Case Report: Personalized therapy in gynecological neuroendocrine neoplasm: a case of BRCA2-mutated ovarian neuroendocrine carcinoma treated with PARP-inhibitor.

Introduction: Neuroendocrine neoplasms (NENs) of the female genital tract are rare and typically aggressive malignancies, accounting for only 1-2% of gynecologic tumors. The majority (54%) are located in the cervix. Ovarian neuroendocrine carcinomas (O-NECs) represent less than 1% of all ovarian cancers and 16% of all gynecologic NENS; these tumors are associated with poor prognosis, with an overall survival (OS) ranging from 11 to 20 months and progression-free survival (PFS) between 12-14.71 months. To date, approximately 923 cases have been reported in the literature and owing to their rarity no standardized treatment protocols have been established. Materials and methods: We retrospectively reviewed all cases of NENs of female genital tract treated at the Gynecologic Oncology Unit of Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy. Moreover, we describe an interesting case of a 66-year-old woman with O-NEC and harboring a BRCA2 mutation. Patient achieved a pathological complete response following platinum-based chemotherapy and subsequently received a maintenance therapy with PARP-inhibitor. Results: From 2005 to June 2025, a total of 42 women with NENs of the female genital tract were treated at the Gynecologic Oncology Unit of Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy): 59% originated from cervix, 29% from endometrium and 12% from ovaries. Median OS and PFS of patients with O-NEC were consistent with literature data (15 and 11 months, respectively); all patients underwent surgery followed by platinum-etoposide chemotherapy and then follow up. In May 2024, a 66-year-old woman underwent exploratory laparoscopy for a large pelvic mass (121×83×137 mm) associated with hemoperitoneum, bilateral grade 3 hydronephrosis and rectum infiltration. Final histopathological diagnosis was of small cell ovarian neuroendocrine carcinoma (SCNEC), FIGO stage IV, due to the presence of the hepatic metastasis. Next-generation sequencing (NGS) performed on tumor tissue revealed a pathogenetic BRCA2 mutation. Following multidisciplinary tumor board discussion, patient received 4 cycles of carboplatin-etoposide chemotherapy with an excellent radiological response and significant tumor marker reduction (CA125: 477→9.4 U/ml; NSE: 629→8.9 ng/mL; CEA: 560→16.9 ng/mL). The histopathology report, performed after interval debulking surgery, confirmed a complete pathological response. She completed systemic treatment with two additional cycles of chemotherapy and then, she started compassionate-use maintenance therapy with PARP inhibitor based on the presence of the BRCA2 mutation. Today, after 12 months to the end of chemotherapy, patient has not evidence of recurrence disease, she is in good clinical condition and maintenance treatment with PARP inhibitor is still ongoing. To the best of our knowledge, only 1 prior case of BRCA2-mutated O-NEC patient treated with PARP-inhibitor has been reported in literature, with a PFS of 2 months, suggesting limited efficacy of PARP inhibitors in this setting. However, our case may indicate a potential benefit in selected patients. Conclusion: O-NECs are rare and poorly characterized malignancies, lacking standardized diagnostic and therapeutic protocols. Therefore, comprehensive characterization of individual cases is crucial to improve knowledge and patient outcomes. This case highlights the pivotal role of molecular profiling in identifying candidates for personalized therapeutic approaches. Further experiences are needed to expand current knowledge and evaluate the potential benefit of PARP inhibitors in BRCA-mutated O-NEC patients.