The incidence of ovarian cancer is increasing every year, and one of the most common malignancies of the gynecological disease, ranking third after cervical and uterine cancer. In 2017, there were 22,440 estimated new diagnoses of ovarian cancer and 14,080 deaths from the disease in the USA; deaths were higher than from endometrial cancer but lower than from cervical cancer [1].

In Japan, the BRCA gene test was previously covered by health insurance only for “patients with recurrent or metastatic breast cancer or newly diagnosed advanced ovarian cancer”, but its eligibility criteria were expanded in 2020. Particularly in the treatment of advanced ovarian cancer, BRCA gene testing has increased treatment options for new and recurrent cases, and it is anticipated to help improve the prognosis. This article outlines a new treatment strategy for patients with a BRCA gene mutation, based on the association between ovarian cancer and BRCA genes and the results of related clinical trials conducted to date.

In the USA, Norquist et al. reported that the frequency of germline mutations in 1915 cases of epithelial ovarian cancer was 15% for BRCA1 and BRCA2 combined (BRCA1: 8.5%, BRCA2: 6.3%). By histological type, the frequencies were 16% in high-grade serous carcinoma, 6% in low-grade serous carcinoma, 9% in endometrioid carcinoma, and 7% in clear cell carcinoma. No mutation was noted in mucinous carcinoma [2]. In Japan, Sakamoto et al. reported that germline BRCA mutations were identified in 12.6% of 95 patients with ovarian cancer (BRCA1: 5 patients, BRCA2: 7 patients) [3]. In the analysis of 230 patients by Hirasawa et al., the frequency was 11.8% (BRCA1: 19 patients, BRCA2: 8 patients). By histological type, 22 of the 27 patients (81.5%) had high-grade serous carcinoma, 2 patients had endometrioid carcinoma, and 2 patients had clear cell carcinoma (7.4% each) [4].

Guidelines on the recommendations for the BRCA gene test are slightly different among countries. The National Comprehensive Cancer Network (NCCN) [5], Society of Gynecologic Oncology [6], and American College of Obstetricians and Gynecologists [7] guidelines propose that BRCA gene testing should be considered in all ovarian cancer patients, regardless of family history. However, the guidelines of the European Society for Medical Oncology, France, Germany, Netherlands, Spain, and the UK (the National Institute for Health and Care Excellence) state that testing should be considered on the basis of whether the patient has a family history of breast or ovarian cancer [8-11]. The guidelines published by the Scottish Intercollegiate Guidelines Network in Scotland also state that the test should be considered for all patients with non-mucinous ovarian or fallopian tube cancer, regardless of family history [12].

Thus, there are several issues that need to be discussed in the future, such as whether BRCA gene testing should be recommended for all patients with ovarian cancer or for patients who are likely to test positive due to their family history or histological type and the point in time when the test should be performed.

BRCA1 is a gene located on chromosome 17 (at 17q21.32) cloned by Miki et al. The gene is characterized by a very large exon 1 and plays an important role in DNA repair [13]. BRCA2 is a gene located on chromosome 13 (at 13q12.3) identified by Wooster et al. [14].

According to a report by Chen et al., the proportions of people with a BRCA1 mutation who develop breast cancer and ovarian cancer by the age of 70 years are estimated to be 57% (95% confidence interval [CI]: 47%-66%) and 40% (95% CI: 35%-46%), respectively, whereas those of people with a BRCA2 mutation are 49% (95% CI: 40%-57%) and 18% (95% CI: 13%-23%), respectively [15]. Additionally, the Consortium of Investigators of Modifiers of BRCA1/2 published a report on the positions of gene mutations and the risks of breast and ovarian cancers in 19581 BRCA1 mutation carriers and 11900 BRCA2 mutation carriers. According to this report, the occurrence of nonsense or frameshift mutations in the central part of the coding region of BRCA1/2 increases the risk of ovarian cancer and decreases the risk of breast cancer. However, mutations in the 5’ and 3’ regions increase the risk of breast cancer and decrease the risk of ovarian cancer [16]. As the mechanism causing these differences in the risks of breast and ovarian cancers, the possible involvement of gene repair is considered; however, the whole picture is yet to be elucidated.

Genetic counseling for patients with a BRCA mutation is important for their blood relatives. When there are multiple breast cancer patients within a family, the breast cancer is called “familial breast cancer”. Familial breast cancer caused by single-gene abnormality is called “hereditary breast cancer”. Of all hereditary breast cancers, 60%-70% are hereditary breast and ovarian cancer (HBOC) caused by BRCA1/2 mutations, which includes a high rate of ovarian cancer. In Japan, a surveillance system has been established for the treatment of HBOC by linking genetic and cancer treatments. This has increased the number of treatment options based on BRCA gene diagnosis, contributing to significant advances in cancer treatment.

The greatest benefit of the BRCA gene test in people at risk for HBOC is the option of risk reduction surgery. According to the NCCN guidelines, risk-reducing salpingo-oophorectomy (RRSO) is recommended in patients with a BRCA gene mutation at the age of 35-40 years. If the patient has a family member with a history of ovarian cancer at a younger age, their age should be considered to determine the appropriate timing for RRSO [17]. In 2009, Rebbeck et al. reported that RRSO can reduce the risk of ovarian cancer by 79% [18]. In a prospective cohort study of 2482 patients with a BRCA mutation, Domeckek et al. reported that RRSO reduced all-cause mortality by 60%. A meta-analysis by Marchetti et al. also reported 68% reduction in all-cause mortality [19,20]. However, because early menopause increases the risk of cardiovascular events, hormone replacement therapy after RRSO is essential. To obtain fully informed consent from the patients about the procedure, genetic counseling is crucial.

Indeed, germline genetic testing should be ordered to all newly diagnosed patients with epithelial ovarian cancer to detect germline pathogenic variants (gPVs) in all genes associated with epithelial ovarian cancer susceptibility. What about the somatic mutations? The last decade, tumor sequencing to identify potentially targetable somatic mutations is increasingly being used in high-grade serous epithelial ovarian cancer and influences decisions on patient treatment. Beyond germline, poly ADP-ribose polymerase (PARP) inhibitors may be effective in somatic BRCA1/2 mutations as well [21].

Adenine dinucleotide poly (ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair. PARP plays a part in the repair of both single-strand breaks and double-strand breaks (DSB) in DNA, which occurs by base excision repair and homologous recombination (HR), respectively [22-24]. To date, 17 members of the PARP family have been identified, with PARP1 being the most abundant in cells. PARP2 and PARP3 are also involved in DNA repair. BRCA1/2 genes play an important role in DNA DSB repair. In cells in which BRCA1/2 gene function is disrupted, the inhibition of PARP causes a failure in the mechanism of DNA repair via HR, resulting in cell death (Fig. 1). Cell death caused by the simultaneous damage of two mechanisms, such as PARP and BRCA1/2 as described here, is called synthetic lethality. Accordingly, PARP inhibitors are considered to be effective in patients with mutations in BRCA1/2 genes.

Fig. 1.

Mechanism of synthetic lethality by PARP inhibitors. BRCA1/2 genes play an important role in the repair of DNA double-strand breaks. In cells with disrupted BRCA1/2 gene function, poly (ADP-ribose) polymerase inhibition causes a failure in the DNA repair mechanism by homologous recombination. This leads to synthetic lethality.

PARP inhibitors for ovarian cancer include olaparib, rucaparib, and niraparib, but their indications differ from country to country (Table 1).

In Japan, only olaparib is covered by health insurance. BRCA gene testing is not required for maintenance therapy in platinum-sensitive recurrent cancers. However, for maintenance therapy following initial chemotherapy, PARP inhibitors can be used only in patients with germline BRCA mutations, but with no restriction on histological types.

In contrast, in the USA, relapse treatment with PARP inhibitors is indicated for “maintenance therapy for platinum-sensitive recurrent high-grade serous epithelial ovarian, fallopian tube, or peritoneal cancer with a germline or somatic BRCA mutation”, whereas in Europe, it is indicated for “maintenance therapy for platinum-sensitive recurrent high-grade serous epithelial ovarian, fallopian tube, or peritoneal cancer regardless of BRCA mutation status”. In other words, in the USA, patients with platinum-sensitive recurrent cancer are not allowed to receive olaparib unless they have a germline BRCA mutation. Recently, the indications for maintenance therapy after initial chemotherapy have been expanded to include patients with high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a germline or somatic BRCA mutation in both the USA and European countries.

Although rucaparib and niraparib have been approved for use in platinum-sensitive recurrences in the USA, they are currently used in global clinical trials in Japan and are highly anticipated to contribute to the future treatment of ovarian cancer.

In the USA, niraparib has been approved for use in maintenance therapy after initial and relapse treatment, but with no restriction on whether the patient has a BRCA mutation. However, in patients with a history of three or more regimens of chemotherapy, the use of niraparib is allowed only in patients who are positive for homologous recombination deficiency. In Europe, the drug has not been approved for use in maintenance therapy following the first-time chemotherapy and can be used only as maintenance therapy in relapse treatment. Recurrent patients eligible for niraparib are only those with platinum-sensitive recurrent high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

In both the USA and Europe, rucaparib has been approved for the treatment of germline or somatic BRCA mutation-positive epithelial ovarian, fallopian tube, and peritoneal cancer with a history of two or more chemotherapy regimens. However, in Europe, the use is limited to the treatment of platinum-sensitive recurrences. Rucaparib can also be used for maintenance therapy in recurrent disease, regardless of germline or somatic BRCA mutation status, but its use is limited to platinum-sensitive recurrences in Europe. The histological type is also limited to high-grade serous carcinoma and endometrioid carcinoma.

In addition, veliparib is a promising molecular-targeted agent for high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer [25]. VELIA/GOG-3005 (an international, phase 3, placebo-controlled trial) involved patients with previously untreated stage III or IV high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer. VELIA/GOG-3005 assessed the efficacy of veliparib added to first-line induction chemotherapy with paclitaxel and carboplatin and continued as maintenance monotherapy. Patients were randomly assigned, in a 1 : 1 : 1 ratio, to one of the three arms: the control arm (patients treated with chemotherapy plus placebo followed by placebo maintenance), the veliparib-combination-only arm (those treated with chemotherapy plus veliparib followed by placebo maintenance), and the veliparib-throughout arm (those treated with chemotherapy plus veliparib followed by veliparib maintenance). Combination chemotherapy and maintenance therapy consisted of 6 and 30 cycles, respectively. The primary endpoint was progression-free survival (PFS) in the veliparib-throughout arm relative to the control arm, as assessed by the investigator based on the hierarchical testing in BRCA mutation, HRD (including BRCA mutation), and whole populations by log-rank tests.

Of the 1140 patients enrolled in the study, 26% had BRCA mutations and 55% had HRD. In the BRCA mutation cohort, the median PFS in the veliparib-throughout arm (108 patients) was 34.7 months, as compared with 22.0 months in the control arm (92 patients; hazard ratio [HR] for progression or death, 0.44; 95% confidence interval [CI], 0.28-0.68; P 0.001) [26].

However, at this stage, the number of overall survival (OS) events is not sufficiently accumulated, so Japan, USA and Europe are waiting for approval application until the OS becomes mature.

In Japan, olaparib is the only PARP inhibitor approved for coverage by health insurance. This section describes the clinical trials that verified the usefulness of olaparib maintenance therapy in patients with BRCA gene mutation-positive ovarian cancer (Table 2).

There are available studies evaluating the antiangiogenic agent cediranib with the PARP inhibitor olaparib in the ovarian cancer patients. This session describes the completed or ongoing clinical trials (Table 3).

NCT01116648, a randomized, open-label, phase II study designed to evaluate the combination of cediranib, an antiangiogenic agent, and olaparib versus olaparib alone, has been completed. First, preclinical synergy between olaparib and cediranib was explored to determine whether ovarian cancer cell invasion and microvascular endothelial cell tube formation were inhibited in vitro. Women with relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or with deleterious germline BRCA1/2 mutations were enrolled in the study. Patients were randomly assigned to the single-agent arm (olaparib capsules 400 mg twice daily) or the experimental arm (cediranib 30 mg daily and olaparib capsules 200 mg twice daily) until disease progression.

The interim analysis showed that the experimental arm exhibited significantly longer PFS (17.7 months) than the single-agent arm did (9.0 months; HR: 0.42; P = 0.005). However, these results should be meticulously interpreted owing to the small size of each subgroup. Moreover, it would be interesting if a single-agent arm of cediranib, which could act as a comparator for the experimental arm, was included in the study design. A post-hoc exploratory analysis revealed that in the subset of patients with wild-type or unknown BRCA status, the experimental arm showed a statistically significant improvement compared with the single-agent arm for both median PFS (16.5 versus 5.7 months, HR 0.32; P = 0.008) and objective response rate (ORR; 76% versus 32%; P = 0.006). The authors proposed that this difference could be attributed to great synergy between olaparib and cediranib in the setting of hypoxia, potentially leading to alterations in the expression of DNA damage response genes. Patients with BRCA mutation showed a reduced tendency toward increased activity in the experimental arm and reduced impact on the endpoints of PFS (19.4 versus 16.5 months) and ORR (84% versus 63% benefit). Overall, ideal administration of the combination of cediranib plus olaparib may be possible for patients with an intact HR repair phenotype [33]. Finally, the most recently updated analysis showed that OS did not differ significantly in the entire study population (44.2 versus 33.3 months, HR 0.64; P = 0.11) [34].

Additional trials are ongoing to evaluate combined treatment with PARP inhibitors and anti-angiogenic agents. In the GY004 trial, olaparib monotherapy or olaparib plus cediranib therapy was compared with standard platinum-based chemotherapy in patients with platinum-sensitive recurrent ovarian cancer [35]. In the ICON 9 trial, maintenance therapy with cediranib plus olaparib was compared with olaparib alone within the same setting [36]. Three other phase II/III trials are currently ongoing for patients with platinum-resistant disease.

The COCOS study randomly assigned patients to one of four treatment groups: single-agent group (either olaparib or cedilanib), combination group, or standard chemotherapy group [37]. In the OCTOVA study, patients with germline BRCA mutations were randomly assigned to receive olaparib alone, olaparib plus cediranib, or weekly paclitaxel [38]. Finally, only patients with wild-type BRCA treated with at least three prior lines of therapy were recruited into the CONCERTO trial (study of cediranib in combination with olaparib) [39].

Current studies have raised important concerns regarding whether PARP inhibitors may help enhance the response to immune checkpoint inhibition or other immunotherapeutic approaches. Recently, the MEDIOLA study and the TOPACIO trial (combination trials of immune checkpoint blockade with PARP inhibitors) were presented at the European Society of Gynaecological Oncology Congress in 2018 (Table 4). This section briefly describes these two clinical trials.

Advances in our understanding of resistance to PARP inhibitors may yield novel insights into the basic mechanisms of the DNA damage response. Individual PARP inhibitors have different chemical structures and diverse off-target effects [44]. Thus, application of secondary PARP inhibitors may be useful for the treatment of resistant tumors. The most common mechanism underlying resistance is restoration of homology-directed DNA repair owing to secondary reversion mutations [45].

Many studies have evaluated pharmacological methods for reversing resistance to PARP inhibitors. Knockdown of cyclin-dependent kinase 12 (CDK12) results in concomitant downregulation of DNA repair proteins, thereby leading to the development of a “BRCAness” phenotype [46]. In vitro evidence suggests that pharmacological inhibition of CDK12 with Dinaciclib reverses acquired resistance to PARP inhibitors [47]. Furthermore, inhibition of the cell cycle regulator WEE1 causes cells to enter the S-phase of the cell cycle, thereby accelerating the accumulation of DNA DSBs in the context of HRD and PARP inhibition [48]. With the aim of overcoming homologous recombination-induced resistance to PARP inhibitors, Boussios et al. reported that combined inhibition of CDK12 or WEE1 could be effective [49].

Indications for PARP inhibitors vary from country to country. The choice of treatment should be based on the indications specified in the country. Among them, olaparib has been shown to have favorable therapeutic outcomes as maintenance therapy for advanced/recurrent ovarian cancer as demonstrated by the aforementioned clinical studies. Additionally, when used in patients with a BRCA mutation, the outcomes are even more favorable [27-30]. In Japan, the initial treatment recommended for patients with advanced ovarian cancer is to establish a histological diagnosis followed by BRCA gene testing and administer olaparib as maintenance therapy to those with a BRCA mutation who had an adequate response to platinum-based chemotherapy. In contrast, for patients without a BRCA mutation, one of the treatment options is combination/maintenance therapy with bevacizumab, which has been shown to prolong PFS by GOG 218 [50] and ICON7 [51]. In recurrent patients, indications differ among countries. In Japan, for patients with a BRCA mutation diagnosed with platinum-sensitive recurrent cancer, olaparib is recommended as maintenance therapy after an adequate response to platinum-based chemotherapy. For patients without a BRCA gene mutation, one of the treatment options is combination/maintenance therapy with bevacizumab, which has been shown to prolong PFS in GOG 213 [52] and OCEANS [53]. However, one important thing to consider is that bevacizumab can be administered even in patients with a platinum-resistant recurrence, while olaparib can be administered only in patients with a platinum-sensitive recurrence. The use of olaparib in patients with a BRCA gene mutation is useful as a new treatment strategy, and it is anticipated to help improve the prognosis of ovarian cancer. Furthermore, we look forward to future research on the usefulness of other molecular-targeted agents and immune checkpoint inhibitors.

T.S. contributed to the design and coordination of the review, and drafting the manuscript. T.B. contributed to the design of the review and drafting the manuscript. K.K., H.K., N.J., H.T., A. K., E.T., T. N., M.K. contributed to the conception, design, and coordination of the review and drafting the manuscript.

Thanks to all the peer reviewers and editors for their opinions and suggestions.

The authors declare no conflict of interest.