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Patients with relapsed/refractory high-risk neuroblastoma (HRNBL) have poor prognoses. Recent studies found that BARD1 harbored the most significantly enriched pathogenic/likely-pathogenic germline mutations in neuroblastoma patients1. Such mutations, when engineered to neuroblastoma cell-lines, can cause homologous recombination repair (HRR) deficiency, conferring sensitivity to PARP inhibitors (PARPi)2. We report the first response of a child with neuroblastoma and a BARD1 germline mutation to a PARPi. The patient was diagnosed at 22 months with metastatic HRNBL. After induction therapy (chemotherapy, surgery), she received salvage therapy (cyclophosphamide/topotecan, irinotecan/temozolomide) for persistent bone marrow (BM) disease, followed by autologous stem cell transplantation, radiation, and isotretinoin. At the end of therapy, her disease progressed with 30% BM involvement.

ter induction therapy (chemotherapy, surgery), she received salvage therapy (cyclophosphamide/topotecan, irinotecan/temozolomide) for persistent bone marrow (BM) disease, followed by autologous stem cell transplantation, radiation, and isotretinoin. At the end of therapy, her disease progressed with 30% BM involvement. The patient transferred to our institution and achieved stable disease (by INRC criteria)3 following 2 cycles of irinotecan, temozolomide, and dinutuximab (anti-GD2 antibody) and 2 cycles of cyclophosphamide, topotecan, and dinutuximab. Paired tumor-normal whole-exome analysis identified a pathogenic germline heterozygous frameshift in BARD1, but no other known driver variants (Fig. S1 and S2). Based on this finding and supporting pre-clinical data1,2, treatment was changed to talazoparib (PARPi) plus irinotecan (as per BMNIRN4). The patient had a complete response (INRC criteria) in the BM compartment (Cycle 2) and continued therapy. Irinotecan was decreased (Cycle 5) then eliminated (Cycle 6) due to thrombocytopenia. BM remained negative for tumor. Focal radiation therapy was administered, concurrently with talazoparib, to 3 minimally avid bone lesions (FDG-PET). Single agent talazoparib was discontinued following Cycle 26. The patient is 32 months off therapy with no clinical evidence of disease (treatment course: Fig. 1a).

penia. BM remained negative for tumor. Focal radiation therapy was administered, concurrently with talazoparib, to 3 minimally avid bone lesions (FDG-PET). Single agent talazoparib was discontinued following Cycle 26. The patient is 32 months off therapy with no clinical evidence of disease (treatment course: Fig. 1a). The patient’s response to talazoparib is likely attributed to bi-allelic loss of BARD1 in the tumor, based on mono-allelic expression (p = 0.015) of the frameshift mutation in RNA-seq5 (Fig. 1b). Immunohistochemical staining of serial BM samples, obtained before talazoparib administration, confirmed somatic BARD1 protein loss (Fig. 1c and S3). When analyzed by a synthetic lethality (SL) network model trained on pediatric cancer data, the patient’s tumor had the highest SL score for PARP2 among 59 profiled neuroblastomas, indicating that the expected SL response might have been primarily mediated by PARP2 inhibition, given its high PARP2 and low PARP1 expression rank (Fig. 1d). The sustained clinical response in our patient demonstrates the potential for exploiting HRR deficiencies in pediatric cancer patients, supporting further evaluation in an expansion cohort of recurrent/refractory solid tumors with germline or somatic alterations in HRR genes in a clinical trial (NCT04901702).