Genetic Landscape in Women with Metastatic Ovarian Cancer Before and During Treatment with PARP Inhibitors

Condition(s) studied

Investigational drug(s) / intervention(s)

buccal cells: custom myeloid gene panel (Myelo-Panel) to identify germline mutations predisposing to cancer development (Thermo Fisher Scientific)

bone marrow cells: Bone marrow cells (optional, for comparison, only in a limited number of patients): * morphological analysis * immunophenotype * cytogenetics/FISH * analysis of CHIP by custom gene panel and high sensitivity NGS

peripheral blood cells: analysis of CHIP by custom gene panel and high sensitivity NGS

bone marrow biopsy: Bone marrow biopsy (optional, for comparison, only in a limited number of patients): * histology * immunohistochemistry

Study summary

Therapy related acute myeloid leukemia and myelodysplasia (t-MN) is a potential late complication of cytotoxic therapy, and it is of particular concern in the treatment of patients with epithelial ovarian carcinoma (EOC) exposed to multiple cycles of platinum-based chemotherapy during the course of their disease. An epidemiological analysis published in 2011 (Gynecologic Oncology) showed that the overall incidence of t-AML is 0.17%, with a median latency to development of leukemia of 4 years (range 0-27 years).

Inhibition of PARP is a potential synthetic lethal therapeutic strategy for the treatment of cancers characterized by specific DNA repair defects, such as those that harbor a BRCA1 or BRCA2 (BRCA1/2) mutation and are therefore deficient in homologous recombination repair. In homologous recombination-deficient tumors, PARP inhibition eliminates an alternative DNA repair pathway essential for maintaining viability, leading to tumor cell death. The estimated prevalence of BRCA1/2 mutations in V2 03/06/2021 2 patients with newly diagnosed high-grade serous ovarian cancer is 20-25% and it might be higher in patients with platinum-sensitive, relapsed ovarian cancer. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations.

Our hypothesis is that these patients are carriers of clonal hematopoiesis of indeterminate potential (CHIP) before treatment with PARPi. CHIP refers to the presence of clonal population(s) of hematopoietic cells with somatic mutations in genes associated with hematological malignancies (e.g. DNMT3A, ASXL1, TET2, TP53 and others), in the absence of morphological evidence of disease.

The proposed study will address the hypothesis that platinum-based chemotherapy may promote the onset of newly developed mutated clones and clonal selection of hematopoietic stem cells harboring somatic mutations.

Moreover, the concomitant presence of germline mutations in cancer predisposing genes might increase the pool of pre-existing hematopoietic clones and/or favor the accumulation of subsequent somatic mutations.

In this context, the inhibition of PARP-mediated repair of DNA lesions created by chemo or radiotherapy can further favor t-MN development.

Eligibility

Primary outcome measure(s)

• Identification of the events and determination of their incidence in study patient's population: — 8 years
  The study is descriptive in nature and no formal statistical testing is necessary or applicable. * Cell blood count abnormalities * Morphological alterations allowing a diagnosis of myelodysplastic syndrome or acute myeloid leukemia * Chromosomal abnormalities * Clonal hematopoiesis and extent of the expansion and evolution of the CHIP clones induced by PARP inhibitors. One of the primary objectives is to estimate the proportion of patients with stable abnormalities in hematologic counts. A patient is defined as having stable abnormalities in hematologic counts if the status "CTCAE grade ≥ 2 and/or platelets \<100,000/mmc" persists for at least two weeks.The 90% confidence interval of the proportion of patients with stable abnormalities in hematologic counts will be calculated using the exact one-sided binomial test.

Trial sites (1)

More European Institute of Oncology trials in Italy

Other trials for the same condition