Molecular and pathologic data to guide selection of patients with endometrioid endometrial cancer for ovarian preservation.

OBJECTIVES: To investigate the association of molecular and pathologic factors with concurrent or recurrent ovarian disease to guide ovarian preservation in endometrioid endometrial cancer. METHODS: Patients with endometrial cancer ≤50 years of age at diagnosis were grouped by elective oophorectomy versus ovarian preservation at staging (January 2010 to June 2021). Tumors were stratified by molecular sub-type and CTNNB1 mutational status with next generation sequencing and immunohistochemistry. Germline data identified patients with Lynch syndrome. Associations between molecular/pathologic features and concurrent ovarian disease in patients electing oophorectomy were compared with the Wilcoxon rank-sum and Fisher's exact tests. Associations with isolated ovarian recurrences in patients who chose ovarian preservation were examined using survival analyses. RESULTS: Among 317 patients with endometrial cancer who underwent bilateral oophorectomy, 27 (9%) had malignant ovarian tumors, of whom 11 (41%) had no gross ovarian involvement on intra-operative survey. For patients with sequencing, concurrent malignant ovarian tumors were diagnosed in 0/14 (0%) POLE, 2/48 (4%) copy number-low/no specific molecular profile, 10/22 (45%) microsatellite instability-high, and 3/6 (50%) copy number-high/TP53abnormal patients (p<0.001). Concurrent malignant ovarian tumors were present in 1/30 (3%) hotspot CTNNB1-mutated versus 10/60 (17%) wildtype/CTNNB1 non-hotspot mutated endometrial cancer patients (p=0.11) and 7/28 (25%) Lynch versus 7/74 (9%) non-Lynch syndrome patients (p=0.06). Concurrent malignant ovarian tumors were present in patients with higher grade endometrial cancer (5% grade 1 vs 20% grade 2 and 24% grade 3; p<0.001), present versus absent lymphovascular space invasion (20% vs 6%; p=0.004), positive versus negative pelvic washings (28% vs 7%; p=0.016), and ≥50% versus <50% myoinvasion (24% vs 7%; p=0.004). Of 103 patients who chose ovarian preservation, four had isolated ovarian recurrences (two had high-risk pathologic features and two had high-risk molecular features). CONCLUSIONS: The integration of molecular and pathologic data may improve risk stratification of pre-menopausal patients with endometrial cancer and enhance candidate selection for ovarian preservation.

Procedural interventions for oligoprogression during treatment with immune checkpoint blockade in gynecologic malignancies: a case series.

OBJECTIVE: To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade. METHODS: Patients with gynecologic cancers treated with immune checkpoint blockade between January 2013 and October 2021 who underwent procedural interventions including surgical resection, interventional radiology ablation, or radiation therapy for oligoprogressive disease were identified. Procedures performed before immune checkpoint therapy initiation or ≥6 months after therapy completion were excluded. Long immunotherapy duration prior to intervention was defined as ≥6 months. Progression-free survival and overall survival were calculated from procedure date until disease progression or death, respectively. RESULTS: During the study period, 886 patients met inclusion criteria and received immune checkpoint blockade therapy. Of these, 34 patients underwent procedural interventions for oligoprogressive disease; 7 underwent surgical resection, 3 underwent interventional radiology ablation, and 24 underwent radiation therapy interventions. Primary disease sites included uterus (71%), ovary (24%), and cervix (6%). Sites of oligoprogression included abdomen/pelvis (26%), bone (21%), lung (18%), distant lymph node (18%), brain (9%), liver (6%), and vagina (3%). Most tumors (76%) did not exhibit microsatellite instability or mismatch repair deficiency. Approximately half (53%) of the patients had long immune checkpoint therapy duration prior to intervention. Median progression-free survival following the procedure was 5.3 months (95% CI, 3.1-9.9), and median overall survival was 21.7 months (95% CI, 14.9-not estimable). Long versus short immune checkpoint therapy duration prior to procedure and length of immune checkpoint therapy had no effect on progression-free or overall survival. CONCLUSIONS: Procedural interventions for patients with oligoprogression on immune checkpoint blockade therapy are feasible and demonstrate favorable outcomes. With expanding use of immune checkpoint therapy, it is important to investigate combined modalities to maximize therapeutic benefit for patients with gynecologic cancers.

Impact of immune infiltration signatures on prognosis in endometrial carcinoma is dependent on the underlying molecular subtype.

OBJECTIVES: Increased numbers of tumor infiltrating lymphocytes (TIL) in endometrial cancer (EC) are associated with improved survival, but it is unclear how this prognostic significance relates to the underlying EC molecular subtype. In this explorative hypothesis-generating study, we sought to define the immune signatures associated with the molecular subtypes of EC (i.e., POLE-mutated, microsatellite unstable (MSI-high), copy number (CN)-low, and CN-high) and to determine their correlation with patient outcomes. METHODS: RNA-sequencing and molecular subtype data of 232 primary ECs were obtained from The Cancer Genome Atlas. Deconvolution of bulk gene expression data was performed using single sample Gene Set Enrichment Analysis (ssGSEA) and Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT). The association of the resultant immune signatures with overall survival was determined across molecular subtypes. RESULTS: Statistically significant differences in enrichment were identified in 16/30 and 6/23 immune gene sets by ssGSEA and CIBERSORT, respectively. Signature of CD8+ cells in ECs of CN-high molecular subtype was associated with improved overall survival by ssGSEA (p = 0.0108), while CD8 signatures did not appear to be prognostic in MSI-high (p = 0.74) or CN-low EC molecular subtypes (p = 0.793). Of all molecular subtypes, CN-high ECs exhibited the lowest levels of CD8+ T cell infiltration. Consistent with antigen-induced T cell activation and exhaustion, enrichment for immunomodulatory receptors was predominantly observed in ECs of MSI-high and POLE-mutated molecular subtypes. CONCLUSIONS: Deconvolution of bulk gene expression data can be used to identify populations of immune infiltrated endometrial cancers with improved survival. These data support the existence of unique mechanisms of immune resistance within molecular subgroups of the disease.

Long-term outcomes of patients with recurrent ovarian cancer treated with a polyvalent vaccine with bevacizumab combination.

BACKGROUND: To characterize the safety, immunogenicity, and outcomes of patients with high-grade serous ovarian cancer (HGSOC) in second or greater remission treated with a polyvalent antigen-KLH plus OPT-821 vaccine construct and bevacizumab. METHODS: Patients with recurrent HGSOC were treated with the vaccine plus bevacizumab at our institution from 01/05/2011 to 03/20/2012. Follow-up continued until 03/2021. Blood/urine samples were collected. "Responders" had an immunogenic response to ≥ 3 antigens; "non-responders" to ≤ 2 antigens. RESULTS: Twenty-one patients were treated on study. One developed a dose-limiting toxicity (grade 4 fever). Two (10%) experienced bevacizumab-related grade 3 hypertension. Thirteen (68%) and 16 (84%) of 19 responded to ≥ 3 and ≥ 2 antigens, respectively (Globo-H, GM2, TF cluster Tn, MUC-1). Four of 21 patients were alive > 5 years post-treatment. Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI: 0.7-cannot estimate), respectively; median OS was 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively. On two-timepoint analysis (baseline, week 17), increased IL-8 exhibited improved PFS (HR as 10-unit increase, 0.43; p = 0.04); increased PDGF exhibited worse OS (HR as 10-unit increase, 1.01; p = 0.02). CONCLUSIONS: This is the longest follow-up of vaccine administration with bevacizumab in patients with ovarian cancer. The vaccine was well tolerated with bevacizumab. Response was not associated with improved survival. On two-timepoint analysis, increased IL-8 was associated with significant improvement in PFS; increased PDGF with significantly worse OS. For all timepoint measurements, cytokine levels were not significantly associated with survival. TRIAL REGISTRATION: NCT01223235.

Management of patients with early-stage ovarian clear cell carcinoma: risk stratification and fertility conservation.

OBJECTIVE: We sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery. METHODS: We retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan-Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression. RESULTS: Of 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (p<0.001) and overall survival (p=0.01). Patients with stage IA/IC1 disease had a 95% 5-year overall survival rate (95% CI 88% to 98%); patients with stage IC2/IC3 disease had a similar 5-year overall survival rate (76%; 95% CI 54% to 88%) to that of patients with stage IIA/IIB disease (82%; 95% CI 54% to 94%). There was no difference in 5-year overall survival in patients with stage IA/IC1 undergoing chemotherapy versus observation (94% vs 100%). Nine patients underwent fertility-sparing surgery and none experienced recurrence. Of five patients who pursued fertility, all had successful pregnancies. CONCLUSIONS: In patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

Microsatellite Instability-High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles.

PURPOSE: Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). EXPERIMENTAL DESIGN: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. RESULTS: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). CONCLUSIONS: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Evaluating the role of aromatase inhibitors in the treatment of low-grade endometrial stromal sarcomas.

Objectives: Endometrial stromal sarcomas (ESS) are rare, accounting for < 1% of all uterine malignancies. Treatment has been guided by small case series and retrospective studies. Endocrine therapy is used in both adjuvant and metastatic settings. Aromatase inhibitors (AIs) are widely used in clinical practice. We sought to evaluate clinical outcomes of AI use in the largest cohort of patients with LGESS to date. Methods: We performed a retrospective study of patients with LGESS treated with an AI at our institution from 1/1998-12/2020. Response was evaluated using RECIST 1.1. The Kaplan-Meier method was used to estimate median progression-free (PFS) and overall (OS) survival. Results: Forty patients were identified. Treatment was well tolerated, with 57.5% experiencing adverse effects. The most common were arthralgias (12 patients, 30%) and hot flashes (9, 22.5%). Two of 11 patients with RECIST-evaluable imaging experienced a partial response to treatment. Median PFS for the entire cohort was 79.2 months (95% CI 39.7 months to NE); the 5-year PFS rate was 59.6% (95% CI 41.8% to 73.6, p = 0.065). Median follow-up for the 29 survivors was 97.9 months (range: 12.6-226.7). The 5-year OS rate was 81.5% (95% CI 64.9-90.7%). One patient who discontinued AI after 10 years of treatment recurred 1 year later. Conclusion: AIs were well tolerated and offered periods of prolonged disease stability, even in the metastatic setting. Our study suggests, however, that response rates may be lower than previously reported. Data on optimal duration of treatment is needed, but the rarity of LGESS is an obstacle to conducting large clinical trials.

Pelvic exenteration for recurrent or persistent gynecologic malignancies: Clinical and histopathologic factors predicting recurrence and survival in a modern cohort.

OBJECTIVES: To explore pre-operative factors and their impact on overall survival (OS) in a modern cohort of patients who underwent pelvic exenteration (PE) for gynecologic malignancies. METHODS: A retrospective review was performed for all patients who underwent a PE from 1/1/2010 through 12/31/2018 at our institution. Inclusion criteria were exenteration due to recurrent or progressive carcinoma of the uterus, cervix, vagina or vulva, with histologically confirmed complete surgical resection of the malignancy. Exclusion criteria included PE for palliation of symptoms without recurrence, and for ovarian or rare histologic malignancies. Univariable and multivariable analysis were performed to identify factors predicting prolonged survival. RESULTS: Overall, 71 patients met the inclusion criteria. Median age at time of exenteration was 62 years (range, 28-86 years). Vulvar cancer was the most common primary diagnosis (32%); 30% had cervical cancer; 23%, uterine cancer; 15%, vaginal cancer. Median OS was 55.1 months (95% confidence interval (CI): 36-not estimable) with a median follow-up time of 40.8 months (95% CI: 1-116.1). On univariable analysis, age > 62 years (hazard ratio (HR) 2.71, 95% CI 1.27-5.79), American Society of Anesthesia (ASA) 3-4 (HR: 3.41 (95% CI 1.03-11.29), and vulvar cancer (HR 4.19 (95% CI 1.17-14.96) predicted worse OS. Tumor size and prior progression-free interval (PFI) did not meet statistical significance in OS analyses. On multivariable analysis, there were no significant factors associated with worse OS. CONCLUSIONS: PE performed with curative intent may be considered a treatment option in well-counseled, carefully selected patients, irrespective of tumor size and PFI before exenteration.

The effects of neoadjuvant chemotherapy and interval debulking surgery on body composition in patients with ovarian cancer.

BACKGROUND: The aim of this study was to quantify changes in body composition during ovarian cancer treatment and relate these changes to rates of complete gross resection (CGR). METHODS: One hundred two patients with stage III or IV ovarian cancer who underwent neoadjuvant chemotherapy (NACT) followed by interval debulking surgery were a part of a prospectively collected database that included computed tomography scans at three time points-diagnosis, following NACT, and following debulking surgery. Skeletal muscle, visceral adipose, and subcutaneous adipose tissue volumes were obtained from a 30-mm volumetric slab beginning at the third lumbar vertebrae. RESULTS: Following NACT, skeletal muscle volume was significantly reduced (352.5 to 335.0 cm3, P < 0.001), whereas adiposity was unchanged. Body mass index (BMI) and skeletal muscle volume were significantly lower in patients who achieved CGR (P < 0.05). When these patients were stratified by BMI, the significant association of skeletal muscle to CGR was limited to patients with a BMI < 25 kg/m2 (P = 0.007). CONCLUSION: Skeletal muscle volume was significantly reduced in patients undergoing NACT for ovarian cancer. Non-overweight patients were more likely to achieve CGR if they had lower skeletal muscle volume. Use of volumetric-based measurement for ascertaining body composition should be explored further.

Clinical outcomes of patients with endometrioid epithelial ovarian cancer following surgical treatment.

BACKGROUND: Endometrioid epithelial ovarian cancer (EEOC) is rare, and its management poorly defined. We examined factors associated with 5-year progression-free survival (PFS) after surgery for EEOC. METHODS: Retrospective study: treatment and outcomes of all EEOC patients undergoing initial surgery at, or presenting to, our institution within 3 months of initial surgery, 1/2002-9/2017. RESULTS: In total, 212 patients were identified. Median follow-up, 63.9 months (range, 0.7-192); median age at diagnosis, 52 years (range, 20-88); disease stage: I, n = 145 (68%); II, n = 47 (22%); III/IV, n = 20 (9%); FIGO grade: 1, 127 (60%); 2, 66 (31%); 3, 17 (8%); unknown, 2 (1%). One hundred twenty-eight (60%) had endometriosis; 75 (35%), synchronous endometrioid endometrial cancer (80%, IA); 101 (48%), complete surgical staging; 8 (5%), positive pelvic lymph nodes (LNs); 6 (4%), positive para-aortic LNs; 176 (97%), complete gross resection; 123 (60%), postoperative chemotherapy; 56(28%), no additional treatment. Five-year PFS, 83% (95% confidence interval [CI]: 76.6%-87.8%); 5-year overall survival (OS), 92.7% (95% CI: 87.7%-95.8%). Age, stage, and surgical staging were associated with improved 5-year PFS, and younger age at diagnosis with improved 5-year OS (p < 0.001). Chemotherapy did not improve 5-year PFS in IA/IB versus observation, but improved survival in IC (hazard ratio [HR]: 1.01, 95% CI: 0.22-4.59, p = 0.99; HR: 0.17, 95% CI: 0.04-0.7, p = 0.006). CONCLUSIONS: Age, stage, and full surgical staging were associated with improved 5-year PFS. Chemotherapy showed no benefit in IA/IB disease.

Outcomes of incidentally detected ovarian cancers diagnosed at time of risk-reducing salpingo-oophorectomy in BRCA mutation carriers.

OBJECTIVE: Prior data suggested that women with incidentally detected occult invasive ovarian cancer (OIOC) at the time of risk-reducing salpingo-oophorectomy (RRSO) for BRCA mutation may have poorer prognoses than would be expected based on disease stage. We sought to evaluate prevalence and outcomes of patients with OIOC in a tertiary referral center. METHODS: Patients with BRCA mutation undergoing RRSO from 01/2005 to 05/2017 were identified, and their records reviewed. Women with incidentally detected OIOC were included; those with clinical features raising preoperative suspicion for malignancy were excluded. RESULTS: 548 patients with BRCA mutation who underwent RRSO were identified. 26 (4.7%) had an OIOC (median age 55 years; range 42-75); 15(58%) patients, BRCA1; 9(34%), BRCA2; 2(8%) had a mutation in both genes. All OIOCs were high-grade serous: 10 (38%) Stage I; 8 (31%) Stage II; 8(31%) Stage III. 24(92%) patients received adjuvant platinum/taxane therapy. Of Stage III patients, 4 (50%) were identified intraoperatively; the remaining 4 (50%) had microscopic nodal disease on final pathology only. At median follow-up of 67.3 months (28-166) no Stage I patients have recurred; 2 Stage II and 6 Stage III patients recurred. 5-year progression-free survival (PFS) was 72% (95%CI, 50.2-85.7%); median PFS for the cohort was 129 months (95%CI, 75.3-not estimable). 5-year disease-specific survival (DSS) was 96% (95%CI, 76-99%); median DSS not reached. CONCLUSION: Consistent with prior reports, almost 5% of patients had an OIOC at RRSO. The majority with early-stage disease had excellent PFS and DSS outcomes, as would be expected based on disease stage.

Prophylactic Negative Pressure Wound Therapy After Laparotomy for Gynecologic Surgery: A Randomized Controlled Trial.

OBJECTIVE: To estimate the effectiveness of prophylactic negative pressure wound therapy in patients undergoing laparotomy for gynecologic surgery. METHODS: We conducted a randomized controlled trial. Eligible, consenting patients, regardless of body mass index (BMI), who were undergoing laparotomy for presumed gynecologic malignancy were randomly allocated to standard gauze or negative pressure wound therapy. Patients with BMIs of 40 or greater and benign disease also were eligible. Randomization, stratified by BMI, occurred after skin closure. The primary outcome was wound complication within 30 (±5) days of surgery. A sample size of 343 per group (N=686) was planned. RESULTS: From March 1, 2016, to August 20, 2019, we identified 663 potential patients; 289 were randomized to negative pressure wound therapy (254 evaluable participants) and 294 to standard gauze (251 evaluable participants), for a total of 505 evaluable patients. The median age of the entire cohort was 61 years (range 20-87). Four hundred ninety-five patients (98%) underwent laparotomy for malignancy. The trial was eventually stopped for futility after an interim analysis of 444 patients. The rate of wound complications was 17.3% in the negative pressure wound therapy (NPWT) group and 16.3% in the gauze group, absolute risk difference 1% (90% CI -4.5 to 6.5%; P=.77). Adjusted odds ratio controlling for estimated blood loss and diabetes was 0.99 (90% CI 0.62-1.60). Skin blistering occurred in 33 patients (13%) in the NPWT group and in three patients (1.2%) in the gauze group (P<.001). CONCLUSION: Negative pressure wound therapy after laparotomy for gynecologic surgery did not lower the wound complication rate but did increase skin blistering. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02682316. FUNDING SOURCE: The protocol was supported in part by KCI/Acelity.

Exploring the clinical significance of serous tubal intraepithelial carcinoma associated with advanced high-grade serous ovarian cancer: A Memorial Sloan Kettering Team Ovary Study.

OBJECTIVE: To evaluate the clinical significance and genomic associations of concurrent serous tubal intraepithelial carcinoma (STIC) with high-grade serous carcinoma (HGSC) of the ovary in women undergoing primary debulking surgery (PDS). METHODS: All patients who underwent PDS for HGSC between 01/2015 and 12/2018 were captured in a prospectively maintained institutional database. Patients were categorized based on the presence or absence of concurrent STIC noted on final pathology. Demographic, perioperative, and outcomes data were collected, and groups were compared using standard statistical tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. For comparison of differences in somatic alterations between the two cohorts, specimens were sequenced using MSK-IMPACT. RESULTS: Of 306 eligible patients, 87 (28%) had a concurrent STIC lesion (+STIC) and 219 (72%) did not (no-STIC). Demographics and clinicopathological factors were similar between the two cohorts, except for a significantly higher median preoperative CA-125 level in the no-STIC group (423 U/mL vs. 321 U/mL; p=0.029). There were no significant differences in median PFS (22.7 months [95%CI: 18.9-28.4] vs. 27.7 months [95%CI: 25.5-30.5]; p=0.126) and 3- year OS rate (81% [95%CI: 70-88%] vs. 85% [95%CI: 78-90%]; p=0.392) between +STIC and no-STIC patients, respectively. Targeted DNA-sequencing via MSK-IMPACT showed a similar distribution of driver mutations or structural genetic alterations, and affected genetic signaling pathways were similar between the cohorts. CONCLUSIONS: There were no identifiable clinical and genetic differences in patients with HGSC and concurrent STIC. These data suggest a comparable, if not identical, disease process.

Surgical ovarian suppression for adjuvant treatment in hormone receptor positive breast cancer in premenopausal patients.

OBJECTIVE: Ovarian suppression is recommended to complement endocrine therapy in premenopausal women with breast cancer and high-risk features. It can be achieved by either medical ovarian suppression or therapeutic bilateral salpingo-oophorectomy. Our objective was to evaluate characteristics of patients with stage I-III hormone receptor positive primary breast cancer who underwent bilateral salpingo-oophorectomy at our institution. MATERIALS AND METHODS: Premenopausal women with stage I-III hormone receptor positive primary breast cancer diagnosed between January 2010 and December 2014 were identified from a database. Patients with confirmed BRCA1/2 mutations were excluded. Distribution of characteristics between treatment groups was assessed using χ2 test and univariate logistic regression. A multivariate model was based on factors significant on univariate analysis. RESULTS: Of 2740 women identified, 2018 (74%) received endocrine treatment without ovarian ablation, 516 (19%) received endocrine treatment plus ovarian ablation, and 206 (7.5%) did not receive endocrine treatment. Among patients undergoing ovarian ablation 282/516 (55%) received medical ovarian suppression, while 234 (45%) underwent bilateral salpingo-oophorectomy. By univariate logistic analyses, predictors for ovarian ablation were younger age (OR 0.97), histology (other vs ductal: OR 0.23), lymph node involvement (OR 1.89), higher International Federation of Gynecology and Obstetrics (FIGO) stage (stage II vs I: OR 1.48; stage III vs I: OR 2.86), higher grade (grade 3 vs 1: OR 3.41; grade 2 vs 1: OR 2.99), chemotherapy (OR 1.52), and more recent year of diagnosis (2014 vs 2010; OR 1.713). Only year of diagnosis, stage, and human epidermal growth factor receptor 2 (HER-2) treatment remained significant in the multivariate model. Within the cohort undergoing ovarian ablation, older age (OR 1.05) was associated with therapeutic bilateral salpingo-oophorectomy. Of 234 undergoing bilateral salpingo-oophorectomy, 12 (5%) mild to moderate adverse surgical events were recorded. CONCLUSIONS: Bilateral salpingo-oophorectomy is used frequently as an endocrine ablation strategy. Older age was associated with bilateral salpingo-oophorectomy. Perioperative morbidity was acceptable. Evaluation of long-term effects and quality of life associated with endocrine ablation will help guide patient/provider decision-making.

Survival outcomes of acute normovolemic hemodilution in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVE: To describe oncologic outcomes after using acute normovolemic hemodilution (ANH) to reduce requirement for allogenic red blood cell transfusions (ABT) in patients undergoing primary debulking surgery (PDS) for advanced ovarian cancer. METHODS: We performed a post-hoc analysis of a recent prospective trial investigating the safety and feasibility of ANH during PDS for advanced ovarian cancer. We report long-term survival outcomes. We compared demographics, clinicopathological characteristics, survival outcomes in this cohort of Stage IIIB-IVB high-grade serous ovarian cancer patients undergoing ANH (ANH group), with a retrospective cohort of all other patients (standard group) undergoing PDS during the same time period (01/2012-04/2017). Standard statistical tests were used. RESULTS: There were no demographic or clinicopathological differences between ANH (n = 33) and standard groups (n = 360), except for higher median age at diagnosis (57 vs. 62 years, respectively; p = 0.044) and shorter operative time (357 vs. 446 min, respectively; p < 0.001) in the standard group. Cytoreductive outcomes (ANH vs. standard): 0 mm, 69.7 vs. 63.9%; gross residual disease (RD) ≤1 cm, 21.2 vs. 26.9%; >1 cm, 9.1 vs. 9.2% (p = 0.78). RD after PDS was the only independent factor associated with worse progression-free survival (PFS) on multivariable analysis (p < 0.001). Patients with BRCA mutations trended towards improved PFS (p = 0.057). Significant factors for overall survival (OS) on multivariable analysis: preoperative CA125 (p = 0.004), ascites (p = 0.018), RD after PDS (p = 0.04), BRCA mutation status (p < 0.001). After adjustment for potential confounders, ANH was not independently associated with PFS or OS [PFS: HR 0.928 (0.618-1.395); p = 0.721; OS: HR 0.588 (95%CI: 0.317-1.092); p = 0.093]. CONCLUSIONS: ANH is an innovative approach in intraoperative management. It was previously proven to decrease need for ABT while maintaining the ability to achieve complete gross resection and associated benefits.

The impact of tumor fragmentation in patients with stage I uterine leiomyosarcoma on patterns of recurrence and oncologic outcome.

OBJECTIVE: To evaluate the impact of tumor fragmentation on oncologic outcomes in patients with stage I uterine leiomyosarcoma (uLMS). METHODS: We identified all patients diagnosed with stage I uLMS presenting to our institution within three months of primary surgery, 1/2000-1/2019. Patients with recurrent disease were excluded. The non-morcellated group had total hysterectomy without documented specimen fragmentation; the morcellated group, total hysterectomy with documented specimen fragmentation. We defined fragmentation as manual fragmentation or morcellation (via power morcellator or otherwise) of the specimen in peritoneal cavity or vagina. Appropriate statistical analyses were performed. RESULTS: 152 patients met inclusion criteria. 107 (70%) underwent total hysterectomy (non-morcellated); 45 (30%) underwent morcellation. Median age at diagnosis for the entire cohort was 55 years (range 30-91). Median follow-up was 42.1 months (range 1.1-197.8). 40 (26.3%) patients had primary surgery at our institution, 112 (73.7%) at an outside hospital. In total 110 (72.3%) recurred: 72/107 (67.2%) non-morcellated; 38/44 (86.3%) morcellated. Median progression-free survival (PFS) for non-morcellated versus morcellated was 13.8 (95%CI 9.2-20.2) versus 7.3 months (95%CI 3-13.1), HR 1.5 (95%CI 1.02-2.24); P = 0.04. Median overall survival (OS) for non-morcellated versus morcellated was 82.1 (95%CI 52.4-122) versus 47.8 months (95%CI 28.5-129.6), HR 1.1 (95%CI 0.67-1.82); P = 0.7. Among patients with recurrence, 69.4% of non-morcellated recurred at hematogenous sites only, 18.1% recurred in peritoneum only; 28.9% of morcellated recurred at hematogenous sites, 63.2% in peritoneum. Race, lymphovascular invasion, postoperative chemotherapy, were independently associated with PFS. Mitotic index was independently associated with OS. CONCLUSIONS: Tumor fragmentation/morcellation was associated with significantly higher risk of recurrence and a nearly 4-fold increase in peritoneal recurrence. Prognostic biomarkers remain important in predicting oncologic outcomes, independent of fragmentation or treatment.

Pre-operative neoadjuvant chemotherapy cycles and survival in newly diagnosed ovarian cancer: what is the optimal number? A Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVE: Although trials of neoadjuvant chemotherapy in ovarian cancer use 3 neoadjuvant cycles, real-world practice varies. We sought to evaluate the influence of increasing pre-operative cycles on survival, accounting for surgical outcomes. METHODS: We identified 199 women with newly diagnosed ovarian cancer recommended for neoadjuvant chemotherapy who underwent interval debulking surgery from July 2015 to December 2018. Non-parametric tests were used to compare clinical characteristics by neoadjuvant cycles. The Kaplan-Meier method was used to estimate differences in progression-free and overall survival. The log-rank test was used to assess the relationship of covariates to outcome. RESULTS: The median number of neoadjuvant cycles was 4 (range 3-8), with 56 (28%) women receiving ≥5 cycles. Compared with those receiving 3 or 4, women with ≥5 neoadjuvant cycles received fewer or no post-operative cycles (p<0.001) but had no other differences in clinical factors (p>0.05). Complete gross resection rates were similar among those receiving 3, 4, and ≥5 neoadjuvant cycles (68.5%, 70%, and 71.4%, respectively, p=0.96). There were no significant differences in progression-free or overall survival when comparing 3 versus 4 neoadjuvant cycles. However, more cycles (≥5 vs 4) were associated with worse progression-free survival, even after adjustment for BRCA status and complete gross resection (HR 2.20, 95% CI 1.45 to 3.33, p<0.001), and worse overall survival, even after adjustment for histology, response on imaging, and complete gross resection rates (HR 2.78, 95% CI 1.37 to 5.63, p=0.016). The most common reason for receiving ≥5 cycles was extent of disease requiring more neoadjuvant chemotherapy. CONCLUSIONS: Despite maximal cytoreduction, patients receiving ≥5 neoadjuvant cycles have a poorer prognosis than those receiving 3-4 cycles. Future studies should focus on reducing surgical morbidity and optimizing novel therapies in this high-risk group.

Video-assisted thoracic surgery in the primary management of advanced ovarian carcinoma with moderate to large pleural effusions: A Memorial Sloan Kettering Cancer Center Team Ovary Study.

OBJECTIVES: We assessed the utility of video-assisted thoracic surgery (VATS) in defining extent of intrathoracic disease in advanced ovarian carcinoma with moderate-to-large pleural effusions. METHODS: Beginning in 2001, VATS was performed on all patients with suspected advanced ovarian carcinoma and moderate-to-large pleural effusions, evaluating for macroscopic intrathoracic disease. The algorithm recommended primary debulking surgery (PDS) for ≤1 cm, neoadjuvant chemotherapy (NACT)/interval debulking surgery (IDS) for >1 cm intrathoracic disease. We reviewed records of patients undergoing VATS from 10/01-01/19. Differences between treatment groups were tested using standard statistical techniques. RESULTS: One-hundred patients met eligibility criteria (median age, 60; median CA-125 level, 1158 U/mL; medium serum albumin, 3.8 g/dL). Macroscopic pleural disease was found in 70 (70%). After VATS, 50 (50%) underwent attempted PDS (PDS group), 50 (50%) received NACT (NACT/IDS group). Forty-seven (94%) underwent IDS. Median overall survival (OS) for the entire cohort (n = 100) was 44.5 months (95% CI: 37.8-51.7). The PDS group had significantly longer survival than the NACT/IDS group [45.8 (95% CI: 40.5-87.8) vs. 37.4 months (95% CI: 33.3-45.2); p = .016]. On multivariable analysis, macroscopic intrathoracic disease (HR 2.18, 95% CI: 1.14-4.18; p = .019) and age ≥ 65 (HR 1.98, 95% CI: 1.16-3.40; p = .013) were independently associated with elevated death risk. Patients with the best outcome had no macroscopic disease at VATS and underwent PDS (median OS, 87.8 months). CONCLUSIONS: VATS is useful in therapeutic decision-making for PDS vs. NACT/IDS in advanced ovarian cancer with moderate-to-large pleural effusions.

Hematologic changes after splenectomy for ovarian cancer debulking surgery, and association with infection and venous thromboembolism.

INTRODUCTION: The spleen plays a role in the immune and coagulative responses, yet a splenectomy may be required during ovarian cancer surgery to achieve complete cytoreduction. The aim of the study was to correlate hematologic changes with the development of infection and venous thromboembolism in patients undergoing splenectomy. METHODS: This single-institution retrospective review includes all patients undergoing splenectomy during cytoreductive surgery for advanced ovarian cancer, March 2001 to December 2016. We compared postoperative hematologic changes (evaluated daily before discharge) in patients developing infection within 30 days' post-surgery (Infection group) with those who did not (No-Infection group). We also compared patients developing venous thromboembolism with those without. RESULTS: A total of 265 patients underwent splenectomy. Median age was 64 years (range 22-88): 146 (55%) patients had stage IIIC and 114 (43%) patients had stage IV. The majority, 201 (76%) patients underwent splenectomy during primary debulking. A total of 132 (50%) patients comprised the Infection group (most common: urinary tract infection, 54%). Median time from surgery to infection was 8 days (range, 0-29). After initial rise in white blood cell count in both groups, the Infection group had a second peak on postoperative day 10 (median 16.6K/mcL, IQR 12.5-21.2) not seen in the No-Infection group (median 12K/mcL, IQR 9.3-16.3). A total of 40 (15%) patients developed venous thromboembolism, median time of 6.5 days (range, 1-43). All patients demonstrated a continuous rise in platelets during postoperative days 0-15. Thrombocytosis was present in 38/40 (95%) patients with venous thromboembolism vs 183/225 (81%) patients without (P=0.036). Median days with thrombocytosis was higher in venous thromboembolism (8 days, range 1-15) vs non groups (6 days, range 1-16, P=0.049). CONCLUSION: We identified initial leukocytosis after splenectomy in all patients. The Infection group had a second peak in white blood cell count on postoperative day 10, not present in the No-Infection group. Among patients with venous thromboembolism, thrombocytosis was more frequent and of longer duration.