Abstract
Simple SummaryEpithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. In the recent years, the germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes are of key importance not only for genetic counseling purposes, but for its therapeutic implications, as well as somatic mutations, for the latter. The integration of poly-(ADP ribose) polymerase inhibitors (PARPis) as part of the therapeutic options has changed EOC natural history.Epithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 18% of women diagnosed with EOC, and somatic mutations are found in an additional 7%. Testing of BRCA at the primary diagnosis of patients with EOC is recommended due to the implications in the genomic counseling of the patients and their families, as well as for the therapeutic implications. Indeed, the introduction of poly-(ADP ribose) polymerase inhibitors (PARPis) has changed the natural history of patients harboring a mutation in BRCA, and has resulted in a new era in the treatment of patients with ovarian cancer harboring a BRCA mutation.
Highlights
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Relying on the variant allele frequency is not recommended for making decisions about whether a given variant may be in the germline or not, as it can be affected by tissue heterogeneity, tumor heterogeneity or copy number abnormalities [13]
Based on QUADRA clinical trial results [55], Niraparib was approved by the FDA for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who were treated with three or more prior chemotherapy regimens and whose cancer was associated with a homologous recombination deficiency (HRD)positive status defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability and who progressed more than six months after a response to the last platinum-based chemotherapy
Summary
Current guidelines from different scientific societies, such as NCCN, ASCO, ESMOESGO and SGO, strongly recommend the genetic testing of BRCA1/2 for every newly diagnosed patient with a non-mucinous epithelial ovarian cancer (which includes fallopian tube and primary peritoneal cancers) regardless of family history. There is an increased risk of cancers of the ovary, fallopian tube, and peritoneum in BRCA1/2 mutation carriers Those patients are classically diagnosed with high-grade serous adenocarcinomas with a frequency ranging from 67 to 100%, albeit endometrioid and clear cell ovarian cancers have been reported with a frequency similar to the general population [15,16]. About 3–10% of BRCA1/2 mutation carriers who undergo BSO are diagnosed with occult fallopian tube and ovarian cancers Considering this risk, consensus guidelines recommend a complete pathology review and serial sectioning of the ovaries and fallopian tubes to exclude occult cancers or serous intraepithelial tubal carcinomas (STICs) [24]. Many studies demonstrated that germline and somatic BRCA1 and/or BRCA2 mutations are related to a better prognosis in ovarian cancer patients This benefit was demonstrated both in ovarian and breast cancers. The clinical effects of BRCA1 and BRCA2 mutations are commonly analyzed together, but several studies found that, compared with BRCA1 mutation carriers, BRCA2 mutation carriers were associated with an improved platinum-based chemotherapy response and longer PFS [33–35]
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