Abstract
Recent evidence has indicated that the prognosis of women with epithelial ovarian cancer who are BRCA-mutation carriers may be better than for noncarriers. Part of the explanation is a higher sensitivity to platinum and other chemotherapies, as was demonstrated in in vitro studies, as well as a possible different biology. BRCA genes are important in double-strand DNA break repair and in other important processes of the cell cycle. Mutation or reduced activity of BRCA genes leads to a higher vulnerability to DNA damage (caused by chemotherapy and radiotherapy) compared with malignant tumors of noncarriers. New targeted drugs, such as poly (ADP-ribose) polymerase-1 and −2 inhibitors, are currently under investigation, as are new biomarkers that will hopefully lead the way to better treatment and longer survival. Testing for the BRCA mutation should be carried out and used as a guide for therapy in most patients with epithelial ovarian cancer.
Understanding the association between individual cell cycle mechanisms and cancer treatment agents might be of great value to improving cancer prognosis. The alteration of normal cells into cancer cells is a result of multiple steps of genetic changes. These alterations are associated with a cell's replication control, DNA repair, DNA segregation and controlled activity between the cell organelles. During the last decades, accumulated evidence from research has suggested potential targets for the development of agents for improved cancer control [1].
Epithelial ovarian cancer (EOC) is the primary cause of death from gynecologic malignancies in Western countries [2]. More than 75% of EOC patients present with advanced-stage disease (International Federation of Gynaecology and Obstetrics [FIGO] stage III or IV) and despite continuous treatment improvements, the relapse rate is higher than 70% [3]. Approximately 10–15% of EOCs are inherited, and most of them are associated with BRCA (breast cancer susceptibility genes) mutations [3–5]. Studying the specific interaction between individual cell cycle malfunctioning, response to treatment and prognosis might help us to define meaningful subclassifications that could guide us to a personalized and improved treatment.
Tumor suppressor genes are involved in cell proliferation rhythmus, DNA repair and programmed cell death (apoptosis); mutations in these genes could result from cancer development or a higher sensitivity to DNA-damaging chemotherapeutic agents. BRCA1 and BRCA2 are tumor suppressor genes associated with breast and ovarian cancer syndrome. More than 1000 BRCA mutations are reported to the Breast Cancer Information Core (BIC) database [101]. Female BRCA-mutation carriers have a 12–46% lifetime risk of developing ovarian cancer [4,6–8]. BRCA-related breast cancer will not be discussed in this review. Evidence for improved prognosis among ovarian cancer patients who were mutations carrier has been described by several investigators; however, other studies have not confirmed this [9–22].
Hereditary ovarian cancer
BRCA-mutation incidence
The incidence of BRCA1- and BRCA2-mutation carriers in the US general population differs from one individual out of 345 to one out of 1000 [23,24]; 2.3% of Ashkenazi Jews carry one of the three common founder BRCA mutations [24]. BRCA½ mutations are germline mutations that are dominantly inherited from either parent with different levels of penetrance. The most researched BRCA½ mutations are identified mutations in cultural, ethnic or geographically isolated populations. The Ashkenazi Jewish [25] and the Icelandic [26] founder mutations have been extensively studied. Other studies are concentrated in Finnish [27], Dutch [28], French Canadian [29], Polish [30] and Spanish [31] distinctive mutations. Founder mutations are ancestral mutations transferred through generations and tend to be preserved in cultures or populations that keep their genetic resources relatively unmixed with other groups; ethnic and geographic clusters could also carry recurrent mutations. Focusing on defined groups creates an appropriate model for studies of BRCA-mutation carriers in the general population. In the Ashkenazi Jewish population, one out of every 40 individuals carry one of three specific mutations and the prevalence of the mutations in unselected EOC patients is more than 30% [32–35].
EOC & BRCA mutations
Epithelial ovarian cancer appears to be the result of a multistep process of accumulated genetic alterations that are still only partially understood. BRCA1 and BRCA2 mutations are high penetrance, dominantly inherited germline mutations of major susceptibility genes. Hereditary nonpolyposis colorectal cancer is associated with germline mutations in the DNA mismatch repair (MMR) genes, primarily hMLH1 and hMSH2. Approximately 5–15% of EOC cases are reported as family history-related and most of them are associated with germline mutation of BRCA1 and BRCA2 genes (10% of all EOC cases). Hereditary nonpolyposis colorectal cancer and minor mutations account for 10% of inherited cases [4,5,7].
Germline mutations in one allele of either BRCA1 or BRCA2 predispose to breast and ovarian cancers that occur when there is a somatic mutation of the second allele [36]. Knudson's two-hit hypothesis claims that in order to create a carcinogenic mutation, the two alleles of the chromosome have to be mutated [37]. When a germline mutation is inherited and present in all somatic body cells, only one additional site or organ-specific mutation is required for carcinogenesis. Interestingly, despite the importance of BRCA to all body cells, its predisposition to cancer is mainly in the breast and ovary [4,5,7], and not in sporadic cases. One possible explanation for these tissue-specific effects is the frequent exposure to hormonal transformation and cell proliferation throughout a woman's life. In addition, mutations in the BRCA genes have not yet been commonly detected in nonfamilial (or sporadic) cancers, although reduced activity of BRCA as a result of epigenetic changes is evident in sporadic cancers [38,39].
Clinicopathologic characteristic features of BRCA mutation-related EOC
Breast cancer of BRCA-mutation carriers tends to have distinct pathological and clinical manifestation. Interestingly, less distinct clinical and no pathological differences were found between EOCs in carriers and noncarriers [9,10,35]. The median age at diagnosis of ovarian cancer in BRCA1-mutation carriers is 5–10 years earlier than BRCA2 mutation-related and sporadic ovarian cancer cases [35,40,41]. Papillary serous, endometrioid and Müllerian histologies as well as high-grade tumors are frequently described among BRCA mutation-positive tumors [35]. Conversely, ovarian borderline carcinomas and ovarian mucinous tumors occur very infrequently [5].
BRCA mutations
Identification of BRCA mutations
The nature of the genetic changes in ovarian cancer has been studied over the past 20 years. King et al. [41] identified chromosome 17q21 as the probable location of a gene for inherited breast cancer susceptibility and, several months later, Narod et al. [42] determined that the gene linked to this locus was also associated with ovarian cancer and defined a specific genetic basis for combined hereditary breast and ovarian cancer syndrome. The actual BRCA1 susceptibility gene was not identified until 1994 [43]. Determination of the first Ashkenazi Jewish founder mutation BRCA1 185delAG [44] was followed by the identification of BRCA2 on chromosome 13q12-q13 [45] and the description of an Ashkenazi Jewish founder mutation BRCA2 6174delT [46]. A third BRCA founder mutation that is common among Ashkenazi Jews, BRCA1 5382insC, was recognized at the same time [47,48]. Extensive research has been carried out over the last 2 decades and hundreds of other BRCA mutations have been identified and researched in vitro and in vivo for biological, pathological, clinical, prognostic and chemosensitivity characteristics. Based on the accumulated knowledge it is reasonable to assume that different prognosis and response to therapy might be detected when populations of noncarriers are compared with populations of carriers.
Role of BRCA in the cell cycle
The essential role of BRCA genes is preserving chromosomal stability while inactivation of BRCA genes may initiate or promote mutations and carcinogenesis. BRCA is a tumor suppressor gene involved in multiple cell functions, including DNA repair, transcription and cell cycle control. In its biochemical pathway, BRCA interacts with a variety of key proteins involved in normal cell functions.
BRCA genes act as caretakers and gatekeepers [49,50]. Caretaker genes have the ability to repair DNA damage and prevent genomic instability and mutations, while gatekeeper genes control cell division, lifespan and apoptosis, promoting the outgrowth of cancer cells [49–55].
Double-strand DNA break repair
Both BRCA1 and BRCA2 are important in the cellular response to DNA damage, especially in the repair of double-strand DNA breaks (DSBs). BRCA1 mainly acts outside the damage site, arresting the cell cycle and recruiting necessary proteins and enzymes, while BRCA2 acts mainly at the damaged site bound to RAD51 (a recombination enzyme) and additional proteins.
Double-strand breaks are repaired by two major pathways [49,50,53–55], one is an ‘error prone’ mechanism that involves mainly the excision of the damaged site, and the second is a ‘nonerror prone’ mechanism that involves a fascinating process of exact copying of the excised region of DNA. The error-prone mechanism, also termed the nonhomologous end joining, is where the broken DNA ends are religated after excision, with the addition or deletion of nucleotides at the site, leading to error-prone, mutagenic repair. The second preferred pathway for DSB repair is termed homologous DNA recombination, in which the damaged strand is repaired using an intact sister chromatid as a template. The repair by homologous recombination (HR) is an intact, perfect copy generated by DNA replication during the synthesis (S) phase of the cell cycle. HR plays an essential role during DNA replication and prevents chromosomal aberrations. BRCA genes are essential for HR and for proper repair of DSBs that arise spontaneously or are induced by exogenous agents, including chemotherapy and radiotherapy.
BRCA1 & BRCA2 in the cellular response to DNA damage
BRCA1 mainly acts outside the damage site as a gatekeeper at checkpoints and performs various functions in the cellular response to DNA breakage or replication arrest. BRCA1 also acts at the sites of DNA damage and recruits molecules that sense and repair DNA lesions. BRCA2 largely works at sites of DNA damage as a specific mediator for homologous DNA recombination repair. These different processes involve numerous key protein–protein interactions.
The varied roles of BRCA1 are believed to be partly dependent on activating additional enzymes and binding to proteins [54–56]. BRCA1 is reported to interact with the RAD51 recombination enzyme and BRCA2 [55], which are directly involved in the reactions that lead to homologous DNA recombination. However, the interaction between BRCA1 and BRCA2–RAD51 complex may be bridged by sequences of other molecules. There is also evidence that BRCA1 plays a role in the cellular response to DNA breakage by working at the sites where these lesions occur [57–61]. Single-stranded DNA is a trigger for the activation of checkpoints that arrest cell cycle progression during the S phase or at the G2/M boundary; such a role for BRCA1 may also underlie its involvement in checkpoint enforcement [62–65]. BRCA1 is a target for phosphorylation by the protein kinases that signal the presence of DNA breaks [58,59] and start a cascade of events necessary for the cell cycle checkpoint arrest. Those checkpoints are in phases involving DNA modifications, either for replication (S) or before and during mitosis (G2/M). BRCA1 interacts with numerous key proteins. BRCA1 regulates c-Abl activity when involved in apoptosis, suggesting that the role of BRCA1 in checkpoint activation is not directly connected to its functions in homologous DNA recombination [66–68]. GADD45 and p21 proteins are involved in the response to DNA damage, their expression is increased by BRCA1 [69]. In the absence of BRCA functions, DNA damage occurs and p53 is activated at checkpoints to induce arrest [70]; therefore, inactivation of p53/p21 in addition to BRCA mutation is required for tumorigenesis.
In contrast to BRCA1, BRCA2 binds directly to the RAD51 recombination enzyme, which has a catalytic activity that is crucial to HR. RAD51 coats single-stranded DNA substrates to form a helical nucleoprotein filament that invades and pairs with the homologous DNA duplex, initiating strand exchange between the paired DNA molecules [71,72], exchanging the damaged string with an intact one.
BRCA1 apparently functions as a bridging protein, connecting DNA damage and stress response pathways to execute specific cellular responses, such as cell cycle arrest or apoptosis, while BRCA2 with Rad51 are involved in the DNA damage repair process.
Numerical chromosomes aberrations
Inactivation of the BRCA genes also causes aneuploidy [64,73], which is a common feature in cancer cells from BRCA-mutation carriers. The BRCA proteins may also regulate chromosome segregation through participation in the mitotic checkpoint that monitors spindle assembly [71] or by affecting centrosome duplication [64]. These observations raise the question of whether BRCA malfunctioning could interfere with chromosome segregation during mitosis, leading to the generation of daughter cells with abnormal numbers of chromosomes.
BRCA mutations & response to therapy Chemosensitivity in BRCA-mutation carriers
BRCA mutations have a role in a patient's response to chemotherapy, length of survival and could serve as biomarkers for response. These intriguing observations are under extensive investigation with the aim of employing the information to create a more personalized treatment. Reduced efficacy of DNA repair mechanism, mainly homologous DNA recombination DSB repair in the BRCA-mutant population, makes tumor cells more susceptible to cytotoxic drugs.
BRCA1 mutations in preclinical studies, have been suggested to be an important determinant of response to both DNA-damaging chemotherapy (e.g., cisplatin and adriamycin, among others) and taxane-based chemotherapy (e.g., paclitaxel and docetaxel). In vitro studies [73–81] of BRCA1 deficiency, whether through inherited mutation or downregulation of BRCA1, reported increased sensitivity to DNA-damaging agents. Several retrospective clinical studies have supported those data. BRCA1-mutation carriers gain an improvement in survival following neoadjuvant treatment with DNA damage-based chemotherapy compared with nonmutation carriers [82,83]. In addition, reduced BRCA1 protein expression in patients with sporadic EOC was found to correlate with improved survival [84].
Additional preclinical studies support the same assumptions – antisense inhibition of BRCA1 in cisplatin-resistant SKOV3 ovarian cancer cells dramatically sensitized these cells by disruption of BRCA1-dependent DNA repair [85]. Overexpression of BRCA1 in ID8 murine ovarian cancer cells reduced sensitivity to cisplatin and other DNA-damaging agents [86].
In contrast to the increased sensitivity to DNA damage-based chemotherapy, increased resistance to antimicrotubule agents was observed in BRCA1-deficient cells. Overexpression of BRCA1 in MBR62-bcl2 breast cancer cells, reconstitution of exogenous BRCA1, and inhibition of endogenous BRCA1 expression were demonstrated to enhance sensitivity to paclitaxel [76,77,85,86]. Furthermore, BRCA1-deficient murine cells demonstrated a reduced apoptotic response following treatment with taxanes [75,80].
Quinn et al. suggested that BRCA1 is a differential modulator of survival in sporadic ovarian cancer [75]. Specifically, they demonstrated that inhibition of endogenous BRCA1 expression resulted in a significant increase in resistance to the antimicrotubule agents, paclitaxel and docetaxel, and, conversely, an increase in sensitivity to the DNA cross-linking agents, cisplatin and carboplatin. In addition, they demonstrated that the observed differential sensitivity is due to differential regulation of apoptosis by BRCA1. BRCA2 is critically important for the repair of DSBs by HR, and the loss of BRCA2 function probably predisposes to tumor cell death following administration of DNA-damaging chemotherapy [87–91]. Recent studies report the possibility of platinum resistance by secondary mutation and inversion to wild-type BRCA following treatment with platinum [92].
To summarize, the previously mentioned findings suggest that BRCA mutation is a predictor of survival in patients with advanced ovarian carcinoma, probably owing to the increased benefit from platinum-based chemotherapy.
BRCA1 mRNA expression as a predictive marker of response to both platinum agents and taxanes in sporadic ovarian cancer has been assessed by Quinn et al. [75]. Retrospective clinical data suggest that low levels of BRCA1 mRNA correlate with improved outcome in patients on treatment with single-agent platinum, and that patients with high levels of BRCA1 mRNA may gain greater benefit from combination chemotherapy involving platinum salts and taxanes. Therefore, not only BRCA mutation but reduced expression levels of BRCA1 mRNA and protein may predict response to DNA damage-based chemotherapy [76].
Poly (ADP-ribose) polymerase inhibitors as a targeted therapy in BRCA-mutation carriers with EOC
A better understanding of the complex function of BRCA genes has led to the discovery of new groups of drugs and hopefully others will follow. Poly (ADP-ribose) polymerase (PARP)-1 and −2, is a group of polymerases that facilitate single-strand DNA break repair prior to the replication fork. A single-strand DNA break, if not properly repaired, might develop into a DSB upon replication. In BRCA-mutation carriers, DNA DSB repair is impaired and tumor cell damage is significantly increased. PARP is crucial for the repair and PARP inhibitors cause an increase and persistence of single-strand DNA break [93]. Experiments carried out in the 1980s indicated that when encountered by replication forks, these breaks cause fork collapse and the formation of DSBs [94]. Support for the assumption that the HR defect in BRCA-deficient cells is the primary cause of PARP-inhibitor sensitivity is provided by evidence that cells with deficiencies in a number of other HR proteins are also sensitive to PARP inhibitors [95].
Preliminary observations in patients with ovarian cancer treated with PARP1 inhibitors suggested low levels of toxicity, with some promising indicators of responses measured both radiologically and using tumor markers. Promising new clinical information was presented at the American Society of Clinical Oncology (ASCO) 2009 regarding PARP-inhibitor use in ovarian and breast cancer. Audeh et al. presented a Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer [96]. Two doses were evaluated with a significant difference in favor of the higher dose with a response rate of 33% and clinical benefit rate (response rate and CA125 decline) of 57% with mild toxicity. Fong et al. reported a 46% response in 46 ovarian cancer patients with germline mutations who received prior platinum-based therapy [97]. Response to prior platinum-based therapy was an important predictor of response to second-line AZD2281. O'Shaughnessy et al. presented a Phase II study evaluating BSI-201, a PARP1 inhibitor, in combination with gemcitabine/carboplatin, compared with chemotherapy alone for patients with metastatic triple-negative breast cancer [98]. Addition of PARP1 inhibitors resulted in improved median progression-free survival (6.9 vs 3.3 months; HR: 0.342; p < 0.0001) and median overall survival (9.2 vs 5.7 months; HR: 0.348; p = 0.0005) compared with gemcitabine/carboplatin alone. We are awaiting additional information from those and further studies. The predicted sensitivity of BRCA mutation-carrying tumors to PARP inhibitors and other DNA damaging agents led Hennessy et al. to a very innovative research of nongermline mutations [99]. BRCA½ exons/flanking regions were sequenced in 235 high-grade ovarian cancers and 38 ovarian cancer cell lines; 27% of serous ovarian cancers had somatic mutations. The response of nongermline BRCA-mutation carriers warrants investigation. A new generation of similar selective drugs is currently under investigation.
Prognosis of EOC in BRCA-mutation carriers
Most studies reported better prognosis in patients with EOC who are carriers of the BRCA-mutated genes, although other studies have failed to validate those findings and several additional investigations are ongoing. Prognosis of BRCA carriers with EOC was evaluated in a number of studies [9–22]. Those studies have been conducted in different ways; some had a more homogenous population, such as patients with the three common Ashkenazi Jewish mutations, while others evaluated groups with other founder mutations or mixed populations. Different methods of patient collection were used, different methods of statistical analysis and different methods of genetic analysis were employed – all of these and other factors might have contributed to the diverse results. All patients were treated with platinum-based therapies; a smaller fraction was treated with combined platinum- and paclitaxel-based chemotherapy. Most of these studies demonstrated a favorable survival for BRCA-mutation carriers compared with noncarriers, while others did not confirm these observations (
Prognosis of epithelial ovarian cancer patients in BRCA-mutation carrier and noncarriers: studies summary.
HR: Homologous recombination; NS: Not significant.
Expert commentary
Epithelial ovarian cancer is the number one killer among gynecological malignancies, and most patients will die of the disease despite improvement in response to chemotherapy. While disease-free survival and overall survival have been extended by chemotherapies that have emerged during the last 2 decades, recurrence and death rates are high and the search for a better therapy continues. The documentation of improved prognosis in BRCA-mutation carriers has generated extensive research. Studies have demonstrated that defective HR due to BRCA deficiency increases sensitivity to chemotherapeutic agents that cause DNA double-strand lesions, such as mitomycinC, cisplatin, etoposide and anthracyclines, among others, and probably increases resistance to drugs such as taxanes and navelbine. Today's challenge is to clinically demonstrate the superiority of DNA-damaging drugs, such as platinum salts, anthracyclines and others, and, at the same time, to question the role of taxanes and anti-microtubuls drugs in order to better treat this class of patients. Prospective trials evaluating the clinical benefit of drugs from each groups (i.e., DNA-damaging or antimicrotubule drugs) on BRCA-mutation carriers are warranted. A few recent studies have reported secondary platinum resistance by secondary mutation following treatment with platinum; this calls into question the length of improved survival by platinum treatment and calls for additional targeted effective drugs. New groups of targeted drugs, such as PARP inhibitors, are under investigation.
The collective data suggest that BRCA functions as a molecular indicator of response to a range of different chemotherapeutic agents and hopefully prediction of response to a specific agent will become increasingly significant for treatment development. Therefore, we suggest that the BRCA gene classification will be considered in all EOC patients, BRCA levels and BRCA1 mRNA expression level should be considered as a potential predictive marker for response to chemotherapy in both sporadic and inherited ovarian cancer. In addition, information regarding chemosensitivity of additional EOC patients, a group without BRCA mutations but with reduced activity of BRCA, may be revealed. New biomarkers are under investigation and hold the potential to contribute to changing the dismal picture of EOC survival.
For the first time, we may be approaching an era in which subclassification of women with ovarian cancer could lead us to a personalized and targeted treatment that will hopefully benefit patients by enabling considerably longer survival and enhanced quality of life. New targeted drugs, such as PARP inhibitors, are currently under intensive investigation and hold the potential to alter the prognosis of BRCA-mutation carriers. At present, EOC patients who are BRCA-mutation carriers should be treated with platinum-based combination chemotherapy and, if possible, be exposed to PARP inhibitors that appear to have a relatively mild toxicity profile.
The most intriguing and challenging pharmacological research should be directed to drug development based on a specific match between a patient's biology and the therapeutic agent. In addition, discovery of biomarkers is essential for a directed treatment according to the patient's specific and unique tumor vulnerabilities.
Future perspective
Ovarian cancer among BRCA1- and BRCA2-mutation carriers appears to have a better prognosis, mainly due to faulty HR DSB repair. A better understanding of biological processes, of interactions with different chemotherapies and of biomarkers, such as BRCA activity and BRCA1 mRNA, could improve our ability to choose the most effective chemotherapy for these women. BRCA is already evaluated routinely in many centers and different biomarkers are investigated. BRCA levels and BRCA mRNA levels probably will soon be evaluated for regular use. It is not known yet which one of the markers predicts better response to chemotherapy; BRCA mutations, BRCA protein levels or BRCA mRNA expression levels. Platinum-based combinations are crucial for the treatment of BRCA-mutation carriers, other DNA damaging chemotherapies, such as anthracyclines and alkylating agents, may also have a role. As a representative of anthracyclines, the special role of pegylated liposomal doxorubicin is already being studied; temozolomide with PARP inhibitors as representative of the alkylating agents are also being studied. New groups of drugs are now being developed, specifically targeting the ‘weak’ points of tumor cells with mutated or reduced BRCA genes and proteins. A good example is the exacerbated DNA damage caused by PARP inhibitors in BRCA-deficient tumors. PARP inhibitors and other targeted agents are currently evaluated both clinically and preclinically. The role of different PARP inhibitors alone and in combination with carboplatin, temozolomide and other compounds, both in carriers and noncarriers are evaluated in many small groups. Several advanced-phase studies are being conducted evaluating EOC tumor response in BRCA-mutation carriers (e.g., the Dose-finding Study Comparing Efficacy and Safety of a PARP Inhibitor Against Doxil in BRCA+ve Advanced Ovarian Cancer [ICEBERG 3] with AZD2281, KU-0059436) and as maintenance therapy for platinum-sensitive high-grade EOC in carriers and noncarriers. Another PARP1 inhibitor (BSI-201) is also evaluated in carriers. Preliminary reports show antitumor activity with mild toxicity [100]. Guided and targeted therapy will hopefully change the course of this lethal disease at its onset in BRCA-mutation carriers.
Executive summary
Epithelial ovarian cancer (EOC) is the primary cause of death from gynecologic malignancies in Western countries.
A total of 10–15% of EOC are inherited, and most of them are associated with BRCA (breast cancer susceptibility genes) mutations.
BRCA1 and BRCA2 mutations are high-penetrance, dominantly inherited germline mutations of major susceptibility genes, associated with breast and ovarian cancer syndrome.
Female carriers of BRCA mutations have a 12–46% lifetime risk of developing ovarian cancer.
EOC patients who are BRCA-mutation carriers are suggested to have improved prognosis compared with noncarriers.
BRCA genes act as caretakers and gatekeepers. Caretakers have the ability to repair DNA damage and prevent genomic instability and mutations, while gatekeeper genes control cell division, lifespan and apoptosis, promoting the outgrowth of cancer cells.
BRCA1 and BRCA2 are crucial for the repair of double-strand DNA breaks.
BRCA1 acts mainly outside the damage site, arresting cell cycle and recruiting the necessary proteins and enzymes.
BRCA2 acts mainly at the damaged site, bound to RAD51 (a recombination enzyme) and additional recombination proteins.
Inactivation of BRCA genes lead to chromosomal instability and may initiate or promote mutations and carcinogenesis.
Double-strand breaks are repaired by two major pathways: an ‘error-prone’ mechanism and a ‘nonerror-prone’ mechanism.
Nonhomologous end joining pathway, where the broken DNA ends are religated after excision, with the addition or deletion of nucleotides at the site, leads to error-prone, mutagenic repair.
Homologous recombination is the preferred pathway for DNA double-strand break repair; the damaged strand is repaired using an intact sister chromatid as a copying template.
Homologous recombination plays an essential role during DNA replication and prevents chromosomal aberrations.
BRCA genes are essential for homologous recombination and to the proper repair of DNA double-strand breaks that arise spontaneously or are induced by exogenous agents, including chemotherapy and radiotherapy.
Reduced efficacy of DNA-repair mechanism makes tumor cells more susceptible to cytotoxic drugs.
Preclinical and clinical studies have suggested BRCA to be an important determinant in the response to both DNA-damaging chemotherapy (e.g., cisplatin and adriamycin, among others) and taxane-based chemotherapy (e.g., paclitaxel and docetaxel).
BRCA mutation might be a predictor of survival in patients with advanced ovarian carcinoma, probably owing to the increased benefit from platinum-based chemotherapy.
Poly (ADP-ribose) polymerase (PARP)-1 and −2 is a group of polymerases that facilitate DNA single-strand break repair prior to the replication fork. PARP inhibitors cause an increase and persistence of single-strand breaks.
A single-strand DNA break, if not properly repaired, might develop into double-strand breaks upon replication. In BRCA-mutation carriers, DNA double-strand break repair is impaired and tumor cell damage is significantly increased.
Promising new clinical information of the use of PARP inhibitors in ovarian and breast cancer reports anticancer activity and mild toxicity; improved efficacy has been reported in BRCA-mutation carriers.
Footnotes
Acknowledgements
The author would like to thank Vered Granek, PhD, for editorial assistance.
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.