-9
Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107:djv214.
Suszynska M, Ratajska M, Kozlowski P. BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of~ 30,000 cases. J Ovarian Res. 2020;13:1–11.
https://doi.org/10.1186/s13048-020-00654-3 DOI: https://doi.org/10.1186/s13048-020-00654-3
Inderjeeth A-J, Topp M, Sanij E, Castro E, Sandhu S. Clinical application of poly (ADP-ribose) polymerase (PARP) inhibitors in prostate cancer. Cancers (Basel). 2022;14:5922.
https://doi.org/10.3390/cancers14235922 DOI: https://doi.org/10.3390/cancers14235922
Kote-Jarai Z, Jugurnauth S, Mulholland S, Leongamornlert DA, Guy M, Edwards S, et al. A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer. Br J Cancer. 2009;100:426–30.
https://doi.org/10.1038/sj.bjc.6604847 DOI: https://doi.org/10.1038/sj.bjc.6604847
Dudley B, Karloski E, Monzon FA, Singhi AD, Lincoln SE, Bahary N, et al. Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. Cancer. 2018;124:1691–700.
https://doi.org/10.1002/cncr.31242 DOI: https://doi.org/10.1002/cncr.31242
Vietri MT, D’Elia G, Caliendo G, Resse M, Casamassimi A, Passariello L, et al. Hereditary prostate cancer: genes related, target therapy and prevention. Int J Mol Sci. 2021;22:3753.
https://doi.org/10.3390/ijms22073753 DOI: https://doi.org/10.3390/ijms22073753
Peake JD, Noguchi E. Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair. Hum Genet. 2022;141:1811–36.
https://doi.org/10.1007/s00439-022-02462-9 DOI: https://doi.org/10.1007/s00439-022-02462-9
Gruber JJ, Afghahi A, Timms K, DeWees A, Gross W, Aushev VN, et al. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes. Nat Cancer. 2022;3:1181–91.
https://doi.org/10.1038/s43018-022-00439-1 DOI: https://doi.org/10.1038/s43018-022-00439-1
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38:4274–82.
https://doi.org/10.1200/JCO.20.02151 DOI: https://doi.org/10.1200/JCO.20.02151
Kwapisz D, Verret B, Garcia C, André F. Excellent response to olaparib in metastatic HR-positive, HER2-negative breast cancer with BRIP1 mutation. Ann Oncol. 2023;34:315–18.
https://doi.org/10.1016/j.annonc.2023.01.012 DOI: https://doi.org/10.1016/j.annonc.2023.01.012
Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020;26:2487–96.
https://doi.org/10.1158/1078-0432.CCR-20-0394 DOI: https://doi.org/10.1158/1078-0432.CCR-20-0394
de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091–102.
https://doi.org/10.1056/NEJMoa1911440 DOI: https://doi.org/10.1056/NEJMoa1911440
Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505.
https://doi.org/10.1056/NEJMoa1810858 DOI: https://doi.org/10.1056/NEJMoa1810858
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92.
https://doi.org/10.1056/NEJMoa1105535 DOI: https://doi.org/10.1056/NEJMoa1105535
González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381:2391–402.
https://doi.org/10.1056/NEJMoa1910962 DOI: https://doi.org/10.1056/NEJMoa1910962
Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154–64.
https://doi.org/10.1056/NEJMoa1611310 DOI: https://doi.org/10.1056/NEJMoa1611310
Jiang X, Li X, Li W, Bai H, Zhang Z. PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med. 2019;23:2303–13.
https://doi.org/10.1111/jcmm.14133 DOI: https://doi.org/10.1111/jcmm.14133
Ciccone MA, Adams CL, Bowen C, Thakur T, Ricker C, Culver JO, et al. Inhibition of poly (ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells. Gynecol Oncol. 2020;159:869–76.
https://doi.org/10.1016/j.ygyno.2020.09.040 DOI: https://doi.org/10.1016/j.ygyno.2020.09.040
Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764–75.
https://doi.org/10.1158/1078-0432.CCR-13-2287 DOI: https://doi.org/10.1158/1078-0432.CCR-13-2287
Guffanti F, Mengoli I, Damia G. Current HRD assays in ovarian cancer: differences, pitfalls, limitations, and novel approaches. Front Oncol. 2024;14:1405361.
https://doi.org/10.3389/fonc.2024.1405361 DOI: https://doi.org/10.3389/fonc.2024.1405361
Singh HM, Bailey P, Huebschmann D, Berger AK, Neoptolemos JP, Jäger D, et al. Poly (ADP‐ribose) polymerase inhibition in pancreatic cancer. Genes Chromosomes Cancer. 2021;60:373–84.
https://doi.org/10.1002/gcc.22932 DOI: https://doi.org/10.1002/gcc.22932
Buonaiuto R, Neola G, Caltavituro A, Longobardi A, Mangiacotti FP, Cefaliello A, et al. Efficacy of PARP inhibitors in advanced high-grade serous ovarian cancer according to BRCA domain mutations and mutation type. Front Oncol. 2024;14:1412807.
https://doi.org/10.3389/fonc.2024.1412807 DOI: https://doi.org/10.3389/fonc.2024.1412807
Marchetti C, Fagotti A, Fruscio R, Cassani C, Incorvaia L, Perri MT, et al. Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study. ESMO Open. 2025;10:104533.
https://doi.org/10.1016/j.esmoop.2025.104533 DOI: https://doi.org/10.1016/j.esmoop.2025.104533
Milano L, Alenezi WM, Fierheller CT, Serruya C, Revil T, Oros KK, et al. Genetic and molecular analyses of candidate germline BRIP1/FANCJ variants implicated in breast and ovarian cancer. MedRxiv. 2023:2023–7.
https://doi.org/10.1101/2023.07.03.23290133 DOI: https://doi.org/10.1101/2023.07.03.23290133
Long G, Hu K, Zhang X, Zhou L, Li J. Spectrum of BRCA1 interacting helicase 1 aberrations and potential prognostic and therapeutic implication: a pan cancer analysis. Sci Rep. 2023;13:4435.
https://doi.org/10.1038/s41598-023-31109-6 DOI: https://doi.org/10.1038/s41598-023-31109-6
Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MDM, Wendl MC, et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156.
https://doi.org/10.1038/ncomms4156 DOI: https://doi.org/10.1038/ncomms4156
Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482–90.
https://doi.org/10.1001/jamaoncol.2015.5495 DOI: https://doi.org/10.1001/jamaoncol.2015.5495
Thompson ER, Rowley SM, Li N, McInerny S, Devereux L, Wong-Brown MW, et al. Panel testing for familial breast cancer: calibrating the tension between research and clinical care. J Clin Oncol. 2016;34:1455–9.
https://doi.org/10.1200/JCO.2015.63.7454 DOI: https://doi.org/10.1200/JCO.2015.63.7454
Joris S, Denys H, Collignon J, Rasschaert M, de Roodenbeke D, Duhoux FP, et al. Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study. ESMO Open. 2023;8:102041.
https://doi.org/10.1016/j.esmoop.2023.102041 DOI: https://doi.org/10.1016/j.esmoop.2023.102041
Heeke AL, Pishvaian MJ, Lynce F, Xiu J, Brody JR, Chen W-J, et al. Prevalence of homologous recombination–related gene mutations across multiple cancer types. JCO Precis Oncol. 2018;2:1–13.
https://doi.org/10.1200/PO.17.00286 DOI: https://doi.org/10.1200/PO.17.00286
Bogani G, Monk BJ, Powell MA, Westin SN, Slomovitz B, Moore KN, et al. Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer. Ann Oncol. 2024;35:414–28.
https://doi.org/10.1016/j.annonc.2024.02.006 DOI: https://doi.org/10.1016/j.annonc.2024.02.006
Mirza M, Ghamande S, Hanker L, Black D, Raascou-Jensen N, Gilbert L, et al. Dostarlimab plus chemotherapy followed by dostarlimab plus niraparib maintenance therapy among patients with primary advanced or recurrent endometrial cancer in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Gynecol Oncol. 2024;190:S6.
https://doi.org/10.1016/j.ygyno.2024.07.016 DOI: https://doi.org/10.1016/j.ygyno.2024.07.016
Westin SN, Moore K, Chon HS, Lee J-Y, Thomes Pepin J, Sundborg M, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2024;42:283–99. DOI: https://doi.org/10.1200/JCO-24-01660
https://doi.org/10.1200/JCO.23.02132 DOI: https://doi.org/10.1200/JCO.23.02132
Lobbedez FJ, Leary A, Ray-Coquard IL, Asselain B, Rodrigues MJ, Gladieff L, et al. LBA42 Olaparib vs placebo as maintenance therapy after platinum-based chemotherapy in advanced/metastatic endometrial cancer patients: the GINECO randomized phase IIb UTOLA trial. Ann Oncol. 2023;34:S1283–4.
https://doi.org/10.1016/j.annonc.2023.10.036 DOI: https://doi.org/10.1016/j.annonc.2023.10.036
Nakamura K, Aimono E, Tanishima S, Imai M, Nagatsuma AK, Hayashi H, et al. Olaparib monotherapy for BRIP1-mutated high-grade serous endometrial cancer. JCO Precis Oncol. 2020;4:PO-19.
https://doi.org/10.1200/PO.19.00368 DOI: https://doi.org/10.1200/PO.19.00368
Senguttuvan RN, Wei C, Raoof M, Dellinger TH, Wang EW. Complete pathologic response to PARP inhibitor olaparib in a patient with stage IVB recurrent endometrioid endometrial adenocarcinoma. J Clin Med. 2023;12:3839.
https://doi.org/10.3390/jcm12113839 DOI: https://doi.org/10.3390/jcm12113839
Anzellini D, Arcangeli G, Del Bianco S. Complete response of a mutated BRCA2 metastatic clear cell endometrial adenocarcinoma to the poly (ADP ribose) polymerase (PARP) inhibitor olaparib. Cancer Diagn Progn. 2022;2:84.
https://doi.org/10.21873/cdp.10080 DOI: https://doi.org/10.21873/cdp.10080
Wang Q, Zhang F, Gao H, Xu Y. Successful treatment of a patient with brain metastases from endometrial cancer using Niraparib: a case report. Ann Palliat Med. 2021;10:81827.
https://doi.org/10.21037/apm-21-113 DOI: https://doi.org/10.21037/apm-21-113
Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5.
https://doi.org/10.1038/nature11005 DOI: https://doi.org/10.1038/nature11005
Brenner JC, Feng FY, Han S, Patel S, Goyal SV, Bou-Maroun LM, et al. PARP-1 inhibition as a targeted strategy to treat Ewing’s sarcoma. Cancer Res. 2012;72:1608–13.
https://doi.org/10.1158/0008-5472.CAN-11-3648 DOI: https://doi.org/10.1158/0008-5472.CAN-11-3648
Smith MA, Hampton OA, Reynolds CP, Kang MH, Maris JM, Gorlick R, et al. Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673. Pediatr Blood Cancer. 2015;62:91–8.
https://doi.org/10.1002/pbc.25201 DOI: https://doi.org/10.1002/pbc.25201
Kovac M, Blattmann C, Ribi S, Smida J, Mueller NS, Engert F, et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015;6:8940.
https://doi.org/10.1038/ncomms9940 DOI: https://doi.org/10.1038/ncomms9940
Norris RE, Adamson PC, Nguyen VT, Fox E. Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors. Pediatr Blood Cancer. 2014;61:145–50.
https://doi.org/10.1002/pbc.24697 DOI: https://doi.org/10.1002/pbc.24697
Choy E, Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, et al. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer. 2014;14:1–6.
https://doi.org/10.1186/1471-2407-14-813 DOI: https://doi.org/10.1186/1471-2407-14-813
Schafer ES, Rau RE, Berg SL, Liu X, Minard CG, Bishop AJR, et al. Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: a Children’s Oncology Group Phase 1 Consortium study (ADVL1411). Pediatr Blood Cancer. 2020;67:e28073.
https://doi.org/10.1002/pbc.28073 DOI: https://doi.org/10.1002/pbc.28073
Engert F, Kovac M, Baumhoer D, Nathrath M, Fulda S. Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. Oncotarget. 2017;8:48794.
https://doi.org/10.18632/oncotarget.10720 DOI: https://doi.org/10.18632/oncotarget.10720
Kivlin CM, Watson KL, Al Sannaa GA, Belousov R, Ingram DR, Huang K-L, et al. Poly (ADP) ribose polymerase inhibition: a potential treatment of malignant peripheral nerve sheath tumor. Cancer Biol Ther. 2016;17:129–38.
https://doi.org/10.1080/15384047.2015.1108486 DOI: https://doi.org/10.1080/15384047.2015.1108486
Mangoni M, Sottili M, Salvatore G, Meattini I, Desideri I, Greto D, et al. Enhancement of soft tissue sarcoma cell radiosensitivity by poly (ADP-ribose) polymerase-1 inhibitors. Radiat Res. 2018;190:464–72.
https://doi.org/10.1667/RR15035.1 DOI: https://doi.org/10.1667/RR15035.1
Camero S, Ceccarelli S, De Felice F, Marampon F, Mannarino O, Camicia L, et al. PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines. J Cancer Res Clin Oncol. 2019;145:137–52.
https://doi.org/10.1007/s00432-018-2774-6 DOI: https://doi.org/10.1007/s00432-018-2774-6
Venneker S, Kruisselbrink AB, Briaire-de Bruijn IH, de Jong Y, van Wijnen AJ, Danen EHJ, et al. Inhibition of PARP sensitizes chondrosarcoma cell lines to chemo-and radiotherapy irrespective of the IDH1 or IDH2 mutation status. Cancers (Basel). 2019;11:1918.
https://doi.org/10.3390/cancers11121918 DOI: https://doi.org/10.3390/cancers11121918
Yamasaki H, Miyamoto M, Yamamoto Y, Kondo T, Watanabe T, Ohta T. Synovial sarcoma cell lines showed reduced DNA repair activity and sensitivity to a PARP inhibitor. Genes Cells. 2016;21:852–60.
https://doi.org/10.1111/gtc.12387 DOI: https://doi.org/10.1111/gtc.12387
Chudasama P, Mughal SS, Sanders MA, Hübschmann D, Chung I, Deeg KI, et al. Integrative genomic and transcriptomic analysis of leiomyosarcoma. Nat Commun. 2018;9:144.
https://doi.org/10.1038/s41467-017-02602-0 DOI: https://doi.org/10.1038/s41467-017-02602-0
Rosenbaum E, Jonsson P, Seier K, Chi P, Dickson MA, Gounder MM, et al. DNA damage response pathway alterations and clinical outcome in leiomyosarcoma. J Clin Oncol. 2019;37:11048.
https://doi.org/10.1200/JCO.2019.37.15_suppl.11048 DOI: https://doi.org/10.1200/JCO.2019.37.15_suppl.11048
Seligson ND, Kautto EA, Passen EN, Stets C, Toland AE, Millis SZ, et al. BRCA1/2 functional loss defines a targetable subset in leiomyosarcoma. Oncologist. 2019;24:973–9.
https://doi.org/10.1634/theoncologist.2018-0448 DOI: https://doi.org/10.1634/theoncologist.2018-0448
Jonsson P, Bandlamudi C, Cheng ML, Srinivasan P, Chavan SS, Friedman ND, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571:576–9.
https://doi.org/10.1038/s41586-019-1382-1 DOI: https://doi.org/10.1038/s41586-019-1382-1
Dall G, Vandenberg CJ, Nesic K, Ratnayake G, Zhu W, Vissers JHA, et al. Targeting homologous recombination deficiency in uterine leiomyosarcoma. J Exp Clin Cancer Res. 2023;42:1–20.
https://doi.org/10.1186/s13046-023-02687-0 DOI: https://doi.org/10.1186/s13046-023-02687-0
Pan M, Ganjoo K, Karam A. Rapid response of a BRCA2/TP53/PTEN-deleted metastatic uterine leiomyosarcoma to olaparib: a case report. Perm J. 2021;25:20.251.
https://doi.org/10.7812/TPP/20.251 DOI: https://doi.org/10.7812/TPP/20.251
Grignani G, D’Ambrosio L, Pignochino Y, Palmerini E, Zucchetti M, Boccone P, et al. Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group. Lancet Oncol. 2018;19:1360–71.
https://doi.org/10.1016/S1470-2045(18)30438-8 DOI: https://doi.org/10.1016/S1470-2045(18)30438-8
D’Ambrosio L, Merlini A, Brunello A, Ferraresi V, Paioli A, Vincenzi B, et al. LBA91 TOMAS2: a randomized phase II study from the Italian Sarcoma Group (ISG) of trabectedin plus olaparib (T+O) or trabectedin (T) in advanced, metastatic, or unresectable soft tissue sarcomas (STS) after failure of standard treatments. Ann Oncol. 2023;34:S1332.
https://doi.org/10.1016/j.annonc.2023.10.093 DOI: https://doi.org/10.1016/j.annonc.2023.10.093
Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–47.
https://doi.org/10.1038/s41571-018-0113-0 DOI: https://doi.org/10.1038/s41571-018-0113-0
Symington LS. End resection at double-strand breaks: mechanism and regulation. Cold Spring Harb Perspect Biol. 2014;6:a016436.
https://doi.org/10.1101/cshperspect.a016436 DOI: https://doi.org/10.1101/cshperspect.a016436
Brosh RM, Jr, Cantor SB. Molecular and cellular functions of the FANCJ DNA helicase defective in cancer and in Fanconi anemia. Front Genet. 2014;5:372.
https://doi.org/10.3389/fgene.2014.00372 DOI: https://doi.org/10.3389/fgene.2014.00372
Wang W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet. 2007;8:735–48.
https://doi.org/10.1038/nrg2159 DOI: https://doi.org/10.1038/nrg2159
Additional Files
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2025 Alexander D.J. Thooft, Sofie Joris, Celine Jacobs, David Creytens, Sylvie Rottey, Brigitte Maes, Philippe Aftimos, Lore Lapeire
This work is licensed under a Creative Commons Attribution 4.0 International License.
