Abstract
Ovarian cancer is the leading cause of death in women with gynecological cancer, since a large proportion of patients are diagnosed at later stages of the disease. The incidence of ovarian cancer in the general population is 2%, but patients with germline mutations in the BRCA genes have a risk of developing ovarian cancer of up to 2050% with a cumulative risk of ovarian cancer at 70 years of age of 40% in BRCA1 and 18% in BRCA2 mutation carriers. Although it is a chemosensitive tumor, most of the patients after surgery and chemotherapy based on taxanes and platinum will relapse later in life. Due to the high risk of developing ovarian cancer in patients with BRCA germline mutations, new treatments rely increasingly on histological and molecular characteristics of the primary tumor, achieving greater selectivity and lower toxicity compared with standard cytotoxic agents. Poly (ADP-ribose) polymerase (PARPS) inhibitors are the first biologically active agents for patients with ovarian cancer with alterations in the DNA repair pathway, particularly in the high-grade serous subtype of ovarian cancer.
Keywords
- PARP inhibitors
- Olaparib
- Mutant epithelial ovarian cancer
- Tumor suppressor Genes BRCA1 and BRCA2
- Novel therapies for ovarian cancer
1. Introduction
The usual treatment of advanced disease of ovarian cancer is surgery [1] followed by taxane and platinum-based chemotherapy, although a large proportion of patients will relapse throughout their lives. Therefore, current clinical trials focus on the detection of molecular targets that can act more selectively and efficiently on ovarian cancer [2].
It is known that chemotherapy treatments damage the DNA and there are molecules that are responsible for repair and proper maintenance of the genome such as poly (adenosine diphosphate-ribose) polymerase (PARP), which plays a key role in the repair of DNA single-strand breaks; so, researchers have focused on the mechanism for the development of new therapies, including the PARP inhibitors.
Olaparib is the first PARP-inhibitor class recently approved for the treatment of ovarian cancer with mutations in
2. BRCA1 and BRCA2 genes
Most breast cancers and hereditary ovarian cancers are associated with mutations in two genes, breast cancer type 1 and 2 susceptibility genes (
Studies suggest that mutation in p53 favor loss of functionality of the
The
The
Hereditary breast and ovarian cancer (HBOC) syndrome is characterized by an autosomal dominant inheritance with high penetrance, presenting increased susceptibility to breast and ovarian cancer, although it has been shown that
Women with hereditary ovarian cancer may have higher rates of response to chemotherapy and improved survival rates in cases of sporadic cancer.
In 2012, the results of an analysis were published [11] in which data from 26 observational studies on the survival of women with ovarian cancer with germline mutations in
Data from 1,213 cases with a germline mutation in
Detection of
There are over one thousand different mutations to
It is known that the mutation in the
After the diagnosis of breast cancer in a patient with a
Diagnosis in elderly or the absence of family history does not exclude the presence of a germline mutation as approximately 35% of the
The presence of
It is important that families carrying this mutation are informed about the risks of developing various types of cancer, including education about prenatal diagnosis and assisted reproduction. Another option is IVF with previously selected embryos. Although, the decision should finally be made on an individual basis and will depend on the preference of each patient.
3. Patients with ovarian cancer BRCA genes mutations syndrome
Ovarian cancer is the principal cause of death in women with gynecological cancer, due to the late onset of symptoms and the absence of a method for early detection. Nulliparity, early menarche, and late menopause are associated with an increased risk of occurrence; however, the strongest risk factor is the history of ovarian cancer in a first-degree relative [17].
Malignant primary ovarian tumors fall into three main groups: epithelial, sex cord / stromal, and germ cell tumors. Epithelial tumors being ovarian carcinomas (CBs), which are the most common group, represent up to 90% of ovarian cancers. Low-grade and high-grade serous carcinoma (LGSC and HGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC), and clear cell carcinoma (CCC) are the five histological subtypes of OCs that are known. It is important to make a proper histological typing to determine the prognosis and response to different treatments, including cisplatin [18].
A large proportion of ovarian tumors are sporadic, and only a minority is due to an inherited cause.
c-myc amplification or other proteins are needed for proper homologous recombination [21–24]. The loss of function of suppressor gene
The HGSC subtype has a greater sensitivity to PARP inhibitors without a
Studies describe that
In HBOC syndrome, mutations in the
3.1. Prevention of ovarian cancer in women who have mutations in BRCA1 and BRCA2 genes
Primary prevention strategies consist of primarily risk-reducing surgeries, the procedure of choice being prophylactic salpingo-oophorectomy bilateral from 35 to 40 years, or after childbearing. Some experts also recommend prophylactic hysterectomy to dry the small portion of remaining fallopian knotweed, although 92% of fallopian tube neoplasms originate in the middle or distal portion of the tube [34]. Although the final decision will be made by the patient.
Patients with
After prophylactic surgery, one of the most important side effects which can deteriorate the quality of life of patients is premature menopause, with increased risk of osteoporosis and cardiovascular diseases such as hypertension, diabetes, and hypercholesterolemia. So that closer monitoring is recommended for cardiovascular risk [36].
Secondary prevention is early detection strategies in women carrying mutations in the
Despite the greatly reduced risk of developing ovarian cancer after prophylactic surgery, patients should know that a minority (from 3.9% to 4.3%) of them will develop primary peritoneal carcinoma 20 years after the last oophorectomy in patients with
4. Inhibitors of poly (ADP -ribose) polymerase
The preservation of the genetic code by DNA repair is essential for proper cell function. Currently, there is a better understanding of the DNA repair pathways, so it has been studied more carefully for potential drug targets [40].
There are at least five ways engaged in DNA repair, two of them involved in the repair of double-strand breaks (error-prone, non–homologous, end–joining, predominantly active in G1 cells, and error-free HRR, which predominates in dividing cells) [41].
The major DNA repair pathways are direct repair, mismatch repair (MMR), the base excision repair (BER), nucleotide excision repair (NER), and double-strand break repair recombination, which includes both non-homologous, end-joining and homologous recombination repair (HRR) [41,42].
There are certain external agents such as ionizing radiation producing damaging DNA strand breaks. Normal cells have the ability to repair this damage by a protection mechanism maintaining its normal function, but the tumor cells’ ability to repair DNA is a radio-resistance mechanism. In recent years, studies have identified a number of agents in these pathways such as PARP inhibitors [43].
Poly (ADP-ribose) polymerase (PARP) inhibitors are a new class of targeted agents against ovarian cancer [44–46]. PARP is a nuclear enzyme whose function is to repair single-stranded DNA.
There are three generations of PARP inhibitor. The first generation of inhibitors included nicotinamide analogs. 3-Aminobenzamide was the first PARP inhibitor but was not considered powerful enough compared to the second generation [47]. Currently, clinical trials are aimed at third-generation inhibitors with greater potency and specificity, decreasing side effects, this includes olaparib.
DNA repair is essential for proper cell function. Each cell sustains many thousands of episodes of DNA damage every day, which will be repaired by a wide variety of repair mechanisms [48,49].
The
Other DNA repair pathway, such as the non-homologous, end-joining (NHEJ) pathway, also plays a role in the anti-cancer mechanism of action of PARP inhibitors [50].
PARP inhibitors act by trapping PARP-1 and PARP-2 on the double-strand break and blocks DNA replication, which is more toxic to cells than the accumulation of DNA breaks [51]. Overall, in tumors in where there is an apparent defect in homologous DNA repair (and thus a defect in the repair of double-stranded breaks), they seem to be susceptible to PARP-inhibitor therapy. These include tumors associated with germline or somatic mutations in
There are at least 17 PARP counterparts, with only three PARP-1, PARP-2, and PARP-3s that play a critical role in DNA repair [53,54]. The best known are PARP-1 and PARP-2 [55, 56], and the most studied PARP-1.
PARP-1 was the first to be reported in 1963 [57]. Durkacz [58] stated that modulating PARP1 could enhance the effect of chemotherapy.
PARP-1 contains three functional domains: the N-terminal DNA-binding domain (DBD), the center self-modification domain (DMA), and the C-terminal catalytic domain (CD). The DBD is involved in recognition of DNA-strand breakage and in the binding of PARP-1 to DNA. AMD can interact with many DNA damage response proteins and the CD includes a PARP signature motif and catalyzes the formation of PAR [59]. PARP-1 is essential for base excision repair (BER).
PARP-1 also contributes to other cellular processes such as gene transcription, and the regulation of the chromatin structure, to restart stalled replication forks due to nucleotide depletion or collisions with bulky lesions [52].
PARP-1 has been used in in vitro studies in combination with chemotherapy, to demonstrate its ability to inhibit the classical mechanisms of DNA repair, showing also increased distribution of cytotoxicity to the tumor, increasing their exposure by improving vascular perfusion. This resulted in further studies with PARP-1.
The DNA repair biology has allowed us to identify patients most likely to respond to treatment with PARP inhibitors [60].
PARP inhibitors act by synthetic lethality, which occurs when two independent conditions alone do not cause cell death but in combination are lethal. It occurs when a patient has an alteration in the homologous recombination (HR) such as in carriers of a mutation in
PARP-2 cooperates with PARP-1 to synthesize poly (ADP-ribose) [pADPr] after damage in the DNA chain [41]. PARP-3 suppresses error-prone NHEJ [52, 64,65] while associated with PARP-1 for DNA repair. The clinical development of PARP-inhibitors has lead to its use as monotherapy or in combination with chemotherapy agents. Olaparib has been recently approved for the treatment of hereditary breast ovarian cancer syndrome, and other PARP-inhibitors such as veliparib, rucaparib, or niraparib are being studied [66].
4.1. Combination therapy of PARP inhibitors and radiotherapy
The efficacy of radiotherapy in the treatment of cancer have been known for several years either concomitantly with chemotherapy or as adjuvant use in therapy.
New clinical trials not only focus on researching new systemic treatments alone or in combination with other chemotherapy agents but also study their association with radiotherapy. These new therapies are the PARP inhibitors that have shown activity in conjunction with radiation therapy in several cancer cell lines. Data suggest that PARP inhibitors may enhance the effects of radiation in various types of tumors, such as lung cancer, colorectal, and cervical among others [67]. However, the mechanism of action is still unknown, one hypothesis is that it is due to mutual damage (of PARP-inhibitors and radiotherapy) of DNA or whether tumor re-oxygenation contributes to this radio sensitization via the vasoactive effects of the PARP inhibitors remains to be fully determined [43].
A recently published Phase I clinical trial [68] combined low-dose abdominal level fractionated radiotherapy with increasing doses of the PARP-inhibitor veliparib in patients with peritoneal carcinomatosis secondary to advanced malignant solid tumors. Patients were treated with veliparib (80–320 mg daily) for a total of 3 cycles.
The dose of radiotherapy consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1–3 of each cycle. Twenty-two patients were included. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (MPFS) was 4.47 months and median overall survival (MOS) was 13.04 months. In the trial, there were 8 patients with ovarian and fallopian cancers with an observed MPFS of 6.77 months and an MOS of 17.54 months, combined with a higher quality of life. The toxicity grade 3 and 4 lymphopenia were more frequent (68%), anemia (9%), and thrombocytopenia (14%). With these results, the authors concluded that the combination of radiotherapy and veliparib resulted in a stabilization of the response in patients with solid tumors and peritoneal carcinomatosis, especially in the subgroup of patients with ovarian cancer, besides being a well-tolerated regimen.
5. OLAPARIB
Because many cytotoxic agents work by damaging the DNA, there has been a great deal of interest in the use of inhibitors of DNA repair such as new treatments against cancer, especially in patients with mutations in the
Olaparib is a member of the class of N-acylpiperazines formally obtained by condensation of the carboxyl group of 2-fluoro-5 - [(4-oxo-3,4-dihydrophthalazin-1-yl) methyl] benzoic acid with the free amino group of N- (cyclpropylcarbonyl) piperazine.
5.1. Initial clinical trials with OLAPARIB
In 2008, Rottenberg et al. [70] postulated the hypothesis of the use of olaparib (then called AZD2281, KU-0059436) in cancer triple negative breast, because these tumors harbor defects in DNA repair and mutations in
Evers et al. [71] studied sensitivity to conventional cytotoxic drugs AZD2281 in cell lines with
Fong et al. [60] conducted a Phase I clinical trial with escalating doses of mg to 600mg olaparib, in a population of 60 patients, including 22 mutation carriers in the
In this study, patients resistance to platinum response was observed.
A year later, the same team of Fong et al. confirmed previous results by expanding a cohort of patients with mutations in
Seventy five percent of
Kaye et al. published the results of a Phase II trial in 2012. The study included 97 patients with ovarian cancer and
Lederman et al. [76] reported on a Phase II trial; they administered olaparib as a maintenance therapy in patients with recurrent ovarian cancer or fallopian tube or primary peritoneal cancer of high-grade, which was platinum-sensitive. Patients were randomized to receive olaparib 400 mg twice daily or placebo within 8 weeks after the last dose of platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS). A first analysis performed after progression in 57.7% of patients showed that PFS was significantly longer in the olaparib group than in the placebo group. Median PFS was 8.4 months in the olaparib group versus 4.8 months in the placebo group (
In the interim analysis of overall survival (OS), 101 patients (38%) had died: 52 in the olaparib group and 49 in the placebo group. No significant difference in overall survival was observed (
The incidence of adverse events grade 3 or 4 was higher in the olaparib group (35.3%) compared to the placebo group (20.3%). The most common adverse events leading to discontinuation or dose reduction of olaparib were vomiting, nausea, and fatigue. There were no statistically significant differences in quality of life test performed patients.
In another study, Lederman et al. [77] presented test data 19, a second retrospective analysis of OS, and
There were more treatment interruptions and dose reductions in the olaparib group compared to placebo. Adverse effects grade 3 or 4 in the olaparib group were fatigue in 7% vs. 3% in the placebo group, and anemia 5% vs. <1%, respectively. Serious adverse effects were reported in 18% of patients receiving olaparib compared to 9% on placebo. Tolerability was similar regardless of the mutational status.
Although the number of patients treated with somatic
The test of olaparib superiority over the placebo in platinum-sensitive patients demonstrated that patients relapsed after treatment. In addition, it was shown that
After the results of test data19 were published, olaparib was approved by EMA as a maintenance therapy after response to platinum-based chemotherapy in relapsed platinum-sensitive ovarian cancer, fallopian tube, and primary peritoneal cancers patients with a
Before starting treatment with olaparib, they confirmed the presence of a
It also assessed the efficacy and tolerability of olaparib in combination with chemotherapy followed by maintenance olaparib versus chemotherapy alone in patients with high-grade serous ovarian cancer, including primary peritoneal and fallopian tubes, platinum-sensitive who had received three or more lines of platinum-based chemotherapy. AM Oza et al. [78] published data based on chemotherapy combination of carboplatin (area under the curve [AUC] 4 mg / mL per min) plus paclitaxel (175 mg / m2) every 21 days with olaparib 200 mg twice daily (during days 1–-10 of each cycle of 21 days), 6 total cycles followed olaparib maintenance monotherapy (400 mg twice daily) until disease progression or unacceptable toxicity, compared to chemotherapy alone (carboplatin AUC 6 mg / mL paclitaxel 175 mg / m2) without maintenance. The primary endpoint was PFS, the secondary efficacy endpoints were overall survival; percentage change in tumor size; the proportion of patients with an objective response according to RECIST; cancer antigen 125 (CA-125) response.
The results concluded that the PFS was higher in the olaparib plus chemotherapy group (median 12.2 months) compared with chemotherapy alone (median of 9.6 months).
Not only olaparib has been studied in combination with chemotherapy, but their association was also analyzed with cediranib, an anti-angiogenic agent with activity against the VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. In Phase I clinical trials, combination responses and manageable toxicities were observed, so that a Phase II clinical trial was developed aimed at demonstrating whether their combination would result in increased PFS versus olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. The trial was conducted by Liu [79].
They recruited women with ovarian (HGSC and EC), fallopian tube or primary peritoneal cancer, or patients with a
Because of the mechanism of action of olaparib, the use of PARP inhibitor in other tumors with mutations in the
And 298 patients were evaluated, of whom 193 had ovarian cancer, 62 had breast cancer, 23 had advanced pancreatic cancer, and 8 patients with advanced prostate cancer. The remaining 12 patients had a range of cancers, including cancers of the biliary tract, bladder, colorectum, lung, esophagus, and uterus.
The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1) in patients with ovarian cancer, 12.9% (eight of 62; 95% CI, 5.7 to 23.9) in breast, 21.7% (five of 23; 95% CI, 7.5 to 43.7) in pancreatic, and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in prostate cancers. In 42% of all patients, stable disease was observed after 8 weeks of treatment, up to 46.8% having achieved stabilization in cases of breast cancer. Overall median duration of the response was 208 days (ovarian cancer, 225 days; breast cancer, 204 days; pancreatic cancer, 134 days; prostate cancer, 327 days). Median time to onset of response was 56.0 days (ovarian cancer, 56.5 days; breast cancer, 54.5 days; pancreatic cancer, 113.0 days; prostate cancer, 54.5 days). The objective response rate (restricted to those with measurable disease at baseline) was 29.3% (95% CI, 23.9 to 35.2).
A similar response rate for patients with a
The most common side effects were fatigue, nausea, and vomiting. About 54% of patients experienced grade 3 toxicity, most frequently fatigue and anemia, 40.3 % of patients had to modify (interruption and / or reduction) olparib dose due to adverse effects. Nine patients died as a result of severe adverse effects.
After these results, they concluded that the response to olaparib is independent of the anatomical organ of origin, provided that there is a mutation in
Despite the demonstrated efficacy of PARP inhibitors in patients with
5.2. Phase III clinical trials
Currently, there are two Phase III trials underway with olaparib, both sponsored by Astra Zeneca: SOLO 1 (NCT01844986) and SOLO2 (NCT01874353). Both are multi-center, double-blind, in which randomly assigned patients (2: 1) receive 300 mg of olaparib daily maintenance in patients diagnosed with high-grade serous or endometrioid ovarian cancer, primary peritoneal including and / or fallopian tube cancer with a
Not only they are testing olaparib, but there are also other Phase III trials with PARP inhibitors, such as veliparib, rucaparib, and niraparib, trying to improve the identification of patients who might best respond to PARP inhibitors [80] and reducing associated toxicities.
5.3. Combination therapy of OLAPARIB with other therapeutic agents
Olaparib has been tested in several clinical trials in combination with other chemotherapy because it was thought that it could increase sensitivity to chemotherapy by inhibiting DNA repair which could be responsible for drug resistance. This has been associated with topotecan [85], dacarbazine [86], paclitaxel [87], and cisplatin and gemcitabine [88]. In several Phase I clinical trials, myelosuppression increased in the combination therapy versus monotherapy, especially with topotecan and cisplatin.
Olaparib has also been studied in combination with bevacizumab. Dean et al. [89] designed a Phase I clinical trial, as they hypothesized that bevacizumab antiangiogenic activity and hypoxia inducing DNA damage may enhance olaparib therapeutic activities. They showed that a dose of olaparib 400 mg twice daily in combination with Avastin 10mg / kg every two weeks was tolerated well. They are considering the combination for future clinical trials.
5.4. Dosage
The recommended lynparza® (olaparib) dose is 400 mg (eight capsules) twice a day, i.e., a total daily dosage of 800 mg. Treatment should begin before eight weeks of completion of the last cycle of chemotherapy with a regimen containing platinum. Continual treatment is recommended until disease progression. The recommended dose is reduced to 200 mg orally twice daily (total daily dose 400 mg). Elderly patients require a dose reduction initially, and it can be administered in patients with mild renal impairment (creatinine clearance> 50 mL / min).
5.5. Adverse reactions
Among the most frequent toxicities in clinical trials are hematologic toxicity with mild to moderate anemia, lymphopenia, neutropenia, and thrombocytopenia at manageable levels. Other frequently observed side effects are headache, fatigue, decreased appetite, abdominal discomfort, nausea, vomiting, diarrhea, and dyspepsia.
Another event that was observed was the development of myelodysplastic / AML syndrome, in only a small number of patients receiving olaparib alone or in combination with other antineoplastic during clinical trials. All had previously received platinum-based chemotherapy regimens, radiation, and other DNA-damaging agents.
There have been cases of pneumonitis, some of them being fatal. If patients are treated with Lynparza, respiratory symptoms such as cough, dyspnea, and fever should be closely monitored. If there is any alteration in the chest radiography, treatment must be stopped and the patient is treated appropriately. Paralyzer can cause birth defects if given to pregnant women. A reliable contraception should be recommended during treatment and one month after the last dose [90,63].
6. Mechanisms of resistance to PARP inhibitors
Targeted therapy based on the patient’s mutation status is the future of the treatment of ovarian cancer.
7. Conclusions
The context of the
8. Future directions
Tumors with alterations in DNA repair lead to a defective HR, based on synthetic lethality and being very sensitive to PARP inhibitors. This happens with HGSC
We have studied the operation of Rad5 using antibody detection of Rad5 as new response PARP-inhibitors biomarkers, although initial results suggest that is not sufficient, specific and sensitive for use in clinical application, so we need to keep looking for new biomarkers or methods that help us to identify the appropriate patients for treatment with PARP inhibitors [52]. As not all genes responsible for DNA repair are known, another option that has not yet been implemented is to apply functional tests of DNA-repair capability, this would help us identify the abnormalities and tumors suitable for treatment with PARP inhibitors [95], the molecules involved in
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