Dario Trapani

Germline BRCA pathogenic variants and hematologic adverse events in patients with ovarian carcinoma receiving PARP inhibitors: a retrospective cohort study

Abstract Background Patients with a germline BRCA pathogenic variant (gBRCA-PV) and advanced high grade ovarian carcinoma (aHGOC) experience higher hematologic adverse events (HAEs) when receiving platinum salts and ionizing radiations, compared to non-carriers, due to a possible higher susceptibility of the hemopoietic stem cells to DNA targeting agents. However, the incidence of PARP inhibitor (PARPi)-related HAEs according to the gBRCA-PV status is currently unknown. Patients and Methods We conducted a single-center retrospective cohort study to describe the occurrence of HAEs in patients with aHGOC receiving ≥8 weeks of maintenance PARPi in any line of therapy, comparing gBRCA-PVs carriers to non-carriers. HAEs were manually identified by searching the patients’ electronic medical records and classified by CTCAE v5.0. The main endpoint was the incidence rate of any HAE (ie, anaemia, neutropenia, or thrombocytopenia) of grade 2 or more (G ≥ 2). Results One hundred and sixty-six patients were included; 95 (57%) had a gBRCA-PV. In total, 162 incident cases of G ≥ 2 HAEs were reported over 255.3 person-years. The incidence rates of G ≥ 2 HAEs were 1003/1000 person-years in gBRCA-PV carriers and 993/1000 person-years in non-carriers. No difference in the incidence rate of G ≥ 2 HAEs emerged comparing gBRCA-PV carriers to non-carriers (crude-incidence rate ratio [IRR]: 1.01; 95% CI: 0.72, 1.43; P = .96), even after adjusting for the type of PARPi (Mantel-Haenszel IRR: 0.99; 95% CI: 0.67, 1.46). Conclusion Patients with aHGOC and a gBRCA-PV do not experience higher PARPi-related HAEs compared to non-gBRCA-PV carriers, unlike platinum salt-related HAEs.

Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms

Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status. We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers. A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers. The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.

Platinum-based chemotherapy and PARP inhibitors for patients with a germline BRCA pathogenic variant and advanced breast cancer (LATER-BC): retrospective multicentric analysis of post-progression treatments

Patients with breast cancer (BC) harbouring a germinal BRCA pathogenic variant (gBRCA-PV) may have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP inhibitors (PARPi). As reported in ovarian cancer, however, sensitivity and resistance to these treatments could partially overlap. In patients with a gBRCA-PV and advanced BC (aBC), it remains unclear whether prior exposure to PARPi/PBC affects tumour response to subsequent PBC/PARPi, respectively. We conducted a retrospective, multicentric study to investigate the clinical benefit of post-PBC PARPi and vice versa in patients with a gBRCA-PV and aBC. Patients included had received (neo)adjuvant PBC and then PARPi in advanced setting (group 1), PBC followed by PARPi (group 2) or PARPi followed by PBC (group 3), both in advanced setting. We reported median progression-free survival (mPFS) and disease control rate (DCR) in each group. A total of 67 patients from six centres were included. PARPi-mPFS in advanced setting was 6.1 months in patients in group 1 (N = 12), while PARPi-DCR was 67%. In group 2 (N = 36), PARPi-mPFS was 3.4 months and PARPi-DCR was 64%. Age  6 months were associated with longer PARPi-PFS; previous PBC-PFS > 6 months and PBC in first to second line were associated with longer PARPi-DCR. Patients in group 3 (N = 21) reported a PBC-mPFS of 1.8 months and a PBC-DCR of 14%. PARPi-PFS ≥ 9 months and PARPi-FI ≥ 6 months were associated with better PBC-DCR. Sensitivity and resistance to PARPi and PBC partially overlap in patients with a gBRCA-PV and aBC. Evidence of PARPi activity emerged in patients who progressed on previous PBC.