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Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management

Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management REVIEW ARTICLE Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management Renata Rodrigues da Cunha Colombo Bonadio, Rodrigo Nogueira Fogace, Vanessa Costa Miranda, Maria del Pilar Estevez Diz Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. Bonadio RR, Fogace RN, Miranda VC, Dis MP. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics. 2018;73(suppl 1):e450s *Corresponding author. E-mail: rrccbonadio@gmail.com Ovarian cancer patients with homologous recombination deficiencies exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors, have been observed. Germline mutations in the BRCA 1/2 genes are the most well-known mechanisms of homologous recombination deficiency. However, other mechanisms, such as germline and somatic mutations in other homologous recombination genes and epigenetic modifications, have also been implicated in homologous recombination deficiency. The epidemiology and implications of these other mech- anisms need to be better understood to improve the treatment strategies for these patients. Furthermore, an evaluation of various diagnostic tests to investigate homologous recombination deficiency is essential. Compre- hension of the role of homologous recombination deficiency in ovarian cancer also allows the development of therapeutic combinations that can improve the efficacy of treatment. In this review, we discuss the epidemio- logy and management of homologous recombination deficiency in ovarian cancer patients. KEYWORDS: Ovarian Cancer; Homologous Recombination Deficiency; PARP Inhibitors; BRCA Mutation. Homologous recombination deficiency and ’ INTRODUCTION PARP inhibitors In ovarian cancer, patients harboring BRCA 1/2 mutations DNA breaks are repaired via different mechanisms to exhibit different patterns of clinical behavior and respond protect the genome. For example, double-stranded breaks to treatment differently. The BRCA gene plays a role in are repaired by HR and non-homologous end joining repairing DNA repair via homologous recombination (HR), (NHEJ) (1). HR is more efficient at maintaining genomic and mutation of this gene leads to HR deficiency (HRD). stability because it uses a homologous template, whereas HRD can also occur due to other mechanisms, such as ger- NHEJ is error-prone. mline mutations, somatic mutations and epigenetic modifi- Unrepaired DNA damage can result in accumulated muta- cations of other genes involved in the HR pathway. Ovarian tions and unregulated cell division, and HRD is thus related cancers with these alterations behave similarly to those with to cancer susceptibility (2,3). Moreover, large amounts of BRCA mutations, and this behavior is termed the ‘‘BRCA- DNA damage can lead to cell apoptosis. However, when ness’’ phenotype. only HR is deficient, the activities of other DNA repair Using poly (ADP-ribose) polymerase (PARP) inhibitors in mechanisms can prohibit the accumulation of excessive DNA patients with HRD compromises two pathways of DNA damage and apoptosis (2). repair, resulting in synthetic lethality. Recent studies have Base excision repair (BER) serves as another DNA repair confirmed that the efficacy of PARP inhibitors is improved mechanism that acts on single-stranded breaks, and mem- not only in ovarian cancers displaying germline or somatic bers of the PARP protein family play essential roles in the BRCA mutations but also in cancers in which HRD is caused BER mechanism. PARPs bind to single-stranded break sites by other underlying etiologies. and initiate the repair process, and these proteins are targe- In this review, we discuss how to evaluate HRD as well as ted in oncology via the use of PARP inhibitors. the epidemiology and management of HRD in ovarian cancer. As mentioned previously, HRD by itself does not always induce cellular apoptosis. However, when PARP inhibitors are used in HRD cells, impairment of these Copyright & 2018 CLINICS – This is an Open Access article distributed under the two DNA repair mechanisms together results in synthetic terms of the Creative Commons License (http://creativecommons.org/licenses/by/ lethality. In other words, mutations occurring in one of 4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. two genes separately do not result in apoptosis, but the impairment of both genes simultaneously leads to cell No potential conflict of interest was reported. death (synthetic lethality). In this situation, the accumu- Received for publication on November 11, 2017. Accepted for lation of DNA damage might be sufficient to induce publication on February 5, 2018 cell death (apoptosis), and clinical trials showing the Commemorative Edition: 10 years of ICESP benefits of PARP inhibitors in HRD cancers support this DOI: 10.6061/clinics/2018/e450s concept (4,5). 1 HRD in ovarian cancer CLINICS 2018;73(suppl 1):e450s Bonadio RR et al. Mechanisms implicated in homologous the investigation of HRD regardless of the underlying genetic or epigenetic mechanism responsible. A high LOH (X14-16%), recombination deficiency The most described etiology of HRD is the mutation of for example, suggests the presence HRD. In the ARIEL2 trial, which evaluated rucaparib in platinum-sensitive recurrent genes involved in HR repair. Mutations can occur in ger- mline cells, which represent individual characteristics, or ovarian cancer, LOH-high was defined by NGS using a cutoff of 14%. The results showed that patients with BRCA 1/2 wild- somatic cells, which is a trait of tumor cells. Germline BRCA 1 and BRCA 2 mutations are the most type and LOH-high benefited from rucaparib (9). LOH can also be evaluated together with telomeric allelic imbalance and well-known HRD etiology. Germline mutations are impor- large-scale transitions to generate an HRD score (MyChoice tant not only for treatment decisions but also for the evalua- HRD test, Myriad Genetics Inc., Salt Lake City, Utah). tion of cancer susceptibility and prevention strategies for Patients determined to have HRD (defined as any tumor that the patients and their relatives. BRCA 1/2 are involved in hereditary breast and ovarian cancer syndrome, and numer- scored X42 on the MyChoice HRD test) benefited from maintenance niraparib in the NOVA trial (4). ous trials evaluating PARP inhibitors have been performed on patients presenting germline BRCA 1/2 mutations (5–8). Despite the ability of NGS to assess many genes during germline or somatic mutation screening, the implications of Patients without BRCA 1/2 mutations presented similar cli- nical behaviors and responses to PARP inhibitors (4,9), and some mutations remain unknown. Moreover, NGS cannot evaluate HRD due to other etiologies, such as epigenetic these patients define the ‘‘BRCAness’’ phenotype (10,11). The mechanisms underlying BRCAness are varied and include modifications. Thus, functional evaluations of HRD can help overcome these limitations. somatic BRCA 1/2 mutations and germline or somatic muta- tions in other genes related to HR repair. In conclusion, each of these tests have different properties and can be used in a complementary manner. Another possible etiology of HRD is the epigenetic modi- fication of HR genes, such as methylation of the BRCA 1 promoter. Gene expression signatures present in germline Epidemiology of HRD in ovarian cancer BRCA1 mutations were also observed in BRCA1-methylated Approximately 41-50% of ovarian carcinomas are esti- cancers (12). However, the implication of epigenetic mod- mated to exhibit HRD (17,18). However, the frequency ifications in HRD remain controversial. While Cunningham of HRD varies according to the method utilized for its et al. reported a survival advantage in patients with BRCA 1 evaluation (germline mutations, somatic mutations or HRD promoter hypermethylation compared with BRCA wild-type score) and histological subtype. Table 1 shows the frequen- patients (13), other researchers found no survival advantage cies of HRD in different studies according to the histolo- (14,15) or worse survival for patients with the methylated gical subtype. phenotype (16). Pennington et al. (19) found HR gene germline mutations in 24% of patients with epithelial ovarian cancer and soma- tic mutations in 9% of these patients. Elvin et al. (18) eval- How to evaluate homologous uated the presence of BRCA mutations or LOH in different recombination deficiency histological subtypes. The serous subtype was associated HRD can be tested using three main strategies: with a higher prevalence of HRD, with 43.8% of the patients presenting BRCA mutations (BRCAmut, 18.7%) or BRCA Germline mutation screening of genes related to HR wild-type/LOH-high (BRCAwt/LOH-high, 25.1%). Other repair; epithelial ovarian carcinomas also exhibited elevated propor- somatic mutation screening of genes related to HR repair; tions of HRD which occurred in 37.6% of endometrioid (12.6% and BRCAmut and 25% BRCAwt/LOH-H), 23.5% of carcino- evaluation of a genomic scar, which represents the geno- sarcoma (8.2% BRCAmut and 15.3% BRCAwt/LOHH) mic instability secondary to HRD. An HRD score can be and 12.6% of clear cell histologies (4.7% BRCAmut and 8.9% calculated based on the loss of heterozygosity (LOH), BRCAwt/LOHH). The mucinous subtype, however, exhib- telomeric allelic imbalance, and large-scale transitions. ited no BRCA mutations, and only 8.1% of the patients Germline mutation screening can be performed using next presented with BRCAwt/LOH-H. Upon specifically eval- generation sequencing (NGS) analysis of DNA from blood, uating the presence of somatic mutations, Aghajanian et al. which has the advantage of being easy to obtain. Moreover, the identification of a germline mutation allows the possibility of genetic counseling. Table 1 - Frequency of homologous recombination deficiency Somatic mutation screening, on the other hand, is perfo- according to the histological subtype. rmed on DNA from tumor samples. This analysis can eval- Method Elvin et al. Norquist et al. Pennington et al. uate any mutation (germline and/or somatic) in HR genes (N=4114) (18) (N=1915) (21) (N=367) (19) and is thus a broader evaluation, which is helpful for defining treatment strategies, such as the use of PARP inhibitors. How- BRCA + HR gene HR gene LOH-H mutations mutations ever, when a mutation is identified with this strategy, germline analysis of normal cells is still necessary to determine whether Serous 43.8% 27% 31% the mutation is germline or somatic (present in only the tumor) Endometrioid 37.6% 23.8% 27% (17). Limitations of somatic screening include the variability of Carcinosarcoma 23.5% - 33% Clear Cell 13.6% 21.4% 26% tumor samples available and intratumoral heterogeneity, which Epithelial NOS 47.7% - - potentially compromises the representativeness of the sample. Mucinous 8.1% 28.6% 0% Finally, HRD can be assessed in a more functional way. When HRD is present, genomic alterations accumulate, and LOH-H: Loss of heterozygosity; HR: homologous recombination; NOS: not allelic imbalances can result in a ‘‘genomic scar ’’, allowing otherwise specified. 2 CLINICS 2018;73(suppl 1):e450s HRD in ovarian cancer Bonadio RR et al. Table 2 - Frequency of germline mutations in ovarian carcinoma. (N) TCGA (14) Pennington et al. (19) Cunningham et al. (13) Harter et al. (49) Norquist et al. (50) Yates et al. (51) (316) (390) (899) (522) (1915) (299) BRCA1 8.5% 13.4% 3.5% 15.3% 9.5% 9% BRCA2 6.3% 4.6% 3% 5.6% 5.1% 5.4% EMSY PTEN 0% RAD51C 0.7% 3% 2.5% 0.6% 1% RAD51D 1% 0.6% 0.6% RAD50 0.2% 0.2% ATM/ATR 0.4% 0.6% 0.5% FANC 0.7% BARD1 0.5% 0% 0.2% 0.5% BRIP1 1% 0.4% 1.4% 2.5% CHEK1 0.25% 0.2% CHEK2 0.7% 0.6% 0.6% FAM175A 0.5% 0.2% 0.2% NBN 0.25% 0.4% 0.5% 0.5% PALB2 0.5% 1.1% 0.6% 0.5% MRE11A 0.4% 0.1% MMR 0.6% 0.5% TP53 0% 0.3% FANC: Fanconi anemia complementation group; MMR: mismatch repair genes. found similar prevalences of somatic mutations in high-grade Table 3 - Frequency of somatic gene changes (mutation, deletion or amplification) in ovarian carcinoma. serous ovarian carcinoma (HGSOC) and other histologies (16% vs 18%, respectively, p=0.07). Once again, no somatic (N) TCGA Pennington Cunningham Hahnen Aghajanian mutations in HR genes were observed in mucinous ovarian (14) et al. (19) et al. (13) et al. (52) et al. (20) cancer. (316) (390) (279) (431) (260) In relation to high-grade versus low-grade serous carci- BRCA1 3.2% 4.9% 2% 3% 4.4% noma, Norquist et al. (21) found a significant difference in the BRCA2 2.9% 1.5% 1.4% 1.4% 2.2% EMSY 8% germline and somatic mutation rates of HR genes, which PTEN 7% 4.4% were 10.9% for low-grade versus 27% for HGSOC (odds ratio RAD51C 0.3% 0.3% (OR), 0.33; 95% confidence interval (CI), 0.1-0.8; p=0.02). RAD51D 0.2% Regarding the specific genes compromised, in an evalua- RAD50 0.6% ATM/ATR 2% 0.8% 0.2% 2.2% tion of HR gene mutations in ovarian cancer patients who FANC 5% 0.2% 0.3% participated in the GOG 218 and GOG 262 trials, Norquist BARD1 0.6% et al. (21) showed germline or somatic mutations in BRCA1 BRIP1 0.5% 0.6% CHEK1 0% 0.3% gene in 12.3% of the cases, in BRCA2 gene in 6.5% and in CHEK2 0.3% 0.8% 0.3% other non-BRCA HR genes in 6.8%. Elvin et al. (18) reported FAM175A similar results, with mutations in BRCA 1 gene in 11.6% of the NBN 0.3% PALB2 0.2% 0.3% cases and BRCA 2 gene in 5.7%. MRE11A 0.3% BRCA mutations occur more frequently in HGSOC, with MMR 0.4% 20% of these patients presenting germline or somatic muta- TP53 tions in BRCA 1 or BRCA 2 (21). However, in the Norquist FANC: Fanconi anemia complementation group; MMR: mismatch repair et al. study (21), other histologies also presented consider- genes. able rates of BRCA 1 or 2 mutations (approximately 9% for endometrioid ovarian cancer, 11% for clear cell ovarian cancer and 8% for low-grade serous ovarian cancer). Alsop et al. (22) Treatment of ovarian cancer with HRD exclusively evaluated the frequencies of germline BRCA 1 and HRD carcinomas exhibit an increased responsiveness to BRCA 2 mutations, finding mutations in 17% of patients cytotoxic chemotherapy, especially platinum agents, in diffe- with HGSOC, 8.4% of patients with the endometrioid rent treatment lines (19,23-25). Platinum agents act via directly histology and 6.3% of patients with the clear cell histology. damaging DNA, and when HRD is present, the reduction of Somatic BRCA 1 and BRCA 2 mutations occur less often, with DNA repair increases the accumulation of DNA damage, prevalences of 2-5% and 2-3%, respectively (14,19). leading to apoptosis. Pennington et al. showed that somatic The frequency of changes (mutation, deletion or amplifica- BRCA 1/2 mutations and mutations in other HR genes predict tion) in each non-BRCA HR gene is much lower and more platinum responsiveness and positively impact overall survi- heterogeneous. Table 2 lists the genes implicated in HR repair val, similar to germline BRCA 1/2 mutations (19). and the frequencies of germline mutations reported in dif- Regarding PARP inhibitors, their benefit in HRD was first ferent studies. Table 3 describes the frequencies of somatic shown in patients with BRCA 1/2 mutations. In a phase I gene changes. NGS was utilized in all the studies described in trial, the activity of olaparib was evaluated in heavily pre- the tables. Blood samples were utilized in trials that evaluated treated patients (mainly ovarian and breast cancer patients) germline mutations, and tumor samples were utilized in trials (26). Twelve of the 23 patients harboring BRCA mutations evaluating somatic gene mutations. presented a response or stable disease for at least 4 months, 3 HRD in ovarian cancer CLINICS 2018;73(suppl 1):e450s Bonadio RR et al. while no response was observed in patients without BRCA response to the last treatment (29). PFS was improved in the mutations. three nested cohorts: patients with BRCA mutations (median A benefit of olaparib in patients with BRCA mutations PFS, 16.6 months vs 5.4 months; hazard ratio, 0.23; 95% CI, was also suggested in the phase II study 19 trial (27). This 0.16-0.34; po0.0001), patients with HRD (including BRCA- trial evaluated olaparib maintenance in platinum-sensitive mut and BRCAwt/high-LOH carcinomas) (median PFS, 13.6 patients with or without BRCA mutations and showed months vs 5.4 months; hazard ratio, 0.32; 95% CI, 0.24-0.42; improved progression free survival (PFS) in comparison to po0.0001) and the intention-to-treat population (median PFS, that of patients receiving the placebo (8.4 months versus 10.8 months versus 5.4 months; hazard ratio, 0.36; 95% CI, 4.8 months; hazard ratio, 0.35; 95% CI, 0.25-0.49; po0.001). 0.30-0.45; po0.0001). In a non-nested subgroup analysis, However, the benefit was greater in patients with BRCA the absolute gain in median PFS was 4.3 months for BRCA mutations (11.2 vs 4.3 months; hazard ratio, 0.18; 95% CI, wild-type patients with LOH-high (9.7 months vs 4 months; 0.10-0.31; po0.0001) than in BRCA wild-type patients (7.4 vs hazard ratio, 0.44; po0.001) and 1.3 months for those with 5.5 months; hazard ratio, 0.54; 95% CI, 0.34-0.85, p=0.0075). LOH-low (6.7 months vs 5.4 months; hazard ratio, 0.58; Furthermore, in a post hoc analysis, when excluding patients p=0.0049). who crossed over to olaparib after progression, an improved In conclusion, the trials show that the benefits of PARP overall survival with olaparib was observed in the group with inhibitors extend beyond BRCA 1/2 mutations. Patients with BRCA mutations (hazard ratio, 0.52; 95% CI, 0.28-0.97) (28). HRDs of different etiologies might benefit from these drugs, Another single-arm phase II study evaluated olaparib in increasing the number of patients who might benefit from patients with germline BRCA mutations previously treated these treatments. Some studies also showed a statistically with at least three lines of chemotherapy (5). The results were significant benefit for the PFS of patients with HR profi- impressive in this heavily pretreated population, with a ciency, but the clinical relevance of the gain in this scenario response rate of 31.1% in ovarian cancer patients, a median was smaller. PFS of 7 months and a median overall survival of 16.6 months. These results lead to the Food and Drug Administration (FDA) approval of olaparib for this scenario. Perspectives Recently, results of the phase III SOLO 2 trial were pub- Studies are ongoing to investigate whether combinations lished, showing that patients with BRCA mutations that had of PARP inhibitors and other drugs might improve their previously received at least two lines of chemotherapy benef- efficacy in patients with or without HRD. ited from olaparib maintenance after response to platinum- As mentioned previously, when HRD is present, the use based chemotherapy for the treatment of relapsed ovarian of PARP inhibitors induces synthetic lethality. In patients cancer. The risk of progression was reduced by 70%, with an without HRD, using drugs in combination might exert a absolute gain in PFS of 13.6 months (median PFS of 19.1 months similar effect, defined as ‘contextual’ synthetic lethality (30). with olaparib versus 5.5 months with the placebo; hazard ratio, Hypoxic conditions, for example, appear to downregulate 0.3; 95% CI, 0.22-0.41; po0.0001). DNA repair and generate genomic instability (30,31). Thus, Another PARP inhibitor, niraparib, also demonstrated the combination of antiangiogenic agents and PARP inhibi- efficacy in patients with ovarian cancer with or without tors represents a potential mechanism underlying contextual BRCA mutations. The NOVA trial showed that as a main- synthetic lethality. In a phase II trial, olaparib was combined tenance therapeutic, niraparib improves the PFS of platinum- with the VEGFR inhibitor cediranib, and an improved in PFS sensitive patients (4). In that trial, the presence of BRCA was observed (17.7 months versus 9 months with olaparib mutations and HRD determined using the Myriad Genetics alone; hazard ratio, 0.42; 95% CI, 0.23-0.76; p=0.005) (32). HRD score were investigated. While a benefit was observed Upon subgroup analysis, patients with HR proficiency bene- in all subgroups, the PFS of patients with BRCA mutations fited the most from the synergism of the two drugs (PFS of (21.0 months vs 5.5 months; hazard ratio, 0.27; 95% CI, 0.17- 16.5 vs 5.7 months with olaparib alone; hazard ratio, 0.32; 0.41) and BRCA wild-type/HRD-high (20.9 months vs p=0.008). Patients with germline BRCA mutations had a good 11.0 months; hazard ratio, 0.27; 95% CI, 0.08-0.90) was increa- response to olaparib alone, as expected, and an improvement sed to a greater extent than that of BRCA wild-type/HRD-low trendinPFS wasobserved withthe combination(PFSof patients (6.9 months vs 3.8 months; hazard ratio, 0.58; 95% CI, 19.5 months vs 16.5 months with olaparib alone). 0.36-0.92). For patients with HRD who develop resistance to PARP The phase II Ariel 2 trial also confirmed the benefit of inhibitors, the association of VEGFR and PARP inhibitors PARP inhibitors to patients with HRD in general (9). In this represents a potential strategy to overcome resistance. Thus, trial, rucaparib was used in advanced ovarian cancer patients a study evaluating the combination of cediranib and olaparib previously treated with two or more lines of chemotherapy in advanced ovarian cancer after progression on a PARP (regardless of their platinum sensitivity). HRD was assessed inhibitor is currently ongoing (ClinicalTrials.gov, NCT02681237). by evaluating both BRCA germline mutations and LOH. Once PI3K inhibitors are also associated with decreased HR repair. again, the response rate (RR) and PFS were higher in BRCA Preclinical studies showed that PI3K inhibitors decrease the germline mutation carrier patients (RR, 69%; PFS, 12.8 months; expression of RAD51 and are synergistic with olaparib (33,34). hazard ratio, 0.27; 95% CI, 0.16-0.44; po0.0001) and BRCA In addition to PI3K and VEGFR inhibitors, other agents wild-type LOH-high patients (RR, 39%; PFS, 5.7 months; that decrease DNA repair with the potential to function syn- hazard ratio, 0.62; 95% CI, 0.42-0.9; p=0.011)thaninBRCA ergistically with PARP inhibitors include inhibitors of CHK1, wild-type/LOH-low patients (RR, 11%; PFS, 5.1 months). ATR, Wee, BET (35-39). Preclinical studies have shown pro- The phase III Ariel 3 trial showed that rucaparib also mising results when these agents are used in combination improved the PFS as a maintenance therapeutic in ovarian with PARP inhibitors. cancer patients in comparison with the placebo after treat- Furthermore, cytotoxic chemotherapy might potentiate the ment with at least two lines of platinum-based therapy with effect of PARP inhibitors via the association of DNA damage 4 CLINICS 2018;73(suppl 1):e450s HRD in ovarian cancer Bonadio RR et al. and inhibition of DNA repair. In a phase I trial, the com- the LOH, telomeric allelic imbalance, and large-scale transi- bination of olaparib and carboplatin yielded an overall RR of tions. Each of these options has advantages and disadvan- 44% in patients with germline BRCA mutations and ovarian tages, and they should be used in a complementary manner. cancer (40). Future studies on PARP inhibitors should continue to vali- Another important point to consider is that adaptive date the clinical utility of these strategies to assess HRD. resistance develops over time when a drug is used as mono- Finally, the combination of PARP inhibitors with other therapy, and combination therapy could help avoid or retard drugs is promising. Currently, contextual synthetic lethality the development of adaptive resistance. and strategies to overcome adaptive resistance have been Different mechanisms are implicated in the resistance to studied using a combination of PARP inhibitors and other PARP inhibitors. In BRCA-mutated tumors, the development drugs, such as cytotoxic chemotherapy, angiogenesis inhibi- of secondary reversion mutations that restore BRCA func- tors, MEK inhibitors and immunotherapy. These combina- tion and HR activity appears to be an important mechanism tions might improve the efficacy of PARP inhibitors even underlying resistance (41,42). in patients without HRD, extending the benefit of these Resistance might also occur upon the activation of signal- drugs even further. We eagerly await further results from ing cascades implicated in tumorigenesis, such as the PI3K/ these studies. AKT and RAS/MAPK pathways (34,43). As mentioned previously, PI3K inhibitors improve the ’ AUTHOR CONTRIBUTIONS activity of olaparib (33,34), and PARP and MEK inhibitors also function synergistically when used in combination both Bonadio RR, Fogace RN, Miranda VC and Dis MP contributed to the in vitro and in vivo (43). RAS mutant lines, for example, are conception and design of the study, data collection, data analysis, and resistant to PARP inhibitors but sensitive to the combination manuscript writing and revision. of PARP and MEK inhibitors (43). 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Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management

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Abstract

REVIEW ARTICLE Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management Renata Rodrigues da Cunha Colombo Bonadio, Rodrigo Nogueira Fogace, Vanessa Costa Miranda, Maria del Pilar Estevez Diz Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. Bonadio RR, Fogace RN, Miranda VC, Dis MP. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics. 2018;73(suppl 1):e450s *Corresponding author. E-mail: rrccbonadio@gmail.com Ovarian cancer patients with homologous recombination deficiencies exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors, have been observed. Germline mutations in the BRCA 1/2 genes are the most well-known mechanisms of homologous recombination deficiency. However, other mechanisms, such as germline and somatic mutations in other homologous recombination genes and epigenetic modifications, have also been implicated in homologous recombination deficiency. The epidemiology and implications of these other mech- anisms need to be better understood to improve the treatment strategies for these patients. Furthermore, an evaluation of various diagnostic tests to investigate homologous recombination deficiency is essential. Compre- hension of the role of homologous recombination deficiency in ovarian cancer also allows the development of therapeutic combinations that can improve the efficacy of treatment. In this review, we discuss the epidemio- logy and management of homologous recombination deficiency in ovarian cancer patients. KEYWORDS: Ovarian Cancer; Homologous Recombination Deficiency; PARP Inhibitors; BRCA Mutation. Homologous recombination deficiency and ’ INTRODUCTION PARP inhibitors In ovarian cancer, patients harboring BRCA 1/2 mutations DNA breaks are repaired via different mechanisms to exhibit different patterns of clinical behavior and respond protect the genome. For example, double-stranded breaks to treatment differently. The BRCA gene plays a role in are repaired by HR and non-homologous end joining repairing DNA repair via homologous recombination (HR), (NHEJ) (1). HR is more efficient at maintaining genomic and mutation of this gene leads to HR deficiency (HRD). stability because it uses a homologous template, whereas HRD can also occur due to other mechanisms, such as ger- NHEJ is error-prone. mline mutations, somatic mutations and epigenetic modifi- Unrepaired DNA damage can result in accumulated muta- cations of other genes involved in the HR pathway. Ovarian tions and unregulated cell division, and HRD is thus related cancers with these alterations behave similarly to those with to cancer susceptibility (2,3). Moreover, large amounts of BRCA mutations, and this behavior is termed the ‘‘BRCA- DNA damage can lead to cell apoptosis. However, when ness’’ phenotype. only HR is deficient, the activities of other DNA repair Using poly (ADP-ribose) polymerase (PARP) inhibitors in mechanisms can prohibit the accumulation of excessive DNA patients with HRD compromises two pathways of DNA damage and apoptosis (2). repair, resulting in synthetic lethality. Recent studies have Base excision repair (BER) serves as another DNA repair confirmed that the efficacy of PARP inhibitors is improved mechanism that acts on single-stranded breaks, and mem- not only in ovarian cancers displaying germline or somatic bers of the PARP protein family play essential roles in the BRCA mutations but also in cancers in which HRD is caused BER mechanism. PARPs bind to single-stranded break sites by other underlying etiologies. and initiate the repair process, and these proteins are targe- In this review, we discuss how to evaluate HRD as well as ted in oncology via the use of PARP inhibitors. the epidemiology and management of HRD in ovarian cancer. As mentioned previously, HRD by itself does not always induce cellular apoptosis. However, when PARP inhibitors are used in HRD cells, impairment of these Copyright & 2018 CLINICS – This is an Open Access article distributed under the two DNA repair mechanisms together results in synthetic terms of the Creative Commons License (http://creativecommons.org/licenses/by/ lethality. In other words, mutations occurring in one of 4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. two genes separately do not result in apoptosis, but the impairment of both genes simultaneously leads to cell No potential conflict of interest was reported. death (synthetic lethality). In this situation, the accumu- Received for publication on November 11, 2017. Accepted for lation of DNA damage might be sufficient to induce publication on February 5, 2018 cell death (apoptosis), and clinical trials showing the Commemorative Edition: 10 years of ICESP benefits of PARP inhibitors in HRD cancers support this DOI: 10.6061/clinics/2018/e450s concept (4,5). 1 HRD in ovarian cancer CLINICS 2018;73(suppl 1):e450s Bonadio RR et al. Mechanisms implicated in homologous the investigation of HRD regardless of the underlying genetic or epigenetic mechanism responsible. A high LOH (X14-16%), recombination deficiency The most described etiology of HRD is the mutation of for example, suggests the presence HRD. In the ARIEL2 trial, which evaluated rucaparib in platinum-sensitive recurrent genes involved in HR repair. Mutations can occur in ger- mline cells, which represent individual characteristics, or ovarian cancer, LOH-high was defined by NGS using a cutoff of 14%. The results showed that patients with BRCA 1/2 wild- somatic cells, which is a trait of tumor cells. Germline BRCA 1 and BRCA 2 mutations are the most type and LOH-high benefited from rucaparib (9). LOH can also be evaluated together with telomeric allelic imbalance and well-known HRD etiology. Germline mutations are impor- large-scale transitions to generate an HRD score (MyChoice tant not only for treatment decisions but also for the evalua- HRD test, Myriad Genetics Inc., Salt Lake City, Utah). tion of cancer susceptibility and prevention strategies for Patients determined to have HRD (defined as any tumor that the patients and their relatives. BRCA 1/2 are involved in hereditary breast and ovarian cancer syndrome, and numer- scored X42 on the MyChoice HRD test) benefited from maintenance niraparib in the NOVA trial (4). ous trials evaluating PARP inhibitors have been performed on patients presenting germline BRCA 1/2 mutations (5–8). Despite the ability of NGS to assess many genes during germline or somatic mutation screening, the implications of Patients without BRCA 1/2 mutations presented similar cli- nical behaviors and responses to PARP inhibitors (4,9), and some mutations remain unknown. Moreover, NGS cannot evaluate HRD due to other etiologies, such as epigenetic these patients define the ‘‘BRCAness’’ phenotype (10,11). The mechanisms underlying BRCAness are varied and include modifications. Thus, functional evaluations of HRD can help overcome these limitations. somatic BRCA 1/2 mutations and germline or somatic muta- tions in other genes related to HR repair. In conclusion, each of these tests have different properties and can be used in a complementary manner. Another possible etiology of HRD is the epigenetic modi- fication of HR genes, such as methylation of the BRCA 1 promoter. Gene expression signatures present in germline Epidemiology of HRD in ovarian cancer BRCA1 mutations were also observed in BRCA1-methylated Approximately 41-50% of ovarian carcinomas are esti- cancers (12). However, the implication of epigenetic mod- mated to exhibit HRD (17,18). However, the frequency ifications in HRD remain controversial. While Cunningham of HRD varies according to the method utilized for its et al. reported a survival advantage in patients with BRCA 1 evaluation (germline mutations, somatic mutations or HRD promoter hypermethylation compared with BRCA wild-type score) and histological subtype. Table 1 shows the frequen- patients (13), other researchers found no survival advantage cies of HRD in different studies according to the histolo- (14,15) or worse survival for patients with the methylated gical subtype. phenotype (16). Pennington et al. (19) found HR gene germline mutations in 24% of patients with epithelial ovarian cancer and soma- tic mutations in 9% of these patients. Elvin et al. (18) eval- How to evaluate homologous uated the presence of BRCA mutations or LOH in different recombination deficiency histological subtypes. The serous subtype was associated HRD can be tested using three main strategies: with a higher prevalence of HRD, with 43.8% of the patients presenting BRCA mutations (BRCAmut, 18.7%) or BRCA Germline mutation screening of genes related to HR wild-type/LOH-high (BRCAwt/LOH-high, 25.1%). Other repair; epithelial ovarian carcinomas also exhibited elevated propor- somatic mutation screening of genes related to HR repair; tions of HRD which occurred in 37.6% of endometrioid (12.6% and BRCAmut and 25% BRCAwt/LOH-H), 23.5% of carcino- evaluation of a genomic scar, which represents the geno- sarcoma (8.2% BRCAmut and 15.3% BRCAwt/LOHH) mic instability secondary to HRD. An HRD score can be and 12.6% of clear cell histologies (4.7% BRCAmut and 8.9% calculated based on the loss of heterozygosity (LOH), BRCAwt/LOHH). The mucinous subtype, however, exhib- telomeric allelic imbalance, and large-scale transitions. ited no BRCA mutations, and only 8.1% of the patients Germline mutation screening can be performed using next presented with BRCAwt/LOH-H. Upon specifically eval- generation sequencing (NGS) analysis of DNA from blood, uating the presence of somatic mutations, Aghajanian et al. which has the advantage of being easy to obtain. Moreover, the identification of a germline mutation allows the possibility of genetic counseling. Table 1 - Frequency of homologous recombination deficiency Somatic mutation screening, on the other hand, is perfo- according to the histological subtype. rmed on DNA from tumor samples. This analysis can eval- Method Elvin et al. Norquist et al. Pennington et al. uate any mutation (germline and/or somatic) in HR genes (N=4114) (18) (N=1915) (21) (N=367) (19) and is thus a broader evaluation, which is helpful for defining treatment strategies, such as the use of PARP inhibitors. How- BRCA + HR gene HR gene LOH-H mutations mutations ever, when a mutation is identified with this strategy, germline analysis of normal cells is still necessary to determine whether Serous 43.8% 27% 31% the mutation is germline or somatic (present in only the tumor) Endometrioid 37.6% 23.8% 27% (17). Limitations of somatic screening include the variability of Carcinosarcoma 23.5% - 33% Clear Cell 13.6% 21.4% 26% tumor samples available and intratumoral heterogeneity, which Epithelial NOS 47.7% - - potentially compromises the representativeness of the sample. Mucinous 8.1% 28.6% 0% Finally, HRD can be assessed in a more functional way. When HRD is present, genomic alterations accumulate, and LOH-H: Loss of heterozygosity; HR: homologous recombination; NOS: not allelic imbalances can result in a ‘‘genomic scar ’’, allowing otherwise specified. 2 CLINICS 2018;73(suppl 1):e450s HRD in ovarian cancer Bonadio RR et al. Table 2 - Frequency of germline mutations in ovarian carcinoma. (N) TCGA (14) Pennington et al. (19) Cunningham et al. (13) Harter et al. (49) Norquist et al. (50) Yates et al. (51) (316) (390) (899) (522) (1915) (299) BRCA1 8.5% 13.4% 3.5% 15.3% 9.5% 9% BRCA2 6.3% 4.6% 3% 5.6% 5.1% 5.4% EMSY PTEN 0% RAD51C 0.7% 3% 2.5% 0.6% 1% RAD51D 1% 0.6% 0.6% RAD50 0.2% 0.2% ATM/ATR 0.4% 0.6% 0.5% FANC 0.7% BARD1 0.5% 0% 0.2% 0.5% BRIP1 1% 0.4% 1.4% 2.5% CHEK1 0.25% 0.2% CHEK2 0.7% 0.6% 0.6% FAM175A 0.5% 0.2% 0.2% NBN 0.25% 0.4% 0.5% 0.5% PALB2 0.5% 1.1% 0.6% 0.5% MRE11A 0.4% 0.1% MMR 0.6% 0.5% TP53 0% 0.3% FANC: Fanconi anemia complementation group; MMR: mismatch repair genes. found similar prevalences of somatic mutations in high-grade Table 3 - Frequency of somatic gene changes (mutation, deletion or amplification) in ovarian carcinoma. serous ovarian carcinoma (HGSOC) and other histologies (16% vs 18%, respectively, p=0.07). Once again, no somatic (N) TCGA Pennington Cunningham Hahnen Aghajanian mutations in HR genes were observed in mucinous ovarian (14) et al. (19) et al. (13) et al. (52) et al. (20) cancer. (316) (390) (279) (431) (260) In relation to high-grade versus low-grade serous carci- BRCA1 3.2% 4.9% 2% 3% 4.4% noma, Norquist et al. (21) found a significant difference in the BRCA2 2.9% 1.5% 1.4% 1.4% 2.2% EMSY 8% germline and somatic mutation rates of HR genes, which PTEN 7% 4.4% were 10.9% for low-grade versus 27% for HGSOC (odds ratio RAD51C 0.3% 0.3% (OR), 0.33; 95% confidence interval (CI), 0.1-0.8; p=0.02). RAD51D 0.2% Regarding the specific genes compromised, in an evalua- RAD50 0.6% ATM/ATR 2% 0.8% 0.2% 2.2% tion of HR gene mutations in ovarian cancer patients who FANC 5% 0.2% 0.3% participated in the GOG 218 and GOG 262 trials, Norquist BARD1 0.6% et al. (21) showed germline or somatic mutations in BRCA1 BRIP1 0.5% 0.6% CHEK1 0% 0.3% gene in 12.3% of the cases, in BRCA2 gene in 6.5% and in CHEK2 0.3% 0.8% 0.3% other non-BRCA HR genes in 6.8%. Elvin et al. (18) reported FAM175A similar results, with mutations in BRCA 1 gene in 11.6% of the NBN 0.3% PALB2 0.2% 0.3% cases and BRCA 2 gene in 5.7%. MRE11A 0.3% BRCA mutations occur more frequently in HGSOC, with MMR 0.4% 20% of these patients presenting germline or somatic muta- TP53 tions in BRCA 1 or BRCA 2 (21). However, in the Norquist FANC: Fanconi anemia complementation group; MMR: mismatch repair et al. study (21), other histologies also presented consider- genes. able rates of BRCA 1 or 2 mutations (approximately 9% for endometrioid ovarian cancer, 11% for clear cell ovarian cancer and 8% for low-grade serous ovarian cancer). Alsop et al. (22) Treatment of ovarian cancer with HRD exclusively evaluated the frequencies of germline BRCA 1 and HRD carcinomas exhibit an increased responsiveness to BRCA 2 mutations, finding mutations in 17% of patients cytotoxic chemotherapy, especially platinum agents, in diffe- with HGSOC, 8.4% of patients with the endometrioid rent treatment lines (19,23-25). Platinum agents act via directly histology and 6.3% of patients with the clear cell histology. damaging DNA, and when HRD is present, the reduction of Somatic BRCA 1 and BRCA 2 mutations occur less often, with DNA repair increases the accumulation of DNA damage, prevalences of 2-5% and 2-3%, respectively (14,19). leading to apoptosis. Pennington et al. showed that somatic The frequency of changes (mutation, deletion or amplifica- BRCA 1/2 mutations and mutations in other HR genes predict tion) in each non-BRCA HR gene is much lower and more platinum responsiveness and positively impact overall survi- heterogeneous. Table 2 lists the genes implicated in HR repair val, similar to germline BRCA 1/2 mutations (19). and the frequencies of germline mutations reported in dif- Regarding PARP inhibitors, their benefit in HRD was first ferent studies. Table 3 describes the frequencies of somatic shown in patients with BRCA 1/2 mutations. In a phase I gene changes. NGS was utilized in all the studies described in trial, the activity of olaparib was evaluated in heavily pre- the tables. Blood samples were utilized in trials that evaluated treated patients (mainly ovarian and breast cancer patients) germline mutations, and tumor samples were utilized in trials (26). Twelve of the 23 patients harboring BRCA mutations evaluating somatic gene mutations. presented a response or stable disease for at least 4 months, 3 HRD in ovarian cancer CLINICS 2018;73(suppl 1):e450s Bonadio RR et al. while no response was observed in patients without BRCA response to the last treatment (29). PFS was improved in the mutations. three nested cohorts: patients with BRCA mutations (median A benefit of olaparib in patients with BRCA mutations PFS, 16.6 months vs 5.4 months; hazard ratio, 0.23; 95% CI, was also suggested in the phase II study 19 trial (27). This 0.16-0.34; po0.0001), patients with HRD (including BRCA- trial evaluated olaparib maintenance in platinum-sensitive mut and BRCAwt/high-LOH carcinomas) (median PFS, 13.6 patients with or without BRCA mutations and showed months vs 5.4 months; hazard ratio, 0.32; 95% CI, 0.24-0.42; improved progression free survival (PFS) in comparison to po0.0001) and the intention-to-treat population (median PFS, that of patients receiving the placebo (8.4 months versus 10.8 months versus 5.4 months; hazard ratio, 0.36; 95% CI, 4.8 months; hazard ratio, 0.35; 95% CI, 0.25-0.49; po0.001). 0.30-0.45; po0.0001). In a non-nested subgroup analysis, However, the benefit was greater in patients with BRCA the absolute gain in median PFS was 4.3 months for BRCA mutations (11.2 vs 4.3 months; hazard ratio, 0.18; 95% CI, wild-type patients with LOH-high (9.7 months vs 4 months; 0.10-0.31; po0.0001) than in BRCA wild-type patients (7.4 vs hazard ratio, 0.44; po0.001) and 1.3 months for those with 5.5 months; hazard ratio, 0.54; 95% CI, 0.34-0.85, p=0.0075). LOH-low (6.7 months vs 5.4 months; hazard ratio, 0.58; Furthermore, in a post hoc analysis, when excluding patients p=0.0049). who crossed over to olaparib after progression, an improved In conclusion, the trials show that the benefits of PARP overall survival with olaparib was observed in the group with inhibitors extend beyond BRCA 1/2 mutations. Patients with BRCA mutations (hazard ratio, 0.52; 95% CI, 0.28-0.97) (28). HRDs of different etiologies might benefit from these drugs, Another single-arm phase II study evaluated olaparib in increasing the number of patients who might benefit from patients with germline BRCA mutations previously treated these treatments. Some studies also showed a statistically with at least three lines of chemotherapy (5). The results were significant benefit for the PFS of patients with HR profi- impressive in this heavily pretreated population, with a ciency, but the clinical relevance of the gain in this scenario response rate of 31.1% in ovarian cancer patients, a median was smaller. PFS of 7 months and a median overall survival of 16.6 months. These results lead to the Food and Drug Administration (FDA) approval of olaparib for this scenario. Perspectives Recently, results of the phase III SOLO 2 trial were pub- Studies are ongoing to investigate whether combinations lished, showing that patients with BRCA mutations that had of PARP inhibitors and other drugs might improve their previously received at least two lines of chemotherapy benef- efficacy in patients with or without HRD. ited from olaparib maintenance after response to platinum- As mentioned previously, when HRD is present, the use based chemotherapy for the treatment of relapsed ovarian of PARP inhibitors induces synthetic lethality. In patients cancer. The risk of progression was reduced by 70%, with an without HRD, using drugs in combination might exert a absolute gain in PFS of 13.6 months (median PFS of 19.1 months similar effect, defined as ‘contextual’ synthetic lethality (30). with olaparib versus 5.5 months with the placebo; hazard ratio, Hypoxic conditions, for example, appear to downregulate 0.3; 95% CI, 0.22-0.41; po0.0001). DNA repair and generate genomic instability (30,31). Thus, Another PARP inhibitor, niraparib, also demonstrated the combination of antiangiogenic agents and PARP inhibi- efficacy in patients with ovarian cancer with or without tors represents a potential mechanism underlying contextual BRCA mutations. The NOVA trial showed that as a main- synthetic lethality. In a phase II trial, olaparib was combined tenance therapeutic, niraparib improves the PFS of platinum- with the VEGFR inhibitor cediranib, and an improved in PFS sensitive patients (4). In that trial, the presence of BRCA was observed (17.7 months versus 9 months with olaparib mutations and HRD determined using the Myriad Genetics alone; hazard ratio, 0.42; 95% CI, 0.23-0.76; p=0.005) (32). HRD score were investigated. While a benefit was observed Upon subgroup analysis, patients with HR proficiency bene- in all subgroups, the PFS of patients with BRCA mutations fited the most from the synergism of the two drugs (PFS of (21.0 months vs 5.5 months; hazard ratio, 0.27; 95% CI, 0.17- 16.5 vs 5.7 months with olaparib alone; hazard ratio, 0.32; 0.41) and BRCA wild-type/HRD-high (20.9 months vs p=0.008). Patients with germline BRCA mutations had a good 11.0 months; hazard ratio, 0.27; 95% CI, 0.08-0.90) was increa- response to olaparib alone, as expected, and an improvement sed to a greater extent than that of BRCA wild-type/HRD-low trendinPFS wasobserved withthe combination(PFSof patients (6.9 months vs 3.8 months; hazard ratio, 0.58; 95% CI, 19.5 months vs 16.5 months with olaparib alone). 0.36-0.92). For patients with HRD who develop resistance to PARP The phase II Ariel 2 trial also confirmed the benefit of inhibitors, the association of VEGFR and PARP inhibitors PARP inhibitors to patients with HRD in general (9). In this represents a potential strategy to overcome resistance. Thus, trial, rucaparib was used in advanced ovarian cancer patients a study evaluating the combination of cediranib and olaparib previously treated with two or more lines of chemotherapy in advanced ovarian cancer after progression on a PARP (regardless of their platinum sensitivity). HRD was assessed inhibitor is currently ongoing (ClinicalTrials.gov, NCT02681237). by evaluating both BRCA germline mutations and LOH. Once PI3K inhibitors are also associated with decreased HR repair. again, the response rate (RR) and PFS were higher in BRCA Preclinical studies showed that PI3K inhibitors decrease the germline mutation carrier patients (RR, 69%; PFS, 12.8 months; expression of RAD51 and are synergistic with olaparib (33,34). hazard ratio, 0.27; 95% CI, 0.16-0.44; po0.0001) and BRCA In addition to PI3K and VEGFR inhibitors, other agents wild-type LOH-high patients (RR, 39%; PFS, 5.7 months; that decrease DNA repair with the potential to function syn- hazard ratio, 0.62; 95% CI, 0.42-0.9; p=0.011)thaninBRCA ergistically with PARP inhibitors include inhibitors of CHK1, wild-type/LOH-low patients (RR, 11%; PFS, 5.1 months). ATR, Wee, BET (35-39). Preclinical studies have shown pro- The phase III Ariel 3 trial showed that rucaparib also mising results when these agents are used in combination improved the PFS as a maintenance therapeutic in ovarian with PARP inhibitors. cancer patients in comparison with the placebo after treat- Furthermore, cytotoxic chemotherapy might potentiate the ment with at least two lines of platinum-based therapy with effect of PARP inhibitors via the association of DNA damage 4 CLINICS 2018;73(suppl 1):e450s HRD in ovarian cancer Bonadio RR et al. and inhibition of DNA repair. In a phase I trial, the com- the LOH, telomeric allelic imbalance, and large-scale transi- bination of olaparib and carboplatin yielded an overall RR of tions. Each of these options has advantages and disadvan- 44% in patients with germline BRCA mutations and ovarian tages, and they should be used in a complementary manner. cancer (40). Future studies on PARP inhibitors should continue to vali- Another important point to consider is that adaptive date the clinical utility of these strategies to assess HRD. resistance develops over time when a drug is used as mono- Finally, the combination of PARP inhibitors with other therapy, and combination therapy could help avoid or retard drugs is promising. Currently, contextual synthetic lethality the development of adaptive resistance. and strategies to overcome adaptive resistance have been Different mechanisms are implicated in the resistance to studied using a combination of PARP inhibitors and other PARP inhibitors. In BRCA-mutated tumors, the development drugs, such as cytotoxic chemotherapy, angiogenesis inhibi- of secondary reversion mutations that restore BRCA func- tors, MEK inhibitors and immunotherapy. These combina- tion and HR activity appears to be an important mechanism tions might improve the efficacy of PARP inhibitors even underlying resistance (41,42). in patients without HRD, extending the benefit of these Resistance might also occur upon the activation of signal- drugs even further. We eagerly await further results from ing cascades implicated in tumorigenesis, such as the PI3K/ these studies. AKT and RAS/MAPK pathways (34,43). As mentioned previously, PI3K inhibitors improve the ’ AUTHOR CONTRIBUTIONS activity of olaparib (33,34), and PARP and MEK inhibitors also function synergistically when used in combination both Bonadio RR, Fogace RN, Miranda VC and Dis MP contributed to the in vitro and in vivo (43). RAS mutant lines, for example, are conception and design of the study, data collection, data analysis, and resistant to PARP inhibitors but sensitive to the combination manuscript writing and revision. of PARP and MEK inhibitors (43). 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Published: Aug 3, 2018

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