Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.

Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.

Gene expression of non-homologous end-joining pathways in the prognosis of ovarian cancer.

Ovarian cancer is the deadliest gynecologic malignancy in women, with a 46% five-year overall survival rate. The objective of the study was to investigate the effects of non-homologous end-joining (NHEJ) genes on clinical outcomes of ovarian cancer patients. To determine if these genes act as prognostic biomarkers of mortality and disease progression, the expression profiles of 48 NHEJ-associated genes were analyzed using an array of statistical and machine learning techniques: logistic regression models, decision trees, naive-Bayes, two sample t-tests, support vector machines, hierarchical clustering, principal component analysis, and neural networks. In this process, the correlation of genes with patient survival and disease progression and recurrence was noted. Also, multiple features from the gene set were found to have significant predictive capabilities. APTX, BRCA1, PAXX, LIG1, and TP53 were identified as most important out of all the candidate genes for predicting clinical outcomes of ovarian cancer patients.

In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a rare, biologically aggressive variant of endometrial cancer with a high recurrence rate and poor prognosis. HER2 overexpression (3+ positivity) by IHC and/or FISH ERBB2 gene amplification is detected in approximately one-third of patients with USC. Clinical trials incorporating trastuzumab with standard chemotherapy have recently demonstrated improved progression-free and overall survival in advanced-stage or recurrent USC that overexpresses HER2. However, a large number of patients with USC eventually developed resistance to trastuzumab. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload recently approved by the Food and Drug Administration (FDA) for multiple tumor indications. Here, we investigated the in vitro and in vivo efficacy of T-DXd in primary USC cell lines and xenografts with different HER2 expression. T-DXd-induced cell growth suppression in HER2-overexpressing cell lines in vitro, increased early and late apoptosis as assessed by annexin and propidium iodide staining, and, similarly to trastuzumab, T-DXd-induced significant antibody-dependent cellular cytotoxicity in the presence of peripheral blood lymphocytes. While negligible activity was detected against USC cell lines with low HER2 expression, T-DXd demonstrated significant bystander killing against USC tumors with low/negligible HER2 when such cells were admixed with HER2 3+ tumor cells in vitro. T-DXd showed tumor growth suppression in in vivo USC PDX models that overexpress HER2 at 3+ levels, prolonging survival when compared with controls, with minimal toxicity. Future clinical trials are warranted in patients with USC failing trastuzumab treatment.

Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib.

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, largely due to metastasis and drug resistant recurrences. Fifteen percent of ovarian tumors carry mutations in BRCA1 or BRCA2, rendering them vulnerable to treatment with PARP inhibitors such as olaparib. Recent studies have shown that TGFß can induce "BRCAness" in BRCA wild-type cancer cells. Given that TGFß is a known driver of epithelial to mesenchymal transition (EMT), and the connection between EMT and metastatic spread in EOC and other cancers, we asked if TGFß and EMT alter the susceptibility of EOC to PARP inhibition. Epithelial EOC cells were transiently treated with soluble TGFß, and their clonogenic potential, expression, and function of EMT and DNA repair genes, and response to PARP inhibitors compared with untreated controls. A second epithelial cell line was compared to its mesenchymal derivative for EMT and DNA repair gene expression and drug responses. We found that TGFß and EMT resulted in the downregulation of genes responsible for homologous recombination (HR) and sensitized cells to olaparib. HR efficiency was reduced in a dose-dependent manner. Furthermore, mesenchymal cells displayed sensitivity to olaparib, cisplatin, and the DNA-PK inhibitor Nu-7441. Therefore, the treatment of disseminated, mesenchymal tumors may represent an opportunity to expand the clinical utility of PARP inhibitors and similar agents.

Vesical clear cell adenocarcinoma of Müllerian origin treated conservatively with partial cystectomy.

A 71-year-old woman presented with an intravesical bladder mass found to be a clear cell adenocarcinoma of Müllerian origin with positive PAX-8 staining after transurethral resection. Partial cystectomy along with total hysterectomy were performed, and final pathology revealed no residual tumour and extensive endometriosis. She declined adjuvant therapy and was dispositioned to surveillance.

Financial toxicity in patients with gynecologic malignancies: a cross sectional study.

OBJECTIVE: To evaluate financial toxicity and assess its risk factors among patients with gynecologic cancers. METHODS: This is a cross sectional study that included 2 survey tools, as well as patient demographics, disease characteristics, and treatment regimen. Financial toxicity is measured by validated Comprehensive Score for Financial Toxicity (COST) tool. Participants were also asked to complete a 55-question-survey on attitudes and perspectives surrounding cost of care. Descriptive statistics was used to report patient demographics. Spearman's rank correlation was calculated to assess the relation between financial toxicity and patient/disease related variables. Graphpad Prism Software Version 8.0 was used for analyses. RESULTS: A total of 50 patients with various gynecologic malignancies were enrolled. Median COST score was 20.5 (range, 1-33). Sixty-five percent of the patients reported being in debt due to their cancer care and 4% filed bankruptcy. Correlation analysis showed that COST score was correlated with age (r=-0.3, p=0.028), malignancy type (r=0.3, p=0.039) and income (r=0.3, p=0.047). Ovarian cancer patients had significantly less financial toxicity (median COST score=23) when compared to patients with other gynecologic malignancies (median COST score=17, p=0.043). When scores were dichotomized into low (score ≥22) and high toxicity (score <22), 58% (29/50) of the patients were noted to have high financial toxicity. Enrollment to a clinical trial did not significantly alleviate financial burden. CONCLUSION: Financial toxicity is a significant burden even among highly insured gynecologic oncology patients. Age, malignancy type and income were correlated with high financial burden.

Flow Cytometric Analyses of p53-Mediated Cell Cycle Arrest and Apoptosis in Cancer Cells.

Phenotypic analysis of the effects of a gene of interest may be limited because stable expression of some genes leads to adverse consequences in cell survival, such as disturbance of cell cycle progression, senescence, autophagy, and programmed cell death. One of the best examples is tumor suppressor p53. p53 functions as a tumor suppressor by inducing cell cycle arrest and apoptosis in response to genotoxic and environmental insults. The choice and timing of either pathways induced by p53 depend on cellular context, cell types, and the degree of cellular/genomic damage (For review, see (Chen J, Cold Spring Harb Perspect Med 6:a026104, 2016)). The uncertainty makes the studies on the long-term effects of p53 in cells challenging. This chapter describes a method of flow cytometric analysis of ectopic expression of p53 to better quantify cell cycle distribution and apoptosis in cells treated with DNA damaging agents. The method can be easily adapted to other genes of interest to study their contributions to the fate of variety of cell types in response to endogenous or exogenous stresses.

Two Plasmid-Based Systems for CRISPR/Cas9 Mediated Knockout of Target Genes.

CRISPR/Cas9-based gene editing is a recent advance that allows for the knockout or alteration of target genes within mammalian cells. Many variations of the technique exist, but here we describe two systems of plasmid-based CRISPR gene knockout which together allow for the selective knockout of virtually any gene target. Compared with other CRISPR-based systems, these plasmids have the advantages of delivering all the necessary components in one plasmid, choice of multiple selectable markers, and choice of route of administration into target cells. In addition, potential off-target effects from one system (dependent upon selection of target gene) can be overcome through use of the second system. Strategies for optimizing the knockout process and selection of finished cell lines are also presented.

In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer.

Poly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of BRCA mutation and restoration of HR repair in EOC lead to PARP inhibitor resistance and reduced clinical efficacy of PARP inhibitors. We have previously shown that triapine, a small molecule inhibitor of ribonucleotide reductase (RNR), impaired HR repair and sensitized HR repair-proficient EOC to PARP inhibitors. In this study, we performed in silico screening of small molecule libraries to identify novel compounds that bind to the triapine-binding pocket on the R2 subunit of RNR and inhibit RNR in EOC cells. Following experimental validation of selected top-ranking in silico hits for inhibition of dNTP and DNA synthesis, we identified, DB4, a putative RNR pocket-binding inhibitor markedly abrogated HR repair and sensitized BRCA-wild-type EOC cells to the PARP inhibitor olaparib. Furthermore, we demonstrated that the combination of DB4 and olaparib deterred the progression of BRCA-wild type EOC xenografts and significantly prolonged the survival time of tumor-bearing mice. Herein we report the discovery of a putative small molecule inhibitor of RNR and HR repair for combination with PARP inhibitors to treat PARP inhibitor-resistant and HR repair-proficient EOC.

Prescribed medical cannabis in women with gynecologic malignancies: A single-institution survey-based study.

Research within a gynecologic oncology population has lagged behind the uptake in use of medical cannabis for symptom control. This study seeks to evaluate patient experience with prescribed medical cannabis obtained through licensed dispensaries in women with gynecologic malignancies. A 43-item survey exploring patient experience with medical cannabis was administered to women with gynecologic malignancies who used medical cannabis prescribed by a gynecologic oncologist. Thirty-six eligible patients were approached for consent, and 31 patients returned completed surveys (86%). Ninety-three percent had advanced or recurrent disease; 74% were receiving chemotherapy or immunotherapy. Eighty-three percent reported medical cannabis provided relief from cancer or treatment-related symptoms including decreased appetite (41%), insomnia (41%), neuropathy (41%), anxiety (35%), nausea (29%), joint pain (29%), bone pain (29%), abdominal pain (25%), and depression (19%). Eighty percent of patients reported medical cannabis worked the same or better than other traditional medications for management of their cancer or treatment-related symptoms, and 83% reported medical cannabis had an equivalent or better side effect profile. Of the subset of patients using medical cannabis for pain, 63% reported a reduction in opioid use. Patients perceive that medical cannabis was useful for relief of cancer and treatment-related symptoms, suggesting medical cannabis may be a reasonable alternative or adjunct therapy. Medical cannabis was well tolerated and may have the potential to improve neuropathic pain and decrease opioid use.

Corrigendum to "Phase II evaluation of copanlisib, a selective inhibitor of Pi3kca, in patients with persistent or recurrent endometrial carcinoma harboring PIK3CA hotspot mutations: An NRG oncology study (NRG-GY008)" [Gynecol. Oncol. Rep. 31 (2020) 100532].

[This corrects the article DOI: 10.1016/j.gore.2019.100532.].

Opsoclonus-ataxia syndrome and mature ovarian teratoma in an adolescent.

•Ovarian teratomas have been implicated in multiple paraneoplastic syndromes.•Opsoclonus-ataxia syndrome is a rare entity that may be secondary to a paraneoplastic, infectious, or idiopathic process.•Opsoclonus-ataxia syndrome may be associated with ovarian teratoma in both children and adults.•Prompt gynecologic involvement for teratoma resection is warranted.

Phase II evaluation of copanlisib, a selective inhibitor of Pi3kca, in patients with persistent or recurrent endometrial carcinoma harboring PIK3CA hotspot mutations: An NRG Oncology study (NRG-GY008).

PURPOSE: NRG Oncology conducted a phase II trial to assess the antitumor activity and tolerability of copanlisib, a selective inhibitor of PIK3CA, in persistent or recurrent endometrial carcinoma harboring hotspot PIK3CA mutations. PATIENTS AND METHODS: Eligible patients had endometrial cancer with endometrioid, serous or mixed histology, a somatic PIK3CA gene mutation, measurable disease, and GOG performance status ≤2. Treatment consisted of IV copanlisib (60 mg weekly, day 1, 8 and 15 of 28-day cycle) until disease progression or prohibitive toxicity. The primary endpoints of the study were objective tumor response as assessed by RECIST 1.1 and to determine the nature and degree of toxicity of copanlisib as assessed by CTCAE version 4. The study used a 2-stage group sequential design. RESULTS: Eleven patients were enrolled onto stage I of the treatment trial. Five patients had endometrioid, four serous and two had a tumor of mixed histology. The most common PIK3CA mutation was Q546X (n = 3) in exon 9. The most common grade 3 or 4 AE was hyperglycemia. No grade 5 adverse events were reported. No clinical responses were detected. Six patients had a best overall response of stable disease. Of 11 who initiated treatment, 10 progressed on treatment. One patient with stable disease on copanlisib withdrew from treatment secondary to relocation. The median progression-free survival (PFS) was 2.8 months; at 6 months 27% were alive, progression-free. The median overall survival (OS) was 15.2 months. Due to the lack of CR/PR continuation of accrual to the second stage of accrual was not warranted. CONCLUSION: Copanlisib is well tolerated but has limited activity as a single agent in this population.

Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002).

PURPOSE: Patients with persistent/recurrent cervical cancer following platinum-based chemotherapy have limited therapeutic options. The Gynecologic-Oncology-Group conducted a phase II trial to assess efficacy and tolerability of nivolumab, an immune checkpoint inhibitor, in persistent/recurrent cervical carcinoma. PATIENTS AND METHODS: Key eligibility criteria included persistent/recurrent cervical cancer, failure of prior systemic therapy and ECOG PS 0-1. Nivolumab 3 mg/kg was given IV every 2 wk. until disease progression or intolerable toxicity. Response was assessed every 8 wk. for 6 months and every 12 wk. thereafter. The primary endpoints were objective response as assessed by RECIST 1.1. The study used a 2-stage group sequential design. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1%. RESULTS: Of 26 enrolled patients with persistent/recurrent cervical cancer, 25 were evaluable for response/toxicity with a median age of 45. 36% had ECOG PS of 1, and 100% had received one prior systemic chemotherapy regimen. PD-L1 expression (≥1%) was identified in 77.3% of tumor samples. As of 03/05/19, all patients were off study treatment; median follow-up for survival status was 32 months (range, 2-41.5). There were 21 (84%) patients with a treatment-related adverse event (TRAE) and most were grades 1-2. Six (24%) patients had grade 3 TRAEs with 1 discontinuing nivolumab due to hepatic toxicity. No grade 5 TRAEs occurred, and 2 patients had grade 4 TRAEs. One confirmed partial response (4%; 90% CI, 0.4%-22.9%), duration of response 3.8 months. Thirty-six percent of patients had stable disease (SD) (9/25; 90% CI, 20.2%-54.4%); the median duration of SD was 5.7 months (range, 3.5-12.7). Estimated PFS and OS at 6 months were 16% and 78.4%, respectively. CONCLUSION: Single agent nivolumab exhibited low antitumor activity and an acceptable safety profile in patients with persistent/recurrent cervical cancer previously treated with platinum-based chemotherapy.

Ten-Year Comparison Study of Type 1 and 2 Endometrial Cancers: Risk Factors and Outcomes.

AIMS: To compare baseline risk factors for type 1 vs. 2 endometrial cancers and analyze these risk factors for association with overall survival and time to recurrence. METHODS: Retrospective review of 816 consecutive endometrial cancer cases was conducted with diagnosis from January 2005 to December 2010 and clinical course until 2016. Risk factors, treatment, recurrence, and death were compared using 2 sample t tests, χ2 test and Cox Regression models. RESULTS: There were 550 cases of type 1 and 266 cases of type 2 cancer. Patients with type 2 disease were older (p < 0.001), less obese (p = 0.03), non-white (p < 0.001), and menopausal (p = 0.02). There was no difference in use of oral contraceptives, hormone replacement therapy (HRT), smoking, or major cardiovascular disease. Cox Regression models showed that type 2 disease (p < 0.001) and advanced stage (p = 0.001) were associated with recurrence. CONCLUSIONS: Consistent with previous literature, our analysis found that type 2 cancer is more common in non-white, older, and less obese patients and associated with higher mortality and recurrence. However, inconsistent with previous literature, we found no association between type 2 cancer and diabetes mellitus or use of HRT. These factors should be considered when approaching patients with endometrial cancer.

Extended duration of dilator use beyond 1 year may reduce vaginal stenosis after intravaginal high-dose-rate brachytherapy.

BACKGROUND: Vaginal dilators (VD) are recommended following vaginal or pelvic radiotherapy for patients with endometrial carcinoma (EC) to prevent vaginal stenosis (VS). The time course of VS is not fully understood and the optimal duration of VD use is unknown. METHODS: We reviewed 243 stage IA-II EC patients who received adjuvant brachytherapy (BT) at an academic tertiary referral center. Patients were instructed to use their VD three times per week for at least 1-year duration. The primary outcome was development of grade ≥ 1 VS using CTCAEv4 criteria during the follow-up period. The log-rank test and multivariable Cox proportional hazards modeling were used to evaluate the effect of VD use (noncompliance vs. standard compliance [up to 1 year] vs. extended compliance [over 1 year]) on VS. RESULTS: The median follow-up was 15.2 months over the 5-year study period. At 15 months, the incidence of VS was 38.8% for noncompliant patients, 33.5% for those with standard compliance, and 21.4% for those with extended compliance (median time to grade ≥ 1 VS was 17.5 months, 26.7 months, and not yet reached for these groups, respectively). On multivariable Cox regression analysis, extended compliance remained a significant predictor of reduced VS risk when compared to both noncompliance (HR 0.38, 95% CI 0.18-0.80, p = 0.012) and standard compliance (HR 0.43, 95% CI 0.20-0.89, p = 0.023). CONCLUSIONS: The risk of VS persists beyond 1 year after BT. Extended VD compliance beyond 1 year may mitigate this risk.

Combination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer.

PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, the treatment of HRR-proficient EOC with PARP inhibitors remains challenging. The objective of this study was to determine whether the combination of triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor), and the PARP inhibitor olaparib synergized against BRCA wild-type and HRR-proficient EOC in xenograft mouse models. In addition, the mechanisms by which cediranib augmented the efficacy of triapine and olaparib were investigated. BRCA-wild type and PARP inhibitor-resistant EOC cell lines were implanted subcutaneously (s.c.) into nude mice or injected intraperitoneally (i.p.) into SCID-Beige mice. Mice were then treated i.p. with olaparib, cediranib, triapine, various double and triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID-Beige mice were measured to evaluate the effectiveness of the treatment to delay tumor growth and prolong the survival time of mice. In both xenograft mouse models, the combination of triapine, olaparib and cediranib resulted in marked suppression of BRCA-wild type EOC growth and significant prolongation of the survival time of mice, with efficacy greater than any double combinations and single drugs. Furthermore, we identified that cediranib abrogated pro-survival and anti-apoptotic AKT signaling, thereby enhancing the efficacy of triapine and olaparib against BRCA-wild type EOC cells. Taken together, our results demonstrate a proof-of-principle approach and the combination regiment holds promise in treating BRCA-wild type and PARP inhibitor-resistant EOC.

Impact of carboplatin hypersensitivity and desensitization on patients with recurrent ovarian cancer.

PURPOSE: Hypersensitivity reactions (HSRs) to chemotherapy is an ongoing issue in cancer treatments. Strategies to induce tolerance and maximize chemotherapy efficacy include desensitization protocols. The precise impact of these protocols, however, in the long-term treatments remains unclear. We aim to compare overall survival (OS) in hypersensitive patients treated with carboplatin desensitization to patients without hypersensitivity reactions. We also sought to identify new risk factors for HSRs and reconfirm that the DNA repair enzyme, germline BRCA1/2 (gBRCA1/2), is a risk factor for hypersensitivity. EXPERIMENTAL DESIGN: Retrospective study in patients with ovarian cancer tested for gBRCA1/2 mutations who received more than six infusions of carboplatin from August 2005 to November 2016. Two-sided Fisher exact, Student's t test and Gehan-Breslow-Wilcoxon test were used for statistical analysis. Univariate and multivariate analyses were completed to identify independent predictors of survival. Statistical significance was set with a two-sided p value of 0.05. RESULTS: Ninety-one patients with gBRCA1/2 testing met inclusion. Forty patients (44%) were gBRCA1/2-deficient and 51 (56%) were gBRCA1/2-proficient. Patients with gBRCA1/2 deficiencies had a higher likelihood of developing carboplatin hypersensitivity, HR 6.433 (95% CI: 1.868-22.149). None of the patients with carboplatin hypersensitivity were given PARP inhibitors prior to the development of HSRs. The patients with recurrent advanced stage (III-IV) ovarian cancer had a higher likelihood of developing carboplatin hypersensitivity, HR 4.783 (1.008-22.689). Moreover, we found that hypersensitive patients who underwent carboplatin desensitization had a 48-month longer OS than patients without hypersensitivity to carboplatin not undergoing carboplatin desensitization (p = 0.0094). A subgroup analysis indicated that gBRCA1/2-proficient hypersensitive patients undergoing carboplatin desensitization had a 43-month longer OS than gBRCA1/2-proficient patients without HSRs (p = 0.034). CONCLUSIONS: We confirmed that gBRCA1/2 deficiency and advanced stage are independent risk factors for development of carboplatin hypersensitivity in ovarian cancer patients. Our study also shows improved OS in hypersensitive patients receiving CD compared to non-hypersensitive patients, independent of gBRCA1/2.

Targeting Cyclin-Dependent Kinases for Treatment of Gynecologic Cancers.

Ovarian, uterine/endometrial, and cervical cancers are major gynecologic malignancies estimated to cause nearly 30,000 deaths in 2018 in US. Defective cell cycle regulation is the hallmark of cancers underpinning the development and progression of the disease. Normal cell cycle is driven by the coordinated and sequential rise and fall of cyclin-dependent kinases (CDK) activity. The transition of cell cycle phases is governed by the respective checkpoints that prevent the entry into the next phase until cellular or genetic defects are repaired. Checkpoint activation is achieved by p53- and ATM/ATR-mediated inactivation of CDKs in response to DNA damage. Therefore, an aberrant increase in CDK activity and/or defects in checkpoint activation lead to unrestricted cell cycle phase transition and uncontrolled proliferation that give rise to cancers and perpetuate malignant progression. Given that CDK activity is also required for homologous recombination (HR) repair, pharmacological inhibition of CDKs can be exploited as a synthetic lethal approach to augment the therapeutic efficacy of PARP inhibitors and other DNA damaging modalities for the treatment of gynecologic cancers. Here, we overview the basic of cell cycle and discuss the mechanistic studies that establish the intimate link between CDKs and HR repair. In addition, we present the perspective of preclinical and clinical development in small molecule inhibitors of CDKs and CDK-associated protein targets, as well as their potential use in combination with hormonal therapy, PARP inhibitors, chemotherapy, and radiation to improve treatment outcomes.

MicroRNA signatures discriminate between uterine and ovarian serous carcinomas.

Synchronous endometrial and ovarian malignancies occur in 5% of women presenting with endometrial cancer and 10% of patients presenting with ovarian malignancy. When a high-grade serous carcinoma concurrently involves both ovary and endometrium, pathological determination of whether they are synchronous primaries or metastatic tumors from one primary site can be challenging. MicroRNAs (miRNA) are 22-nucleotide noncoding RNAs that are aberrantly expressed in cancer cells and may inherit their cellular lineage characteristics. We explored possible differential miRNA signatures that may separate high-grade ovarian serous carcinoma from primary endometrial serous carcinoma. Forty-seven samples of histologically pure high-grade serous carcinoma of both uterine (16 case) and ovarian primaries (31 cases) were included. Expression of 384 mature miRNAs was analyzed using ABI TaqMan Low-Density Arrays technology. A random forest model was used to identify miRNAs that together could differentiate between uterine and ovarian serous carcinomas. Among 150 miRNAs detectable at various levels in the study cases, a panel of 11-miRNA signatures was identified to significantly discriminate between ovarian and uterine serous carcinoma (P < .05). A nested cross-validated convergent forest plot using 6 of the 11 miRNA signature was eventually established to classify the tumors with 91.5% accuracy. In conclusion, we have characterized a miRNA signature panel in this exploratory study that shows significant discriminatory power in separating primary ovarian high-grade serous carcinoma from its endometrial counterpart.