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DNA Damage Repair and the Emerging Role of Poly(ADP-ribose) Polymerase Inhibition in Cancer Therapeutics

      Abstract

      Purpose

      As a result of improved understanding of DNA repair mechanisms, poly(ADP-ribose) polymerase inhibitors (PARPi) are increasingly recognized to play an important therapeutic role in the treatment of cancer. The aim of this article is to provide a review of PARPi function in DNA damage repair and synthetic lethality and to demonstrate how these mechanisms can be exploited to provide new PARPi-based therapies to patients with solid tumors.

      Methods

      Literature from a range of sources, including PubMed and MEDLINE, were searched to identify recent reports regarding DNA damage repair and PARPi.

      Findings

      DNA damage repair is central to cellular viability. The family of poly(ADP-ribose) polymerase proteins play multiple intracellular roles in DNA repair, but function primarily in the resolution of repair of single-strand DNA breaks. Insights through the discovery of germline BRCA1/2 mutations led to the understanding of synthetic lethality and the potential therapeutic role of PARPi in the treatment of cancer. Further understanding of DNA damage repair and the concept of BRCA-like tumors have catalyzed PARPi clinical investigation in multiple oncologic settings.

      Implications

      PARPi hold great promise in the treatment of solid tumors, both as monotherapy and in combination with other cancer therapeutics. Multiple PARPi clinical trials are currently underway. Further understanding of aberrant DNA repair mechanisms in the germline and in the tumor genome will allow clinicians and researchers to apply PARPi most strategically in the era of personalized medicine.

      Key words

      Introduction

      Maintenance of genetic integrity is central to cellular viability. Disrupting genomic stability through the introduction of DNA damage compromises genetic accuracy with resultant mutations leading to cell death or pathology. Cellular mechanisms exist to protect DNA integrity, specifically through a DNA damage response (DDR) system that provides surveillance for and repair of DNA damage to decrease mutation burden.
      The hallmark of cancer cells is genomic instability introduced by various insults that lead to DNA damage. Investigating the predisposition of patients with heritable breast cancer led to the identification of BRCA1/2, genes encoding tumor suppressor genes involved in DDR with the goal to maintain genomic instability. Since that landmark discovery, increased understanding of BRCA-mediated carcinogenesis and DDR mechanisms has led in turn to a growing arsenal of anticancer therapies. Cancer therapeutics used to induce DNA damage, such as radiation therapy and chemotherapy, now includes targeted therapies to DDR proteins, in the form of poly(ADP-ribose) polymerase inhibitors (PARPi). Fully understanding the caretaker role of poly(ADP-ribose) polymerase (PARP) in development of both inherited and sporadic cancer development will allow clinicians to fully exploit this class of anticancer agent either as monotherapy or synergistically with additional targeted agents or traditional chemotherapeutics.
      Our aim is to provide a review of PARP function in DNA damage repair and synthetic lethality, and demonstrate how these mechanisms can be exploited to provide new PARPi-based therapies to patients with solid tumors.

      Methods

      Literature from a range of sources, including PubMed and MEDLINE, were searched to identify recent reports regarding DNA damage repair and PARPi.

      Results

      DNA Damage Repair

      The DNA damage response (DDR) system evolved to detect and repair the tens of thousands of potentially mutagenic endogenously and exogenously acquired DNA lesions that typically accrue each day.
      • Lindahl T.
      • Barnes D.E.
      Repair of endogenous DNA damage.
      • Hoeijmakers J.H.
      Genome maintenance mechanisms for preventing cancer.
      This system encompasses multiple redundant DNA repair pathways that repair lesions with the aim to mitigate DNA damage and preserve genomic stability. These include repair of more commonly encountered single-stranded breaks (SSBs), small DNA lesions or modifications affecting single base pairs, and more lethal double-stranded breaks (DSBs).
      SSBs most commonly occur as direct consequence of daily cellular operations, such as oxidation by reactive oxygen species. Repair of lesions induced by ultraviolet radiation and alkylating agents generate SSBs with repair of isolated nucleotide defects, such as with endonuclease removal of DNA lesions detected by mismatched repair DNA surveillance systems or by removal of photodimer lesions or chemotherapy-induced crosslinks. Ultimately, these lesions may also prevent actively replicating polymerases from traversing the lesion. These SSBs are detected and repaired by pathways that include base-excision repair, which is the major pathway of SSB repair (BER). The SSB pathway is composed of several proteins that systematically repair DNA by removal of lesions, regeneration of sequence by polymerases, and sealing the break with ligases with several regulator proteins. Specifically, this includes removal of lesions with damage-specific DNA glycosylases (for example UNG, NEIL, and MYH) and endonucleases (APE1 and FEN1), which creates an SSB. This break is then stabilized by PARP1, which binds the SSB, and then recruits the DNA-repair scaffolding protein XRCC1. XRCC1 interacts with DNA polymerase β and DNA ligase to replicate the DNA and repair the SSB.

      Curtin NJ, DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 12. 801-17

      • Carter R.J.
      • et al.
      Base Excision Repair, a Pathway Regulated by Posttranslational Modifications.
      Additional mechanisms to repair specific DNA lesions include nucleotide excision repair, mismatch repair, and direct repair mechanisms that correct erroneous methylation or alkylation by use of enzymes (eg, O6-methylguanine DNA methyltransferase).
      Whereas the BER pathway repairs the most common DNA lesions, DSBs are the most deleterious and lethal lesions. DSBs can result from stalled and subsequent collapsed replication forks, such as inter- and intrastrand crosslinking, ionizing radiation, or chemotherapy (topoisomerase inhibitors and platinum agents). Additionally, DSBs may accumulate with persistence of unrepaired SSBs or defective repair pathways. Four major pathways repair DSBs. Each pathway is interconnected with signaling molecules capable of activating downstream cellular events affecting cell fate, such as cell cycle arrest, cell death, or tumorigenesis. These pathways include classical nonhomologous end joining (c-NHEJ), alternate- EJ (alt-EJ), single-strand annealing (SSA), and homologous recombination (HR).
      • Ceccaldi R.
      • Rondinelli B.
      • D’Andrea A.D.
      Repair Pathway Choices and Consequences at the Double-Strand Break.
      • O’Connor M.J.
      Targeting the DNA Damage Response in Cancer.
      DSBs repaired by the first pathway, c-NHEJ, rely upon rapid blunt-ended enzymatic ligation, whereas the alternate pathways generate overhangs for repair involving polymerases. The benefit of c-NHEJ is its rapid kinetics that may be useful in suppressing chromosomal translocations. However, the repair process does not involve sequence homology with replication and is highly error-prone. Alternatively, the end clipping that generates staggered overhangs can be repaired by the alt-EJ, SSA, or HR pathway. However, despite some homology-dependent repair, both alt-EJ and SSA result in loss of genetic information, and are also notoriously error-prone. For example, SSA repair results in deletion of DNA between areas of repeats, or microhomologous regions, whereas alt-EJ, a pathway using PARP1 and XRCC/DNA ligase III, has demonstrated its tendency to join DSBs on separate chromosomes resulting in translocations. The advantage of the fourth major DSB repair pathway, HR, is its dependence on a sister chromatid template for high-fidelity repair. It is considered error-free repair. The cell cycle phase dictates the predominant DSB repair pathway with end resection and HR predominating in the S phase and G2 phase when sister chromatid templates are available. Cyclin-dependent kinase-mediated phosphorylation of multiple proteins mediates these pathways and includes ataxia telangiectasia mutated (ATM) kinase-dependent phosphorylation, which promotes end-resection and HR.
      • Ceccaldi R.
      • Rondinelli B.
      • D’Andrea A.D.
      Repair Pathway Choices and Consequences at the Double-Strand Break.
      • O’Connor M.J.
      Targeting the DNA Damage Response in Cancer.
      The HR pathway is composed of MRN DSB surveillance protein complexes that bind each DNA strand at site of lesion. The MRN complex is composed of the MRE11 endonuclease, the rad50 tethering protein that links the 2 MRN complexes, and the NBS1 protein that activates down-stream regulator ATM. BRCA1 and its binding partner, CtIP, interact with MRN to resect DNA ends, and recruit RAD51 recombinase to search for homologous regions for strand invasion and template-generation. Interaction between HR DBS repair pathway and BER SSB pathways are suggested because PARP1 has been shown to complex and modify MRN. This suggests a PARP1 role in regulating HR.
      • Croteau D.
      • et al.
      Overview of DNA Repair Pathways. DNA Repair and Cancer.
      The DDR pathway involves not only damage-sensing proteins, MRN in the case of DSB and PARP1 for SSBs, but also encompasses the multiple downstream effectors regulating cycle events and directing cell fate.
      • Marechal A.
      • et al.
      DNA damage sensing by the ATM and ATR kinases.

      BRCA1/2

      In contrast to sporadic cancers, many heritable cancers develop genomic instabilities that have been linked to defects in DNA repair proteins.
      • Negrini S.
      • Gorgoulis V.G.
      • Halazonetis T.D.
      Genomic instability--an evolving hallmark of cancer.
      Well-known examples of this phenomenon include BRCA1 and BRCA2. The epidemiologic observation that patients with a family history of breast cancer were at increased risk of developing breast cancer led to the localization of highly penetrant genetic loci on chromosomes 17q and 13q, which conferred increased risk to development of breast and ovarian cancer and prostate cancers.
      • Hall J.M.
      • et al.
      Linkage of early-onset familial breast cancer to chromosome 17q21.
      • Easton D.F.
      • et al.
      Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium.
      • Wooster R.
      • et al.
      Identification of the breast cancer susceptibility gene BRCA2.
      BRCA1/2 were ultimately identified as the tumor-suppressor genes whose loss of function predisposed cells to the development of early breast and ovarian cancer.
      • Futreal P.A.
      • et al.
      BRCA1 mutations in primary breast and ovarian carcinomas.
      • Miki Y.
      • et al.
      A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
      The BRCA1 and BRCA2 mutations predisposed cells to faulty repair of DSBs, thereby setting the stage for future tumorigenesis. It is now known that BRCA1/2 are involved in HR repair of double-stranded DNA breaks as part of the DDR.

      PARP1/2

      PARP1 and PARP2 belong to a superfamily of proteins primarily involved in cellular stress-response pathways. PARP1/2, identified by their localization to DNA lesions, are DDR proteins involved in the resolution of repair of SSBs and comprise the majority of cellular PARP activity.
      • Szanto M.
      • et al.
      Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein.
      • Ame J.C.
      • Spenlehauer C.
      • de Murcia G.
      The PARP superfamily.
      PARP1/2 protein structure includes DNA-binding domains along with an enzymatic domain that catalyzes the addition of a posttranslational biopolymer in the form of mono, oligo, or poly (ADP) ribosyl units to acceptor proteins, a process known as PARylation.
      • Sousa F.G.
      • et al.
      PARPs and the DNA damage response.
      In the case of PARP1, the enzymatic auto-PARylation with a ribosyl-based tag leads to recruitment of additional DDR proteins to the site of DNA lesion. PARP has been shown to be a conductor of signaling for initiation of repair of SSB as well as DSB. These modifications are implicated in a variety of additional functions, including recruitment and docking of the BER repair complex that mediates SSB repair. However, the role of PARP1 is not limited to SSB repair, but also is associated with transcriptional regulation through epigenetic changes, chromatin remodeling, and interaction with transcriptional proteins, and also promotes HR repair by stabilizing stalled replication forks.
      • Beck C.
      • et al.
      Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3.
      • Bai P.
      Biology of Poly(ADP-Ribose) Polymerases: The Factotums of Cell Maintenance.
      • Xie S.
      • et al.
      Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair.
      PARPs have also been linked to checkpoint signaling through discovery of their association with key cell cycle regulators, including ATM and ataxia telangiectasia and Rad3-related protein (ATR), which are key DNA damage sensors.
      • Haince J.F.
      • et al.
      Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents.
      Although a direct link between PARP and checkpoint control has not been shown, there is an association between PARP1 and ATM and ATR binding domains.
      Strong implications that PARP1 may negatively regulate ATR-mediated S-phase checkpoint is implicated by the direct interaction between PARP1 and the ATR domain. In addition, p53 interactions with PARP have been identified.
      • Sousa F.G.
      • et al.
      PARPs and the DNA damage response.

      Synthetic Lethality and PARPi

      Two genes interact in a synthetically lethal manner when there is synergy between mutations, inducing cell death when they coexist, yet when each mutation is present individually there is cell survival. Although the concept of synthetic lethality originated and matured in the classical genetics of Drosophila and Caenorhabditis elegans, it is its extension to cancer genetics with induction of a mutation phenotype chemically that led to the discovery of PARPi.
      • Sharom J.R.
      • Bellows D.S.
      • Tyers M.
      From large networks to small molecules.
      • Kaelin Jr, W.G.
      The concept of synthetic lethality in the context of anticancer therapy.
      Treatment of BRCA mutant tumors with PARPi exemplifies the first successful application of synthetic lethal concept to cancer therapy.
      • Audeh M.W.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
      • Fong P.C.
      • et al.
      Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
      Preclinical studies conducted by Bryant et al
      • Bryant H.E.
      • et al.
      Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
      and Farmer et al
      • Farmer H.
      • et al.
      Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
      demonstrated the effectiveness of combining double-stranded DNA repair mutations found in BRCA1- and BRCA2-mutated tumors with PARPi-induced defects in single-stranded DNA repair. Lethal genomic instability with dual inhibition of SSB repair via the BER pathway with PARP inhibition with underlying HR defects induced cell death.
      The underlying mechanisms of defective DNA repair by PARPi has been defined by its inhibition of critical DNA repair functions that are mediated by PARP, specifically, the inhibition of DNA repair and transcriptional modulation.
      • Helleday T.
      The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings.
      • Feng F.Y.
      • et al.
      Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function.
      PARPi cytotoxicity occurs by 2 mechanisms. The first is PARP inhibition of the enzymatic domain responsible for PARylation. In absence of drug effect, autoPARylation allows for both stabilization of the repair complex and PARP1 dissociation from the DNA lesion after recruitment of BER repair complex machinery.
      • Satoh M.S.
      • Lindahl T.
      Role of poly(ADP-ribose) formation in DNA repair.
      This dissociation is required for passage of the BER repair complex and successful repair of ssDNA (single strand DNA). Unmodified protein remained tightly DNA-bound. Another mechanism, known as PARP trapping, appears to be unrelated to its catalytic domain.
      • Murai J.
      • et al.
      Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors.
      • Murai J.
      • et al.
      Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.
      Binding of PARPi at the DNA lesion traps PARP and blocks passage of repair complexes past the replication fork. PARP1- and PARP2-DNA trapping has been proposed as an independent mechanism of cell death that is the rationale for synergy with traditional chemotherapy agents, including topo I and II inhibitors, and DNA alkylating and cross-linking agents like platinums.
      • Curtin N.J.
      • Szabo C.
      Therapeutic applications of PARP inhibitors: anticancer therapy and beyond.

      Detection of Homologous Recombination Deficiency and BRCAness

      The first successful clinical translation of synthetic lethality with PARP inhibition occurred in BRCA-mutated breast and ovarian cancer, with clinical response seen in patients with germline BRCA mutations and metastatic disease.
      • Xie S.
      • et al.
      Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair.
      Since then, PARP inhibitors have gone on to show clinical effectiveness in a variety of BRCA-mutated cancers. However, several interesting observations have stemmed from these trials. First, not all patients with BRCA mutations appeared to respond equally to PARPi. Second, some patients without germline BRCA mutations had measurable clinical benefit. These observations have led researchers to explore the role of PARPi in populations beyond germline BRCA patients, particularly given that germline mutations in BRCA1/2 account for only 5% to 10% of breast and approximately 15% of ovarian cancers.
      • Campeau P.M.
      • Foulkes W.D.
      • Tischkowitz M.D.
      Hereditary breast cancer: new genetic developments, new therapeutic avenues.
      • Pal T.
      • et al.
      BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.
      Efforts to identify BRCA-like features of tumors has led to the search for BRCAness, a homologous recombination-deficient (HRD) BRCA phenotype in the absence of a germline BRCA mutation. Detecting homologous recombination deficiency has included various approaches, including molecular profiling approaches that include sequencing and expression profiling of BRCA-deficient tumors to assess for alternate BRCA silencing and HRD gene profiles, clinical parameters suggesting dysfunction in the HR pathway using surrogates such platinum-free intervals to quantitate platinum-therapy hypersensitivity, and genomic screens to detect structural defects implicating faulty repair of DSBs. Structural defects in the genome of a tumor can be assessed to obtain history regarding mutational load and repair mechanisms utilized to mitigate potential mutations. These may include large deletions, translocations, telomeric allelic imbalances, loss of heterozygosity (LOH), or large scale transitions that result in genomic scarring.
      • Watkins J.A.
      • et al.
      Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.
      Efforts to identify a BRCA-like signature include identifying additional HR mutations in PARPi-sensitive tumors, such as ovarian and breast cancer.
      The Cancer Genome Atlas Network
      In a whole exome study of 489 Stage IV ovarian tumors, 33% were found to have deficient BRCA expression, either through somatic and germline BRCA1/2 mutations (20%) or by BRCA1 epigenetic silencing (11%). Clinical correlation suggested BRCA1/2 status conferred sensitivity to platinum chemotherapy. Increased mutation frequency in other HR genes were also identified in the cancer genome atlas (TCGA) sequencing effort that included EMSY, PTEN, RAD51C hypermethylation, ATM or ATR mutation, and Fanconi anemia genes. Taken together, HR defects were identified in approximately half of the tumors. TGCA analysis of 507 women with breast cancer not only identified germline mutations in HR genes, including BRCA1/2, ATM, PTEN, and RAD51C amongst others, but also confirmed a high-rate of HR defects in triple-negative breast cancers (TNBC).
      The Cancer Genome Atlas Network
      Comprehensive molecular portraits of human breast tumours.
      Tumor responsiveness to platinum chemotherapy is used as a surrogate clinical marker for HRD and efforts to identify genomic signatures of platinum-sensitive tumors is another approach to predicting which patients might benefit from PARPi. For example, Konstantinopoulos et al
      • Konstantinopoulos P.A.
      • et al.
      Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.
      used publicly available genomic sequencing of ovarian cancer tumors with either germline or somatic BRCA1/2 mutations to develop a BRCAness phenotype that correlated with platinum- sensitivity and predicted in vitro PARPi sensitivity and predilection for rad51 foci defects, a surrogate of HRD. Furthermore, BRCA1/2-associated breast and ovarian tumors share pathologic and molecular features with TNBC and high-grade serous ovarian cancers, respectively.
      • Futreal P.A.
      • et al.
      BRCA1 mutations in primary breast and ovarian carcinomas.
      • Turner N.
      • Tutt A.
      • Ashworth A.
      Hallmarks of ‘BRCAness’ in sporadic cancers.
      • Lancaster J.M.
      • et al.
      BRCA2 mutations in primary breast and ovarian cancers.
      Additional platinum-responsive and BRCA-associated tumor types have been genomically mined to identify associated mutations that might predict PARPi responsiveness.
      Indirect genomic evidence of defective DNA repair includes genomic scarring and LOH. Screening assays for the HRD-LOH search for the genomic scars that accumulate in BRCA-mutated tumors; these assays are undergoing validation in attempts to identify PARPi sensitivity.
      • Lord C.
      • et al.
      BRCAness revisited.
      Development of HRD scores by studying ovarian and breast cancers deficient in BRCA1/2 and RAD51 were used to generate data regarding genomic patterns to develop predictive HRD-LOH scoring.
      • Abkevich V.
      • et al.
      Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.
      • Popova T.
      • et al.
      Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.
      Clinical trials are ongoing using LOH score as marker of HRD that may predict PARPi sensitivity or platinum hypersensitivity. Attempts to validate HRD genomic biomarker assays in metastatic TNBCs, known to have high correlation with HR defects and BRCA mutations, have shown promising prediction of platinum sensitivity. Platinum sensitivity has been correlated by high HRD-LOH scores in a variety of cancers, suggesting a role for PARPi predicted by germline and somatic mutations in HRD proteins, including BRCA1/2, RAD51, and others with rationale to include these in clinical trials with PARPi.
      • Pennington K.P.
      • et al.
      Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
      • Telli M.L.
      • et al.
      Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
      • Isakoff S.J.
      • et al.
      TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer.
      Additionally, the results of ARIEL2, a Phase II prospective study in which HRD-LOH scores were combined with next-generation sequencing to predict PARPi responsiveness in ovarian cancer patients, showed the combined high-HRD scores predicted responsiveness in non-BRCA mutated tumors and correlated with increased ORR compared with low-HRD predictive algorithm (45% in BRCA-like tumors vs 21% in a non-BRCA cohort).
      • McNeish I.A.
      • et al.
      Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis.
      As mentioned earlier, with the advent of next-generation sequencing, screening for non-BRCA mutations in DDR genes affecting HR repair pathways has been increasingly studied. Preclinical data support that individual DDR protein deficiencies may confer PARP sensitivity. For example, ATM depletion in breast cancer cells has been shown to cause PARPi susceptibility.
      • Gilardini Montani M.S.
      • et al.
      ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition.
      Additional in vitro assessments have implicated PI3K/AKT protein INPPD loss to be associated with increasing cell susceptibility to PARPi, olaparib, in ovarian cell lines similar to BRCA1 and PTEN knockdown.
      • Ip L.R.
      • et al.
      Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment.
      This mechanism is believed to be due to ultimate instability of the ATM-BRCA1-ATR complex resulting in loss of DNA damage repair. In ovarian cancer, deleterious germline (24%) or somatic (9%) mutations in BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D has been identified.
      • Pennington K.P.
      • et al.
      Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
      With molecular characterization of available expression profile data, correlation with HRD and platinum sensitivity in ovarian cancers has been demonstrated.
      • Konstantinopoulos P.A.
      • et al.
      Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.
      For this reason, it has been proposed that ovarian tumors with mutations in other DNA repair genes, including RAD53, ATM, PALB2, and CHEK2 may benefit from platinum-based chemotherapy and/or PARPi.
      • Euhus D.
      Genetic testing today.

      Clinical Application of PARP Inhibition in Solid Tumor Cancer Therapeutics

      As a result of improved understanding of DNA repair mechanisms and recognition of the potential therapeutic role of PARPi in cancer treatment, clinical trials have been carefully designed and subsequently have demonstrated benefit of PARPi in a variety of solid tumor subtypes. Although much of the clinical benefit has been observed in those patients with germline BRCA1/2 mutations, emerging data suggest a therapeutic predictive role for BRCA-like tumor signatures and PARPi sensitivity, used either as monotherapy or in combination with other treatments.

      Ovarian Cancer

      The first landmark clinical demonstration of PARPi efficacy and synthetic lethality in solid tumors was a Phase I trial of olaparib published in 2009.
      • Fong P.C.
      • et al.
      Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
      The study cohort included 60 patients with advanced solid tumors; of those, 22 patients harbored a germline BRCA1 or BRCA2 mutation. Though clinical response was limited to BRCA-carriers, response was remarkable in that selected cohort, observed in 63% of evaluable patients (12 out of 19). Given that the majority of this cohort was composed of patients with ovarian cancer, the Phase I data supported further cohort expansion specifically for germline BRCA-carriers with advanced ovarian, primary peritoneal, and fallopian tube cancers. Among 50 enrolled patients taking olaparib as monotherapy, a clinical benefit rate of 46% was observed overall.
      • Fong P.C.
      • et al.
      Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
      Perhaps the most notable observation was the dramatic difference in benefit rates among platinum-sensitive tumors compared with platinum-resistant and refractory tumors (69% vs 46% vs 23%).
      Additional Phase II clinical trials in BRCA-associated high-grade serous ovarian cancers have demonstrated significant effects of olaparib monotherapy as treatment for progressive disease, with benefit greatest in, but not limited to, those patients with platinum-sensitive tumors.
      • Audeh M.W.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
      Olaparib has also been studied for use as maintenance therapy in relapsed disease after treatment with platinum agents, in patients with or without germline BRCA mutations. In one such Phase II study, progression-free survival (PFS) was extended from 4.8 to 8.4 months in all patients, but in those patients with either germline or somatic BRCA1/2 mutations, there was significant improvement of PFS to 11.2 months.
      • Lancaster J.M.
      • et al.
      BRCA2 mutations in primary breast and ovarian cancers.
      • Kaye S.B.
      • et al.
      Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly(ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.
      • Scott C.L.
      • et al.
      Poly (ADP-ribose) polymerase inhibitors: recent advances and future development.
      Together, these data led to approval by European Medicines Agency as maintenance therapy for platinum-responsive advanced disease with either germline or somatic BRCA mutations.
      • Ledermann J.
      • et al.
      Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
      • Ledermann J.
      • et al.
      Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
      Based on these results and the acceptable safety profile in which grade 3 or higher adverse effects included nausea, vomiting, and anemia, the European Medicines Agency approved olaparib as maintenance therapy agent in relapsed platinum-sensitive ovarian cancer with germline or somatic BRCA mutations. Separately, the US Food and Drug Administration offered accelerated approval for olaparib monotherapy for advanced ovarian cancer in patients harboring germline BRCA1/2 mutations who have progressed on 3 or more lines of chemotherapy. This indication was based on combined results of olaparib monotherapy Phase II trials, including results published by Kaufman et al
      • Kaufman B.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
      that showed tumor response rate of 31%, with 54.6% of patients being progression-free at 6 months, and a median overall survival of 16 months. However, serious adverse events included 2 patients with development of acute myeloid leukemia (AML) and 1 patient with myelodysplastic syndrome (MDS). Based on risk-benefit assessment, with risk of treatment, including concern for secondary cancers with unclear benefit demonstrated due to small sample size and confounding factors associated with retrospective identification of BRCA mutation status in the 2012 Phase II trial, the Food and Drug Administration Oncologic Drug Advisory Committee voted against approval of maintenance olaparib in platinum-sensitive recurrent ovarian cancer with recommendation to await results of Phase III SOLO-2 trial data.

      FDA Briefing Document. ODAC Meeting, 2014. Olaparib NDA.

      The use of olaparib in these select, BRCA-specific, advanced ovarian cancer settings remain the only approved clinical applications of PARPi in solid tumors to date. Multiple clinical trials are currently underway to investigate the role of PARPi in BRCA-mutant tumors in advanced and maintenance settings, with several Phase III trials actively recruiting patients (Table 1).
      Table IOpen Phase-III trials of poly(ADP-ribose) polymerase inhibitors in solid tumors
      US National Library of Medicine. Clinical Trials.gov [online]. Data last accessed Feb 2, 2016.
      MalignancyPoly(ADP-ribose) polymerase inhibitorsNCI/trialTreatmentPopulation
      OvarianVeliparibNCT02470585Velparib with carboplatin and paclitaxel and as continuous maintenance therapyNewly diagnosed Stage III and IV ovarian/fallopian tube/peritoneal cancer
      Cediranib/olaparibNCT02446600Olaparib or cediranib plus olaparib vs platinum-based chemotherapyRecurrent platinum-sensitive ovarian/fallopian tube/peritoneal cancer
      NiraparibNCT02655016Niraparib maintenance vs placeboHRD-positive advanced ovarian cancer, after platinum-based chemotherapy
      RucaparibNCT01968213/ARIEL3Rucaparib switch maintenance vs placeboPlatinum-sensitive ovarian, fallopian tube/peritoneal caner
      OlaparibNCT02282020/SOLO3Olaparib vs physician’s choiceRelapsed BRCA-associated ovarian cancer
      OlaparibNCT02477644/PAOLA-1Olaparib vs placebo concurrent with chemotherapy and in maintenanceNewly diagnosed Stage III and IV ovarian/fallopian tube/peritoneal cancer
      OlaparibNCT02392676Olaparib maintenance vs placeboBRCA- or HRD-positive advanced ovarian cancer, after platinum-based chemotherapy
      BreastVeliparibNCT02163694Carboplatin and paclitaxel ± veliparibHer2-negative metastatic/locally advanced BRCA-associated breast cancer
      VeliparibNCT02032277/BrightnessStandard chemo plus carboplatin/veliparib vs standard chemo plus carbo/placeboEarly stage triple-negative breast cancers, neoadjuvant setting
      TalazoparibNCT01945775/EMBRACATalazoparib vs physician’s choiceMetastatic BRCA-associated breast cancer
      NiraparibNCT01905592/BRAVONiraparib vs physician’s choiceHer2-negative metastatic/locally advanced BRCA-associated breast cancer
      OlaparibNCT02032823/OlympiaOlaparib vs placeboAdjuvant treatment for Her2 negative, high risk BRCA-associated primary breast cancer
      PancreaticOlaparibNCT02184195/POLOOlaparib vs placeboBRCA-associated metastatic pancreatic adenocarcinoma, stable after first line platinum chemotherapy
      LungVeliparibNCT02264990Veliparib plus carboplatin/paclitaxel vs physician’s choiceAdvanced non-squamous non–small cell lung cancer, current or former smokers
      VeliparibNCT02106546Carboplatin/paclitaxel ± veliparibAdvanced squamous non–small cell lung cancer
      Central nervous systemVeliparibNCT02152982Temozolomide ± veliparibNewly diagnosed glioblastoma multiforme
      NCT = national cancer institute.
      Two noteworthy observations from the landmark PARPi ovarian cancer trials and others suggest potential benefit of PARPi in BRCA-like ovarian cancer settings. The first important observation was that some ovarian cancer patients who did not harbor a germline BRCA-mutation still derived significant benefit from olaparib treatment and maintenance therapies, with response rates in one such trial of 50%.
      • Scott C.L.
      • et al.
      Poly (ADP-ribose) polymerase inhibitors: recent advances and future development.
      • Gelmon K.A.
      • et al.
      Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
      Second, a correlation between PARPi response and platinum sensitivity was repeatedly observed.
      • Fong P.C.
      • et al.
      Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
      • Lee J.M.
      • et al.
      Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
      • Liu J.F.
      • et al.
      A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.
      Together, these observations along with supporting preclinical data suggest that acquired and/or non-BRCA related germline DNA repair deficiencies may play a role in PARPi sensitivity. As described above, this concept known as BRCAness describes a phenotype arising in sporadic cancers that do not harbor germline BRCA mutations, but share similar features to BRCA-associated tumors, such as HRD and resultant sensitivity to DNA cross-linking agents such as platinums.
      • Benafif S.
      • Hall M.
      An update on PARP inhibitors for the treatment of cancer.
      These key observations have guided the design of further therapeutic PARPi clinical trials, both in ovarian cancer and other solid tumors. For example, ARIEL2 is an ongoing Phase II trial examining the role of rucaparib in platinum-sensitive relapsed ovarian cancer, and aims to identify a predictive molecular signature of HRD in this cohort, with results discussed above. A Phase III trial, ARIEL3, is planned once the specific signature has been identified. Several other studies of PARPi in non-BRCA–associated ovarian cancer are currently underway, using PARPi either as monotherapy or in combination with ionizing radiation, chemotherapy, antiangiogenics, or targeted PI3K inhibition
      • Benafif S.
      • Hall M.
      An update on PARP inhibitors for the treatment of cancer.
      • Liu J.F.
      • et al.
      Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
      • Swisher E.M.
      • et al.
      ARIEL 2/3: An integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response.
      (Table 1).

      Breast Cancer

      The clinical benefit of PARPi in breast cancer was first established in 2010 with a Phase II trial of olaparib monotherapy in patients with germline BRCA mutations and advanced breast cancer, which demonstrated an overall response rate of 42% (11 out of 26) and PFS of 5.7 months.
      • Tutt A.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
      However, unlike ovarian cancer, studies of PARPi in non-BRCA associated breast cancers, specifically in TNBC, have reported disappointing results. For instance, a study of olaparib monotherapy for unselected advanced TNBC patients had zero responders among a cohort of 37 patients.
      • Gelmon K.A.
      • et al.
      Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
      Some theorize this poor response may reflect biologic heterogeneity of breast disease, unlike a more homogenous phenotype of high-grade serous ovarian cancer.
      • Scott C.L.
      • et al.
      Poly (ADP-ribose) polymerase inhibitors: recent advances and future development.
      • Tutt A.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
      • Lehmann B.D.
      • et al.
      Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
      As such, many ongoing clinical trials of PARPi in breast cancer focus solely on germline BRCA-associated breast cancers, in both early and advanced disease (Table 1).
      However, PARPi may still play an important therapeutic role in non-BRCA–associated breast cancer in the future, when used in combination with other agents. Recent studies have suggested that those TNBC with a BRCA-like phenotype may harbor an HRD signature similar to BRCA1-associated breast cancers, which may predict response to platinum agents. A Phase III proof-of-concept clinical trial, the TNT trial, was designed to test the efficacy of carboplatin compared with docetaxel in patients with advanced TNBC, with and without germline BRCA mutations.
      • Lord C.
      • et al.
      BRCAness revisited.
      • Balko J.M.
      • et al.
      Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
      • Kilburn L.S.
      ‘Triple negative’ breast cancer: a new area for phase III breast cancer clinical trials.
      • Tutt A.
      • et al.
      The TNT trial: a randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative of BRCA1/2 breast cancer (CRUK/07/012) [abstract].
      Although there was no observed difference in unselected patients, those patients with germline BRCA mutations demonstrated improved response rates and longer PFS with carboplatin when compared with docetaxel or those patients without germline mutations. As such, current research is underway to develop a clinical assay of HRD in breast cancer, to predict chemotherapy sensitivity in TNBC, and further define a potential role for PARPi
      • McNeish I.A.
      • et al.
      Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis.
      • Telli M.L.
      • et al.
      Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105.
      (Table 1). Similar to ovarian cancer, other early-phase studies of TNBC and PARPi include combination trials with other agents such as antiangiogenics and PI3K inhibition.
      • Benafif S.
      • Hall M.
      An update on PARP inhibitors for the treatment of cancer.

      Prostate Cancer

      Similar to the developing roles of PARPi and HRD in breast cancer, recent trials of PARPi in prostate cancer patients demonstrate benefit both for patients with germline BRCA mutations as well as those patients with BRCA-like tumors. Early-phase trials in patients with BRCA mutations and metastatic castration-resistant prostate cancer (mCRPC) have demonstrated small numbers of patients with PFS or measurable responses with duration of up to 34 months with PARPi monotherapy.
      • Fong P.C.
      • et al.
      Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
      • Sandhu S.K.
      • et al.
      Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer.
      Sporadic prostate cancer patients included in a Phase I trial of niraparib also appeared to derive clinical benefit, suggesting a role for targetable BRCAness in this tumor type.
      • Sandhu S.K.
      • et al.
      Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer.
      Using next-generation tumor sequencing techniques, multiple researchers have demonstrated that nearly 20% of mCRPC tumors have at least 1 mutation conferring HRD and BRCAness, including BRCA1/2, ATM, and CDK12.
      • Beltran H.
      • et al.
      Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity.
      • Robinson D.
      • et al.
      Integrative clinical genomics of advanced prostate cancer.
      Most recently, the TO-PARP Phase II clinical trial in mCRPC patients demonstrated clinical benefit to PARPi monotherapy and tumors with BRCAness features.
      • Mateo J.
      • et al.
      DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
      In a cohort of 49 men with unselected mCRPC treated with olaparib, 33% (16 out of 49) had clinical response. Among 16 patients whose tumors were identified to have a mutation (either somatic or germline) in a gene conferring HRD, including BRCA1/2, ATM, the FANC pathway genes, and CHEK2, response rates approached 88% (14 out of 16). Further studies of PARPi as monotherapy and in combination with other therapies in BRCA- and non-BRCA–related prostate cancers are currently underway
      • O’Sullivan C.C.
      • et al.
      Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors.
      (Table 1).

      Pancreatic Cancer

      Although BRCA1/2-associated pancreatic cancer is rare, it comprises up to 19% of familial pancreatic cancer cases. PARPi has shown activity in this subgroup, with a recent Phase II trial of olaparib monotherapy in BRCA-associated solid tumors where 13 of 23 patients with metastatic pancreatic cancer achieved clinical benefit.
      • Lord C.
      • et al.
      BRCAness revisited.
      Other studies suggest similar platinum sensitivity in BRCA-associated pancreatic cancers as seen in other BRCA-associated cancers, suggesting a potential role for PARPi in combination with other therapies.
      • Benafif S.
      • Hall M.
      An update on PARP inhibitors for the treatment of cancer.
      As such, veliparib has been studied in unselected pancreatic cancer patients in combination with concurrent FOLFOX chemotherapy in metastatic pancreatic cancer patients, with a response rate of 18% in 18 evaluable patients. Several genes associated with HRD have been found in pancreatic tumors, including 24% of tumors with either a germline or somatic BRCA1/2 or PALB2 mutation, with another 8% with an ATM mutation.
      • Kaufman B.
      • et al.
      Olaparib monotherapy in patients with advanced cancer and a germ-line BRCA 1/2 mutation: an open-label phase II study.
      • Waddell N.
      • et al.
      Whole genomes redefine the mutational landscape of pancreatic cancer.
      • Biankin A.V.
      • et al.
      Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
      • Kim H.S.
      • et al.
      Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients.
      Further studies to examine the role of PARPi as monotherapy and in combination with other therapies in advanced disease and/or as maintenance therapy are currently underway (Table 1).

      Other Solid Tumors

      Several other tumor types with BRCA mutations and/or BRCA-like features are currently being studied for potential therapeutic PARPi applications. For example, 5% of gastric cancers harbor germline BRCA mutations, and another 13% to 21% display loss of tumor-based ATM expression.
      • Ledermann J.
      • et al.
      Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
      • Kim H.S.
      • et al.
      Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients.
      A recent Phase II trial in metastatic gastric cancer of olaparib in combination with paclitaxel chemotherapy followed by olaparib maintenance therapy appeared to improve overall survival versus placebo groups, warranting development of a Phase III trial that is currently underway
      • Lord C.
      • et al.
      BRCAness revisited.
      (Table 1).
      Other solid tumor types that appear to have PARPi sensitivity are those that potentially harbor BRCAness and HRD. Tumor types currently under study with PARPi as monotherapy or in combination with chemotherapy or radiation therapy in Phase I and II trials include PTEN-deficient endometrial cancer, cervical cancer, colorectal carcinoma, esophageal cancer, melanoma, small cell and non–small cell lung cancer, Ewing sarcoma, squamous cell carcinoma of the head and neck, and glioblastoma multiforme.
      • O’Sullivan C.C.
      • et al.
      Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors.

      Conclusions

      PARPi hold great promise in the treatment of solid tumors, both as monotherapy and in combination with other cancer therapeutics. However, challenges remain. Although PARPi appear remarkably effective in some settings, such as ovarian cancer, not all patients respond equally to PARPi, tumor types vary in terms of PARPi sensitivity, and mechanisms of resistance to PARPi remain poorly understood. Further understanding of aberrant DNA repair mechanisms in the germline and in the tumor genome is needed, in addition to many more targeted Phase III clinical trials, to allow clinicians to apply PARPi most strategically in the era of personalized medicine.

      Conflicts of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      All authors contributed equally to all aspects of the manuscript. No financial support.

      References

        • Lindahl T.
        • Barnes D.E.
        Repair of endogenous DNA damage.
        Cold Spring Harb Symp Quant Biol. 2000; 65: 127-133
        • Hoeijmakers J.H.
        Genome maintenance mechanisms for preventing cancer.
        Nature. 2001; 411: 366-374
      1. Curtin NJ, DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 12. 801-17

        • Carter R.J.
        • et al.
        Base Excision Repair, a Pathway Regulated by Posttranslational Modifications.
        Mol Cell Biol. 2016; 36: 1426-1437
        • Ceccaldi R.
        • Rondinelli B.
        • D’Andrea A.D.
        Repair Pathway Choices and Consequences at the Double-Strand Break.
        Trends Cell Biol. 2016; 26: 52-64
        • O’Connor M.J.
        Targeting the DNA Damage Response in Cancer.
        Mol Cell. 2015; 60: 547-560
        • Croteau D.
        • et al.
        Overview of DNA Repair Pathways. DNA Repair and Cancer.
        CRC Press, 2013: p1-24
        • Marechal A.
        • et al.
        DNA damage sensing by the ATM and ATR kinases.
        Cold Spring Harb Perspect Biol. 2013; 5: a012716
        • Negrini S.
        • Gorgoulis V.G.
        • Halazonetis T.D.
        Genomic instability--an evolving hallmark of cancer.
        Nat Rev Mol Cell Biol. 2010; 11: 220-228
        • Hall J.M.
        • et al.
        Linkage of early-onset familial breast cancer to chromosome 17q21.
        Science. 1990; 250: 1684-1689
        • Easton D.F.
        • et al.
        Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium.
        Am J Hum Genet. 1993; 52: 678-701
        • Wooster R.
        • et al.
        Identification of the breast cancer susceptibility gene BRCA2.
        Nature. 1995; 378: 789-792
        • Futreal P.A.
        • et al.
        BRCA1 mutations in primary breast and ovarian carcinomas.
        Science. 1994; 266: 120-122
        • Miki Y.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
        Science. 1994; 266: 66-71
        • Szanto M.
        • et al.
        Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein.
        Cell Mol Life Sci. 2012; 69: 4079-4092
        • Ame J.C.
        • Spenlehauer C.
        • de Murcia G.
        The PARP superfamily.
        Bioessays. 2004; 26: 882-893
        • Sousa F.G.
        • et al.
        PARPs and the DNA damage response.
        Carcinogenesis. 2012; 33: 1433-1440
        • Beck C.
        • et al.
        Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3.
        Exp Cell Res. 2014; 329: 18-25
        • Bai P.
        Biology of Poly(ADP-Ribose) Polymerases: The Factotums of Cell Maintenance.
        Mol Cell. 2015; 58: 947-958
        • Xie S.
        • et al.
        Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair.
        Mol Cell. 2015; 60: 163-176
        • Haince J.F.
        • et al.
        Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents.
        J Biol Chem. 2007; 282: 16441-16453
        • Sharom J.R.
        • Bellows D.S.
        • Tyers M.
        From large networks to small molecules.
        Curr Opin Chem Biol. 2004; 8: 81-90
        • Kaelin Jr, W.G.
        The concept of synthetic lethality in the context of anticancer therapy.
        Nat Rev Cancer. 2005; 5: 689-698
        • Audeh M.W.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 245-251
        • Fong P.C.
        • et al.
        Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
        N Engl J Med. 2009; 361: 123-134
        • Bryant H.E.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Farmer H.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Helleday T.
        The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings.
        Mol Oncol. 2011; 5: 387-393
        • Feng F.Y.
        • et al.
        Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function.
        Mol Cell. 2015; 58: 925-934
        • Satoh M.S.
        • Lindahl T.
        Role of poly(ADP-ribose) formation in DNA repair.
        Nature. 1992; 356: 356-358
        • Murai J.
        • et al.
        Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors.
        Cancer Res. 2012; 72: 5588-5599
        • Murai J.
        • et al.
        Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.
        Mol Cancer Ther. 2014; 13: 433-443
        • Curtin N.J.
        • Szabo C.
        Therapeutic applications of PARP inhibitors: anticancer therapy and beyond.
        Mol Aspects Med. 2013; 34: 1217-1256
        • Campeau P.M.
        • Foulkes W.D.
        • Tischkowitz M.D.
        Hereditary breast cancer: new genetic developments, new therapeutic avenues.
        Hum Genet. 2008; 124: 31-42
        • Pal T.
        • et al.
        BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.
        Cancer. 2005; 104: 2807-2816
        • Watkins J.A.
        • et al.
        Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.
        Breast Cancer Res. 2014; 16: 211
        • The Cancer Genome Atlas Network
        Integrated genomic analyses of ovarian carcinoma. 2011; 474: 609-615
        • The Cancer Genome Atlas Network
        Comprehensive molecular portraits of human breast tumours.
        Nature. 2012; 490: 61-70
        • Konstantinopoulos P.A.
        • et al.
        Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.
        J Clin Oncol. 2010; 28: 3555-3561
        • Turner N.
        • Tutt A.
        • Ashworth A.
        Hallmarks of ‘BRCAness’ in sporadic cancers.
        Nat Rev Cancer. 2004; 4: 814-819
        • Lancaster J.M.
        • et al.
        BRCA2 mutations in primary breast and ovarian cancers.
        Nat Genet. 1996; 13: 238-240
        • Lord C.
        • et al.
        BRCAness revisited.
        Nat Rev Cancer. 2016; 16: 110-120
        • Abkevich V.
        • et al.
        Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.
        Br J Cancer. 2012; 107: 1776-1782
        • Popova T.
        • et al.
        Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.
        Cancer Res. 2012; 72: 5454-5462
        • Pennington K.P.
        • et al.
        Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
        Clin Cancer Res. 2014; 20: 764-775
        • Telli M.L.
        • et al.
        Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
        Clin Cancer Res. 2016; (1-10 [Epub ahead of print])
        • Isakoff S.J.
        • et al.
        TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer.
        J Clin Oncol. 2015; 33: 1902-1909
        • McNeish I.A.
        • et al.
        Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis.
        J Clin Oncol. 2015; (ASCO Annual Meeting (May 29–June 2, 2015). Vol 33, No 15_suppl (May 20 Supplement), 2015: 5508)
        • Gilardini Montani M.S.
        • et al.
        ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition.
        J Exp Clin Cancer Res. 2013; 32: 95
        • Ip L.R.
        • et al.
        Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment.
        Oncotarget. 2015; 6: 10548-10562
        • Euhus D.
        Genetic testing today.
        Ann Surg Oncol. 2014; 21: 3209-3215
        • Fong P.C.
        • et al.
        Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
        J Clin Oncol. 2010; 28: 2512-2519
        • Kaye S.B.
        • et al.
        Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly(ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.
        J Clin Oncol. 2012; 30: 372-379
        • Scott C.L.
        • et al.
        Poly (ADP-ribose) polymerase inhibitors: recent advances and future development.
        J Clin Oncol. 2015; 33: 1397-1406
        • Ledermann J.
        • et al.
        Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
        N Engl J Med. 2012; 366: 1382-1392
        • Ledermann J.
        • et al.
        Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
        Lancet Oncol. 2014; 15: 852-861
        • Kaufman B.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
        J Clin Oncol. 2015; 33: 244-250
      2. FDA Briefing Document. ODAC Meeting, 2014. Olaparib NDA.

        • Gelmon K.A.
        • et al.
        Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
        Lancet Oncol. 2011; 12: 852-861
        • Lee J.M.
        • et al.
        Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
        J Natl Cancer Inst. 2014; (dju089): 106
        • Liu J.F.
        • et al.
        A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.
        Eur J Cancer. 2013; 49: 2972-2978
        • Benafif S.
        • Hall M.
        An update on PARP inhibitors for the treatment of cancer.
        Onco Targets Ther. 2015; 8: 519-528
        • Liu J.F.
        • et al.
        Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
        Lancet Oncol. 2014; 15: 1207-1214
        • Swisher E.M.
        • et al.
        ARIEL 2/3: An integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response.
        J Clin Oncol. 2014; 32 (suppl 15s; abstr TPS5619): 380s
        • Tutt A.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 235-244
        • Lehmann B.D.
        • et al.
        Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
        J Clin Invest. 2011; 121: 2750-2767
        • Balko J.M.
        • et al.
        Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
        Cancer Discov. 2014; 4: 232-245
        • Kilburn L.S.
        ‘Triple negative’ breast cancer: a new area for phase III breast cancer clinical trials.
        Clin Oncol (R Coll Radiol). 2008; 20: 35-39
        • Tutt A.
        • et al.
        The TNT trial: a randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative of BRCA1/2 breast cancer (CRUK/07/012) [abstract].
        Presented at the 2014 San Antonio Breast Cancer Symposium, San Antonio, Texas2014 (Abstract S3-01)
        • Telli M.L.
        • et al.
        Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105.
        J Clin Oncol. 2015; 33: 1895-1901
        • Sandhu S.K.
        • et al.
        Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer.
        Ann Oncol. 2013; 24: 1416-1418
        • Beltran H.
        • et al.
        Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity.
        Eur Urol. 2013; 63: 920-926
        • Robinson D.
        • et al.
        Integrative clinical genomics of advanced prostate cancer.
        Cell. 2015; 161: 1215-1228
        • Mateo J.
        • et al.
        DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
        N Engl J Med. 2015; 373: 1697-1708
        • O’Sullivan C.C.
        • et al.
        Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors.
        Front Oncol. 2014; 4: 42
        • Kaufman B.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germ-line BRCA 1/2 mutation: an open-label phase II study.
        J Clin Oncol. 2013; 31s (abstr 11024)
        • Waddell N.
        • et al.
        Whole genomes redefine the mutational landscape of pancreatic cancer.
        Nature. 2015; 518: 495-501
        • Biankin A.V.
        • et al.
        Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
        Nature. 2012; 491: 399-405
        • Kim H.S.
        • et al.
        Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients.
        Pathobiology. 2013; 80: 127-137
      3. US National Library of Medicine. Clinical Trials.gov [online]. Data last accessed Feb 2, 2016.