Gene expression markers in peripheral blood and outcome in patients with platinum-resistant ovarian cancer: A study of the European GANNET53 consortium.

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer.

Clonal hematopoiesis (CH) driven by mutations in the DNA damage response (DDR) pathway is frequent in patients with cancer and is associated with a higher risk of therapy-related myeloid neoplasms (t-MNs). Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes. DDR-driven CH was detected in 35% of patients and was associated with longer duration of prior PARPi treatment. TP53- and PPM1D-mutated clones exhibited substantially higher clonal expansion rates than DNMT3A- or TET2-mutated clones during treatment. Expansion of DDR clones correlated with HSP90i exposure across the three study arms and was partially abrogated by the presence of germline mutations related to homologous recombination deficiency. Single-cell DNA sequencing of selected samples revealed clonal exclusivity of DDR mutations, and identified DDR-mutated clones as the origin of t-MN in two investigated cases. Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.

Part I of GANNET53: A European Multicenter Phase I/II Trial of the Hsp90 Inhibitor Ganetespib Combined With Weekly Paclitaxel in Women With High-Grade, Platinum-Resistant Epithelial Ovarian Cancer-A Study of the GANNET53 Consortium.

Background: Stabilized mutant p53 protein (mutp53) is a novel target in epithelial ovarian cancer. Due to aberrant conformation, mutp53 proteins depend on folding support by the Hsp90 chaperone. Hsp90 blockade induces degradation of mutp53, resulting in tumor cell cytotoxicity and increased sensitivity to chemotherapeutics. Preclinical synergy of the Hsp90 inhibitor ganetespib combined with paclitaxel provided the rationale for testing the combination in platinum-resistant ovarian cancer (PROC) patients in the GANNET53 trial (NCT02012192). Methods: Eligible patients had high-grade PROC with ≤ 4 prior lines of chemotherapy. Weekly paclitaxel (80 mg/m2) and increasing doses of ganetespib (100, 150 mg/m2) were given i.v. on days 1, 8, 15 in a 28 days cycle until disease progression or unacceptable toxicity. Endpoints were safety and determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade 4 toxicity (with exceptions) occurring in cycles 1&2. Results: Ten patients (median age 59 years; range 43-70) were enrolled. No DLT occurred in cohort 1 (4 patients treated with paclitaxel + ganetespib 100 mg/m2), nor in cohorts 2 and 3 (6 patients treated with paclitaxel + ganetespib 150 mg/m2). The most common adverse event (AE) related to ganetespib was transient grade 1/2 diarrhea (n = 6). Related grade 1/2 AEs in >2 patients included QTc prolongation (n = 4), nausea (n = 3), anemia (n = 3), headache (n = 3), fatigue (n = 3), and dyspnoea (n = 3). Most frequently related grade 3/4 AEs were diarrhea (n = 3) and neutropenia (n = 2). There was 1 death on study due to hemorrhage from a duodenal ulcer. Three patients discontinued study treatment due to serious AEs (digestive hemorrhage n = 1, cardiac failure n = 1, abdominal pain and vomiting n = 1), 6 due to progressive disease, one due to investigator and patient decision. Two patients achieved a partial response (ORR 20%) and 4 patients a stable disease (disease control rate of 60%). Median PFS was 2.9 months (1.6 months in cohort 1 at 100 mg/m2 ganetespib, 5.1 months in cohorts 2+3 at 150 mg/m2 ganetespib). Conclusions: The combination of ganetespib 150 mg/m2 with paclitaxel 80 mg/m2 once weekly for 3 out of 4 weeks was generally well-tolerated with no DLTs, and therefore chosen for the randomized phase II trial.