Daniela Russo

Ovarian Cancer Translational Activity of the Multicenter Italian Trial in Ovarian Cancer (MITO) Group: Lessons Learned in 10 Years of Experience

Ovarian cancer is the most lethal gynecological cancer, and despite years of research, with the exception of a BRCA mutation driving the use of PARP inhibitors, no new prognostic/predictive biomarkers are clinically available. Improvement in biomarker selection and validation may derive from the systematic inclusion of translational analyses into the design of clinical trials. In the era of personalized medicine, the prospective centralized collection of high-quality biological material, expert pathological revision, and association to well-controlled clinical data are important or even essential added values to clinical trials. Here, we present the academic experience of the MITO (Multicenter Italian Trial in Ovarian Cancer) group, including gynecologists, pathologists, oncologists, biostatisticians, and translational researchers, whose effort is dedicated to the care and basic/translational research of gynecologic cancer. In our ten years of experience, we have been able to collect and process, for translational analyses, formalin-fixed, paraffin-embedded blocks from more than one thousand ovarian cancer patients. Standard operating procedures for collection, shipping, and processing were developed and made available to MITO researchers through the coordinating center’s web-based platform. Clinical data were collected through dedicated electronic case report forms hosted in a web-based electronic platform and stored in a central database at the trial’s coordinating center, which performed all the analyses related to the proposed translational researches. During this time, we improved our strategies of block management from retrospective to prospective collection, up to the design of a prospective collection with a quality check for sample eligibility before patients’ accrual. The final aim of our work is to share our experience by suggesting a guideline for the process of centralized collection, revision processing, and storing of formalin-fixed, paraffin-embedded blocks for translational purposes.

Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the randomized, phase II MITOEND 3 trial

Poly (ADP-ribose) polymerase (PARP) inhibitor use in endometrial cancer (EC) requires predictive biomarkers, currently lacking in clinical practice. This study assessed the incidence of homologous recombination deficiency (HRD) using genomic loss of heterozygosity (gLOH) and a machine learning-based HRD scar signature (HRDsig). MITO END 3 was a multicenter, phase II trial of advanced EC patients randomly assigned to receive platinum-based chemotherapy ± avelumab. Of 125 patients, 102 had tumor samples available for sequencing with FoundationOne®CDx. HRD was evaluated using gLOH (cut-off ≥16%, based on ARIEL3) and HRDsig (cut-off ≥0.7, validated pan-cancer). Among 102 evaluable samples, 5 were HRDsig-positive, 90 HRDsig-negative, and 7 HRDsig unknown. gLOH was high in 10 cases, low in 53, and not assessable in 39. Most HRDsig-positive (4/5) and gLOH-high (8/10) tumors were of endometrioid histology and carried TP53 mutations. None were microsatellite instability-high. A small subgroup of advanced EC patients shows HRD positivity by gLOH or HRDsig, potentially identifying those most likely to benefit from PARP inhibitors. These tumors are typically endometrioid with TP53 mutations.