Niraparib

Precision medicine for hereditary tumors in gynecologic malignancies

Masayuki Sekine and Takayuki Enomoto
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Abstract

Genomic medicine for gynecologic tumors is characterized by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Poly ADP-ribose polymerase (PARP) inhibitor, olaparib, and the immune check- point inhibitor, pembrolizumab, which are drugs that show sensitivity to each hereditary tumor, have begun to spread in clinical practice for gynecologic malignancies. In clinical use, platinum sensitivity is used as a clinical surrogate marker for olaparib sensitivity, and microsatellite instability is used as a biological surro- gate marker for pembrolizumab sensitivity. BRCA genetic testing and microsatellite instability test have been used as companion diagnostics before starting olaparib and pembrolizumab treatment, respectively. Homologous recombination deficiency test could be used for companion diagnostic of olaparib combination with bevacizumab in first-line maintenance treatment and niraparib without re-administration of platinum agents in the treatment of recurrence. The approval of the three drugs has been changing the treatment of gynecologic malignancies. Furthermore, preventive medical care has been covered by insurance since April 2020 for breast and/or ovarian cancer patients with germline BRCA1/2 mutation in Japan. This review article outlines the current status and future prospects of precision medicine for gynecologic hereditary tumors focusing on HBOC and LS.

Key words: Hereditary Tumor, Hereditary breast and ovarian cancer, Lynch syndrome, PARP inhibitor, Risk-reducing surgery.

Introduction

A relatively large number of hereditary tumors involved in the development of gynecologic tumors have been reported (Table 1). Among them, genomic medicine for gynecologic tumors is character- ized by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). HBOC caused by germline BRCA1/2 gene mutation (gBRCAm) is predicted to be responsible for about 5% of all breast cancers and 15% of all ovarian cancers.1–4 LS caused by germline mis- match repair (MMR) gene mutation is predicted to be responsible for about 5% of all endometrial cancers and 3% of all ovarian cancers.5
Poly ADP-ribose polymerase (PARP) inhibitor, olaparib, and the immune checkpoint inhibitor, pembrolizumab, which are drugs that show sensitiv- ity to each hereditary tumor, have begun to spread in clinical practice for gynecologic malignancies. In clini- cal use, platinum sensitivity is used as a clinical surro- gate marker for olaparib sensitivity, and microsatellite instability (MSI) is used as a biological surrogate marker for pembrolizumab sensitivity (Table 2). Furthermore, Niraparib was approved in Japan for use regardless of BRCA mutation status in the first-line maintenance treatment of ovarian cancer.
BRCA genetic testing and MSI test have been used as companion diagnostics before starting olaparib and treatment of recurrent patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemo- therapy in January 2018. In June 2019, based on the results of SOLO 1, olaparib was approved for the main- tenance treatment of patients with germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian Biomarker HRD MMR deficiency tube, or primary peritoneal cancer who are in complete Surrogate marker Platinum sensitivity (clinical) Microsatellite instability (biological) or partial response to first-line platinum-based chemo- therapy.11 In addition to the indication, olaparib could pembrolizumab treatment, respectively. In the field of gynecologic oncology, there are still few molecular target drugs that can be used in comparison to other areas, however, the approval of the two drugs men- tioned above has been changing the treatment of gynecologic malignancies. In addition, preventive medical care has been covered by insurance since April 2020 for breast and/or ovarian cancer patients with gBRCAm in Japan.6 This review article outlines the current status and future prospects of precision medicine for gynecologic hereditary tumors focusing on HBOC and LS.

Hereditary Breast and Ovarian Cancer (HBOC) Indication of PARP inhibitors

In Japan, based on the results of Study 19 and SOLO 2 trial,7–10 olaparib was approved for the maintenance be used for its combination with bevacizumab for first-line maintenance treatment of patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first- line platinum-based chemotherapy and whose cancer is associated with homologous recombination defi- ciency (HRD) positive status defined by deleterious BRCA mutation and/or genomic instability based on the results of PAOLA-1 trial.12 Furthermore, the HRD test, Myriad myChoice® CDx (Myriad Genetic Labora- tories, SaltLake City, USA), was approved as a com- panion diagnostic for olaparib to determine HRD status of the patients. Patients continued bevacizumab in the maintenance setting and started olaparib after a minimum of 3 weeks and up to a maximum of 9 weeks following their last chemotherapy dose. The recommended olaparib dose is 300 mg taken orally twice daily, and when used with olaparib, the rec- ommended bevacizumab dose is 15 mg/kg intrave- nously every 3 weeks.
In September 2020, niraparib was approved for use in the maintenance treatment of platinum-sensitive recur- rent patients and first-line maintenance treatment of all- comer patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy based on the results of ENGOT-OV16/ NOVA and PRIMA trial.13,14 In addition, niraparib was approved for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD-positive status based on the results of QUADRA trial.15 HRD is defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability in patients with disease progression greater than 6 months after response to the last platinum-based chemotherapy.
For first-line maintenance treatment, olaparib can be administered to the patient with BRCAm or HRD-positive in complete or partial response to platinum-based chemotherapy. Therefore, genetic counseling for HBOC may be required as a result of companion diagnostics. On the other hand, nilaparib can be administered to all-comer patients, so gBRCA test and HRD tests are not always necessary. For maintenance treatment of platinum-sensitive recurrent patients, olaparib or nilaparib can be administered to the patient with- out results of a companion diagnostic. It should be noted that for platinum-sensitive recurrent cancers with a history of the treatment of three or more regimens, HRD testing is required as a companion diagnostic when using niraparib without re- administration of platinum agents.

Genetic testing for BRCA mutation in ovarian cancer patients

In Japan, indications for BRCA genetic testing covered by insurance, so far, include the following situations1; companion diagnostics for using olaparib in first-line maintenance treatment,2 ovarian and/or breast cancer patients with suspected HBOC based on family history and/or past history, and3 as panel test for cancer patients who have completed standard treatment. The BRACAnalysis® (Myriad Genetic Laboratories, SaltLake City, USA) and FoundationOne® CDx (Foun- dation Medicine, Inc., Cambridge, USA) for companion diagnostic was approved to determine the indication for the PARP inhibitor olaparib. The BRACAnalysis® is used as gBRCAm test, on the other hand, the FoundationOne® CDx detects tumor BRCA mutations (tBRCAm) including both gBRCAm and somatic BRCA mutation (sBRCAm). The eligibility of BRCA genetic testing as a companion diagnostic for the use of olaparib are1: patients who were diagnosed with FIGO stage III/IV epithelial ovarian/fallopian tube/perito- neal cancer for first-line maintenance treatment, and2 patients who are maintaining their response to initial platinum-based chemotherapy.
Recently, Enomoto et al. determined prevalence rates of gBRCAm in the Japan CHARLOTTE study.3 In stages I–II and stages III–IV ovarian cancer, the prevalence of gBRCAm was 4.9% and 24.1%, respec- tively. The prevalence of gBRCAm by primary disease site was shown in Figure 1. The prevalence of gBRCAm in epithelial ovarian, primary peritoneal, and fallopian tube cancer were 12.7%, 21.1%, and 29.2%, respectively. BRCA mutation rate was lowest in epithelial ovarian cancer (12.7%) and highest in fallopian tube cancer (29.2%). For epithelial ovarian and primary peritoneal cancers, the frequency of BRCA1 mutation was higher than that of BRCA2 mutation, whereas, for fallopian tube, BRCA1 or BRCA2 mutation rate was the same at 14.6%.3 Mitamura et al. reported that the proportion of fallopian tube and peritoneal cancer was significantly higher in BRCA2+ (40.5%) compared with BRCA1+ (15.4%) and BRCA (no pathogenic variant, 12.8%).16,17
Regarding the mutation rate for each histological type, Sekine et al. reported that high-grade serous car- cinoma (HGS) accounts for 80% of ovarian cancers with gBRCAm.18,19 As a result of the Japan CHAR- LOTTE study,3 the prevalence of gBRCAm by histo- logical type is presented in Table 3. In stage I–IV patients with high-grade serous, gBRCA mutation rate was 28.5%, low-grade serous was 20%, endometrioid was 6.7%, and clear-cell was 2.1%. On the other hand, in mucinous and seromucinous ovarian cancer, the prevalence was 0%. There are divisions of opinion regards whether or not mucinous type is included in applicable patients of the companion diagnostics. As results of the Japanese study, the explanation before the companion diagnostic should include the follow- ing contents: (1) the gBRCA mutation rate in stage III/ IV cases was 24.1%, and (2) the rate depends on histological types.
The Myriad myChoice® HRD test could be used for companion diagnostic of olaparib combination with bevacizumab in first-line maintenance treatment and niraparib without re-administration of platinum agents in the treatment of recurrence.20 The HRD test can detect both tBRCAm and HRD. It will be impor- tant to discuss whether or when to perform the HRD test or the gBRCAm test. The significance of con- ducting the gBRCAm testing is as follows: (1) to predict the super-responders for PARP inhibitors, (2) to contribute to the prevention of secondary cancer in the patient, (3) to evaluate the cancer risk in the patient’s family in detail, and (4) to select fertility preservation surgery in young ovarian cancer patients. On the other hand, the following problems have been pointed out in the HRD test21: (1) the assay method is not yet well established, (2) cut-off line set- tings differ depending on the clinical trial, and (3) whether the genetic characteristics of the tumor at the time of recurrence are reflected when the material removed in the first surgery is used.

Risk-reducing salpingo-oophorectomy (RRSO)

Since April 2020, preventive medical care has been covered by insurance for breast and/or ovarian can- cer patients in HBOC carriers in Japan. Items of medi- cal treatment covered by insurance for patients with suspicion of HBOC are: (1) Guidance and management fee for explaining the necessity of gBRCA genetic testing, (2) gBRCA genetic testing, (3) Genetic counseling about the results of gBRCA genetic testing, (4) risk-reducing salpingo-oophorectomy (laparotomy or laparoscopy), and Contralateral risk-reducing mas- tectomy (CRRM) and breast reconstruction for breast cancer patients with gBRCAm, (5) Bilateral risk- reducing mastectomy (BRRM) and breast reconstruc- tion for ovarian cancer patients with gBRCAm, and (6) breast MRI surveillance for patients with gBRCAm who did not receive RRM.6
The NCCN guidelines recommend that gBRCAm carriers have RRSO if they are 35–40 years old.22 For women who do not opt for an RRSO between the ages of 30 and 35 years old, surveillance with a com- bination of transvaginal ultrasounds (TVUS) and CA125 tests is based on the judgment of the attending physician, although it is specified that the benefits are not established. Meta-analysis of the breast/ovarian cancer risk-reducing effect of RRSO showed that ovar- ian cancer risk was reduced by 79% and breast cancer risk by 51%.23 Domcheck and Marchetti et al. showed that RRSO reduced all-cause mortality by 60% and 68%, respectively, in both pre- and post-menopausal women.24,25 A prospective trial of prophylactic salpingectomy with delayed oophorectomy (PSDO) has begun, with salpingectomy at age 40 and oopho- rectomy at age 50.26,27 However, the NCCN guide- lines state that the protective effect of salpingectomy alone against ovarian and peritoneal cancer has not been demonstrated.22 Furthermore, salpingectomy alone is not expected to decrease the risk of develop- ing breast cancer, so it is not a standard risk-reduction treatment.

Lynch Syndrome (LS)

Epidemiology and causative genes

LS is a condition that increases the risk of developing hereditary tumors, especially colorectal cancer, in addition to endometrial, ovarian, stomach, small intestinal, hepatobiliary system, renal pelvis, and ure- teral cancer. When multiple adenomas develop in the large intestine, it is called hereditary non-polyposis colorectal cancer (HNPCC), to distinguish it from familial adenomatous polyposis (FAP), but recently, many people tend to refer to this disease as “Lynch syndrome.”
About 2%–4% of all colorectal cancers are caused by embryonic cell mutations in MMR genes, MSH2, MLH1, MSH6, PMS2, and EPCAM.28–32 It was reported that approximately 80% of cases have a mutation in MSH2 or MLH1 genes, 10% in the MSH6 gene, and <10% in the PMS2 gene.33–35 Clinical characteristics and diagnosis For endometrial cancer in LS, highly differentiated endometrial adenocarcinomas are common, and although obesity is not primarily involved, endome- trial adenocarcinomas develop from the lower uterine segment more often than other endometrial cancer.36 Colorectal cancer is reported to frequently develop in the right colon (cecum, ascending colon, and trans- verse colon). It is frequently a mucinous carcinoma or poorly differentiated adenocarcinoma, with a compar- atively favorable prognosis.37–39 The hereditary colorectal cancer treatment guide-lines recommend diagnosing it in three steps, primary screening, secondary screening, and testing for a confirmed diagnosis.40 First, determine that the patient satisfies the Amsterdam II criteria,41 or the revised Bethesda criteria (primary screening), then conduct a microsatellite instability (MSI) test or immunohistological test (secondary screening).42,43 If an abnormality is found during secondary screening, a germline genetic test of MMR genes needs to be considered at one’s own expense. MMR genetic testing will lead to a confirmed diagnosis of this syndrome. Immune checkpoint inhibitor for MSI-high solid cancers The MSI test is insurance-approved for two indica- tions: a companion diagnostic for pembrolizumab decision making and use for screening LS. Pembrolizumab is a monoclonal antibody against PD-1, which binds to PD-1 on inactivated T cells to inhibit the binding to PD-L1/L2 on cancer cells and immune cells and reactivate T cells. MSI is a DNA repair error in the microsatellite region of DNA that is repaired by MMR protein complex, but when the MMR function is lost, the error is not repaired. There- fore, MSI is a phenomenon showing a different number of repeats from normal genomic DNA. Cancer cells deficient in MMR function are called “MSI-High tumors” and are relatively frequent in gastrointestinal and gynecologic cancers such as endometrial, gastric, small intestine, colorectal, and cervical cancer.44 It has been reported that MSI-High tumors have about 25 times more somatic gene mutations than tumors other than MSI-High,45,46 and that tumor-specific anti- gen (neo-antigen) expression is high. Therefore, it is thought that it becomes easier to recognize T cells. The MSI Test Kit (FALCO) was insured in December 2018 and targets locally advanced or metastatic MSI- High solid tumors. The MSI test kit uses five types of microsatellite regions as markers to determine MSI. “MSI-H (MSI-High)” when 2 or more markers are posi- tive, “MSI-L (MSI-Low)” when 1 marker is positive, “MSS (MS Stable)” when the positive marker is 0. When testing to determine the indication of pembrolizumab, only “MSI-H” is indicated. In the case of MSI-H, it is necessary to consider the possibility of LS, perform genetic counseling such as listening to detailed family history, and consider MMR genetic test as a definitive diagnosis. Akagi et al. reported that the overall frequency of MSI-H was 3.72% in the results of 26 237 MSI tests in Surveillance and risk-reducing surgery for LS Colorectal cancer surveillance is known to extend the life span of individuals, but its effectiveness for other cancer types is still unclear. The cumulative risk for diagnosis of each cancer type through age 80 years in MMR gene carriers was shown in Table 4. As a rough estimate, the risk of individuals with germline MMR gene mutation was reported as follows: colorectal cancer: 30%–50%; endometrial cancer: 20%–50%; and ovarian cancer: 5%–30%.28,32,49–60The cumulative risk of developing the disease depends on the mutated gene, and the estimated average age of presentation also varies depending on the mutated gene. With regards to recommended monitoring by the hereditary colorectal cancer guidelines, a TVUS and endometrial examination once every 1 or 2 years as a gynecological examination for women from the age of 30–35 and an abdominal ultrasound once every 1 or 2 years for 30–35 year olds. Regarding surveillance of endometrial cancer, endometrial biopsy once every 1 or 2 years is a reasonable strategy based on its sensitivity and the procedure-related risk.61–63 TVUS is not recommended for its effectiveness in premenopausal women; how- ever, routine TVUS may be considered according to the physician’s decision but should not be the routine examination for postmenopausal women.61–64 Schmeler and Tzortzatos et al. reported that hysterectomy reduced the incidence of endometrial can- cer.65,66 There is currently no consistent view on hysterectomies for risk reduction, and a consensus has not been reached. NCCN guidelines rec- ommended that hysterectomy has not been shown to reduce endometrial cancer mortality, but can reduce the incidence of endometrial cancer, so a hysterec- tomy is a risk-reducing option that can be considered. The timing of hysterectomy can be individualized based on whether childbearing is complete, family history, underlying disease, and MMR mutated gene.32 Concerning surveillance of ovarian cancer, TVUS and serum CA-125 levels have not demonstrated enough sensitivity or specificity to support a routine recommendation. This recommendation is the same as for HBOC. On the other hand, RRSO may reduce the incidence of ovarian cancer for LS.62,65,67,68 NCCN guidelines recommended that the decision and timing of RRSO should be individualized and should be con- sidered according to the patient’s childbearing plan, menopause status, comorbidities, family history, and MMR mutated gene.32 The risks for ovarian cancer of MSH6 and PMS2 mutation carriers is relatively low (1%–13%), so there is not sufficient evidence of recom- mendation for RRSO in MSH6 and PMS2 mutation car- riers.52,69,70 As of April 2021, preventive medical care has not been covered by insurance for LS patients. Conclusion The treatment of gynecologic cancer is changing rap- idly, especially in ovarian cancer. Olaparib and pembrolizumab, which are highly sensitive to patients with mutations in the BRCA or MMR genes, are widely used clinically and the HRD test was adopted as a companion diagnostic for PARP inhibitors. In December 2020, the Japanese Society of Gynecologic Oncology published “Concepts for conducting an HRD test as a companion diagnostic for ovarian cancer patients.”21 The statements insisted that the gBRCAm positive rate for patients with stage III and IV ovarian cancer in Japan is reported to be 24.1%, but the rate of sBRCAm positive and gBRCAwt is as low as around 5%–7%. Therefore, patients with tBRCAm are more likely to identify gBRCAm, so the patients need to be able to adequately receive genetic counseling and additional genetic testing. 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