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.

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.

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.

Platinum desensitization in patients with carboplatin hypersensitivity: A single-institution retrospective study.

OBJECTIVES: The carboplatin desensitization (CD) protocol presented here allows patients with either a positive skin test or a prior hypersensitivity reaction (HSR) to safely, rapidly and effectively continue with carboplatin infusions. Newly described factors can identify patients at risk for developing adverse events during CD. METHODS: A retrospective review was performed on patients with gynecologic cancer who underwent CD between 2005 and 2014. The CD protocol uses a four-step dilution process over 3.5h. RESULTS: 129 patients underwent CD and completed a total of 788cycles. The desensitization protocol prevented HSRs in 96% (753 out of 788) of these cycles. Patients achieved an average of 6.1cycles (SD±4.55, range 0-23) with CD. The CD protocol allowed 73% (94 of 129) of the patients to undergo carboplatin infusion without reaction. Patients with moderate to life-threatening HSRs (grade 2 through 4) were 10.5years younger at initial CD than patients with grades 0 or 1 HSRs (52.3 vs. 63, P = 0.0307). One patient death occurred during her thirteenth desensitization cycle. The HSR in this case was complicated by pre-exisiting pulmonary hypertension. CONCLUSIONS: This is the largest study of its kind showing a safe, effective and rapid (3.5h) CD protocol. The majority of patients with a history of either carboplatin hypersensitivity reaction or a positive skin test completed the CD protocol without HSRs. Age was identified as a risk factor for HSR severity during CD. Age can be employed along with pre-load dependent cardiac conditions as a way to help risk stratify patients undergoing CD.

Adjuvant Therapy Use and Survival in Stage II Endometrial Cancer.

OBJECTIVE: Radiotherapy (RT) is an established adjuvant treatment for stage II endometrioid endometrial carcinoma (EEC). The role of chemotherapy (CT) in stage II EEC is less proven. We used the National Cancer Data Base to identify factors associated with adjuvant CT in stage II EEC and to explore whether receipt of CT was associated with improved overall survival (OS). METHODS/MATERIALS: Women diagnosed in 2010 to 2013 with International Federation of Obstetrics and Gynecology stage II EEC (grades 1-3) after hysterectomy and bilateral salpingo-oophorectomy were identified in the National Cancer Data Base. Multivariable logistic regression was used to identify covariates associated with receipt of CT. Overall survival among patients receiving RT, CT, or chemoradiotherapy (CRT) after surgery was compared using Kaplan-Meier estimates, the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: We identified 6102 stage II EEC patients. There were 358 patients (6%) who received adjuvant CT alone and 525 (9%) who received CRT; the remainder received RT alone (n = 1906; 31%) or no adjuvant treatment (n = 3313; 54%). The presence of lymphovascular invasion (odds ratio, 3.58; P < 0.001) and grade 3 disease (odds ratio, 3.40; P < 0.001) was strongly associated with receipt of CT or CRT. The OS at 3 years for the entire cohort was 89%. On multivariable analysis, CT versus RT was associated with worse OS (hazard ratio [HR], 2.12 [95% confidence interval, 1.46-3.06]; P < 0.001), whereas CRT versus RT was not associated with improved OS (HR, 1.07 [95% confidence interval, 0.71-1.62]; P = 0.781). After propensity score matching, there remained no difference in OS between RT and CRT (HR, 1.14; P = 0.614). CONCLUSIONS: Patients with stage II EEC have an excellent prognosis, and most undergo observation or receive adjuvant RT in the United States. Receipt of CT (alone or with RT) was not associated with an OS advantage compared with RT alone in this observational cohort. Randomized trials will help clarify the role of CT in stage II patients.

Triapine potentiates platinum-based combination therapy by disruption of homologous recombination repair.

BACKGROUND: Platinum resistance may be attributable to inherent or acquired proficiency in homologous recombination repair (HRR) in epithelial ovarian cancer (EOC). The objective of this study was to evaluate the efficacy of the small molecule inhibitor triapine to disrupt HRR and sensitise BRCA wild-type EOC cells to platinum-based combination therapy in vitro and in vivo. METHODS: The sensitivity of BRCA wild-type cancer cells to olaparib, cisplatin, carboplatin, doxorubicin, or etoposide in combination with triapine was evaluated by clonogenic survival assays. The effects of triapine on HRR activity in cells were measured with a DR-GFP reporter assay. The ability of triapine to enhance the effects of the carboplatin-doxil combination on EOC tumour growth delay was determined using a xenograft tumour mouse model. RESULTS: Platinum resistance is associated with wild-type BRCA status. Triapine inhibits HRR activity and enhances the sensitivity of BRCA wild-type cancer cells to cisplatin, olaparib, and doxorubicin. However, sequential combination of triapine and cisplatin is necessary to achieve synergism. Moreover, triapine potentiates platinum-based combination therapy against BRCA wild-type EOC cells and produces significant delay of EOC tumour growth. CONCLUSIONS: Triapine promises to augment the clinical efficacy of platinum-based combination regimens for treatment of platinum-resistant EOC with wild-type BRCA and proficient HRR activity.

MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib.

BACKGROUND: Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer. This study examines the differential effects of AKT inhibition with cisplatin and olaparib therapy in BRCA1/2-deficient versus wild-type EOC. METHODS: PEO1, a chemosensitive BRCA2-mutant serous ovarian adenocarcinoma, and PEO4, a reverted BRCA2-proficient line from the same patient after the development of chemotherapeutic resistance, were primarily used for the study. In PEO1, MK-2206 demonstrated moderate to strong synergism with cisplatin and olaparib at all doses, while demonstrating antagonism at all doses in PEO4. RESULTS: Baseline phospho-AKT activity in untreated cells was upregulated in both BRCA1- and 2-deficient cell lines. MK-2206 prevented cisplatin- and olaparib-induced AKT activation in the BRCA2-deficient PEO1 cells. We propose that BRCA-deficient EOC cells upregulate baseline AKT activity to enhance survival in the absence of HR. Higher AKT activity is also required to withstand cytotoxic agent-induced DNA damage, leading to strong synergism between MK-2206 and cisplatin or olaparib therapy in BRCA-deficient cells. CONCLUSIONS: MK-2206 shows promise as a chemosensitization agent in BRCA-deficient EOC and merits clinical investigation in this patient population.

When alcohol is the answer: Trapping, identifying and quantifying simple alkylating species in aqueous environments.

Alkylating agents are a significant class of environmental carcinogens as well as commonly used anticancer therapeutics. Traditional alkylating activity assays have utilized the colorimetric reagent 4-(4-nitrobenzyl)pyridine (4NBP). However, 4NBP based assays have a relatively low sensitivity towards harder, more oxophilic alkylating species and are not well suited for the identification of the trapped alkyl moiety due to adduct instability. Herein we describe a method using water as the trapping agent which permits the trapping of simple alkylating electrophiles with a comparatively wide range of softness/hardness and permits the identification of donated simple alkyl moieties.

Who benefits from chemoradiation in stage III-IVA endometrial cancer? An analysis of the National Cancer Data Base.

OBJECTIVE: Adjuvant therapy for advanced endometrial cancer (AEC) is not standardized. We investigated whether regional radiotherapy with chemotherapy (CRT) compared to chemotherapy alone (CT) was associated with improved overall survival (OS) in an AEC cohort and among subgroups by stage and histologic grade. METHODS: Women who received CT or CRT after hysterectomy and bilateral salpingo-oophorectomy for FIGO stage III-IVA AEC diagnosed in 2004-2012 were identified in the National Cancer Data Base. Multilevel modeling was used to identify covariates associated with treatment selection. OS was compared using Kaplan-Meier estimates, the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: We identified 9837 patients, of whom 6358 (65%) received CT and 3479 (35%) received CRT. Median follow-up was 59.6months. OS was higher in patients receiving CRT compared to CT (70% v 55% at 5years, log-rank P<0.001). Controlling for stage, histologic grade, tumor size, age, comorbidity and race, CRT remained independently associated with improved OS (HR 0.63, 95% CI 0.57-0.70, P<0.001). When stratified by stage and histologic grade, there was a significant OS benefit for stage IIIA, IIIB, IIIC, grade 2, and grade 3 (all P<0.001), a trend for stage IVA (P=0.06), but no benefit for grade 1 (P=0.91). On multivariable subgroup analyses, these findings persisted, including lack of benefit in grade 1 patients (HR 0.72, P=0.14). These results were further confirmed after propensity score matching. CONCLUSIONS: Adjuvant CRT for AEC was associated with improved OS, except for patients with well-differentiated disease, who fared equally well with CT alone.

Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: A retrospective review.

OBJECTIVE: To describe the clinical outcome and tolerability of weekly ixabepilone (16-20mg/m(2) days 1, 8, 15 of a 28-day cycle)±biweekly bevacizumab (10mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. METHODS: A single-institution retrospective review was performed inclusive of all patients who received ≥2cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. RESULTS: A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1-10) prior lines of chemotherapy. Patients completed a mean of 4.7±2.9cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7months (range:2-30). Median PFS and OS were 5.2 and 9.6months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0months, p=0.01, HR 0.2, 95% CI 0.05-0.77; 9.6 versus 4.2months, p=0.02, HR 0.58, 95% CI 0.04-0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. CONCLUSIONS: Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations.

The clinical impact of gynecologic MRI.

OBJECTIVE. This study assessed the clinical impact of pelvic MRI performed after the diagnosis of an indeterminate pelvic mass on ultrasound or CT. MATERIALS AND METHODS. The radiologic records of 567 patients who underwent pelvic MRI at our hospital from 2004 to 2006 were reviewed. Of these patients, 214 patients underwent pelvic MRI for evaluation of a gynecologic mass detected on a preceding ultrasound or CT examination; this group of patients constituted the basis of our study. The imaging and clinical records from the database were used for our analysis. The medical records were reviewed for the impact of the radiologic findings on patient treatment, and the results were tabulated for the findings of the first modality, whether the first modality provided a diagnosis, what management plan would be made according to the first modality, and what management plan would be made as a result of the MRI. The adequacy of the imaging study was assessed on the basis of either obtaining an accurate exact diagnosis or ascertaining at the minimum whether the mass was benign or malignant. Further endpoints included specificity and sensitivity of the individual modalities in the diagnosis of a specific gynecologic mass and whether clinical management was altered. Exact binomial CIs were computed for individual proportions. RESULTS. The clinical management of the patient was altered as a result of MRI in 77% of the cases (CI = 0.70-0.82). Surgery was avoided in 36% (CI = 0.29-0.43), and surgery was changed to a more appropriate method (laparoscopy vs laparotomy, involvement or not of a gynecologic oncologist) in an additional 17% (CI = 0.12-0.23). CONCLUSION. Without having undergone MRI, many of the women and girls in this study would have undergone unnecessary surgery; a more costly type of surgery; or long-term follow-up with the associated financial costs, personal and physical costs, and mental costs from the resultant anxiety of an unresolved indeterminate mass.

Factors Predictive of Improved Survival in Patients With Brain Metastases From Gynecologic Cancer: A Single Institution Retrospective Study of 47 Cases and Review of the Literature.

OBJECTIVE: The reported incidence of brain metastasis from epithelial ovarian cancer (EOC), endometrial cancer (EC), and cervical cancer (CC) is exceedingly rare. As the long-term survival for patients with gynecologic cancer increases, there has been a corresponding increase in the number of diagnosed intracranial metastases. We seek to report our experience with managing brain metastatic disease (BMD) in patients with gynecologic cancer. METHODS: A retrospective review of all patients with EOC, EC, and CC at our institution revealed 47 patients with concurrent BMD between 2000 and 2013. Demographic data, risk factors, treatment modalities, progression-free data, and overall survival data were collected. RESULTS: Median survival time in patients with brain metastasis from EOC, EC, and CC was 9.0, 4.5, and 3.0 months, respectively. Two-year overall survival rates were 31.6%, 13.6%, and 0%, respectively. Patients received surgery, radiation therapy alone, palliative care, or radiation plus surgery. Radiation combined with surgical resection resulted in a significant hazards ratio of 0.36 (95% confidence interval, 0.15-0.86), compared with radiation alone. CONCLUSIONS: Our report provides a large single-institution experience of brain metastases from gynecologic cancer. Patients with BMD have poor prognoses; however, treatment with multimodal therapy including surgical resection and radiation may prolong overall survival.

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.

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.

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.

Poly (ADP-ribose) polymerase inhibitors: on the horizon of tailored and personalized therapies for epithelial ovarian cancer.

PURPOSE OF REVIEW: Management of the epithelial ovarian cancer (EOC) remains a therapeutic challenge, with continued poor overall survival (OS). Given low chemotherapy response rates for recurrent disease and short survival times, new treatment options with improved therapeutic indices for targeting cancer's vulnerability are urgently needed in this patient population. RECENT FINDINGS: In this review, we summarize the recent development and clinical evaluations of inhibitors of poly (ADP-ribose) polymerase (PARP) as novel targeting agents for EOC. PARP inhibitors exploit synthetic lethality to target DNA repair defects in hereditary breast and ovarian cancer.In recent clinical trials, EOC patients with BRCA mutations exhibited favorable responses to the PARP inhibitor olaparib compared with patients without BRCA mutations. Additionally, olaparib has been reported to augment the effects of cisplatin and carboplatin on recurrence-free survival and OS in mice bearing BRCA1/2-deficient tumors.Given that hereditary EOC with deleterious BRCA1/2 mutations and BRCAness sporadic EOC are profoundly susceptible to synthetic lethality with PARP inhibition, it is imperative to identify a population of EOC patients that is likely to respond to PARP inhibitors. Recent studies have identified the gene expression profiles of DNA repair defects and BRCAness that predict clinical outcomes and response to platinum-based chemotherapy in EOC patients. SUMMARY: Ovarian cancer continues to carry the highest mortality among gynecologic cancers in the western world. Clinical development of PARP inhibitors that target DNA repair defects in cancer is a novel and imperative stride in individualized identification of molecular characteristics in management of ovarian cancer.

A survey of gynecologic oncologists regarding the end-of-life discussion: a pilot study.

OBJECTIVES: To identify the practices and attitudes of gynecologic oncologists regarding the end-of-life discussion. METHODS: A pilot survey was sent to 1105 members of the Society of Gynecologic Oncologists (SGO). The survey consisted of 20 questions and was sent via the website Survey Monkey. RESULTS: Response rate was 12.8%. Sixty percent of respondents were male, most ranged between 30 and 60 years of age and more than half performed 5-10 major surgeries per week. More than half of respondents (53.9%) deferred the End of Life discussion until the patient had sustained a major change in functional and/or medical status. Thirty percent initiated it at the first recurrence or progression of disease. Forty three percent of respondents characterized the discussion as an on-going process. Patients' age, social support, health insurance, and co-morbidities had no influence on the discussion, and neither did the tumor's site of origin or grade. More respondents initiated the discussion in advanced stage cancer (57%) and after salvage chemotherapy institution (54%). Forty four percent of respondents reported that "understanding and acceptance" was the initial response by patient when counseled about withdrawal of care. This increased to 86% when the issue was revisited. Confusion or reluctance to discuss the subject were initially reported to be 12% and 19%, respectively, but decreased to 2% and 3%, respectively, when withdrawal of care was subsequently addressed with the patient. CONCLUSIONS: This pilot survey sheds a light on attitudes and practices about the end-of-life discussion that deserve to be further studied.

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.

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.