19.09.2014

Journal article on ovarian cancer 3c

In young women with HGSC or CCC, the possibility of hereditary conditions such as BRCA1 or BRCA2 mutations or Lynch syndrome must be considered. Of the most common histologic subtypes of ovarian cancer, serous carcinoma occurs most often, followed by CCC and EC, which are diagnosed with almost equal frequency. HGSCs are characterized by papillary (Figure 1A), glandular, solid, and transitional (Figure 1B) patterns. As previously noted, it is now well-established that HGSC and LGSC represent two distinctly different disease entities rather than grades of the same tumor.[3,6-8,41-43] Serous carcinomas were traditionally graded as well-differentiated, moderately differentiated, and poorly differentiated. Although HGSCs are thought to arise from the ovarian surface epithelium or cortical inclusion cysts, no definite precursor lesions have been identified.
Conversely, LGSC is thought to arise from preexisting cystadenoma or serous borderline tumor (SBT) that eventually progresses to invasive carcinoma.
Although patients with low-grade neoplasms usually have recurrences that are low-grade tumors, we have encountered cases of LGSC either coexisting with HGSC or recurring as HGSC. In most cases, immunohistochemical stains are not necessary for making a diagnosis of either HGSC or LGSC.
Lastly, from a clinical standpoint, although LGSC presents in younger women and is resistant to chemotherapy, overall survival is better than that of patients who have HGSC.[7,8,41,62] While HGSC responds well to chemotherapy initially, patients frequently experience recurrence and succumb to the disease. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics.
We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Phthalates are commonly used as plasticizers in the manufacturing of flexible polyvinyl chloride products.
Phthalates are ubiquitous environmental toxicants to which humans are exposed on a daily basis (1).
Phthalates are non-covalently bound to plastics, meaning they frequently leach from these items into environmental sources such as in the atmosphere, soil and sediments, and natural water bodies (10–12).
The widespread production of phthalates, their use in commonly used products, and their presence in the environment leads to daily human exposure via oral ingestion, inhalation, and dermal contact. Once consumed, phthalates are rapidly metabolized in the gut, liver, and blood by esterases and lipases. As mentioned, the vast majority of the population is exposed to phthalates on a daily basis, but the level of exposure to each phthalate differs. Interestingly, certain individuals are exposed to much higher levels of phthalates than the general population. Important for the topic of this review, women have a phthalate exposure profile that is different than that in men. Exposure to phthalates is a public health concern because several have been identified as reproductive and developmental toxicants and endocrine-disrupting chemicals (EDCs). The ovary is the female gonad responsible for reproduction and is a primary component of the female endocrine system.
One of the primary functions of the ovary is the development and maturation of follicles to allow for ovulation of the oocyte for subsequent fertilization.
Ovarian follicle assembly then occurs around the sixth to ninth month of gestation in the human and around post-natal day 3 in the rodent in which the most immature follicle type, the primordial follicle, is formed (50, 51). Once the primordial follicle population is established, the follicle is destined to three fates: to remain quiescent for varying lengths of time to constitute the ovarian reserve, to directly undergo atresia, which is follicular programed cell death via apoptosis, or to activate into the growing population of follicles to become primary follicles, a process termed primordial follicle recruitment.
Once activated, primary follicles contain a larger oocyte that has initiated growth surrounded by a single layer of cuboidal granulosa cells. Preantral follicles then develop further into antral follicles, which are the most mature follicle type in the ovary. Not all follicles are destined to develop and ovulate, and in fact, approximately 99% of follicles undergo atresia. Another primary function of the ovary is to produce sex steroid hormones, a process termed ovarian steroidogenesis.
The steroid hormones produced by the ovary act on numerous target tissues associated with reproductive and non-reproductive function. The generation of sex steroid hormones involves several enzymatic reactions in both the theca and granulosa cells. Interestingly, estradiol cannot be synthesized without the strict coordination of both theca cells and granulosa cells and the addition of pituitary-derived FSH and LH. Ovarian cancer (OvCa) accounts for the majority of gynecologic cancer deaths in the United States (1). Preclinical studies demonstrate potential interaction between angiogenesis and DNA damage repair pathways.
PolyADPribose polymerase inhibitors are a novel class of drugs designed to compete with NAD+ for the substrate binding site of PARP, preventing DNA single strand break repair process through the base excision repair pathway (14). The randomized study with the internal translational substudy was approved by the institutional review boards of the participating sites, and written informed consent was obtained from participating patients; clinical study details including drug administration, safety, adverse events, and tumor response have been reported and the schema for treatment is shown in Figure 1 (13).
Blood was collected in citrated CPT cell preparation tubes (BD Vacutainer, Franklin Lakes, NJ, USA). Plasma samples were collected in K2EDTA tubes (BD Vacutainer) and were processed within 2 h of collection.
Peripheral blood mononuclear cell DNA PARylation was measured using a commercial immunoassay according to the manufacturer’s instructions (Trevigen, Gaithersburg, MD, USA) (24).
Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) was performed to assess changes in vascular permeability (Ktrans) and perfusion (Kep) (26). Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. This substudy reports on 13 self-selected participants of the multi-institutional randomized phase-2 study of recurrent platinum-sensitive OvCa patients who were treated with olaparib capsules (200 mg twice a day) and cediranib (30 mg daily) or olaparib capsules alone (400 mg twice a day) until disease progression (13).
It has been reported that inhibition of angiogenesis induces a feedback response with induction of angiogenic precursors (29–31).
Circulating cytokines have been proposed as potential biomarkers of response to anti-angiogenics (32, 33). PolyADPribose polymerase inhibitors activity was measured by polyADPribose (PAR) incorporation into PBMC DNA.
Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies targeting biological pathways. PARPi have shown to enhance cytotoxicity in combination with DNA methylating agents (10, 11), topoisomerase inhibitors (12, 13), platinums (14, 15), alkylating agents (14), and radiation (16, 17) in numerous preclinical studies. DNA damage can occur through various mechanisms from environmental factors such as ultraviolet rays, ionizing radiation, and genotoxic chemicals, to endogenous processes including generation of reactive oxygen species and replication (35). PARP are a family of enzymes that catalyze nicotinamide adenine dinucleotide (NAD+)-dependent ADP-ribosylation of DNA.
PARPi are a class of drugs designed to compete with NAD+ for the substrate binding site of PARP, acting as an effective catalytic inhibitor (47). Understanding DNA repair biology has allowed the identification of patient subsets with high potential for response to PARPi treatment. The BRCA-like behavior has been described based on clinical and molecular features that parallel gBRCAm-associated cancers’ characteristics. Little is known about the underlying cause of hereditary cancer predisposition in melanoma and its impact on the prognosis and therapeutic decisions. PARPi have multiple targets in DNA repair pathways that can potentially promote cancer cell death. Hereditary pancreatic cancer is rare and extremely heterogeneous, and it accounts for approximately 2% of all pancreatic cancer cases.
Interim results from an ongoing phase II study of olaparib monotherapy in gBRCAm-associated advanced solid cancers were recently reported (99). Single-agent olaparib has demonstrated activity in patients with gBRCAm castration resistant prostate cancer (CRPC). Gene fusion between the ERG proto-oncogene and TMPRSS2 promoter is a major genomic alteration observed in approximately 50% of prostate cancers. Other preclinical studies include radiosensitization by rucaparib, most evident in PTEN-deficient prostate cancer cells containing the TMPRSS2-ERG fusion gene (109). Veliparib has also been investigated and shown to enhance the anti-tumor activity of TMZ in prostate cancer xenografts, yielding tumor size reduction in TMZ-resistant PC3-Leu prostate cancer mice (112). Preclinical data suggest the utility of PARPi in tumors deficient in HR and displaying microsatellite instability (MSI) due to mutations in the coding microsatellites of the MRE11A and hRAD50 genes involved in DNA DSB repair (114).
Dozens of potential PARPi have been screened in vitro and in vivo to select candidates for clinical evaluation as a chemosensitizer in CRC (117). Studies have evaluated and validated veliparib as a sensitizer to irinotecan, oxaliplatin, and radiation therapy (RT) in CRC cells (26, 119). Reduced BRCA1 mRNA and protein expression levels have been observed in up to 44% of NSCLC, occurring through various mechanisms such as promoter hypermethylation (121). The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. While the majority of ovarian cancers are sporadic, family history is one of the strongest risk factors. Seidman et al found that among 220 consecutive patients with surface epithelial carcinoma, almost 80% of cases of intra-abdominal carcinomatosis were of serous histology, especially when peritoneal carcinomas, carcinosarcomas, and mixed carcinomas with serous component were included.[30] Thus, it is now well-established that serous carcinomas represent the majority of advanced-stage ovarian cancers. The diagnosis of HGSC is typically straightforward, especially when there is a predominantly papillary pattern with associated psammoma bodies.
While the majority of typical SBTs do not show frankly invasive carcinoma, microinvasion is not uncommon. Boyd and McCluggage have reported seven cases of LGSC that either coexisted with HGSC or recurred as either HGSC or undifferentiated carcinoma.[5] Close examination of the tumor is recommended, since the areas of HGSC may be focal or admixed with areas resembling SBT. However, they are useful in the assessment of post-therapy specimens, in which CCC is often considered in the differential diagnosis, or when a diagnosis must be made using small biopsies. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Large production volumes of phthalates and their widespread use in common consumer, medical, building, and personal care products lead to ubiquitous human exposure via oral ingestion, inhalation, and dermal contact.
They are a group of synthetic chemicals composed of alkyl diesters of phthalic acid and are named based on their varying lengths of alkyl chains (Figure 1).
Chemical structures of common phthalates and their monoester metabolites that are mentioned in this review. The global production and use of phthalates exceeds 18 billion pounds per year, in which the majority of phthalates are used in polyvinyl chloride products (6).
The most common routes of exposure are via oral ingestion from food packaging and use of cosmetic products, but high levels of phthalates are also present in household dust (21, 22). Initially, the phthalate diester is cleaved to its respective hydrolytic monoester where only one alkyl chain remains on the phthalic acid backbone, and interestingly, it is often the monoester metabolites that induce toxicity.
Not surprisingly, the levels are much higher in humans occupationally exposed to phthalates. Both DEP and DEHP are incorporated in medical equipment, and DEP and DBP can be found in the enteric coating of oral medications.
In fact, females at all ages have increased urinary phthalate metabolite levels when compared to men at that same age (23). In females, chronic occupational exposure to high levels of phthalates has been associated with decreased rates of pregnancy and high rates of miscarriage (1, 42).
This heterogeneous organ is comprised of a surface epithelium surrounding the ovary, an outer cortex region containing ovarian follicles, corpora lutea, and stroma, and an inner medulla region containing a vast network of blood vessels, lymphatic vessels, and nerves. The ovarian follicle is the functional unit of the ovary that consists of the oocyte surrounded by two somatic cell types termed the granulosa cells and the theca cells. These follicles are first formed during the later stages of fetal life in the human and during the early post-natal life in the rodent. Primordial follicle recruitment is a tightly regulated process controlled by multidirectional communication between the oocyte, granulosa cells, and surrounding somatic cells that will give rise to the theca cells.
Primary follicles then develop into preantral follicles, also termed secondary and tertiary follicles that contain the oocyte surrounded by at least two layers of cuboidal granulosa cells and two outer theca cell layers. Antral follicles contain the oocyte surrounded by several layers of cuboidal granulosa cells with a fluid filled space, termed the antral space, and two outer theca cell layers.
Therefore, folliculogenesis must remain dynamic to allow for the continual generation of antral follicles to undergo cyclic recruitment for potential ovulation.
At birth, the human ovary contains approximately two million follicles, but by puberty, the number of follicles declines to roughly 400,000 due to atretic demise. Steroidogenesis is primarily conducted by the mature antral follicle and the corpus luteum following ovulation. For reproductive function, steroid hormones act on the ovary itself as well as the brain, pituitary, oviduct, uterus, cervix, vagina, and mammary gland.
Specifically, cholesterol can either be transported into the theca cell cytoplasm via lipoprotein receptors or it can be synthesized de novo. The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Most women with OvCa present with advanced disease, and recurrence is nearly universal leading to incurable disease and limited treatment options (2, 3). Another mechanism of PARPi includes trapping of PARP1 and PARP2 while in complex with damaged DNA, resulting in cytotoxic consequences (15).
The patients who participated in the translational substudies underwent dynamic contrast-enhanced-magnetic resonance imaging (DCE)-MRI and blood collection prior to and on day 3 of treatment. After centrifugation, the samples were aliquoted, immediately frozen, and stored in liquid nitrogen until use. MRI data were analyzed using a two-compartment model based on the general kinetic (GKM) Kety model using commercial software (iCAD, Nashua, NH, USA) as reported (27, 28).
The probability of PFS as a function of time was estimated using the Kaplan–Meier method, with a log-rank test to determine the significance of the differences. Participating patient details are shown in Table 1, demonstrating their representation of the full patient cohort in terms of age, treatment arm distribution, and clinical outcome. Reduction in PBMC PAR incorporation with treatment was observed in both arms, indicating the lower dose of olaparib results in full PAR inhibition and that addition of cediranib does not diminish that olaparib function (Figure 4).
In this study, all patients except one had a reduction with treatment in Ktrans and Kep independent of treatment arm; increase of Kep on day 3 of treatment in one patient was likely due to suboptimal contrast injection timing (Figures 5A,C). Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers.
These preclinical findings are being explored in clinical trials to elucidate the role of PARPi as chemo- and radiosensitizers in various tumor types (18). Highly complex and intertwined repair pathways have evolved to provide broad and redundant mechanisms to address damaged DNA: mismatch repair (MMR), base excision repair (BER), and nucleotide excision repair (NER) for a low fidelity single strand DNA break (SSB) repair mechanism, and HR and non-homologous end-joining (NHEJ) for double-strand DNA breaks (DSBs) (36). PARP1 is the best characterized member of the PARP family, and PARP2 has a similar structure and function with varying affinity for substrates (37). PARP inhibition has been shown to induce phosphorylation of DNA-dependent protein kinase (DNA-Pk), to further stimulate error-prone NHEJ in HR-deficient cells (44, 48, 49). PARP1 binds to DNA single strand break and catalyzes poly(ADP-ribosyl)ation of itself and acceptor proteins, which facilitates recruitment of DNA repair proteins.
The marked susceptibility of patients with gBRCAm has validated gBRCAm as a predictive biomarker for PARPi response in breast and ovarian cancer patients.
The major clinical BRCA-like behavior identified is susceptibility to platinums and other DNA-damaging agents (54–56). Cutaneous melanoma has been associated with mutations in the BRCA2 gene although there are only a few cases reported for uveal melanoma in BRCA2 mutation carriers (80). In the setting of melanoma, altered expression or new mutations in DNA MMR genes, MLH1 and MSH2, have been reported in brain metastases (86). The major component of hereditary pancreatic cancer is the familial pancreatic cancer syndrome.
Prostate cancer in patients with gBRCAm tends to be more aggressive, with a higher likelihood of nodal involvement and distant metastasis with inferior survival outcomes (103). Formation of the TMPRSS2-ERG fusion gene causes aberrant androgen-dependent ERG expression (106) and promotes tumorigenesis (107).


However, no association was noted between loss of PTEN expression by immunohistochemistry and ETS rearrangements by FISH, with radiologic assessment of the anti-tumor activity of niraparib in 18 patients with prostate cancer (110).
This formed the rationale for testing the efficacy and safety of veliparib and TMZ in 26 patients with metastatic CRPC (113).
Preferential cytotoxicity to the PARP1 inhibitor ABT-888 was seen in MSI cell lines containing mutant copies of MRE11A, compared with wild-type or microsatellite stable (MSS) cells (115). A phase II trial is currently evaluating the efficacy of olaparib in metastatic CRC (mCRC) stratified for MSI status (118).
Several phase II studies are evaluating the role of PARPi as a chemosensitizer in patients with advanced and mCRC, irrespective of MSI status (Table 2). One study showed that BRCA1 silencing increased susceptibility to olaparib treatment in NSCLC cell lines (122), providing evidence for possible clinical application in this subset of NSCLCs. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor.
The various histologic subtypes are different in terms of risk factors, precursor lesions, clinical course, patterns of spread, molecular genetics, response to conventional chemotherapy, and prognosis.[2-4] Hence, it is imperative to accurately subtype these tumors based primarily on morphology and immunohistochemistry tests, when necessary. LGSC, on the other hand, is characterized by tumor cells with relative nuclear uniformity, absence of nuclear pleomorphism, and mitotic activity typically < 12 mitoses per 10 high-power fields. Ahmed et al identified TP53 mutations in almost 97% of 145 patients with HGSCs.[59] In mutation-negative cases, p53 dysfunction associated with copy number gain in MDM2 or MDM4 was noted, or the cases were excluded because they represented LGSCs or other malignancies. Recently, several phthalates have been classified as reproductive toxicants and endocrine-disrupting chemicals based on their ability to interfere with normal reproductive function and hormone signaling. Normally, phthalates in their pure form are colorless, odorless, oily liquids with high lipophilic properties, and low solubility in water. The most commonly used phthalate is DEHP, which belongs to a group of phthalates known as dioctyl phthalates. Once in the air, phthalates typically bind to dust particles and are carried back to ground level (7). Depending on the size of the remaining monoester metabolite, the alkyl chain can undergo further oxidative metabolism and ultimately glucuronidation depending on the species (21, 26).
For example, it was estimated that in the 1980s, over 340,000 and 239,149 workers were exposed to DEHP and DEP, respectively (36).
Compared to males, females have higher levels of MEP, MBP, monobenzyl phthalate (MBzP), and MEHP (23). Further, high urinary phthalate levels are associated with pregnancy complications such as anemia, toxemia, and preeclampsia in women (43). The main functions of the ovary include maturation and ovulation of the female gamete (oocyte) for fertilization and secretion of sex steroid hormones necessary for reproductive and non-reproductive health.
Within the ovarian unit, follicles undergo several irreversible developmental transitions, and this process of follicular development is known as ovarian folliculogenesis (Figure 2). The female is born with a finite number of primordial follicles that can mature through the primary, preantral, and antral stages of development. The interaction of these molecular events leads to oocyte association with a single layer of flattened, squamous pre-granulosa cells, thus, the formation of the primordial follicle. This process is gonadotropin-independent and relies on paracrine and autocrine regulation by multiple intrinsic ovarian growth factors that work through several different signaling pathways (46, 58–61). Follicles at this stage, because of the presence of both granulosa and theca cells, are gonadotropin-responsive and begin synthesizing sex steroid hormones.
As antral follicles continue to mature, they produce estradiol and their receptivity to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), increases. Further, of the available follicles at puberty, only about 400 of them will ovulate throughout the reproductive lifespan, whereas the others undergo atresia (50). The process of steroidogenesis involves the enzymatic conversion of cholesterol to 17β-estradiol and other necessary sex steroid hormones to regulate reproductive and non-reproductive health (Figure 3).
Cholesterol is then internalized into the mitochondria via the steroidogenic acute regulatory protein (STAR) (92–94). The tumor-suppressor gene ARHI functions as a regulatory molecule in controlling ovarian cancer cell migration through modulation of Stat3- and FAK-mediated signaling pathways. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and polyADPribose (PAR) incorporation were performed. The optimal way to incorporate new agents into OvCa treatment and when to initiate these agents remains a question. It has been shown that hypoxia leads to downregulation of BRCA1 and RAD51, making hypoxic lung cancer cells more sensitive to PARP inhibitors (PARPi) (10).
Trapped PARP prevents its availability for repair function and secondarily causes replication and transcription fork blockade, and subsequent DNA breakage.
The aim of this translational study is to identify potential predictive biomarker candidates for olaparib and cediranib by assessment of vascular and DNA repair endpoints within the multi-institutional phase 2 study of olaparib and cediranib.
Study treatment, imaging, and blood collection occurred at the Center for Cancer Research, NCI after which the patients continued care at their primary investigational site. Peripheral blood mononuclear cell (PBMC), whole blood DNA, and plasma samples were collected prior to initiation of the study drug(s), and all patients underwent DCE-MRI imaging. Quantitative analysis of circulating plasma VEGF, IL-6, IL-8, and soluble VEGFR-2 were performed using analytically validated custom V-PLEX assay plates on an electrochemiluminescence platform according to the manufacturer’s instructions (Meso Scale Discovery, Gaithersburg, MD, USA) (22).
The cut-off date for PFS and endpoint analysis of this subset was March 31, 2014 consistent with the original study. Not all patients could undergo imaging within the required time frame; Table 1 also includes the number and distribution of patients within each of the substudy elements. We also examined whether XRCC1 DNA polymorphisms correlate with clinical response to PARPi and no significant associations with PFS were observed. This figure depicts non-immune and innate immune cells found throughout the female genital tract, including macrophages, dendritic cells, neutrophils and natural killer (NK) cells.
The clinical development of poly(ADP-ribose) polymerase inhibitors (PARPi), with their selective mechanisms of action involving the DNA damage repair pathways, is an example of this strategy. A large number of clinical trials are exploring the efficacy of combination strategies in malignancies such as non-small cell lung cancer (NSCLC), squamous cell cancer of the head and neck (HNSCC), esophageal, and colorectal cancers (CRCs) (Tables 1 and 2); the results of several phase I and II trials have already been reported (Table 3). The different repair mechanisms are orchestrated by numerous enzymes to ensure the integrity of DNA essential for cell survival.
PARP1 has been implicated in several DNA repair mechanisms including the repair of SSBs through the BER pathway.
More recently, another mechanism of action of PARPi involving PARP1-trapping has been proposed (50). In addition to its reported role in base excision repair, PARP1 plays a role in activating ATM necessary for homologous recombination and inactivating DNA-dependent protein kinase, a key component of non-homologous end-joining.
In a series of pivotal preclinical studies, PARPi were noted to cause selective cytotoxicity for in vitro and in vivo models of BRCA-deficient cells (52, 53). Some of the molecular events described in BRCA-like behavior include epigenetic silencing of BRCA1 through promoter methylation (57–59) and overexpression of EMSY, suppressing BRCA2 transcription (60). A melanoma cell line (MZ7), derived from a patient who received dacarbazine therapy, exhibited a high level of resistance to temozolomide (TMZ) without expressing O(6)-methylguanine-DNA methyltransferase (MGMT), which was related to impaired expression of MSH2 and MSH6 (87).
Although up to 20% of hereditary pancreatic cancer cases are associated with germline mutations in BRCA2, CDKN2A, PRSS1, STKI1, or MMR genes, the major underlying gene defects are still unknown (95).
Trials analyzing the response of these patients to DNA-damaging agents, such as platinums, and identifying the therapeutic targets of this subgroup are urgently needed. Preclinical studies have shown that PARP1 directly interacts with ERG to inhibit ETS gene fusion protein activity.
In a recent study, the observed ability of MSH3 to protect against DSB was exploited by the combination of oxaliplatin and a PARPi, which produced a synergistic cytotoxic effect against CRC cells (116). Twenty-two patients with MSI-negative tumors were enrolled and received a mean number of two cycles.
A future study will assess the utility of olaparib in delaying the time to disease progression in patients with advanced NSCLC who have responded to initial chemotherapy (123). While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. We now know that high-grade serous carcinoma (HGSC), the most common subtype of epithelial ovarian carcinoma, is a different disease from low-grade serous carcinoma (LGSC).
The tumors are generally characterized by micropapillae surrounded by clear spaces (Figure 1C); however, glandular, macropapillary, and single cell patterns can also be seen. Typically only a small amount of tumor is present in these biopsies, and numerous immunohistochemical tests are often performed to exclude other entities.
As a result, the ovarian CSCs have constitutive NF-kB activity, which creates a pro-inflammatory and anti-apoptotic environment, and an inactive Akt pathway, leading to slow proliferation. Phthalates are predominantly used as plasticizers in polyvinyl chloride consumer, medical, and building products to impart flexibility, as matrices and solvents in personal care products, and as excipients in medications and dietary supplements. These hydrolytic monoester and oxidative monoester metabolites, in addition to the parent phthalates, are used as biomarkers to estimate daily human exposure levels (26). Koch and Calafat compiled data from the United States and German populations where urinary metabolites were used to estimate daily exposure levels for other commonly used phthalates, such as DEP, butyl benzyl phthalate (BBP), DBP, and diisobutyl phthalate (DIBP).
Additionally, infants in intensive neonatal care units had levels of DEHP metabolites that were 14 times higher than infants in a low-intensive unit (39). In laboratory animals, phthalates reduce implantations, increase resorptions, decrease fetal weights of offspring, and decrease incidence of pregnancy (44, 45). The follicle contains the gamete (oocyte) surrounded by granulosa cells (shown in red) and theca cells (shown in green), which are somatic cells. During embryonic development, primordial germ cells, which will give rise to oocytes, migrate from the yolk sac to the genital ridge where the undifferentiated gonad resides (47). Primordial follicle quiescence is maintained by factors that suppress follicle activation, whereas primordial follicle recruitment is initiated by factors that activate development. The increase in estradiol initiates the LH surge causing one or multiple follicles to ovulate depending on the species.
Atresia is a coordinated process of follicle degeneration via hormonally controlled apoptosis (63). Prior to the peri-ovulatory period, the antral follicle increases the synthesis of estradiol to promote the ovulatory surge of LH. This process requires both the theca cells and granulosa cells, and involves the enzymatic conversion of cholesterol to 17β-estradiol and other necessary sex steroid hormones. These steroid hormones also act in non-reproductive tissues such as the brain, cardiovascular system, adipose tissue, skin, bone, and liver. Cholesterol is then converted to pregnenolone in the mitochondria via cytochrome-P450 cholesterol side-chain cleavage (CYP11A1) (95, 96). Women whose disease progresses more than 6 months after exposure to platinum agents tend to respond better to subsequent interventions than those with platinum-resistant or refractory disease, making them another important cohort in whom to investigate new directions. PARP1 inhibition also increases VEGFR-2 phosphorylation and subsequent activation of endothelial cell survival in human umbilical vein endothelial cells, an effect, which was reversed by a VEGFR-2 inhibitor (11). CECs were defined as negative for the hematopoietic marker CD45 (leukocyte common antigen), positive for the endothelial markers CD31 and CD146, and negative for the progenitor marker CD133.
The concentrations of the cytokines were determined with recombinant standards and expressed as picograms per milliliter, as reported (23). All p-values are two-tailed and reported without adjustment for multiple comparisons due to the small substudy cohort. All patients had at least stable disease at the first Response Evaluation Criteria in Solid Tumors (RECIST) evaluation after two cycles of treatment, indicating potential benefit but no correlation with the duration of response. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. Early clinical trials have shown significant single-agent activity of PARPi in gBRCAm-associated breast and ovarian cancers (3–5). These data suggest further clinical exploration of PARPi as monotherapy or combinations is warranted in patients not only with gBRCAm-associated breast or ovarian cancer, but also in solid tumors with HR dysfunction. Approximately 5% of cutaneous melanoma and gastric cancers are related to gBRCAm and 5–19% cases of familial pancreatic cancer are attributed to a gBRCAm (30, 31). It recognizes and binds to DNA sites with SSB via its DNA binding domain, then subsequently synthesizes poly(ADP-ribose) (PAR) by transferring ADP-ribose molecules from NAD+ to itself and other acceptor proteins (38). PARPi have been shown to trap PARP1 and PARP2 while in complex with damaged DNA, resulting in cytotoxic consequences (51). Additionally, PARPi attenuates tumor formation in embryonic stem cell-derived teratocarcinoma xenograft models (46). However, most patients eventually progress and some do not tolerate therapy due to immune-related side effects, indicating the need to develop other therapeutic strategies. PARP inhibition with INO-1001 has been shown to restore sensitivity to TMZ in an MMR-deficient xenograft model of malignant melanoma (88), and another PARPi, GPI 15427, enhanced TMZ anti-tumor activity in various cancers, including metastatic melanoma in an orthotopic xenograft mouse model (24). The dose limiting toxicities (DLTs) were elevation of liver transaminases and myelosuppression at the 400-mg dose of INO-1001. BRCA2 mutation prevalence in familial pancreatic cancer patients varies between 5 and 19% (30), and a BRCA2 mutation increases the risk of developing pancreatic cancer by approximately 3.5-fold (96). This yielded a clinical benefit rate of 57% in gBRCAm-associated pancreatic cancer patients.
In turn, inhibition of PARP1 reduces ETS-positive, but not ETS-negative, prostate cancer xenograft growth (108). Recently, a phase II study of olaparib in unselected patients with CRPC was initiated (111).
Another study reporting high correlation between MRE11 mutations and MSI in CRC cell lines as well as primary tumors, found that PARPi preferentially kills MSI cell lines harboring MRE11 mutations (115). Preliminary data indicate no single-agent activity of olaparib against non-MSI-high (MSI-H) mCRC. The role of PTEN mutation and its effect on the susceptibility to PARPi is an area of continued research in lung and other malignancies. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype.
HGSC presents in older women and responds at least initially to chemotherapy but has a worse overall prognosis than LGSC. Less common are tumors such as squamous cell carcinoma, papillary thyroid carcinoma, sebaceous carcinoma, and carcinoid tumors that are typically associated with mature cystic teratomas; these tumor types are beyond the scope of this review.
ECs, on the other hand, are associated with squamous differentiation, adenofibromatous background, and endometriosis.
Both HGSCs and LGSCs have some overlapping characteristics, as well as some distinct immunophenotypic features. Currently, the effects of phthalates on male reproduction are better understood than the effects on female reproduction. As plasticizers, phthalates are present in commonly used items such as flooring, roofing, carpeting, shower curtains, packaging equipment, food and beverage packaging, automotive parts, and even in children’s toys. Dibutyl phthalate (DBP) and diethyl phthalate (DEP) are also produced in high volumes and are among the most commonly used phthalates in consumer products.
Careful attention to the metabolite used for biomonitoring is essential for accurate estimations of daily exposure levels. Based on their use in oral medications, urinary levels of monoethyl phthalate (MEP), the monoester metabolite of DEP, and monobutyl phthalate (MBP), the monoester metabolite of DBP, in women of childbearing age were over 12 and 200 times higher, respectively, than in a reference population (40). These findings are likely attributed to the widespread use of phthalates, in particular MBP, in common cosmetic and personal care products that females use on a daily basis, including perfume, lotion, nail polish, and hairspray. The mechanisms by which phthalates disrupt these endocrine and reproductive events remain unknown.
Following ovulation, the antral follicle differentiates into the corpus luteum, and the granulosa and theca cells become large and small luteal cells, respectively. These germ cells, now termed oogonia, massively proliferate via mitosis and develop in clusters or nests in which squamous pre-granulosa cells surround the oogonia (48). Once the oocyte is released, the remaining granulosa and theca cells differentiate into large and small luteal cells respectively, and the remaining structure is termed the corpus luteum. Although atresia can occur at all stages of follicle development, early antral follicles are most susceptible to death in which apoptosis can occur in both somatic and germ cells.
As ovulation approaches, the peri-ovulatory follicle increases production of progesterone to promote ovulation and formation of the corpus luteum. The hormones produced by the ovary are listed in the white text boxes while the steroidogenic enzymes are listed in blue adjacent to the arrows between hormones. Therefore, proper steroidogenesis is required for fertility as well as for maintenance of cardiovascular, brain, and skeletal health (75–91).


Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Our preliminary work showed that the combination of olaparib and cediranib inhibited invasion of OvCa cells, in a more than additive fashion.
Cediranib is a small-molecule tyrosine kinase inhibitor of VEGFR1–3 and c-kit with modest single agent activity in recurrent OvCa (8, 17). The open dots represent patients whose times at risk were censored on the date of their last contact and were last reported alive and progression-free. Median values of pretreatment IL-8 concentration were not significantly different between the two arms.
Note that epithelial cell receptors CD4, C-C motif chemokine receptor 5 (CCR5), C-X-C motif chemokine receptor 4 (CXCR4) and GalC on endometrial and endocervical cells are not shown in this figure. Response rates (RR) of 31–40% have been reported in gBRCAm ovarian cancer patients with measureable recurrent disease, and the RR and duration of response to PARPi monotherapy has been associated with platinum sensitivity (6, 7). This activates the formation of a DNA repair complex consisting of multiple repair proteins, including DNA ligase III and X-ray repair cross-complementing 1 (XRCC1) (39). In addition, PARP inhibitors have been shown to trap PARP1 on damaged DNA, leading to replication and transcription fork blockage and subsequent double-strand DNA breakage. These findings were translated into a phase I clinical trial of the PARPi, olaparib, in recurrent breast, ovarian, and prostate cancer patients with gBRCAm (4), initiating a new era of possibilities for the use of PARPi as single-agent therapy to treat gBRCAm-associated cancers. Defects in translesion synthesis (TLS) also contribute to carcinogenesis but confer sensitivity to DNA-damaging agents (72, 73), requiring further investigation on sensitivity to PARPi.
These preclinical studies provide evidence that MMR loss of function is a potential predictive biomarker of PARPi responsiveness in patients with metastatic melanoma. Of the 12 patients enrolled, 1 patient had a partial response (PR) and 4 patients had stable disease (SD).
The unique biology of cancer cells with BRCA mutations offers potential therapeutic advantages with agents such as platinums. The data suggest a role for PARPi in MSI-CRC treatment, providing a rationale for clinical studies in this subset of patients. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy.
Briefly, the management of ovarian carcinoma has evolved significantly in the past decade—from primary definitive surgery and debulking followed by chemotherapy, to treating patients with neoadjuvant chemotherapy, especially in the setting of miliary disease that cannot be optimally debulked.[36,37] Pathologic review of post-treatment resections poses some problems—including typing of tumors that have undergone therapy-related changes, such as marked atypia and clear cell changes, as well as identifying minimal residual disease in the presence of inflammation and necrosis. Both tumor types are positive for paired box gene 8 (PAX8) and WT1 expression, as well as estrogen receptor (ER) and progesterone receptor (PR) expression.
As a result, mature or differentiated ovarian cancer cells do not have a constitutive NF-kB pathway, but instead have a highly active Akt pathway. This is of concern because women are often exposed to higher levels of phthalates than men through their extensive use of personal care and cosmetic products.
Interestingly, di(2-ethylhexyl) phthalate (DEHP) is present in common medical devices such as tubing, blood and intravenous bags, dialysis equipment, and in the manufacturing of disposable and surgical gloves (2). Production and importation of DBP was estimated to be between 10 and 50 million pounds in the United States in 2006 (8). For example, it is more accurate to measure oxidative monoester metabolites from high molecular weight phthalates, such as DEHP, than it is to measure the hydrolytic monoester metabolite (26). Based on these exposure levels, phthalates have been identified as top contaminants present in human tissues.
In another study, urinary measurements of MBP were 50 times higher in subjects that reported using oral medications containing DBP than in controls (5). Interestingly, the ovary is a critical regulator of these processes, and the effects of phthalates on ovarian function remain poorly understood. The regulation of follicular atresia involves a balance of pro- and anti-apoptotic factors. Once the follicle has transitioned to the highly vascularized corpus luteum, vast amounts of progesterone as well as estradiol are produced. Progesterone and DHEA are then converted to the androgen androstenedione again via CYP17A1 or HSD3B, respectively (96). All patients had reduction in PAR incorporation, and all except one had reduction in vascular flow on DCE-MRI. The recognition that OvCa may be driven by disordered DNA damage repair led to the development and recent approval of polyADPribose polymerase (PARP) inhibition for therapeutic benefit. In the ICON 6 study, cediranib combined with platinum and paclitaxel standard chemotherapy followed by maintenance cediranib treatment significantly prolonged progression-free survival (PFS) and overall survival (OS) when administered to women with first recurrence of platinum-sensitive OvCa (17). Viability was defined by the absence of 7-aminoactinomycin D (7-AAD) staining, and analysis was restricted to nucleated cells by gating on Hoechst 33342-positive cells (20, 21). Pretreatment values of other cytokines including circulating plasma VEGF, soluble VEGFR-2, and IL-6 examined did not correlate with PFS and was not different between two arms. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers. Emerging evidence suggests that PARPi is an effective therapeutic strategy in subsets of other malignancies that have gBRCAm, such as melanoma, prostate, and pancreatic cancers. The PARylated PARP1 dissociates from DNA as the negative charge of PAR decreases its affinity for DNA, and poly(ADP-ribose) glycohydrolase then degrades the PAR on PARP1 (40).
Homozygous mutation in the PTEN tumor suppressor gene may also lead to HR dysfunction (74). Several phase II studies using PARPi either as a single-agent or in combination with chemotherapy, radiotherapy, or targeted therapy are summarized in Table 3. However, one case series report patients with gBRCAm did not reveal a benefit to first line platinum chemotherapy in the treatment of advanced pancreatic cancer (97), although this needs to be further evaluated in a selected study for pancreatic cancer with gBRCAm.
Two patients on olaparib showed prostate-specific antigen (PSA) and radiologic responses lasting 26 and 34 months, respectively, while the third patient had SD for 10 months.
This study suggested veliparib and TMZ are tolerated well, but with limited clinical activity. Immunohistochemistry was performed on archived tumor samples to quantify MMR and PTEN protein expression. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. Lastly, mucinous carcinoma (MUC) of the ovary is a fairly uncommon disease if metastasis has been excluded, and its outcome is highly variable, based on stage at presentation and type of invasion.[9-11] This review focuses on the clinicopathologic and molecular features of epithelial ovarian cancer, with specific attention to genetic predisposition, morphologic challenges, immunohistochemistry, and molecular features. When the morphologic features are suggestive of serous carcinoma, use of these four markers is sufficient to establish the diagnosis in most cases, and an extensive panel of immunomarkers is usually not necessary. These cells do not have a pro-inflammatory environment, are chemosensitive and proliferate faster.
As matrices and solvents, phthalates are commonly found in consumer and cosmetic products ranging from hairsprays and perfumes to pesticides and wood finishes. In one study, the concentrations of the oxidative monoester metabolites of DEHP, mono(2-ethyl-5-oxohexyl) phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate, were found to be four-fold higher than the hydrolytic monoester metabolite, mono(2-ethylhexyl) phthalate (MEHP) (27). As stated above, measureable levels of phthalates are found in human urine samples tested and in 95% of human blood samples tested (1, 22, 23, 25, 34).
The next sections will provide background on the importance of normal ovarian function for reproductive and non-reproductive health and how EDCs, like phthalates, can disrupt ovarian function. It is here that the oogonia become oocytes, and the oocytes progress through meiosis until they are arrested in the diplotene stage of meiotic prophase I (49).
Therefore, inhibition of both DNA damage repair and angiogenesis pathways would be an important direction to be examined. Additionally, olaparib and cediranib inhibited microvascular endothelial cell tube formation on Matrigel at concentrations well below those clinically attainable in patients. BRCA-like tumors have molecular and clinical characteristics in common with tumors occurring in patients with gBRCAm, which may have implications for PARPi-based therapy (8). PARP has been shown to have a direct involvement in DSB repair in addition to its role in preventing DSB formation by promoting BER. The potency in trapping PARP differs markedly among PARPi, with niraparib (MK-4827) and olaparib having greater potency than veliparib. Increased PARPi sensitivity was shown in a series of cell lines with PTEN mutation or haploinsufficiency, and confirmed in xenograft models using olaparib (74). A phase II trial sought to evaluate the combination of rucaparib and TMZ in patients with metastatic malignant melanoma (90). Preclinical studies have shown single-agent activity of PARPi (98), as well as radiosensitization in combination with chemoradiation in BRCA2-deficient pancreatic cells (25).
Twenty-eight patients were enrolled in the trial and at the time of review, data were available for 18 patients.
The patient on niraparib exhibited primary resistance with development of a new liver lesion and a rise in PSA of nearly threefold at the time of the first reassessment.
Future trials will explore the use of different chemotherapy agents in combination with higher doses of veliparib.
The combination of veliparib and TMZ was well tolerated in the 47 patients treated, with a disease-control rate of 23%. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. Specifically, the ovary is responsible for folliculogenesis, the proper maturation of gametes for fertilization, and steroidogenesis, and the synthesis of necessary sex steroid hormones. Based on their presence in natural water bodies, fish and other aquatic animals are also exposed to phthalates.
In particular to reproduction and development, DEHP and its metabolites are present in 90–100% of amniotic fluid samples from second trimester fetuses, cord blood samples from newborns, breast milk from nursing mothers, and even in human ovarian follicular fluid, indicating their ability to reach the ovary (1, 23, 34, 35). Testosterone and estrone are then converted to the most potent estrogen, estradiol, via CYP19A1 or HSD17B, respectively (96, 97).
Additionally, there is a potential therapeutic role for PARP inhibition in a wider subgroup of solid tumors that may have defective homologous recombination (HR) (9). These subgroups of tumors with germline HR dysfunction constitute a rare population with recognized unmet therapeutic needs, and may be sensitive to treatment with PARPi. In PARP1-deficient cells, ATM-kinase function is compromised leading to a reduction in DNA DSB in response to radiation, indicating a role of PARP1 in ATM activation and HR (38, 41). There is also clinical evidence that olaparib may have a therapeutic utility in PTEN-deficient endometrial cancer (75, 76).
Studies are ongoing to examine single-agent and combination PARPi therapy in BRCA2 mutant pancreatic cancers. Translational studies revealed positive ERG staining by immunohistochemistry, and ERG rearrangements by FISH, as well as either heterozygous or homozygous PTEN allelic loss in all four cases.
Overall, further evaluation of biochemical changes or predictive biomarkers in response to PARPi in advanced prostate cancer is needed.
The results of immunohistochemistry for the MMR and PTEN proteins from 45 archived tumor samples are not yet reported. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations.
Immunohistochemical stains for p16, p53, and Ki-67 are helpful, since HGSCs show diffuse staining for p16 and p53 and an elevated Ki-67 proliferation index, whereas LGSCs show patchy staining for p16, wild-type staining for p53, and a low Ki-67 proliferation index.[38,57,58] This panel is also helpful in detecting focal HGSC in the background of a tumor that is predominantly an LGSC.
Any defect in the regulation of these processes can cause complications for reproductive and non-reproductive health. As excipients, some phthalates are incorporated in the enteric coating of oral medications and in dietary supplements ranging from certain fish oils to probiotics (4, 5). The interplay of these pro- and anti-apoptotic factors primarily converges on the BCL-2 signaling pathway, with its own pro- and anti-apoptotic proteins, to regulate atresia (53–56). Therefore, the utility of PARPi in other solid tumors is potentially greater than was previously envisioned (8). Additionally, there are significant unanswered questions of their use in solid tumors that have molecular and clinical characteristics in common with gBRCAm-associated tumors.
PARP1 has been shown to reduce DSB formation by sensing stalled replication forks and recruiting MRE11 for end processing to initiate HR (42). These findings suggest that PARPi have several mechanisms of action and multiple targets in the DNA repair pathway to potentially induce cancer cell death (Figure 1).
Further studies are needed to investigate whether PTEN loss can serve as a potential biomarker for PARPi sensitivity (77–79).
In total, 12 of the 40 patients required a dose reduction of TMZ secondary to myelosuppression (90).
Therefore, the investigators concluded that the experimental combination regimen could be given safely, and was modestly active (100). It was concluded that, in a heavily pre-treated population of patients with mCRC, the combination of veliparib and TMZ can be safely given, and displayed limited clinical activity. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. The immunophenotypes of the major epithelial ovarian cancer types are summarized in Table 1.
For instance, phthalate-induced defects in folliculogenesis and steroidogenesis can cause infertility, premature ovarian failure, and non-reproductive disorders. Thus, there are multiple means of phthalate exposures due to their presence in a wide range of products used by humans on a daily basis. These preclinical data suggest new strategies for novel combination therapies in recurrent OvCa.
Advances have been made in identifying new therapeutic targets and analyzing response to novel treatments in these patient subgroups and this has led to an explosion of PARPi-based clinical trials extending the patient cohort to include BRCA-like tumors.
Future studies should focus on DNA profiling and the use of predictive biomarkers to select those tumors which are more likely to respond to PARPi. This potentially opens another avenue for therapy utilizing PARPi, although gBRCAm is a very rare event in prostate cancer. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. Presently, there is a paucity of knowledge on the effects of phthalates on normal ovarian function; however, recent work has established the ovary as a target of phthalate toxicity.
Although few studies have investigated the lifespan of phthalates in the environment, phthalates are considered fairly stable in the environment and can persist for quite a long time (7, 18–20). We hypothesized that introduction of angiogenesis inhibitors and PARPi will have activity and examination of the biology should lead to potential predictive biomarkers (7, 12, 13). Thus, HR dysfunction sensitizes cells to PARP inhibition leading to further chromosomal instability, cell cycle arrest, and apoptosis (45, 46).
Ongoing research suggests HR deficiency, rather than a specific mutation in the BRCA genes, may be the main driver of cytotoxicity of PARP inhibition (45).
Myelosuppression was again noted, with 25 patients (54%) requiring a 25% dose reduction in TMZ.
It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. This review summarizes what is currently known about the effects of phthalates on the ovary and the mechanisms by which phthalates exert ovarian toxicity, with a particular focus on the effects on folliculogenesis and steroidogenesis.
Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. Further, this review outlines future directions, including the necessity of examining the effects of phthalates at doses that mimic human exposure.
High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma.
Immunohistochemical markers are routinely employed in the diagnosis of epithelial ovarian carcinomas. Phase I and II trials evaluating E7016 in combination with TMZ in patients with advanced solid tumors and malignant melanoma are ongoing (92, 93). However, molecular testing of these tumors, unlike in endometrial carcinoma, is not routinely used in clinical practice. Eligibility criteria for the phase II study include BRAF wild-type status and no prior treatment with TMZ or PARPi. As substantial progress has been made in the management of malignant melanoma in recent years (94), it remains to be seen whether PARPi will be added to the treatment armamentarium.



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