TWIST1 induces expression of discoidin domain receptor 2 to promote ovarian cancer metastasis.

The mesenchymal gene program has been shown to promote the metastatic progression of ovarian cancer; however, specific proteins induced by this program that lead to these metastatic behaviors have not been identified. Using patient derived tumor cells and established human ovarian tumor cell lines, we find that the Epithelial-to-Mesenchymal Transition inducing factor TWIST1 drives expression of discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase (RTK) that recognizes fibrillar collagen as ligand. The expression and action of DDR2 was critical for mesothelial cell clearance, invasion and migration in ovarian tumor cells. It does so, in part, by upregulating expression and activity of matrix remodeling enzymes that lead to increased cleavage of fibronectin and spreading of tumor cells. Additionally, DDR2 stabilizes SNAIL1, allowing for sustained mesenchymal phenotype. In patient derived ovarian cancer specimens, DDR2 expression correlated with enhanced invasiveness. DDR2 expression was associated with advanced stage ovarian tumors and metastases. In vivo studies demonstrated that the presence of DDR2 is critical for ovarian cancer metastasis. These findings indicate that the collagen receptor DDR2 is critical for multiple steps of ovarian cancer progression to metastasis, and thus, identifies DDR2 as a potential new target for the treatment of metastatic ovarian cancer.

Two sisters with Mayer-Rokitansky-Küster-Hauser syndrome and serous adenocarcinoma of the ovary.

BACKGROUND: Mayer-Rokitansky-Küster-Hauser syndrome is a rare entity with proposed genetic underpinnings. Ovarian carcinoma has well-described genetic associations and syndromes, although much of the etiology of the disease remains unknown. CASES: Two sisters present in the 1970s with primary amenorrhea, 46, XX karyotypes, and absent uteri consistent with MRKH syndrome. In the 2010s, both sisters again present for care. Case 1 presents one sister with stage IIIC serous ovarian adenocarcinoma and negative BRCA panel. Case No 2 presents the other sister with stage IIIC serous ovarian adenocarcinoma and a negative panel for 32 genetic variants associated with ovarian carcinoma. CONCLUSION: The familial association of two rare diseases and negative genetic workup could point to a new genetic understanding of reproductive structure development and ovarian carcinogenesis.

Benefit of combination chemotherapy and radiation stratified by grade of stage IIIC endometrial cancer.

OBJECTIVE: The optimal strategy for adjuvant therapy in stage IIIC endometrial cancer has not been determined. Our aim was to evaluate survival benefit of different treatments and to investigate if benefit varied by histologic grade. METHODS: We identified 199 patients with stage IIIC endometrial cancer from 2000 to 2012 through the Siteman Cancer Center registry. All patients underwent surgical staging followed by no adjuvant therapy (NAT), radiation (RT), chemotherapy (CT) or chemoradiation (CRT). The association between adjuvant treatment and overall survival was explored using Kaplan-Meier plots and multivariable Cox regression analysis. Multivariable analysis was stratified by low- or high-grade to explore the interaction between grade and treatment. RESULTS: Most patients received CRT (50.3%) followed by CT (23.1%), RT (16.1%) and NAT (10.5%). Survival after CRT was superior to NAT (p<0.001), RT (p=0.010) and CT (p<0.001). After adjusting for covariates, treatment with RT, CT and CRT led to a 57% (p=0.024), 62% (p=0.003) and 83% (p<0.001) reduction in risk of death compared to NAT, respectively. With CRT as the reference, the adjusted hazard of death was higher with NAT (5.94, p<0.001), RT (2.56, p=0.009) and CT (2.24, p=0.004). Stratifying by grade, RT and CRT led to a 67% (p=0.039) and 85% (p<0.001) reduction in death, compared to NAT in low-grade patients. CT and CRT led to a 72% (p=0.003) and 83% (p<0.001) reduction in death, compared to NAT in high-grade patients. CONCLUSIONS: Our findings suggest that CRT should be the preferred adjuvant treatment strategy for patients with stage IIIC endometrial cancer.

The effect of a multidisciplinary palliative care initiative on end of life care in gynecologic oncology patients.

OBJECTIVES: To evaluate the effect of palliative care (PC) consultation on hospice enrollment and end-of-life care in gynecologic oncology patients. METHODS: A retrospective chart review of gynecologic oncology patients who died 1year before and after 2014 implementation of a PC initiative for patients at a single NCI-designated comprehensive cancer center. Patient demographics, admission and procedural history, anti-cancer therapy, and end-of- life care were collected retrospectively. Data was analyzed using Student's t-test, Mann-Whitney U test, Chi-Square test, or Fisher's exact test. RESULTS: We identified 308 patients. Median age at death was 63years (range 17 to 91). Most patients were white (78.2%), married (47.4%), and had ovarian (35.7%) or uterine cancers (35.4%). Introduction of the PC initiative was associated with increased PC consultations (40%, 53%, p=0.02), increased hospice enrollment (57%, 61%, p=0.29), and fewer procedures in the last 30days of life (44%, 31%, p=0.01). The rate of enrollment to inpatient hospice doubled from 12.5% to 25.7% (p=0.02) while time from inpatient hospice enrollment to death increased from 1.9 to 6.0days (p=0.02). Time from outpatient hospice enrollment to death increased from 26.2 to 35.4days (p=0.18). PC consultation was associated with a doubling of outpatient (40%) and inpatient (80%) hospice enrollment. CONCLUSIONS: The PC quality improvement initiative was associated with more palliative care consults, increased rates of inpatient and outpatient hospice utilization, increased time on hospice, and fewer procedures in the last 30days of life, although most women were not enrolled until the last days of life.

Endometrial adenosarcoma in the setting of a germline DICER1 mutation: A case report.

•DICER1 mutations play a significant role in gynecologic malignancy.•DICER1 may be involved in the sarcomagenesis of endometrial adenosarcoma.•The knowledge of a genetic mutation can help clarify a patient's medical history.

AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer.

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer.

Clinicopathologic characteristics and survival of patients with gynecologic malignancies metastatic to the brain.

OBJECTIVE: No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment. METHODS: This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t-test (for marker expression) and Kaplan-Meier test (for correlations). RESULTS: On univariate analysis, primary ovarian disease, CA-125<81units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p<0.0001). None of the molecular markers were significantly associated with survival. CONCLUSIONS: Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases.

Cost-effectiveness analysis of sentinel lymph node biopsy in the treatment of early-stage vulvar cancer.

OBJECTIVE: The objective of this study was to determine the costs and outcomes of inguinal-femoral lymph node dissection (IF-LND) versus sentinel lymph node biopsy (SLNB) for the management of early-stage vulvar cancer. METHODS: A cost-effectiveness model compared 2 different strategies for the management of early-stage vulvar cancer: (1) vulvectomy and SLNB and (2) vulvectomy and IF-LND. Probabilities of inguinal-femoral node metastases and recurrence rates associated with each strategy were estimated from published data. Actual payer costs of surgery and radiation therapy were obtained using 2012 CPT codes and Medicare payment information. Rates and costs of postoperative complications including lymphedema, lymphocyst formation, and infection were estimated and included in a separate model. Cost-effectiveness ratios were determined for each strategy. Sensitivity analyses were performed to evaluate pertinent uncertainties in the models. RESULTS: For the estimated 3000 women diagnosed annually with early-stage vulvar cancer in the United States, the annual cost of the SLNB strategy is $65.2 million compared with $76.8 million for the IF-LND strategy. Three-year inguinal-femoral recurrence-free survival was similar between groups (96.9% vs 97.3%). This translates into a lower cost-effectiveness ratio for the SLNB strategy ($22,416), compared with the IF-LND strategy ($26,344). When adding complication costs to the model, cost-effectiveness ratios further favor the SLNB strategy ($23,711 vs $31,198). Sensitivity analysis revealed that the SLNB strategy remained cost-effective until the recurrence rate after a negative sentinel lymph node approaches 9%. CONCLUSIONS: Sentinel lymph node biopsy is the most cost-effective strategy for the management of patients with early-stage vulvar cancer due to lower treatment costs and lower costs due to complications.

Tertiary prevention of cervical cancer.

Human pappilomavirus (HPV) has been recognized as the most common sexually transmitted disease in the world and over 100 different HPV types have been identified. Persistent HPV infection has been closely linked to the development of invasive cervical cancer. Although surgical and ablative therapies have been the mainstay of treatment, vaccination against the main oncogenic type of HPV is a reasonable preventive strategy for HPV-induced cervical cancer.