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Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Anti‐HER2 therapy is indicated for erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2‐mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2‐mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor‐normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2‐amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2‐mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2‐amplified. Compared to ERBB2‐wildtype ECs (with or without ERBB2 amplification), ERBB2‐mutated/non‐amplified ECs were enriched for the microsatellite instability‐high (MSI‐H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2‐mutated/non‐amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2‐wildtype and ERBB2‐amplified ECs. ERBB2 amplification is a known driver of copy number‐high/TP53‐abnormal high‐grade endometrial carcinoma and is associated with HER2 overexpression. In this retrospective cohort of clinically annotated endometrial carcinomas, ERBB2 pathogenic mutations define a distinct and non‐overlapping subgroup of tumors, typically with low levels of HER2 expression, high tumor mutational burden, microsatellite instability‐high status, and low‐grade endometrioid histology.

BackgroundThe 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system includes lymphovascular invasion quantification as a staging criterion for endometrioid endometrial carcinomas; no lymphovascular invasion and focal invasion (≤4 vessels involved) are grouped as one category, and substantial invasion as another.ObjectiveTo assess the association between lymphovascular invasion and oncologic outcomes.MethodsWe retrospectively identified patients with FIGO 2009 stage I endometrioid endometrial cancer treated surgically with total hysterectomy and lymph node assessment at two tertiary care centers between January 1, 2012, and December 31, 2019. Lymphovascular space invasion was categorized as focal (<5 vessels involved), substantial (≥5 vessels involved), and no lymphovascular invasion using WHO criteria.ResultsOf 1555 patients included, 65 (4.2%) had substantial, 119 (7.7%) had focal, and 1371 (88.2%) had no lymphovascular invasion. Median age was 64 years (range 24–92). Thirty-five patients (53.8%) with substantial, 44 (37%) with focal, and 115 (8.4%) with no lymphovascular invasion had stage IB disease (p<0.001); 21 (32.3%) with substantial, 24 (20.2%) with focal, and 91 (6.6%) with no lymphovascular invasion had grade 3 disease (p<0.001). Thirty-six patients (55.4%) with substantial, 80 (67.2%) with focal, and 207 (15.1%) with no lymphovascular invasion received adjuvant treatment (p<0.001). Median follow-up was 61.5 months (range 0.8–133.9). Five-year progression-free survival rates were 68.7% (substantial), 70.5% (focal), and 90.7% (no invasion) (p<0.001). On multivariate analysis, any lymphovascular invasion was associated with increased risk of progression/death (adjusted HR (aHR)=1.84 (95% CI 1.73 to 1.96) for focal; 2.17 (95% CI 1.96 to 2.39) for substantial). Compared with focal, substantial lymphovascular invasion was associated with an aHR for disease progression of 1.18 (95% CI 1.00 to 1.39).ConclusionsFocal and substantial lymphovascular invasion were associated with increased risk of disease progression and do not appear to be prognostically distinct. Focal versus no lymphovascular invasion have different prognostic outcomes and should not be combined into one category.

Objective The aim of this study was to compare oncologic and perioperative outcomes of robot-assisted laparoscopy (RA) and conventional laparoscopy (LSC) in apparent clinically uterine-confined, high-grade adenocarcinoma. Methods A retrospective review was conducted to identify patients with newly diagnosed high-grade uterine adenocarcinoma treated at our institution between 1 January 2009 and 30 June 2021. Exclusion criteria included bulky extrauterine disease, no lymph node assessment, or synchronous tumors. Clinicopathologic details were obtained from medical records. Postoperative complications were classified using the Memorial Sloan Kettering Cancer Center Surgical Secondary Events system, and statistical analysis was performed using appropriate tests. Results Of 901 patients identified, 748 (83%) underwent RA and 153 (17%) underwent LSC. Median age was 65 years (range 25–92) and median body mass index was 30 kg/m 2 (range 15–60). Overall, 650 patients (72%) had 2009 International Federation of Obstetrics and Gynecology (FIGO) stage I disease. Forty-one patients (4.6%) converted to laparotomy—26 (3.5%) from RA versus 15 (9.8%) from LSC ( p  = 0.02). Postoperative complications occurred in 81 patients (9.0%), with no significant differences in type or rate between groups. Median operative time was 192 mins (range 88–936) for RA versus 168 mins (range 90–372) for LSC ( p  = 0.002). Median follow-up was 52 months (range 1–163) for RA and 66 months (range 7–165) for LSC. Four-year progression-free survival (PFS) and disease-specific survival (DSS) were similar between groups. Multivariate analysis showed stage, histology, peritoneal cytology, and lymphovascular invasion predicated a decrease in PFS and DSS. Conclusions RA demonstrated comparable oncologic outcomes to LSC in patients with high-grade endometrial carcinoma, with no significant difference in postoperative complications or long-term survival.

Introduction/BackgroundTo identify the anatomic distribution of endometrial cancer recurrences among the different molecular subtypes and evaluate the prognostic significance of molecular subtypes in the recurrent setting.MethodologyAll patients with endometrial cancer who had their initial staging surgery performed at our institution between 2014 and 2023 and had a biopsy-proven recurrence and molecular subtyping of their primary tumor were included in the study. Sites of recurrence were determined by clinical and imaging review.ResultsA total of 186 patients met the inclusion criteria and were included in the study. Tumor molecular subtypes were as follows: copy number-high (CN-H)/TP53 abnormal, 121 (65%); microsatellite instability-high (MSI-H), 34 (18%); copy number-low (CN-L)/no specific molecular subtype (NSMP), 29 (16%); and POLE ultramutated, 2 (1%). CN-H tumors were most likely to present with extrapelvic recurrence, even after stratification by stage I disease at initial diagnosis (19/27, 70%). Of the 15 patients who presented with isolated vaginal cuff recurrence, the most likely histology was endometrioid. The absence of a TP53 mutation and the presence of either CTNNB1, PTEN, or RB1 mutation were more likely to be associated with isolated vaginal cuff recurrence (p<0.01). At the time of recurrence, overall survival was shortest in CN-H endometrial cancers (median: 31 months) and longest in POLE-ultramutated cancers (no mortality observed), with intermediate survival noted in the CN-L and MSI-H subtypes (p<0.001).ConclusionIn patients with recurrent endometrial cancer, TCGA molecular subtyping remains informative for oncologic outcomes and patterns of recurrence.DisclosuresNone.

IntroductionTo compare long-term oncologic outcomes in women with apparent uterine confined (or early-stage) endometrioid endometrial cancer undergoing minimally invasive surgical (MIS) staging with or without robotic assistance (RA).MethodsWe performed a retrospective chart review of all patients with apparent early-stage endometrioid endometrial cancer diagnosed at Memorial Sloan Kettering Cancer Center between January 2008 and January 2018. Clinicopathologic, surgical, and survival data were collected. Appropriate statistical methods were applied.ResultsOf 1728 patients, 1389 (80.4%) underwent RA-laparoscopy, and 339 (19.6%) laparoscopy. Median age at diagnosis was 60 years, range (24–92), median body mass index (BMI) at diagnosis was 30.2 kg/m2, range (15.1–71.2). Patient demographics and tumor characteristics were similar in the two groups. Perioperative complications were similar in both groups (9.9% vs 7.7%, p=0.2). A higher proportion of patients in the RA group were discharged on day 0 (19.2% v 5.3%, p<0.001). Median follow-up was similar in the RA vs. laparoscopy group (55.7 months vs 52.9 months, p=0.37). Comparing the RA and laparoscopic groups, the recurrence rate (9.5% vs. 7.4%, p=0.22), 5-year progression-free survival (88.5% vs. 90%, p=0.38), and 5-year overall survival (89% v 89%, p=0.74) were not significantly different.Conclusion/ImplicationsIn apparent early-stage endometrioid endometrial cancers, surgical staging using RA-laparoscopy was not associated with any significant increase in adverse survival outcomes compared to laparoscopy.

Introduction/BackgroundSentinel lymph node mapping (SLN) is becoming universally adopted as the method of choice to assess nodal spread in early-stage endometrial cancer, however the oncologic outcomes of this have not been specifically evaluated in patients with UCC. Our objective was to assess oncologic outcomes among patients with uterine confined UCC undergoing SLN versus lymph node dissection (LND).MethodologyPatients who underwent surgical management for newly diagnosed UCC between 10/1996 and 6/2021 were retrospectively identified and allocated to SLN or LND groups. Patients with successful bilateral SLN and backup LND were treated as LND (n=4). Patients with unilateral mapping requiring hemipelvis LND and those with empty nodal packets were excluded from analysis (n=3). Appropriate statistical tests were used.ResultsEighty-nine patients met inclusion criteria: 40 (45%) underwent SLN and 49 (55%) LND. Forty-two (86%) patients in LND underwent paraaortic LND vs 3 (7%) in SLN (p<0.001). Sixty-eight (76%) patients had FIGO-stage I/II, 17 (19%) FIGO-stage III, and 4 (5%) FIGO-stage IV. Age, BMI, FIGO-stage, depth of myoinvasion, lymph-vascular invasion, and washing status did not differ between groups. Thirty-five (88%) patients in SLN received adjuvant therapy and 42(86%) in LND (P=0.8). The adjuvant therapies used were: chemotherapy alone (0% SLN vs 17% LND), radiation alone (34% SLN vs 45% LND), and chemoradiation (66% SLN vs 38% LND) (P=0.01), Median follow-up time was 38 months (range, 2–117) for SLN and 61 months (range, 7–235) for LND. Three-year progression-free survival (PFS) was 79% (SE ± 7%) for SLN and 64% (SE ± 8%) for LND (P=0.1). Three-year overall survival (OS) was 89% (SE ± 6%) for SLN and 83% (SE ± 6%) for LND (P=0.05). On multivariate analysis, only FIGO-stage was found to be associated with decrease in both PFS and OS.Abstract #274 Figure 1Kaplan-Meier Curve comparing overall survival for SLN vs LND[Figure omitted. See PDF]ConclusionSLN and LND yielded similar oncologic outcomes when used in staging uterine-confined UCC.DisclosuresDr. Abu-Rustum reports grant funding from GRAIL paid to the institution. Dr. Leitao is an ad-hoc speaker for Intuitive Surgical, Inc., has consulted for Medtronic, and has served on the advisory boards of Ethicon/Johnson & Johnson and Immunogen.

Introduction/BackgroundLympho-vascular space invasion (LVSI) in cervical cancer (CC) is an adverse prognostic feature, often prompting radical treatment, even in early-stage disease. However, the imperative for aggressive intervention has recently been questioned considering the associated morbidities. This study aims to appraise the outcomes of non-radical surgery in stage IA1-IB1 CC with LVSI.MethodologyPatients with International Federation of Obstetrics and Gynecology (FIGO) 2018 stage IA1-IB1 CC who underwent non-radical surgery (type A hysterectomy or conization) between 1/1/2009–12/31/2019 were retrospectively identified. Repeat conization was permitted. All patients underwent bilateral sentinel lymph node (SLN) mapping or lymphadenectomy. Patients with positive nodes, incomplete nodal evaluation, or histology other than squamous or grade 1/2 adenocarcinoma were excluded.ResultsSeventy-one patients met inclusion criteria, 26(37%) with LVSI and 45(63%) without. Median age was 36 years (range, 23–71). Thirty-one patients (44%) had stage IA1, 15(21%) stage IA2, and 25(35%) stage IB1 disease; 36 tumors (51%) were adenocarcinoma and 35(49%) squamous histology.For primary treatment, 68 patients (96%) underwent conization and 3(4%) hysterectomy. Of the 68 patients, 4(6%) had SLN, 40(59%) required repeat conization with SLN, 20(29%) hysterectomy with SLN, and 4(6%) hysterectomy with SLN after repeat conization (figure 1).Patients with LVSI were younger (33 vs 40 years, P<.001) and more likely to have squamous histology (69% vs 38%, P=.04) and stage IA1 disease (61% vs 33%, P=.06). Of 26 patients with LVSI, 3 (all with stage IA1 disease) underwent hysterectomy. Rates of positive endocervical curettage following first conization (36% vs 35%) and of residual disease on final specimen (27% vs 40%) were not different between groups.Median follow-up was 62 months (range, 1–157). No recurrences or deaths occurred among patients with LVSI vs 2 recurrences among patients without.Abstract 184 Figure 1Sankey chart showing surgical pathway from diagnoasis to final procedure (N=71)ConclusionLess radical surgery may be safe for select patients with stage IA1-IB1 cervical cancer with positive LVSI and negative nodes.DisclosuresKara Long-Roche reports travel support from Intuitive Surgical.Mario M. Laitao Jr. is an ad hoc speaker for Intuitive Surgical, Inc., has consulted for Medtronic, and has served on the advisory boards of Ethicon/Johnson & Johnson and Immunogen.Elizabeth Jewell Reports personal fees from Covidien/MedtronicDennis Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE.Nadeem R. Abu-Rustum reports grant funding from GRAIL paid to the institution.