Current practices on genetic testing in ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is probably the tumor type with the highest percentage of hereditary cases observed, irrespectively of selection criteria. A fourth to a fifth of unselected epithelial EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA repair pathways. BRCA1 and BRCA2 predisposing PVs were the first to be associated to ovarian cancer, with the advent in DNA sequencing technologies leading to the discovery and association of additional genes which compromise the homologous recombination (HR) pathway. In addition, PVs genes involved in mismatch repair (MMR) pathway, account for 10-15% of hereditary EOC. The identification of women with HR deficient ovarian cancers has significant clinical implications concerning chemotherapy regimen planning and development and use of targeted therapies as well. More specifically, in patients with BRCA1/2 PVs or HR deficiency maintenance treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, either in the first line setting or in recurrent disease, improves the progression-free survival. But also patients with HR proficient tumors show a benefit. Therefore, genetic testing in ovarian cancer has a prognostic and predictive value. In this review, we discuss which ovarian cancer patients should be referred for genetic counseling and how to perform genetic testing. We also discuss the timing of genetic testing and its clinical relevance to BRCA status.

Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes

“…Most of the hereditary ovarian cancers are linked to BRCA1/2 mutations, especially in high-grade serous EOC. An analysis allows for genetic testing in relatives; if identified in asymptomatic carriers, preventative measures can be offered to reduce their risk of ovarian cancer [122]. Otherwise, if negative, they can be reassured their risk is similar to the general population risk.…”

“…Otherwise, if negative, they can be reassured their risk is similar to the general population risk. Risk-reducing options in BRCA1/2 carriers include a bilateral salpingo-oophorectomy (BSO), which is invasive compared with regular surveillance; that is, it is not always reliable in identifying the early stages [122]. A BSO is performed between the ages of 35 and 40 in BRCA1 carriers and 40 and 45 in BRCA2 carriers due to the late onset and can reduce the risk of ovarian cancer by 96% [123][124][125].…”

“…Careful counselling is required with planned pregnancies; menopausal symptoms can be induced, which have their own implications on quality of life and physical health (e.g., cardiovascular), and the use of hormone replacement therapy [123]. An analysis of mutations also allows tailored treatment planning, including PARP inhibitors, which have reformed ovarian cancer management [122]. Studies have found improved progression-free survival with olaparib and an efficacy of niraparib and rucaparib as maintenance treatments [122,126].…”

“…An analysis of mutations also allows tailored treatment planning, including PARP inhibitors, which have reformed ovarian cancer management [122]. Studies have found improved progression-free survival with olaparib and an efficacy of niraparib and rucaparib as maintenance treatments [122,126]. These studies examined recurrent EOC in particular and are summarised in Table 2.…”

The tumor-agnostic treatment for patients with solid tumors: a position paper on behalf of the AIOM- SIAPEC/IAP-SIBioC-SIF Italian Scientific Societies

“…the ARIEL3, PAOLA-1, PRIMA, phase III ENGOT-OV16/NOVA) where the HRD score was validated as biomarker of PARP-I sensitivity. Nevertheless, based on the variability and the complexity of the different genetic phenomena which can arise in ovarian cancers, the existing assays should improve their accuracy when prescribed and used in a complementary way (Fostira et al, 2020). Consequently, the validation of an academic HRD assay is strongly encouraged in order to obtain a reliable pipeline to routinely use in laboratory of molecular diagnostics and genomics.…”