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Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

To evaluate postoperative and oncologic outcomes associated with pelvic exenteration for non-ovarian gynecologic malignancies.This was a retrospective review of patients who underwent pelvic exenteration for non-ovarian gynecologic malignancies at our institution from 1/1/2010-12/31/2019. Palliative exenteration cases were excluded from survival analysis. Postoperative complications were early (≤30 days) or late (31-180 days). Complications were graded using a validated institutional scale. Major complications were considered grade ≥ 3. Categorical variables were compared using the chi-square test, and the Kaplan-Meier method was used for survival analysis.Of 100 patients identified, 89 underwent pelvic exenteration for recurrent disease, 5 for palliation, 5 for primary disease, and 1 for persistent disease. Thirty percent had cervical, 27% vulvar, 24% uterine, and 19% vaginal cancer. Sixty-two percent underwent total, 30% anterior, and 8% posterior exenteration. No deaths occurred intraoperatively or within 30 days of surgery. Six patients died after 30 days. Ninety-seven experienced a perioperative complication-49 early, 1 late, and 47 both. Fifty experienced a major complication-22 (44%) early, 19 (38%) late, and 9 (18%) both. No variables were statistically associated with complication development. The 3-year progression-free survival rate was 61.0%; the 3-year overall survival rate was 61.6%. Of 58 surviving patients, 16 (28%) and 4 (7%) were alive after 5 and 10 years, respectively.The overall complication rate for pelvic exenteration remains high. No variables demonstrated association with complication development as the rate was nearly 100%. The low rate of perioperative mortality is likely due to improved perioperative care.

OBJECTIVE: To assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND). METHODS: We identified newly diagnosed CS patients who underwent primary surgical management from January 1996–December 2019. The SLN cohort underwent SLN biopsy alone with bilateral SLNs identified. The systematic LND cohort did not undergo SLN biopsy. RESULTS: Ninety-nine patients underwent SLN biopsy, and 100 patients underwent systematic LND. There was no difference by age, stage, body mass index, myoinvasion (

Our understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear.We conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks (Arm 2) in patients with endometrial carcinoma. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. Patients were stratified by mismatch repair (MMR) status and carcinosarcoma histology. Using a Simon two-stage minimax design, we determined 40 patients per arm would provide 90% power and Type 1 error of 10%.Eighty-two patients were enrolled; 77 were evaluable for toxicity (Arm 1: 38, Arm 2: 39) and 75 evaluable for efficacy (Arm 1: 37, Arm 2: 38). Patient were stratified by MMR status (Arm 1: 5, Arm 2: 4 were MMR-deficient). The ORR in Arm 1 was 10.8% (one-sided 90% CI: 4.8-100%); the ORR in Arm 2 was 5.3% (one-sided 90% CI: 1.4-100%). Since the primary endpoint of ORR was not met, 24-week PFS was not compared to historical controls per protocol specification. No new safety signals were identified.In these patients with predominantly MMR-proficient endometrial cancer, there was limited response with single-agent and combined immune checkpoint blockade. The pre-specified efficacy thresholds were not met for further evaluation. A deeper understanding of potential mechanisms of resistance to immunotherapy in MMR-proficient endometrial cancer is needed for the development of novel therapeutic approaches.

To compare outcomes of patients with premalignant endometrial pathology undergoing hysterectomy with or without sentinel lymph node (SLN) removal. Outcomes of interest included surgical adverse events (AEs), cancer status on final pathology, postoperative treatment, and The Cancer Genome Atlas (TCGA) molecular risk profiles.We retrospectively identified patients with premalignant pathology on preoperative endometrial biopsy who underwent hysterectomy with or without SLN mapping/excision at our institution from 01/01/2017-12/31/2021. Clinical, pathologic, surgical, and TCGA profiling data were abstracted. Appropriate statistical tests were used.Of 221 patients identified, 161 (73%) underwent hysterectomy with SLN excision and 60 (27%) underwent hysterectomy without SLN excision. Median age and body mass index were similar between groups. Median operative time was 130 min for those who underwent SLN mapping/excision versus 136 min for those who did not (p = 0.6). Thirty-day postoperative AE rates were 9% (n = 15/161) and 13% (n = 8/60), respectively (p = 0.9). Ninety-eight (44%) of 221 patients had grade 1-2 endometrioid endometrial cancer on final pathology (4 [4%] were stage IB or higher). Ten (10%) of 98 patients, all within the SLN group, received adjuvant treatment. Among all patients, of 33 (15%) with TCGA molecular classification data, 27 (82%) had copy number-low, 3 (9%) microsatellite instability-high, 2 (6%) POLE-ultramutated, and 1 (3%) copy number-high disease.SLN assessment appears safe, detects a small number of occult nodal metastases for those upstaged, and provides additional staging information that can guide adjuvant treatment. SLN mapping should be discussed in preoperative counseling and offered using a shared decision-making approach.

ObjectiveIn 2018, evidence-based surgical guidelines were introduced to identify appropriate patients with low-grade endometrioid endometrial cancer for ovarian conservation. We sought to identify trends and demographic shifts associated with guideline implementation.MethodsWe identified women treated for endometrioid endometrial cancer at our institution from January 2010 to June 2021. Eligibility criteria included age ≤50 years, normal-appearing ovaries on preoperative imaging, no family history of hereditary breast and ovarian cancer syndrome or Lynch syndrome, and no hormone receptor-positive malignancy. Trends in ovarian conservation were examined with the Cochran-Armitage trend test or in a logistic regression model. Associations between ovarian conservation and clinicodemographic factors before and after guideline implementation were compared using Wilcoxon rank-sum and Fisher’s exact tests.ResultsOf 420 women ≤50 years of age undergoing surgery for endometrioid endometrial cancer, 355 (85%) met the criteria for ovarian conservation—267 (75%) before and 88 (25%) after guideline implementation. Median patient age was 45 years (range 25–50); 62% were non-Hispanic White, 10% Hispanic White, 8% non-Hispanic Black, 0% Hispanic Black, and 20% Asian. Patients were significantly more likely to choose ovarian conservation after (48%) compared with before guideline implementation (21%) (pConclusionsAfter guideline implementation, ovarian conservation increased and uptake disparities across demographic groups decreased.

Purpose: Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types. Experimental Design: TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution). Results: TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%–18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. Conclusions: TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

Pelvic exenteration (PE) is one of the most challenging gynecologic oncologic surgeries and is an overriding term for different procedures that entail radical en bloc resection of the female reproductive organs and removal of additional adjacent affected pelvic organs (bladder, rectum, anus, etc.) with concomitant surgical reconstruction to restore bodily functions. Multimodality cross-sectional imaging with MRI, PET/CT, and CT plays an integral part in treatment decision-making, not only for the appropriate patient selection but also for surveillance after surgery. The purpose of this review is to provide a brief background on pelvic exenteration in gynecologic cancers and to familiarize the reader with the critical radiological aspects in the evaluation of patients for this complex procedure. The focus of this review will be on how imaging can aid in treatment planning and guide management.

Objectives: To compare clinical and pathologic characteristics of women with surgical stage I endometrial cancer by location of first recurrence; to describe characteristics of isolated vaginal recurrence. Methods: All women with surgical stage I endometrial carcinoma treated at two major cancer centers from 2009-2017 were identified. Surveillance was done at standard intervals and consisted of symptom assessment and pelvic exam. Imaging was ordered as clinically indicated. Appropriate statistical analyses were used to compare isolated with extra-vaginal recurrences. Vaginal recurrence in the presence of other sites of disease were included in the extra-vaginal recurrence group. Results: 2817 women were analyzed. Median age at diagnosis was 61 years (range 26-92 yrs). At a median follow-up of 36 months (range, 0-139 mos). 280 (10%) recurred: 61 (2%) isolated vaginal, 219 (8%) extra-vaginal (which included 18 cases with a vaginal component). Of the 61 isolated vaginal recurrences, 42 (69%) were located at the cuff, 19 (31%) along the vaginal canal (Figure 1). All isolated recurrences were clinically detected on exam, except for 1 (2%) detected by imaging; endometrioid histology and Grade II were the most common findings (85% and 44%, respectively).Median time to recurrence after initial diagnosis for isolated vaginal recurrence was 11 months (range, 1-68 mos); for extra-vaginal recurrence, 20 months (range, 1-98 mos) (p Download : Download high-res image (134KB) Download : Download full-size image Conclusions: Isolated vaginal recurrences in stage I endometrial cancer are detected earlier than non-vaginal recurrences, likely due to frequency of clinical exams after initial staging surgery. Surgical approach does not seem to impact overall or isolated recurrence. Adjuvant IVRT alone after primary surgery carries a 2% risk of isolated cuff recurrence.

Objectives: To evaluate the perioperative outcomes and oncologic outcomes of patients undergoing pelvic exenteration, first described by Alexander Brunschwig in 1948, for non-ovarian gynecologic malignancies at a comprehensive cancer center. Methods: All patients who underwent exenteration at our institution from 1/2010-12/2019 were identified. Patients with non-ovarian gynecologic malignancies were included. Patients undergoing palliative exenteration were included for perioperative outcomes but excluded from the survival analysis. Post-operative complications were defined as early (≤30 days) and delayed (31-180 days). Complications were graded using a validated institutional secondary surgical events system. Major complications were defined as Grade 3 or above which would, at minimum, require surgical, endoscopic, or radiological intervention. Appropriate statistical analyses were performed. Results: One-hundred patients were identified. Eighty-nine (89%) received treatment for recurrent disease, 5 (5%) for primary disease, 1 (1%) for persistent disease, and 5 (5%) received palliative treatment. The most common cancer type was cervical (n=30, 30%), followed by vulvar (n=27, 27%), uterine (n=24, 24%), and vaginal (n=19, 19%). The most common histologies were squamous cell carcinoma (n=61, 61%), endometrioid carcinoma (n=18, 18%), and adenocarcinoma (n=13, 13%). Sixty-two (62%) patients had total exenteration, 30 (30%) anterior exenteration, 8 (8%) posterior exenteration. The median age at time of surgery was 61.3 years (range, 28-86 years). There were no intraoperative deaths or deaths within 30 days of surgery. Six patients expired within the delayed time frame, including 1 (16.7%) from respiratory failure and 5 (83.3%) from aggressive progression of disease. Ninety-seven (97%) patients experienced a perioperative complication: 49 (50%) early, 1 (1%) delayed, 47 (48%) both early and delayed. Fifty/100 patients (50%) had a major complication: 22/50 (44%) early, 19/50 (38%) delayed, 9/50 (18%) both early and delayed. We did not identify any variables statistically associated with the development of a complication, including exenteration type, initial malignancy type, conduit type, operative time, estimated blood loss, or tumor volume. The median follow-up time for the entire cohort was 27.6 months (range, 1.0-117.5). The median follow-up time for survivors was 38.0 months (range, 1.0-117.5). The 3-year PFS was 61.0%, and the 3-year OS was 61.6%. There are 58 total survivors (58%), of whom 16 (28%) and 4 (7%) remain alive after 5 and 10 years, respectively. Conclusions: The complication rate for pelvic exenteration remains high, although we identified no variables showing association with the development of a complication. However, the lack of perioperative mortality, and improved oncologic outcomes, exemplify the advancements of this surgical approach since its inception.

B-ZIP transcription factors heterodimerize with dominant negative designs, termed A-ZIPs, in a dimerization specific manner and inhibit its ability to bind DNA. Different A-ZIPs produce unique phenotypes in vivo suggesting that they have distinct B-ZIP heterodimerization partners. However, the identification of the in vivo heterodimerization partners of different A-ZIPs remains problematic. To identify the in vivo heterodimerization partners, a chimeric protein containing two ubiquitin motifs at the N-terminal of the A-ZIP domain was designed. The presence of ubiquitin reduced the concentration of specific co-transfected B-ZIP proteins. The ubiquitin enhanced degradation of the B-ZIP heterodimeric partner is inhibited by the proteasome inhibitor MG-132. These ubiquitin tagged A-ZIP dominant negatives may be more active in vivo because their endogenous heterodimerization partners are degraded more efficiently. This may be a general strategy to identify protein interaction partners.