SYNE1 Mutation Is Associated with Increased Tumor Mutation Burden and Immune Cell Infiltration in Ovarian Cancer.

SYNE1, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. SYNE1 alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between SYNE1 mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the SYNE1 mutation frequency, association with TMB, and downstream effects of SYNE1 mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer Genome Atlas (TCGA). Bioinformatics analyses were performed. In our cohort of 50 patients, 16 had a SYNE1 mutation, and 15 had recurrent disease. Median TMB for SYNE1 mutated patients was 25 compared to 7 for SYNE1 wild-type patients (p < 0.0001). Compared to the TCGA cohort, our cohort had higher SYNE1 mutation rates (32% vs. 6%, p < 0.001). Gene expression related to immune cell trafficking, inflammatory response, and immune response (z > 2.0) was significantly increased in SYNE1 mutated patients. SYNE1 mutation is associated with increased TMB and immune cell infiltration in ovarian cancer and may serve as an additional biomarker for immunotherapy response.

Uterine Corpus Malignancies in Appalachia Kentucky: Incidence, Survival, and Related Health Disparities.

OBJECTIVES: Uterine cancer is the nation's most common gynecologic malignancy, but it is understudied in the geographically and socioeconomically diverse state of Kentucky (KY). Our aim was to assess the frequency, distribution, and survival of uterine corpus malignancies in KY, and specifically the differences between Appalachia (AP) and non-Appalachia (NAP) KY. METHODS: This population-based cohort study used Surveillance, Epidemiology, and End Results data and the Kentucky Cancer Registry to study uterine corpus malignancy between January 1, 2000 and December 31, 2014. The analysis looked at the incidence between diagnoses in AP and NAP. The evaluation criteria included tumor histology (type I, type II, sarcoma, and mixed uterine malignancy), age, race, smoking status, stage at diagnosis, insurance status, and county of residence at diagnosis. RESULTS: The overall age-adjusted incidence rate and survival are similar for US and KY populations; however, histologic types and distribution differ. Compared with the United States, the incidence of corpus cancers in KY is higher for type I (P = 0.03), but lower for type II (P = 0.003), sarcoma (P = 0.006), and mixed (P < 0.001). AP KY has a higher incidence of type I (P < 0.0001) and mixed malignancy (P = 0.04), younger age at diagnosis (P < 0.0001), larger non-Hispanic white population (P < 0.0001), fewer smokers (P = 0.002), and more uninsured and Medicaid recipients (P < 0.0001) compared with NAP KY. The hazard ratio for death is similar in AP and NAP KY (0.896; 95% confidence interval 0.795-1.009). CONCLUSIONS: Type I and mixed uterine corpus cancers have a higher age-adjusted incidence and a younger age at diagnosis in AP compared with NAP KY.

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

Significance of Lymphovascular Space Invasion by the Sarcomatous Component in Uterine Carcinosarcoma.

OBJECTIVE: The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS: This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I-IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS: Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36-2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39-2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION: In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.

Proposal for a Risk-Based Categorization of Uterine Carcinosarcoma.

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVE: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR). METHODS: Patients with measurable disease, acceptable organ function, performance status ≤ 2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of ≥40% with 90% power. RESULTS: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported. CONCLUSIONS: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615].

Significance of venous thromboembolism in women with uterine carcinosarcoma.

OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P=0.012), non-Asian race (HR 6.28, P<0.001), large body habitus (HR per kg/m2 1.04, P=0.014), residual disease at surgery (HR 3.04, P=0.003), tumor size ≥5cm (HR 2.73, P=0.003), and stage IV disease (HR 2.12, P=0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P<0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P=0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%CI 1.05-2.04, P=0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.

Survival outcome of women with stage IV uterine carcinosarcoma who received neoadjuvant chemotherapy followed by surgery.

BACKGROUND AND OBJECTIVES: To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. METHODS: This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. RESULTS: The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. CONCLUSION: Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.

Population-Based Analysis of Patient Age and Other Disparities in the Treatment of Ovarian Cancer in Central Appalachia and Kentucky.

OBJECTIVES: Adherence to National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer treatment improves patient outcomes. The aim of this study was to assess disparities associated with ovarian cancer treatment in the state of Kentucky and central Appalachia. METHODS: Data on patients diagnosed as having ovarian cancer from 2007 through 2011 were extracted from administrative claims-linked Kentucky Cancer Registry data. NCCN compliance was defined by stage, grade, surgical procedure, and chemotherapy. Selection criteria were reviewed carefully to ensure data quality and accuracy. Descriptive analysis, logistic regression, and Cox regression analyses were performed to examine factors associated with guidelines compliance and survival. RESULTS: Most women were aged 65 years or older (62.5%) and had high-grade (65.9%) and advanced-stage (61.0%) ovarian cancer. Two-thirds of cases (65.9%) received NCCN-recommended treatment for ovarian cancer. The hazard ratio of death for women who did not receive NCCN-compliant care was 62% higher compared with the women who did receive NCCN-compliant treatment. Results from the logistic regression showed that NCCN-compliant treatment was more likely for women aged 65 to 74 years compared with women aged 20 to 49 years, late-stage compared with early-stage cancers, receipt of care at tertiary care hospitals, and privately insured compared with Medicaid or Medicare. CONCLUSIONS: When the treatment of ovarian cancer did not follow NCCN recommendations, patients had a significantly higher risk of death. Women were less likely to receive NCCN-compliant care if they were younger (20-49 years), had early-stage disease, did not have private insurance, or had care provided at a nontertiary care hospital.

Prospective validation of an intraoperative algorithm to guide surgical staging in early endometrial cancer.

OBJECTIVES: Prospectively validate an intraoperative surgical staging algorithm to stratify patients with early endometrial cancer by risk of lymph node metastasis. METHODS: Subjects with endometrial cancer clinically confined to the uterus were prospectively enrolled at an academic cancer center between Jan 2012 and Jun 2015. Study participants were stratified intraoperatively into two groups based on risk of nodal involvement using cell type, tumor grade, myometrial invasion, and tumor size in accordance with an established protocol from the Mayo Clinic. Low risk (LR) subjects received extrafascial hysterectomy with bilateral salpingo-oophorectomy; high risk (HR) patients received complete surgical staging including bilateral pelvic and para-aortic lymphadenectomy. RESULTS: Of the 200 subjects enrolled, 194 were eligible for analysis. The algorithm identified 132 (68%) HR and 62 (32%) LR cancers. Of the HR subjects, 126 had lymphadenectomy performed with 14 (11%) positive for nodal metastases. Five HR subjects experienced disease recurrence. Of the 62 LR cancers, two patients developed disease recurrence. Ten LR cancers were upgraded to HR on final pathology due to lesion size (6) and grade (4). None of these patients experienced disease recurrence. The algorithm demonstrated 90% sensitivity (18/20) and 36% specificity (62/174) as determined by positive lymph nodes and/or disease recurrence. CONCLUSIONS: Intraoperative assessment of early endometrial cancer can be used to determine the extent of surgical staging. The studied algorithm has low specificity and modifications are necessary to better match the surgical procedure to the risk of metastatic cancer.

Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma.

BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma.

OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P<0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P=0.02). When stratified by disease-free interval, women with a disease-free interval ≥6months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P=0.002); conversely, in women with a disease-free interval <6months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P=0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P=0.019). CONCLUSION: Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6months.

Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma.

OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

First International Consensus Report on Adnexal Masses: Management Recommendations.

The First International Consensus Conference on Adnexal Masses was convened to thoroughly examine the state of the science and to formulate recommendations for clinical assessment and management. The panel included representatives of societies in the fields of gynecology, gynecologic oncology, radiology, and pathology and clinicians from Europe, Canada, and the United States. In the United States, there are approximately 9.1 surgeries per malignancy compared to the European International Ovarian Tumor Analysis center trials, with only 2.3 (oncology centers) and 5.9 (other centers) reported surgeries per malignancy, suggesting that there is room to improve our preoperative assessments. The American College of Obstetricians and Gynecologists Practice Bulletin on "Management of Adnexal Masses," reaffirmed in 2015 (Obstet Gynecol 2007; 110:201-214), still states, "With the exception of simple cysts on a transvaginal ultrasound finding, most pelvic masses in postmenopausal women will require surgical intervention." The panel concluded that patients would benefit not only from a more conservative approach to many benign adnexal masses but also from optimization of physician referral patterns to a gynecologic oncologist in cases of suspected ovarian malignancies. A number of next-step options were offered to aid in management of cases with sonographically indeterminate adnexal masses. This process would provide an opportunity to improve risk stratification for indeterminate masses via the provision of alternatives, including but not limited to evidence-based risk-assessment algorithms and referral to an "expert sonologist" or to a gynecologic oncologist. The panel believed that these efforts to improve clinical management and preoperative triage patterns would ultimately improve patient care.

Serial ultrasonographic evaluation of ovarian abnormalities with a morphology index.

OBJECTIVE: Transvaginal ultrasonography with tumor morphology index (MI) has been used to predict the risk of ovarian malignancy. Our objective was to analyze changes in serial MI scores for malignant and non-malignant ovarian tumors in a large and asymptomatic population. METHODS: Eligible subjects participated in the University of Kentucky Ovarian Cancer Screening Program and had abnormalities that included cysts, cysts with septations, complex cysts with solid areas, and solid masses. Analysis included: MI, change in MI (delta MI), delta MI per scan and per month, number and duration of scans. RESULTS: From 1987 to 2012, 38,983 women received 218,445 scans. Of the 7104 eligible subjects, 6758 tumors were observed without surgery and 472 were surgically removed. Eighty-six percent (5811) of observed tumors were resolved. There were 74 malignant and 272 non-malignant tumors. Eighty-five percent of malignancies had MI ≥5 at decision for surgery. The risk of malignancy based on MI was: MI=5 (3%), MI=6 (3.7%), MI=7 (12.6%), MI=8 (26.7%), MI=9 (27.8%), MI=10 (33.3%). The mean delta MI per month decreased for tumors that resolved (delta MI -1.0, p<0.001) or persisted without surgery (delta MI -0.7, p<0.001). For abnormalities surgically removed, the mean delta MI per month increased significantly more for malignancies than for benign tumors (delta MI +1.6 vs. +0.3, p<0.001). CONCLUSIONS: The mean MI for malignant ovarian tumors increases over time, while non-malignant tumors have a decreasing or stable MI. Serial MI analysis can improve the prediction of ovarian malignancy by reducing false-positive results, thereby decreasing the number of operations performed for benign abnormalities.

The effect of ovarian imaging on the clinical interpretation of a multivariate index assay.

OBJECTIVE: The purpose of this study was to investigate the relationship between imaging and the multivariate index assay (MIA) in the prediction of the likelihood of ovarian malignancy before surgery. STUDY DESIGN: Subjects were recruited in 2 related prospective, multiinstitutional trials that involved 44 sites across the United States. Women had ovarian imaging, biomarker analysis, and surgery for an adnexal mass. Ovarian tumors were classified as high risk for solid or papillary morphologic condition on imaging study. Biomarker and imaging results were correlated with surgical findings. RESULTS: Of the 1110 women who were enrolled with an adnexal mass on imaging, 1024 cases were evaluable. There were 255 malignant and 769 benign tumors. High-risk findings were present in 46% of 1232 imaging tests and 61% of 1024 MIA tests. The risk of malignancy increased with rising MIA scores; similarly, the likelihood of malignancy was higher for high-risk, compared with low-risk, imaging. Sensitivity and specificity for the prediction of malignancy were 98% (95% CI, 92-99) and 31% (95% CI, 27-34) for ultrasound or MIA; 68% (95% CI, 58-77) and 75% (95% CI, 72-78) for ultrasound and MIA, respectively. For computed tomography scan or MIA, sensitivity was 97% (95% CI, 92-99) and specificity was 22% (95% CI, 16-28); the sensitivity and specificity for computed tomography scan and MIA were 71% (95% CI, 62-79) and 70% (95% CI, 63-76). Only 1.6% of ovarian tumors were malignant when both tests indicated low risk. A logistic regression model to predict risk of malignancy is presented. CONCLUSION: An understanding of how pelvic imaging influences the MIA score can help clinicians better interpret the malignant risk of an ovarian tumor.

Clinical performance of a multivariate index assay for detecting early-stage ovarian cancer.

OBJECTIVE: We sought to analyze the effectiveness of a multivariate index assay (MIA) in identifying early-stage ovarian malignancy compared to clinical assessment, CA 125-II, and modified American Congress of Obstetricians and Gynecologists (ACOG) guidelines among women undergoing surgery for an adnexal mass. STUDY DESIGN: Patients were recruited in 2 related prospective, multi-institutional trials involving 44 sites. All women had preoperative imaging and biomarker analysis. Preoperative biomarker values, physician assessment of ovarian cancer risk, and modified ACOG guideline risk stratification were correlated with surgical pathology. RESULTS: A total of 1016 patients were evaluable for MIA, CA 125-II, and clinical assessment. Overall, 86 patients (8.5%) had primary-stage I/II primary ovarian malignancy, with 70.9% having stage I disease and 29.1% having stage II disease. For all early-stage ovarian malignancies, MIA combined with clinical assessment had significantly higher sensitivity (95.3%; 95% confidence interval [CI], 88.6-98.2) compared to clinical assessment alone (68.6%; 95% CI, 58.2-77.4), CA 125-II (62.8%; 95% CI, 52.2-72.3), and modified ACOG guidelines (76.7%; 95% CI, 66.8-84.4) (P < .0001). Among the 515 premenopausal patients, the sensitivity for early-stage ovarian cancer was 89.3% (95% CI, 72.8-96.3) for MIA combined with clinical assessment, 60.7% (95% CI, 42.4-76.4) for clinical assessment alone, 35.7% (95% CI, 20.7-54.2) for CA 125-II, and 78.6% (95% CI, 60.5-89.8) for modified ACOG guidelines. Early-stage ovarian cancer in postmenopausal patients was correctly detected in 98.3% (95% CI, 90.9-99.7) of cases by MIA combined with clinical assessment, compared to 72.4% (95% CI, 59.8-82.2) for clinical assessment alone, 75.9% (95% CI, 63.5-85.0) for CA 125-II, and 75.9% (95% CI, 63.5-85.0) for modified ACOG guidelines. CONCLUSION: MIA combined with clinical assessment demonstrated higher sensitivity for early-stage ovarian malignancy compared to clinical assessment alone, CA 125-II, and modified ACOG guidelines with consistent performance across menopausal status.

Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.

PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279.

PURPOSE: To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. METHODS: Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. RESULTS: Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. CONCLUSION: Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer.

SELDI-TOF MS analysis of ovarian cyst fluids revealed that peaks m/z 8696 and 8825 discriminate malignant, borderline, and benign tumors. These peaks correspond to isoforms of apoA2. ELISA demonstrates that apoA1, A2, B, C2, C3, and E cyst fluid concentrations are uncorrelated and higher in malignant ovarian tumors, but only apoA2, apoE, and age are independent classifiers of malignant ovarian tumors, yielding 55.1% sensitivity, 95% specificity, and 88.1% accuracy to discern malignant from benign and borderline tumors. These data suggest that lipoprotein metabolism is dysregulated in ovarian cancer and that apoA2 and apoE warrant further investigation as ovarian tumor biomarkers.