Investigation of discrepant mismatch repair immunohistochemistry and microsatellite instability polymerase chain reaction test results for gynecologic cancers using next-generation sequencing.

Gynecologic cancers are routinely screened for DNA mismatch repair (MMR) gene mutations using immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) for microsatellite instability (MSI) to enable selection of immune checkpoint inhibitor therapy and screen for Lynch syndrome. The limited data that compare IHC and MSI in endometrial tumors have shown discordance rates of 5-10%. We reviewed MMR/MSI results in gynecologic cancers and used next-generation sequencing (NGS) to interrogate discrepancies. Of the 328 cases with both IHC and MSI results, 256 (78.0%) were microsatellite stable (MSS) with preserved MMR (pMMR), 64 (19.5%) cases were MSI-High (MSI-H) with MMR deficient (dMMR), 2 cases showed subclonal loss of MLH1 and PMS2 with MSI-H, and 6 cases were discordant. Overall, there was a 98.2% (322/328) IHC/MSI concordance. Discordant cases were retested and/or subject to NGS. Of the six discrepant cases, five showed dMMR with MSS and one showed pMMR with MSI-H. One dMMR/MSI-L case showed loss of PMS2 with a germline pathogenic mutation. The pMMR/MSI-H case was found to harbor pathogenic variants in MLH1 and MSH6. One of the two cases with subclonal populations demonstrated MSI-H in the dMMR area and MSS in the pMMR area. These results emphasize the importance of selecting the appropriate tumor tissue for both IHC and molecular testing and demonstrate that NGS can help resolve discrepant MMR and MSI results.

Potential pathogenetic link between angiomyofibroblastoma and superficial myofibroblastoma in the female lower genital tract based on a novel MTG1-CYP2E1 fusion.

Angiomyofibroblastoma and superficial myofibroblastoma are distinctive benign mesenchymal tumors occurring in the female lower genital tract. Despite their significant overlapping clinicopathologic features, including the presence of bland-looking spindle or oval cells with myofibroblastic or myoid differentiation, the tumors have been regarded as separate entities. Although subepithelial, hormone-sensitive mesenchymal cells of the female lower genital tract are considered as their potential common progenitor cells, their potential kinship or pathogenetic similarities remain elusive. Based on the identification of a novel RNA sequencing-based MTG1-CYP2E1 fusion transcript in an angiomyofibroblastoma index case, we investigated an additional ten samples of the tumor and its site-specific histological mimics, including eight superficial myofibroblastomas, four deep angiomyxomas, four cellular angiofibromas, three fibroepithelial stromal polyps, and eight non-site-specific mesenchymal tumors occurring in the female lower genital tract. Using reverse transcription-polymerase chain reaction, we showed that the MTG1-CYP2E1 fusion transcripts were consistently detectable in angiomyofibroblastomas (5/5, 100%) and often in superficial myofibroblastomas (3/5, 60%) but were not detected in the other examined site-specific or non-site-specific mesenchymal tumors. Our immunohistochemical experiments showed that CYP2E1, an isoenzyme belonging to the cytochrome P450 superfamily, exhibited increased positivity in tumors with MTG1-CYP2E1 than was observed in fusion-negative tumors (RR = 6.56, p = 0.001). The results of our study provide further evidence supporting the assertion that angiomyofibroblastoma and superficial myofibroblastoma represent phenotypic variants of site-specific mesenchymal tumors and share a common oncogenic mechanism.

Evaluation of Micro Satellite Instability and Mismatch Repair Status in Different Solid Tumors: A Multicenter Analysis in a Real World Setting.

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the IdyllaTM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.

Identification of novel ALK rearrangements in gynecologic clear cell carcinoma.

Clear cell carcinomas (CCCs) of the gynecologic tract are aggressive tumors with high resistance rate to conventional platinum-based chemotherapies. Currently, the molecular features of these tumors remain largely unknown and there is no targeted therapy available. The aim of our study was to identify anaplastic lymphoma kinase (ALK) translocations, a potential molecular target for therapy. Ninety-seven patients with gynecologic CCC (62 ovarian, 27 uterine corpus and 8 uterine cervical) were screened for ALK rearrangement and ALK copy number gain using an ALK break-apart fluorescence in situ hybridization probe. The genomic landscape of all cases with ALK rearrangements and 10 random cases with ALK copy number gain was queried using a hybrid capture-based DNA next-generation sequencing assay and an Illumina Fusion RNA assay. Findings were then correlated with ALK immunohistochemistry (clone D5F3) expression. ALK rearrangement was detected in 5% (5/97) and ALK copy number gain in 79% (77/97) of gynecologic CCCs. Next-generation sequencing in ALK-rearranged CCCs identified a novel BABAM2-ALK fusion in one case. ALK translocation partners were not identified in the remaining cases. Our findings show that ALK fusion, which is targetable in other cancers, may be a pathogenetic mechanism in a small number of gynecologic CCCs.

The role of sialyltransferases in gynecological malignant tumors.

Sialylation is the addition of sialic acids to the terminus of various glycoconjugates, and it is involved in many essential biological processes, such as cell adhesion, signal transduction, immune regulation, etc. The levels of sialylation in a cell are tightly regulated by two groups of enzymes, sialyltransferases (STs, responsible for sialylation) and sialidases (responsible for desialylation). Many studies have reported that the occurrence, development, and survival rates of tumors are significantly associated with STs' abnormal changes. In recent years, the morbidity and mortality rates of gynecological malignant tumors have been continuously rising, which has caused great harm to women's reproduction and health. Abnormal changes of STs in gynecological malignant tumor cell membranes cause the changes of expression of sialic acids, promoting cell migration and, eventually, leading to tumor metastasis. In this review, we outlined the biological characteristics of STs and summarized the expression profiles of 20 STs in different tumors via transcriptome data from Gene Expression Profiling Interactive Analysis (GEPIA) database. Moreover, STs' functions in four common gynecological tumors (ovarian cancer, cervical cancer, endometrial cancer, and gestational trophoblast tumor) were reviewed.

The Therapeutic Potential of MEK1/2 Inhibitors in the Treatment of Gynecological Cancers: Rational Strategies and Recent Progress.

The mitogen-activated protein kinase (MAPK) pathway is among the key factors in numerous cellular processes involved in tumorigenesis, suggesting it as a potential therapeutic target in gynecological cancer. MAPKs connect gene expression pathways and external stimulations. They include a network consisting of Ras, Raf or MAP3K, MEK or MAP2K, ERK or MAPK. Among these, MEK is an attractive molecular target of novel cancer therapeutics as it joints upstream activators and their corresponding downstream targets. MEK inhibitors were among the first inhibitors of the MAPK pathway entering into clinical trials. Several drugs have recently been developed as MEK inhibitors. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity to treat this malignancy and captured much attention in the past decade. Here, we summarize the role of MAPK/MEK/ERK pathway in the pathogenesis of gynecological cancer, with particular emphasis on MEK inhibitors in clinical settings, including PD-0325901, Selumetinib, Cobimetinib, Refametinib, Trametinib, Pimasertib, MEK162 and WX-554 in gynecologic cancers.

A comprehensive analysis of IDO1 expression with tumour-infiltrating immune cells and mutation burden in gynaecologic and breast cancers.

Gynaecologic and breast cancers share some similarities at the molecular level. The aims of our study are to highlight the similarities and differences about IDO1, an important immune-related gene in female cancers. The NGS data from TCGA of cervical squamous cell carcinoma (CESC), ovarian serous cystadenocarcinoma (OV), uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS) and breast invasive carcinoma (BRCA) were analysed to identify molecular features, and clinically significant and potential therapeutic targets of IDO1. We found IDO1 was significantly up-regulated in four gynaecologic cancers and breast cancer. According to breast cancer PAM50 classification scheme, IDO1 expression was higher in tumours of basal than other subtypes and showed better survival prognosis in BRCA and OV. Through immune infiltration analysis, we found a strong correlation between IDO1 and immune cell populations especially for dendritic cells and T cells. In addition, we investigated the association between IDO1 and tumour mutation burden (TMB) and found that IDO1 was significantly correlated with TMB in BRCA and CESC. GSVA revealed that hallmarks significantly correlated with IDO1 were involved in interferon gamma response, allograft rejection and inflammatory response. We also found PD-L1 and LAG3 were highly positive related to IDO1 in gynaecologic cancers when comparing with their corresponding normal tissues. Our results indicated that IDO1 participated in anti-tumour immune process and is correlated with mutation burden. These findings may expand our outlook of potential anti-IDO1 treatments.

Carcinogenic roles and therapeutic effects of EZH2 in gynecological cancers.

Enhancer of Zeste Homolog 2 (EZH2) is highly expressed in kinds of malignant tumors and related to tumor occurrence, development, and prognosis. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which promotes cell proliferation, migration, and invasion by epigenetic regulation of anti-tumor gene. It can activate numerous tumor-associated signaling pathways and interfere with DNA damage repair. In recent years, large amounts of studies have shown that EZH2 is closely related to gynecologic-related malignancies and can be used as a potential target gene for the treatment of gynecological-related malignancies. This review summarizes the oncogenic function of EZH2 and introduces the recent advances in the development of EZH2 inhibitors. On this basis, future research prospect of EZH2 is proposed.

c-KIT Analysis and Targeted Molecular Sequencing of Mesonephric Carcinomas of the Female Genital Tract.

Mesonephric carcinoma is a rare malignancy, thought to derive from Wolffian remnants. To date, no targeted molecular therapeutic options have been identified. On the basis of limited case reports, c-KIT immunohistochemical expression has been reported in female adnexal tumors of Wolffian origin, and targeted therapy with Imatinib has been attempted with mixed success. Currently, it is unclear whether c-KIT immunohistochemical expression is seen in mesonephric carcinoma, a tumor that is thought to be related to female adnexal tumors of Wolffian origin, and how this correlates with KIT mutational status. In this study, we assessed the immunohistochemical expression of c-KIT and KIT mutational status, in a series of 13 mesonephric neoplasms (5 cervical [including 2 cervical carcinosarcomas], 3 uterine corpora, 4 ovarian, and 1 vaginal/pelvic). The intensity of staining and proportion of cells showing cytoplasmic/membranous staining for c-KIT were recorded. KIT was sequenced using a next-generation sequencing panel that targeted 120 hotspots and 17 exons in 33 known actionable cancer genes. This panel included KIT exons 9, 11, and 13, and 6 hotspots (T670, D816, D820, N822, Y823, A829). Although c-KIT immunohistochemical expression was observed in the majority of mesonephric carcinomas (10/12 cases; 83%), no KIT mutations were detected. This cautions pathologists against the use of c-KIT immunohistochemistry as a surrogate marker for KIT-activating mutations in this setting. Consistent with previous studies, the majority of mesonephric neoplasms (10/13; 77%) harbored KRAS mutations. Additional mutations were found in CTNNB1 (2/13, 15%), TP53 (2/13, 15%), and PIK3CA (1/13, 8%).

PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers.

OBJECTIVE: Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu. METHODS: We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting. RESULTS: We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AKT proteins after afatinib exposure when compared to controls ARK2. CONCLUSIONS: Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.

Inflammatory Myofibroblastic Tumor in Female Genital Tract.

CONTEXT.­: Inflammatory myofibroblastic tumor is a mesenchymal neoplasm of low malignant potential. It was first described in lung, but is known to occur in many extrapulmonary sites including female genital organs, most commonly the uterus. It has a high recurrence rate and a low risk for metastasis. A more recently described aggressive variant, epithelioid myofibroblastic sarcoma with a predilection for the abdominal cavity of males, has also been recently reported to occur in the ovary. This tumor is composed of spindled and epithelioid myofibroblasts in a variably myxoid stroma and commonly shows a fascicular growth pattern with positive staining for desmin, smooth muscle actin, and CD10, which may mimic a smooth muscle or endometrial stromal neoplasm. In the female genital tract it has the potential for being misdiagnosed as a leiomyoma, endometrial stromal tumor, or as a myxoid leiomyosarcoma, resulting in undertreatment or overtreatment. It harbors rearrangements in the ALK gene, resulting in abnormal expression of ALK protein. Immunostaining for ALK is a helpful diagnostic tool. OBJECTIVE.­: To provide a brief review of clinical, histologic, immunohistochemical, and molecular features of inflammatory myofibroblastic tumor with emphasis on possible diagnostic pitfalls in the female genital tract. DATA SOURCES.­: Review of pertinent literature on inflammatory myofibroblastic tumor occurring in the female genital tract and personal experience of the authors. CONCLUSIONS.­: Inflammatory myofibroblastic tumor in the female genital tract can mimic other more common benign and malignant tumors like leiomyoma, leiomyosarcoma, and endometrial stromal sarcoma. Familiarity with clinical and histologic features and use of ALK immunostaining can be critical for correct diagnosis.

Association between MGMT Promoter Methylation and Risk of Breast and Gynecologic Cancers: A Systematic Review and Meta-Analysis.

The role of the promoter methylation of O 6-methylguanine-DNA methyltransferase (MGMT) remains controversial for breast and gynecologic cancers. We conducted a meta-analysis to assess the association between hypermethylation of MGMT promoter and the risk of breast and gynecologic cancers. A comprehensive search was conducted in PubMed and Embase electronic databases up to 19th August 2017 for studies about the association between MGMT promoter hypermethylation and breast and gynecologic cancers. A total of 28 articles including 2,171 tumor tissues and 1,191 controls were involved in the meta-analysis. The pooled results showed that MGMT promoter methylation status was significantly associated with an increased risk of breast and gynecologic cancers (OR = 4.37, 95% CI: 2.68-7.13, P < 0.05). The associations were robust in subgroup analysis based on ethnicity, cancer type, methylation detection method, and control source. This meta-analysis indicated that MGMT hypermethylation was significantly associated with the risk of breast and gynecological cancers, and it may be utilized as a valuable biomarker in early diagnostics and prognostication of these cancers. Further efforts are needed to identify and validate this finding in prospective studies, especially in situation with new methylation testing methods and samples from plasma circulating DNA.

Poly(ADP-Ribose) polymerase 1: a therapeutic hope in gynecologic cancers.

The Poly(ADP-ribose) polymerase-1 (PARP1) is a multifunctional nuclear protein involved in a variety of cellular functions. Recently, its role in the onset, progression and therapy resistance of cancers in general and reproductive cancers in particular has been recognised. The PARP associated signaling is perceived to play a key role in the development, sustenance and relapse of reproductive cancers. This has led to the preclinical and clinical assessment of PARP inhibitors as targeted therapeutic agents in reproductive cancers. In the first part of this review, we have summarized the current status of PARP in the onset, progression and therapy resistance of reproductive cancers. In the second part of the review, we have discussed the translational applications of PARP inhibitors, underscoring the perceived therapeutic opportunities, bottlenecks and the utility of the ongoing clinical trials.

Associations of the glutathione S-transferase P1 Ile105Val genetic polymorphism with gynecological cancer susceptibility: a meta-analysis.

The association between the glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and gynecological cancer susceptibility has been evaluated in many studies. However, the results remain controversial. Thus, this meta-analysis, based on 10 published case-control studies, was designed to clarify the association of the GSTP1 Ile105Val polymorphism with gynecological cancer risk. Our results suggested that there was no significant association between the GSTP1 Ile105Val polymorphism and the risk of gynecological cancer in all genetic models (GG vs. AA: odds ratio [OR] = 1.41, 95% confidence interval [CI] = 0.75-2.26; AG vs. AA: OR = 1.13, 95% CI = 0.74-1.73; AG/GG vs. AA: OR = 1.17, 95% CI = 0.75-1.81; GG vs. AA/AG: OR = 1.38, 95% CI = 0.79-2.42). Similarly, in the subgroup analyses by cancer type, ethnicity, and smoking status, no significant association with any genetic model was observed. In conclusion, the results of our meta-analysis suggest that the GSTP1 Ile105Val polymorphism is not associated with the development of gynecological cancer.

A Review of mTOR Pathway Inhibitors in Gynecologic Cancer.

The treatment of advanced gynecologic cancers remains palliative in most of cases. Although systemic treatment has entered into the era of targeted drugs the antitumor efficacies of current therapies are still limited. In this context there is a great need for more active treatment and rationally designed targeted therapies. The PI3K/AKT/mTOR is a signaling pathway in mammal cells that coordinates important cell activities. It has a critical function in the survival, growth, and proliferation of malignant cells and was object of important research in the last two decades. The mTOR pathway emerges as an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli and, through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including endometrial, cervical, and ovarian cancers. The present study reviewed the available evidence regarding the potential impact of some mTOR pathway inhibitors in the treatment of gynecological cancer. Few advances in medical management have occurred in recent years in the treatment of advanced or recurrent gynecological malignancies, and a poor prognosis remains. Rationally designed molecularly targeted therapy is an emerging and important option in this setting; then more investigation in PI3K/AKT/mTOR pathway-targeted therapies is warranted.

Systematic assessment of HER2/neu in gynecologic neoplasms, an institutional experience.

BACKGROUND: HER2/neu overexpression and/or amplification has been widely studied in a number of solid tumors, primarily in the breast. In gynecologic neoplasms, determination of HER2/neu status has not been well studied as a predictive biomarker in anti-HER2/neu treatment. METHODS: We systematically evaluated the HER2/neu reactions by immunohistochemistry and fluorescent in situ hybridization in malignant gynecologic neoplasms as experienced in our institution. RESULTS: The HER2/neu overexpression or amplification occurred in 8 % of the cancers of the gynecological organs in our series. Majority of the HER2/neu overexpression and/or amplification occurred in clear cell (27 %) and serous (11 %) carcinomas. HER2/neu positivity was also seen in undifferentiated as well as in mixed clear cell and serous carcinomas. Discordant IHC and FISH results (positive by FISH but not IHC) was seen in 2 cases. Majority of the HER2/neu overexpression and/or amplification occurs in the endometrium rather than the ovary. Heterogeneity of the HER2/neu by IHC staining was in < 2 % of the tumors in our series. CONCLUSIONS: We recommend the HER2/neu studies on Müllerian carcinomas of clear cell, serous, and undifferentiated types, particularly when they arise in the endometrium. Since there are some discordant IHC/FISH results, we also propose performing the HER2/neu testing by FISH when the IHC score is less than 3 + .

DNA damage response as a therapeutic target in gynecological cancers.

PURPOSE OF REVIEW: The proven activity of poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated homologous recombination deficient (HRD) ovarian cancer has led to the availability to patients with ovarian cancer of the first targeted therapy with an associated predictive biomarker. Our focus has recently turned towards expanding the clinical utility of PARP inhibitors beyond BRCA mutated ovarian cancer, and to a search for novel targets within DNA damage response (DDR). RECENT FINDINGS: Early trials in unselected patients with ovarian cancer showed responses to PARP inhibition in BRCA-wildtype ovarian cancer, and recent genomic studies have demonstrated that germline or somatic aberrations in other homologous recombination genes are present in a significant proportion of ovarian cancers. In addition, PARP inhibition may be of value in molecularly defined subsets of endometrial or cervical cancers. Novel DDR inhibitors such as ATR, ATM, WEE1 or DNA-PK inhibitors are also being tested in patients. Finally, combinatorial strategies of DDR inhibitors with antiangiogenic agents, phosphoinositide 3-kinase inhibitors or immunotherapies may further increase therapeutic efficacy. SUMMARY: In the future, patients with gynaecological malignancies may be rationally selected for PARP inhibition on the basis of comprehensive evaluation of homologous recombination genomic alterations, or HRD assays. Furthermore, novel DDR inhibitors have the potential to expand the repertoire of therapeutic options available to these patients.

PARP inhibition and gynecologic malignancies: A review of current literature and on-going trials.

The poly (ADP-ribose) polymerase (PARP) family of enzymes is important in several DNA repair pathways. Drugs that inhibit these enzymes have been investigated in many types of cancer, but their application in the treatment of gynecologic malignancies has rapidly evolved - as manifested by the 2014 FDA approval for olaparib in the treatment of recurrent ovarian cancer associated with a germline BRCA mutation (gBRCA). In efforts to broaden their efficacy, current clinical trials have demonstrated benefit of olaparib, and other PARP inhibitors (PARPi), as single agents and in combination with cytotoxic chemotherapy and biologic agents, in wide ranging populations. Although the majority of data for PARPi in gynecologic malignancies has been specifically regarding ovarian cancer, their role in the treatment of uterine and cervical cancer is currently being investigated. This review will serve as a synopsis of seminal trials to date, summarize the breadth of clinical application in on-going studies, query how these results may change future practice, and reflect on questions yet to be answered.

Expression and function of peroxiredoxins in gynecological malignancies.

A large family of peroxiredoxin proteins plays essential roles in the regulation of multiple redox-sensitive cellular activities related to cell signaling, cell proliferation and apoptosis. The involvement of these proteins in protecting cells from oxidative damage, induced by reactive oxygen species, points to their potential role in human cancers. According to some studies, the peroxiredoxin proteins in gynecological malignancies, promote tumors development and progression, whereas others indicate that peroxiredoxin proteins function as onco-suppressors in these cancers. Here, we review the utilization of peroxiredoxin proteins as novel biomarkers for screening and early diagnosis of gynecological malignancies, and as the specific therapy targets and prognostic factors as well.

Emerging strategies for targeting PI3K in gynecologic cancer.

Ovarian, endometrial and cervical cancers are the most prevalent gynecologic cancers in the United States and account for significant mortality. Translational research into these cancers has highlighted the distinctive molecular and genomic profiles of these cancers finding that, even within a disease site, the landscapes and drivers of neoplasia are distinctive. Despite this molecular diversity, activation of the phosphatidylinositol-3-kinase (PI3K) pathway appears to be conserved in subsets of these tumors, suggesting that strategies that antagonize mediators in this signaling cascade could offer anti-tumor efficacy. Extensive pre-clinical and clinical data have demonstrated that single agent targeted therapies lead to modest single agent activity of generally limited duration, even in the setting of innate PI3K pathway activation via mutation or amplification. These findings in the laboratory and clinic have prompted investigations into resistance pathways following PI3K pathway inhibition in order to understand escape pathways and restore tumor cell sensitivity. A next generation of clinical trial investigations will focus on novel combinations in order to define how these important therapeutics can be used in the clinic. This review will present preclinical data that supports the role of the PI3K pathway in ovarian, endometrial and cervical cancers, in addition to discussing the reported clinical trial experience with PI3K pathway inhibition. A specific focus will be on the rationale behind ongoing clinical trials utilizing novel agents in concert with PI3K pathway inhibitors to reverse resistance in populations with and without gain of function alterations in this oncogenic signaling cascade.