Valentina Lombardo

Management of ocular toxicity in patients with gynecologic cancer receiving novel antibody–drug conjugates: a narrative review

Antibody-drug conjugates (ADCs) represent a promising therapeutic approach in gynecologic cancers, particularly ovarian and cervical malignancies. Agents such as mirvetuximab soravtansine, and tisotumab vedotin, targeting folate receptor alpha and tissue factor, respectively, reported clinical efficacy in patients with limited options. However, their use is associated with ocular toxicities, including keratopathy, blurred vision, and dry eye, which may impact adherence and quality of life. This review summarizes current evidence on the incidence, pathophysiology, and clinical presentation of ADC-related ocular adverse events in gynecologic oncology. It also provides practical, evidence-based strategies for the prevention, monitoring, and management of these adverse events. Interventions include prophylactic topical therapies, supportive care measures, treatment delays or dose modifications, and herpes zoster vaccination. Comprehensive management of ocular toxicities is essential to ensure the safe and sustained use of ADCs, preserving both therapeutic benefit and patient well-being. Further research is warranted to optimize preventive and management protocols.

Trabectedin maintenance therapy after liposomal doxorubicin plus trabectedin combination in patients with relapsed ovarian cancer: the randomized, phase II TRAMANT study

TRAMANT was a multicenter, randomized phase II study assessing the non-inferiority of trabectedin (TRB) as maintenance therapy in patients with relapsed ovarian cancer who responded to initial treatment with pegylated liposomal doxorubicin (PLD) + TRB. Patients with partially platinum-sensitive recurrent ovarian cancer, defined by a platinum-free interval of 6-12 months, were randomly assigned to receive either TRB alone or continued combination therapy. The primary endpoint was progression-free survival, with secondary endpoints including overall survival, objective response rate, and quality of life assessments. Sixty-seven patients were enrolled (median age, 59 years; range; 41-74); most had International Federation of Gynecology and Obstetrics stage III disease (70%) and high-grade serous carcinoma (85%). The median time to recurrence after prior platinum therapy was 8.5 months (range; 6-12), and the median follow-up was 24 months (range; 6-44). Patients received a median of 6 cycles in both arms. Median progression-free survival was 9.8 months with TRB and 16.6 months with PLD + TRB; overall survival was comparable (19.1 vs 23.8 months). Grade 3-4 adverse events occurred in 21% (TRB) and 17% (PLD + TRB), with neutropenia and anemia being the most common toxicities. The results suggest that TRB may be a viable maintenance option for patients with relapsed ovarian cancer, providing a sustained response with favorable tolerability. Nonetheless, the small sample size underscores the need for further research to validate these findings. Studies with larger cohorts are necessary to confirm these results and optimize treatment strategies for recurrent ovarian cancer.

PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer has raised increasing concerns about PARPi-related myeloid neoplasms (PrMN). Therapy-related neoplasms, including myelodysplastic syndromes and acute myeloid leukemia, account for 10%-20% of cases. Expanding PARPi indications, longer survival, and aging populations may contribute to rising PrMN incidence. Randomized clinical trials and real-world analyses show a significant risk increase, but data on individual PARPi, treatment lines, and prior therapies are limited. We evaluated PrMN incidence across 17 Italian centers using a 71-item survey distributed to MITO (Multicenter Italian Trials on Ovarian cancer) and MaNGO (Mario Negri Gynecologic Oncology) centers, focusing on patients treated with PARPi outside clinical trials. Of 2320 patients (1254 BRCA-mutated), 56 (2.55%) developed MN: 35 myelodysplastic syndromes and 21 acute myeloid leukemia (2 patients had both, counted once). Among them, 31 had BRCA mutations (2.5%). Incidence by drug was: olaparib 2.5%, niraparib 2%, and rucaparib 3.4%. An unclear correlation emerged between treatment duration and PrMN risk, with a median onset of 18.9 months. Risk increased with additional therapy lines: 0.52% (first), 4.2% (second), 1.8% (third), 10.8% (fourth), and 12.2% (>fourth lines). Among PrMN cases, 4 achieved remission, 4 had partial responses, 8 progressed, and 37 died. While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.

Real-World Analysis of HRD Assay Variability in High-Grade Serous Ovarian Cancer: Impacts of BRCA1/2 Mutation Subtypes on HRD Assessment

The HRD (Homologous Recombination Deficiency) test is considered a genomic alteration useful for guiding therapeutic decisions in patients with ovarian cancer. Some commercial and in house alternative “academic” tests are available. Recent findings indicate that not all BRCA1/2 mutations determine the magnitude of HRD and that some patients carrying BRCA1/2 mutations may exhibit indeterminate or even negative HRD scores. Furthermore, certain therapies (e.g., olaparib and bevacizumab) offer particularly pronounced benefits for high-grade serous ovarian cancer (HGSOC) patients harboring mutations in the DNA-binding domain (DBD) of BRCA1/2. The aim of the present study is to investigate the relationship between the HRD scores and BRCA1/2 status of 51 HGSOC patients (50 BRCA1/2 mutated and 1 wild type). The HRD status was assessed by means of shallow whole-genome sequencing and BRCA1/2 status by the NGS pipeline. We did not find a correlation between the HRD status and type of BRCA1/2 alterations. A strong correlation between the HRD score and age was found. Our paper underlines the need to introduce other biological factors within the algorithms of the HRD evaluation in order to better tailor the HRD status, harmonize the metrics of the HRD assessment, and personalize therapies.

Identification of the novel BRCA1 c.2463_2464delTA mutation in two high grade serous ovarian cancer sisters and potential dosage effects implications: a case report

Ovarian Cancer is one of the leading causes of cancer death among women worldwide and the therapeutic landscape to treat it is constantly evolving. One of the major points of decision for the treatment choice is the presence of some genomic alterations that could confer sensitivity to the new available therapies including inhibitors of poly (ADP-ribose) polymerase (PARPi) with BRCA1 and 2 genes playing the most important role. We performed the search for any somatic and/or germline alteration in patient's samples by next generation sequencing (NGS). On two patients, our bioinformatic tools allowed us to correctly classify the c.2463_2464delTA BRCA1 new variant. The novel BRCA1 c.2463_2464delTA variant which falls into the DNA Binding Domain (DBD) of the BRCA1 gene can be considered as a variant of clinical significance due to the peculiar family and personal history of patients.

Homologous Recombination Deficiency (HRD) Scoring, by Means of Two Different Shallow Whole-Genome Sequencing Pipelines (sWGS), in Ovarian Cancer Patients: A Comparison with Myriad MyChoice Assay

High-grade serous ovarian cancer (HGSOC) patients carrying the BRCA1/2 mutation or deficient in the homologous recombination repair system (HRD) generally benefit from treatment with PARP inhibitors. Some international recommendations suggest that BRCA1/2 genetic testing should be offered for all newly diagnosed epithelial ovarian cancer, along with HRD assessment. Academic tests (ATs) are continuously under development, in order to break down the barriers patients encounter in accessing HRD testing. Two different methods for shallow whole-genome sequencing (sWGS) were compared to the reference assay, Myriad. All these three assays were performed on 20 retrospective HGSOC samples. Moreover, HRD results were correlated with the progression-free survival rate (PFS). Both sWGS chemistries showed good correlation with each other and a complete agreement, even when compared to the Myriad score. Our academic HRD assay categorized patients as HRD-Deficient, HRM-Mild and HRN-Negative. These three groups were matched with PFS, providing interesting findings in terms of HRD scoring and months of survival. Both our sWGS assays and the Myriad test correlated with the patient’s response to treatments. Finally, our AT confirms its capability of determining HRD status, with the advantage of being faster, cheaper, and easier to carry out. Our results showed a prognostic value for the HRD score.