A. Farolfi

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.

Risk of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibitor maintenance line in real-world ovarian cancer patients

Abstract Objective To estimate the risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) secondary to PARP inhibitors (PARPi), based on the line of treatment, in real-world ovarian cancer (OC) patients. Methods Using the TriNetX platform, we compared a cohort (experimental A) of 3402 OC patients treated with first-line maintenance PARPi to a control cohort of 1653 OC patients treated with platinum-based chemotherapy without PARPi. Experimental group B included 356 OC patients treated with PARPi after a platinum-sensitive relapse and was compared to a control cohort of 1503 patients who had not received PARPi after 2 lines of platinum-based chemotherapy. The cohorts were propensity score matched (PSM) 1:1 (experimental A vs control 1 and experimental B vs control 2) for age, race, bevacizumab treatment, and genetic susceptibility to neoplasms. A hazard ratio (HR) was used to compare the incidence of MDS and AML between the matched cohorts. Results In the first-line setting, 2 groups of 1346 matched OC patients (mean age 59.8 ± 10.2 SD) were evaluated. The overall incidence of MDS or AML was 1.9% and 0.1% in the experimental A and control groups, respectively (HR = 2.46; 95% CI 1.27-4.75, P = .006). For the platinum-­sensitive relapse setting, the HR was 1.76 (95% CI 0.42-7.37, P = .432). No significant differences were observed between the various PARPi used. Conclusions Our study indicates that PARPi may increase the risk of MDS or AML after first-line maintenance treatment. No significant differences were found across the types of PARPi used.

Treatment Strategies for Advanced Endometrial Cancer According to Molecular Classification

The management of advanced endometrial cancer (EC) has changed in the last few years due to the introduction of a new molecular classification and the approval of immunotherapy. For a long time, carboplatin plus paclitaxel was considered the standard treatment for first-line advanced EC, since the approval of the combination of chemotherapy plus immunotherapy. For patients with recurrent EC, with previous platinum-based chemotherapy, single-agent immunotherapy or in combination with tyrosine-kinase inhibitor (TKI) has been approved according to mismatch repair status. Ongoing trials are exploring the possibility of a chemo-free future for mismatch repair-deficient (dMMR) EC and new molecular targets are under investigation. The treatment paradigm for advanced EC has shifted from standard chemotherapy for all to a more personalized approach. The aim of this review is to provide an updated therapeutic landscape for the management of patients with advanced/metastatic EC according to their disease history and molecular biology.