Publications by authors named "Nadeem R Abu-Rustum"

295 Publications

Molecular characterization of high-grade serous ovarian cancers occurring in younger and older women.

Gynecol Oncol 2021 Mar 2. Epub 2021 Mar 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Objectives: To determine if the mutational landscapes and genomic features of homologous recombination DNA repair defects (HRD) vary between younger and older patients with high-grade serous ovarian cancer (HGSOC).

Methods: Younger and older women were defined as bottom and top age quartiles, respectively. HGSOCs from 15 younger (median 49 years, range 35-53) and 15 older women (median 72 years, range 70-87) were subjected to whole-exome sequencing (WES). For validation, HGSOC WES data were obtained from The Cancer Genome Atlas (TCGA), including 38 younger (median 45 years, range 34-50) and 30 older women (median 74 years, range 68-84). Mutational profiles, BRCA1/2 status, genomic HRD features, and for TCGA cases RNA-sequencing-based HRD transcriptomic signatures were assessed.

Results: In the institutional cohort, pathogenic germline BRCA1/2 mutations were more frequent in younger (5/15) than older women (0/15, p = 0.042). No somatic BRCA1/2 mutations were identified. HGSOCs from older patients preferentially displayed aging-related mutational signatures and, in contrast to younger patients, harbored CCNE1 amplifications (3/15, 20%). In the TCGA cohort, pathogenic germline BRCA1 (younger 8/38, older 0/30, p = 0.007) but not BRCA2 mutations (young 3/38, older 4/30, p = 0.691) were more frequent in younger patients. Again, no somatic BRCA1/2 mutations were identified. HGSOCs from younger women more frequently displayed genomic features of HRD (all, p < 0.05), a significant HRD gene-signature enrichment, but less frequently CCNE1 amplification (p = 0.05). Immunoreactive CLOVAR subtypes were more common in HGSOCs from younger women, and proliferative subtypes in HGSOCs from older women (p = 0.041).

Conclusions: HGSOC patients diagnosed at an older age less frequently harbor pathogenic BRCA1 germline mutations and genomic features of HRD than younger women. Individualized treatment options, particularly pertaining to use of PARP inhibitors, in older women may be warranted.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.028DOI Listing
March 2021

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

Int J Gynecol Cancer 2021 Mar 4. Epub 2021 Mar 4.

Center for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Queensland, Australia

Introduction: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance.

Methods: A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability.

Results: Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88).

Conclusion: Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.
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http://dx.doi.org/10.1136/ijgc-2020-002315DOI Listing
March 2021

Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer.

Gynecol Oncol 2021 Feb 20. Epub 2021 Feb 20.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Objective: To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs).

Methods: EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410-468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons.

Results: Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.

Conclusions: Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.015DOI Listing
February 2021

Clinicopathologic and Genomic Analysis of -Mutated Endometrial Carcinomas.

Clin Cancer Res 2021 Feb 18. Epub 2021 Feb 18.

Department of Pathology, Memorial Sloan Kettering Cancer Center.

Purpose: Copy number-high endometrial carcinomas (ECs) were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy number alterations (CNAs), low mutational burden (i.e. non-hypermutant), near universal mutation and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant -altered ECs of four histologic types.

Design: -mutated ECs, defined as -mutant tumors lacking microsatellite instability or pathogenic mutations, were identified (n=238) in a cohort of 1,239 ECs 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: -mutated ECs encompassed uterine serous (n=102, 55.1%), histologically ambiguous high-grade EC-NOS (n=44, 23.8%), endometrioid of all tumor grades (n=28, 15.1%), and clear cell (n=11, 5.9%) carcinomas. mutations were significantly more frequent in endometrioid carcinomas, mutations in clear cell carcinomas, and amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. amplification was present at similar frequencies across histologic -mutated 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: -mutated ECs display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of assessment in all -mutated ECs. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4436DOI Listing
February 2021

Socioeconomic inequality and omission of adjuvant radiation therapy in high-risk, early-stage endometrial cancer.

Gynecol Oncol 2021 Feb 14. Epub 2021 Feb 14.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, NY, New York 10065, United States of America. Electronic address:

Objective: Gaps in access to appropriate cancer care, and associated cancer mortality, have widened across socioeconomic groups. We examined whether demographic and socioeconomic factors influenced receipt of adjuvant radiation therapy (RT) in patients with high-risk, early-stage endometrial cancer.

Methods: A retrospective study cohort was selected from 349,404 endometrial carcinoma patients from the National Cancer Database in whom adjuvant RT would be recommended per national guidelines. The study included surgically treated patients with endometrioid endometrial cancer with one of the following criteria: 1) FIGO 2009 stage IB, grade 1/2 disease, age ≥ 60 years; 2) stage IB, grade 3 disease; or 3) stage II disease. Logistic regression analysis was performed to identify factors associated with omission of adjuvant RT. Association between adjuvant RT, covariables, and overall survival (OS) was assessed with multivariable Cox proportional hazards models.

Results: 19,594 patients were eligible for analysis; 47% did not receive adjuvant RT. Omission of adjuvant RT was more prevalent among African-American, Hispanic, and Asian compared to non-Hispanic white patients (OR 0.79, 95%CI: 0.69-0.91; OR 0.75, 95%CI: 0.64-0.87; OR 0.75, 95%CI: 0.60-0.94, respectively). Lower median household income of patient's area of residence, lack of health insurance, treatment at non-academic hospitals, farther distance to treatment facilities, and residence in metropolitan counties were associated with omission of adjuvant RT. Such omission was independently associated with worse OS (HR1.43, p < 0.001).

Conclusion: Adjuvant RT is omitted in 47% of patients with early-stage, high-risk endometrial cancer, which is associated with poor access to appropriate, high-quality care and worse outcome.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.041DOI Listing
February 2021

Genetic characterization of adult primary pleomorphic uterine rhabdomyosarcoma and comparison with uterine carcinosarcoma.

Histopathology 2021 Feb 2. Epub 2021 Feb 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Aims: To characterize the genetic alterations in adult primary uterine rhabdomyosarcomas (uRMSs) and to investigate whether these tumors are genetically distinct from uterine carcinosarcomas (UCSs).

Methods: Three tumors originally diagnosed as primary adult pleomorphic uRMS were subjected to massively parallel sequencing targeting 468 cancer-related genes and RNA-sequencing. Mutational profiles were compared to those from UCSs (n=57) obtained from The Cancer Genome Atlas. Sequencing data analyses were performed using validated bioinformatic approaches.

Results: Pathogenic TP53 mutations and high levels of genomic instability were detected in the three cases. uRMS1 harbored a likely pathogenic YTHDF2-FOXR1 fusion gene. uRMS2 displayed a PPP2R1A hotspot mutation and amplification of multiple genes, including WHSC1L1, FGFR1, MDM2 and CCNE1, whereas uRMS3 harbored an FBXW7 hotspot mutation and an ANKRD11 homozygous deletion. Hierarchical clustering of somatic mutations and copy number alterations revealed that these tumors initially diagnosed as pleomorphic uRMSs and UCSs were similar. Subsequent comprehensive pathologic re-review of the three uRMSs revealed previously un-identified minute pan-cytokeratin-positive atypical glands in one case (uRMS3), favoring its reclassification as UCS with extensive rhabdomyosarcomatous overgrowth.

Conclusions: Adult pleomorphic uRMSs harbor TP53 mutations and high levels of copy number alterations. Our findings underscore the challenge in discriminating between uRMS and UCS with rhabdomyosarcomatous differentiation.
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http://dx.doi.org/10.1111/his.14346DOI Listing
February 2021

Effect of a Predictive Model on Planned Surgical Duration Accuracy, Patient Wait Time, and Use of Presurgical Resources: A Randomized Clinical Trial.

JAMA Surg 2021 Jan 27. Epub 2021 Jan 27.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Accurate surgical scheduling affects patients, clinical staff, and use of physical resources. Although numerous retrospective analyses have suggested a potential for improvement, the real-world outcome of implementing a machine learning model to predict surgical case duration appears not to have been studied.

Objectives: To assess accuracy and real-world outcome from implementation of a machine learning model that predicts surgical case duration.

Design, Setting, And Participants: This randomized clinical trial was conducted on 2 surgical campuses of a cancer specialty center. Patients undergoing colorectal and gynecology surgery at Memorial Sloan Kettering Cancer Center who were scheduled more than 1 day before surgery between April 7, 2018, and June 25, 2018, were included. The randomization process included 29 strata (11 gynecological surgeons at 2 campuses and 7 colorectal surgeons at a single campus) to ensure equal chance of selection for each surgeon and each campus. Patients undergoing more than 1 surgery during the study's timeframe were enrolled only once. Data analyses took place from July 2018 to November 2018.

Interventions: Cases were assigned to machine learning-assisted surgical predictions 1 day before surgery and compared with a control group.

Main Outcomes And Measures: The primary outcome measure was accurate prediction of the duration of each scheduled surgery, measured by (arithmetic) mean (SD) error and mean absolute error. Effects on patients and systems were measured by start time delay of following cases, the time between cases, and the time patients spent in presurgical area.

Results: A total of 683 patients were included (mean [SD] age, 55.8 [13.8] years; 566 women [82.9%]); 72 were excluded. Of the 683 patients included, those assigned to the machine learning algorithm had significantly lower mean (SD) absolute error (control group, 59.3 [72] minutes; intervention group, 49.5 [66] minutes; difference, -9.8 minutes; P = .03) compared with the control group. Mean start-time delay for following cases (patient wait time in a presurgical area), dropped significantly: 62.4 minutes (from 70.2 minutes to 7.8 minutes) and 16.7 minutes (from 36.9 minutes to 20.2 minutes) for patients receiving colorectal and gynecology surgery, respectively. The overall mean (SD) reduction of wait time was 33.1 minutes per patient (from 49.4 minutes to 16.3 minutes per patient). Improved accuracy did not adversely inflate time between cases (surgeon wait time). There was marginal improvement (1.5 minutes, from a mean of 70.6 to 69.1 minutes) in time between the end of cases and start of to-follow cases using the predictive model, compared with the control group. Patients spent a mean of 25.2 fewer minutes in the facility before surgery (173.3 minutes vs 148.1 minutes), indicating a potential benefit vis-à-vis available resources for other patients before and after surgery.

Conclusions And Relevance: Implementing machine learning-generated predictions for surgical case durations may improve case duration accuracy, presurgical resource use, and patient wait time, without increasing surgeon wait time between cases.

Trial Registration: ClinicalTrials.gov Identifier: NCT03471377.
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http://dx.doi.org/10.1001/jamasurg.2020.6361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841577PMC
January 2021

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

Obstet Gynecol 2021 Feb;137(2):334-341

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, the Department of Obstetrics and Gynecology, Weill Cornell Medical College, and the Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York; the Division of Gynecologic Oncology, Hartford Healthcare Cancer Institute, Hartford, Connecticut; the Lehigh Valley Cancer Institute, Allentown, Pennsylvania; and the Miami Cancer Institute, Miami, Florida.

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.
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http://dx.doi.org/10.1097/AOG.0000000000004243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856105PMC
February 2021

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

Gynecol Oncol 2021 Mar 30;160(3):696-703. Epub 2020 Dec 30.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of OB/GYN, Weill Cornell Medical College, New York, NY, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902425PMC
March 2021

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Mod Pathol 2020 Dec 16. Epub 2020 Dec 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.
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http://dx.doi.org/10.1038/s41379-020-00721-6DOI Listing
December 2020

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

Int J Gynecol Cancer 2021 Feb 3;31(2):222-231. Epub 2020 Dec 3.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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 mutations were excluded. Distribution of characteristics between treatment groups was assessed using χ 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.
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http://dx.doi.org/10.1136/ijgc-2020-001966DOI Listing
February 2021

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.

Gynecol Oncol 2021 Jan 17;160(1):51-55. Epub 2020 Nov 17.

Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.042DOI Listing
January 2021

FIGO 2018 stage IB endocervical adenocarcinomas: an international study of outcomes informed by prognostic biomarkers.

Int J Gynecol Cancer 2021 Feb 11;31(2):177-184. Epub 2020 Nov 11.

Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Objective: Prognostic factors for endocervical adernocarcinomas are well known, but little is known about prognostic biomarkers influencing outcome for the newly defined International Federation of Gynecology and Obstetrics (FIGO) 2018 IB sub-stages. The aim of this study was to identify prognostic biomarkers influencing recurrence-free and overall survival for FIGO 2018 stage IB cervical adenocarcinoma sub-types. We sought to identify these factors using a large international multi-institutional series of cases.

Methods: Stage IB endocervical adenocarcinomas were retrospectively collected from nine international institutions; full slide sets (n=464) were used to assign prognostic biomarkers. Inclusion criteria were the following: FIGO stage IB endocervical adenocarcinomas with follow-up in which all paraffin blocks/glass slides were available for review and/or additional studies and the patient was surgically treated from 1985 to 2019. The types of specimens included in the study were conizations, trachelectomies, and simple/radical hysterectomies with or without lymph node samples. We excluded in situ carcinomas, squamous cell carcinomas, adenosquamous carcinomas, tumors with a neuroendocrine component, carcinosarcomas, and any tumor showing clinical, macroscopic, or microscopic features suggesting a lower uterine segment, uterine corpus, or an adnexal primary origin. Tumors treated with neoadjuvant chemotherapy and/or radiation therapy were also excluded, as well as biopsies and loop electrosurgical excision procedures.

Results: Of 464 cases, 225 (48%) were stage IB1, 177 (38%) were stage IB2, and 62 (13%) were stage IB3. Five-year and 10-year recurrence-free survivals were statistically different among stage IB sub-types (p=0.005). Silva pattern of invasion was significant for recurrence-free survival at 5 and 10 years (p=0.04); overall survival and recurrence-free survival were higher in human papillomavirus (HPV)-associated cases (p=0.007 and p=0.001, respectively) and in cases without lymphovascular invasion (p=0.004 and p=0.00001, respectively). Factors that significantly influenced recurrence-free survival were HPV-independent status (p=0.05; HR 2.31; 95% CI 1.02 to 5.46), presence of lymphovascular invasion (p=0.011; HR 3.50; 95% CI 1.33 to 9.19), and presence of lymph node metastasis (p=0.016; HR 2.66; 95% CI 1.20 to 5.90).

Conclusion: HPV status and the presence of lymphovascular invasion are prognosticators in stage IB endocervical adenocarcinoma sub-types. These parameters should be included in future sub-staging modifications of FIGO stage IB endocervical adenocarcinomas and in treatment strategies.
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http://dx.doi.org/10.1136/ijgc-2020-001893DOI Listing
February 2021

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

Gynecol Oncol 2021 Jan 4;160(1):99-105. Epub 2020 Nov 4.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America; Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, United States of America. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779751PMC
January 2021

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.

Int J Gynecol Cancer 2020 Dec 26;30(12):1915-1921. Epub 2020 Oct 26.

Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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 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 ≥ 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.
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http://dx.doi.org/10.1136/ijgc-2020-001641DOI Listing
December 2020

Machine learning-based prediction of microsatellite instability and high tumor mutation burden from contrast-enhanced computed tomography in endometrial cancers.

Sci Rep 2020 10 20;10(1):17769. Epub 2020 Oct 20.

Body Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

To evaluate whether radiomic features from contrast-enhanced computed tomography (CE-CT) can identify DNA mismatch repair deficient (MMR-D) and/or tumor mutational burden-high (TMB-H) endometrial cancers (ECs). Patients who underwent targeted massively parallel sequencing of primary ECs between 2014 and 2018 and preoperative CE-CT were included (n = 150). Molecular subtypes of EC were assigned using DNA polymerase epsilon (POLE) hotspot mutations and immunohistochemistry-based p53 and MMR protein expression. TMB was derived from sequencing, with > 15.5 mutations-per-megabase as a cut-point to define TMB-H tumors. After radiomic feature extraction and selection, radiomic features and clinical variables were processed with the recursive feature elimination random forest classifier. Classification models constructed using the training dataset (n = 105) were then validated on the holdout test dataset (n = 45). Integrated radiomic-clinical classification distinguished MMR-D from copy number (CN)-low-like and CN-high-like ECs with an area under the receiver operating characteristic curve (AUROC) of 0.78 (95% CI 0.58-0.91). The model further differentiated TMB-H from TMB-low (TMB-L) tumors with an AUROC of 0.87 (95% CI 0.73-0.95). Peritumoral-rim radiomic features were most relevant to both classifications (p ≤ 0.044). Radiomic analysis achieved moderate accuracy in identifying MMR-D and TMB-H ECs directly from CE-CT. Radiomics may provide an adjunct tool to molecular profiling, especially given its potential advantage in the setting of intratumor heterogeneity.
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http://dx.doi.org/10.1038/s41598-020-72475-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575573PMC
October 2020

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas.

Mol Oncol 2020 Oct 5. Epub 2020 Oct 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
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http://dx.doi.org/10.1002/1878-0261.12813DOI Listing
October 2020

Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.

JCO Precis Oncol 2020 15;4. Epub 2020 Sep 15.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva.

Methods: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore.

Results: Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in (n = 9; 35%), (4 mutations and 3 copy number alterations; 27%), and (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression.

Conclusion: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations ( or ) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.
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http://dx.doi.org/10.1200/PO.20.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529529PMC
September 2020

Endometrial Cancers in or Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects.

JCO Precis Oncol 2019 29;3. Epub 2019 Aug 29.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline (g) mutations. Biallelic alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in g mutation carriers harbor biallelic alterations and/or features of HRD.

Methods: Of 769 patients with EC who underwent germline panel testing, 10 pathogenic g mutation carriers were identified, and their tumor- and normal-derived DNA was subjected to massively parallel sequencing targeting at least 410 cancer-related genes. Three g-associated ECs were identified in 232 ECs subjected to whole-exome sequencing by The Cancer Genome Atlas. Somatic mutations, copy number alterations, loss of heterozygosity, microsatellite instability (MSI), and genomic HRD features were assessed.

Results: Of the 13 patients included who had EC, eight harbored pathogenic g mutations and five harbored g mutations. Eight (100%) and two (40%) ECs harbored biallelic and alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic mutations. One monoallelic/sporadic g-associated EC had promoter methylation and was MSI high. High large-scale state transition scores, a genomic feature of HRD, were found only in ECs with bi- but not monoallelic alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic g ECs, and the three ECs from The Cancer Genome Atlas with biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3.

Conclusion: A subset of g-associated ECs harbor biallelic alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.
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http://dx.doi.org/10.1200/PO.19.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446423PMC
August 2019

Impact of provider volume on front-line chemotherapy guideline compliance and overall survival in elderly patients with advanced ovarian cancer.

Gynecol Oncol 2020 Nov 16;159(2):418-425. Epub 2020 Aug 16.

The Health Outcomes Research Group, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.

Purpose: We sought to evaluate whether provider volume or other factors are associated with chemotherapy guideline compliance in elderly patients with epithelial ovarian cancer (EOC).

Methods: We queried the SEER-Medicare database for patients ≥66 years, diagnosed with FIGO stage II-IV EOC from 2004 to 2013 who underwent surgery and received chemotherapy within 7 months of diagnosis. We compared NCCN guideline compliance (6 cycles of platinum-based doublet) and chemotherapy-related toxicities across provider volume tertiles. Factors associated with guideline compliance and chemotherapy-related toxicities were assessed using logistic regression. Overall survival (OS) was compared across volume tertiles and Cox proportional-hazards model was created to adjust for case-mix.

Results: 1924 patients met inclusion criteria. The overall rate of guideline compliance was 70.3% with a significant association between provider volume and compliance (64.5% for low-volume, 72.2% for medium-volume, 71.7% for high-volume, p = .02). In the multivariate model, treatment by low-volume providers and patient age ≥ 80 years were independently associated with worse chemotherapy-guideline compliance. In the survival analysis, there was a significant difference in median OS across provider volume tertiles with median survival of 32.8 months (95%CI 29.6, 36.4) low-volume, 41.9 months (95%CI 37.5, 46.7) medium-volume, 42.1 months (95%CI 38.8, 44.2) high-volume providers, respectively (p < .01). After adjusting for case-mix, low-volume providers were independently associated with higher rates of mortality (aHR 1.25, 95%CI: 1.08, 1.43).

Conclusions: In a modern cohort of elderly Medicare patients with advanced EOC, we found higher rates of non-compliant care and worse survival associated with treatment by low-volume Medicare providers. Urgent efforts are needed to address this volume-outcomes disparity.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.104DOI Listing
November 2020

DNA Mismatch Repair-deficient Endometrial Carcinosarcomas Portend Distinct Clinical, Morphologic, and Molecular Features Compared With Traditional Carcinosarcomas.

Am J Surg Pathol 2020 11;44(11):1573-1579

Department of Pathology.

Uterine carcinosarcomas (UCSs) are aggressive neoplasms composed of high-grade malignant epithelial and mesenchymal elements with most (∼90%) showing TP53 abnormalities. A subset, however, shows mismatch repair deficiency (MMR-D). We sought to describe their clinical, morphologic, and molecular features. Clinicopathologic data of MMR-D UCSs were recorded including age, stage, follow-up, mismatch repair and p53 immunohistochemistry (IHC), MLH1 promoter methylation status, and germline alterations, TP53 mutation status, microsatellite instability and mutational burden by massively parallel sequencing. Seventeen (6.2%) MMR-D were identified among 276 UCSs. Of MMR-D UCSs, the median age was 60 years. mismatch repair IHC loss is as follows: MLH1/PMS2 65%, MSH2/MSH6 18%, MSH6 12%, and PMS2 6%. MLH1 promoter methylation and Lynch syndrome was identified in 47% and 12% of cases, respectively. Cases with p53 IHC showed the following patterns: wild-type 70%, aberrant 20%, and equivocal 10%. Of cases with sequencing, 88% were hypermutated and microsatellite instability high. High-grade endometrioid, undifferentiated, and clear cell carcinoma was present in 53%, 41%, and 6% of cases, respectively and 47% also showed a low-grade endometrioid component. Most patients presented at an early stage (67%) and upon follow-up, 18% died of disease, 65% showed no evidence of disease, while 18% are alive with disease. Patients with MMR-D UCS are younger than the reported median age (70 y) for traditional UCS and most do not show p53 abnormalities. Low-grade endometrioid and undifferentiated carcinoma were seen in approximately half of all cases. Although UCSs have a high tendency for early extrauterine spread, most patients in our cohort presented at an early stage and at follow-up were no evidence of disease. MMR-D UCSs display distinct clinical, morphologic, and molecular features compared with traditional UCSs.
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http://dx.doi.org/10.1097/PAS.0000000000001561DOI Listing
November 2020

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.

Gynecol Oncol 2020 Oct 10;159(1):66-71. Epub 2020 Aug 10.

Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541719PMC
October 2020

Radical Trachelectomy for the Treatment of Early-Stage Cervical Cancer: A Systematic Review.

Obstet Gynecol 2020 09;136(3):533-542

Gynecology Service, Department of Surgery, and the Medical Library, Memorial Sloan Kettering Cancer Center, and the Joan & Sanford I. Weill Medical College of Cornell University, New York, New York; and the Department of Obstetrics and Gynecology, Danbury Hospital, Nuvance Health, Danbury, Connecticut.

Objective: To assess surgical, oncologic, and pregnancy outcomes in patients undergoing radical vaginal, abdominal, or laparoscopic trachelectomy for the treatment of early-stage cervical cancer, using a methodic review of published literature.

Data Sources: PubMed, EMBASE, and Cochrane Library sources, including ClinicalTrials.gov, were searched from 1990-2019 with terms "cervical cancer" and "(vaginal, abdominal, open, minimally invasive, or laparoscopic) radical trachelectomy." Grey literature and unpublished data were omitted.

Methods Of Study Selection: After removal of duplicates from a combined EndNote library of results, 490 articles were reviewed using Covidence software. Two reviewers screened titles and abstracts, and then screened full texts. Selection criteria included articles that reported radical trachelectomy with lymph node assessment as primary therapy for cervical carcinoma, with stated follow-up intervals and recurrences.

Tabulation, Integration, And Results: Variables of interest were manually extracted into an electronic database. A total 47 articles that reported on 2,566 women met inclusion criteria. Most tumors were of squamous histology (68.5%), stage IB1 (74.8%), 2 cm or less (69.2%), and without lymphovascular invasion (68.8%). Of planned trachelectomies, 9% were converted intraoperatively to hysterectomy. Separated by route of trachelectomy, 58.1%, 37.2%, and 4.7% were performed using radical vaginal, abdominal, and laparoscopic approaches, respectively. With median follow-up of 48 months (range 2-202 months) across studies, median recurrence rate was 3.3% (range 0-25%); median time to recurrence was 26 months (range 8-44 months). Median 5-year recurrence-free and overall survival were 94.6% (range 88-97.3%) and 97.4% (range 95-99%), respectively. The posttrachelectomy pregnancy rate was 23.9%, with a live-birth rate of 75.1%.

Conclusion: Radical trachelectomy for fertility-preserving treatment of cervical cancer is widely reported in the literature, though publications are mainly limited to case reports and case series. Reported follow-up periods infrequently meet standard oncologic parameters but show encouraging recurrence-free and overall survival rates and pregnancy outcomes. Higher-level evidence needed for meta-analysis is lacking.

Systematic Review Registration: PROSPERO, CRD42019132443.
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http://dx.doi.org/10.1097/AOG.0000000000003952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528402PMC
September 2020

Electronic patient-reported symptom monitoring in patients recovering from ambulatory minimally invasive gynecologic surgery: A prospective pilot study.

Gynecol Oncol 2020 Oct 24;159(1):187-194. Epub 2020 Jul 24.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA.

Objective: To evaluate the feasibility of an electronic symptom-tracking platform for patients recovering from ambulatory surgery.

Method: We assessed user response to an electronic system designed to self-report symptoms. Endpoints included compliance, postoperative symptoms, patient satisfaction. An 8-item symptom inventory (pain, nausea, vomiting, shortness of breath, fever, swelling, discharge, redness) was developed and made available on postoperative days (POD) 2-6. Responses exceeding defined thresholds of severity triggered alerts to healthcare providers. Symptoms, alerts, actions taken, urgent care center (UCC) visits, hospital admissions were tracked until POD 30. Patient satisfaction was evaluated on POD 7. A patient was defined as "responder" if at least 5/8 items on at least 3 PODs were completed. The assessment method was deemed successful if 64/100 patients responded.

Results: 97/102 patients were evaluable; 65 met "responder" criteria (67% responder rate; 95% CI 57-76%). 321 surveys were completed (median 4/patient), 248 (77%) in ≤2 min. Involving caregivers and allowing additional symptom-reporting improved the responder rate to 72% (95% CI 58-84%). Most commonly-reported moderate, severe, very severe symptoms were pain, nausea, swelling; 71% reported moderate to very severe pain on POD 2. Phone calls and adjustment of medications adequately addressed most symptoms. Two patients (2%) presented at UCC before, 6 (6%) after, POD 6; 1 (1%) was admitted. Most agreed or strongly agreed that electronic symptom-tracking was helpful, easy to use, and would recommend it to others.

Conclusion: Electronic symptom-tracking is feasible for patients undergoing ambulatory gynecologic cancer surgery. Symptom burden is high in the early postoperative period. Addressing patient-reported symptoms in a timely, automated manner may prevent severe downstream adverse events, reduce UCC visits and admission rates, and improve outcomes.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380930PMC
October 2020

A prospective multicenter international single-arm observational study on the oncological safety of the sentinel lymph node algorithm in stage I intermediate-risk endometrial cancer (SELECT, SEntinel Lymph node Endometrial Cancer Trial).

Int J Gynecol Cancer 2020 Oct 22;30(10):1627-1632. Epub 2020 Jul 22.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Background: In the primary treatment of apparent uterine-confined endometrial carcinoma, pelvic ± para-aortic lymphadenectomy has been considered the standard of care. Although some retrospective data suggest that the sentinel lymph node algorithm without complete lymphadenectomy can be used without jeopardizing oncologic outcome, prospective data are lacking.

Primary Objectives: To assess the 36 month incidence of pelvic/non-vaginal recurrence in women with pathologically confirmed stage I intermediate-risk endometrioid endometrial carcinoma who have bilateral negative pelvic sentinel lymph nodes.

Study Hypothesis: We hypothesize that patients with stage I, intermediate-risk endometrioid endometrial carcinoma who have bilateral negative pelvic sentinel lymph nodes will demonstrate a pelvic/non-vaginal recurrence rate comparable to historical estimate of stage I, intermediate-risk endometrioid endometrial carcinoma patients (estimated 2.5%).

Trial Design: This prospective multicenter single-arm observational study will follow women with stage I, intermediate risk endometrioid endometrial adenocarcinoma who have undergone successful hysterectomy, bilateral salpingo-oophorectomy, and bilateral sentinel lymph node biopsies, for recurrence. All patients will undergo lymphatic mapping using indocynanine green and will either receive no adjuvant treatment or vaginal brachytherapy only. Patients will be followed for 36 months.

Major Inclusion/exclusion Criteria: Patients will be enrolled in the study cohort if all the following criteria are met: (i) at time of surgery: hysterectomy with bilateral adnexectomy, and successful bilateral pelvic sentinel lymph node mapping; (ii) on final pathology: pathologic stage I, intermediate-risk endometrioid endometrial carcinoma (grade 1 or grade 2 with ≥50% myometrial invasion, or grade 3 with <50% myometrial invasion), negative pelvic peritoneal cytology, and bilateral sentinel lymph nodes negative for malignancy; (iii) recommended adjuvant treatment: vaginal brachytherapy or no adjuvant treatment.

Primary Endpoint: Incidence of pelvic/non-vaginal recurrence at 36 months.

Sample Size: 182 patients for study cohort ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual will be completed in 2023 with results reported in 2026.

Trial Registration: NCT04291612.
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http://dx.doi.org/10.1136/ijgc-2020-001698DOI Listing
October 2020

Comparison of minimally invasive versus open surgery in the treatment of endometrial carcinosarcoma.

Int J Gynecol Cancer 2020 08 20;30(8):1162-1168. Epub 2020 Jul 20.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Objective: The aim of this study was to compare perioperative and oncologic outcomes between minimally invasive and open surgery in the treatment of endometrial carcinosarcoma.

Methods: We retrospectively identified all patients with newly diagnosed endometrial carcinosarcoma who underwent primary surgery via any approach at our institution from January 2009 to January 2018. Patients with known bulky disease identified on preoperative imaging were excluded. The χ and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival, and compared using the log rank test.

Results: We identified 147 eligible patients, of whom 37 (25%) underwent an open approach and 110 (75%) underwent minimally invasive surgery. Within the minimally invasive group, 92 (84%) of 110 patients underwent a robotic procedure and 14 (13%) underwent a laparoscopic procedure. Four minimally invasive cases (4%) were converted to open procedures. Median age, body mass index, operative time, stage, complication grade, and use of adjuvant treatment were clinically and statistically similar between groups. Median length of hospital stay in the open group was 4 days (range 3-21) compared with 1 day (range 0-6) in the minimally invasive group (p<0.001). The rates of any 30-day complication were 46% in the open and 8% in the minimally invasive group (p<0.001). The rates of grade 3 or higher complications were 5.4% and 1.8%, respectively (p=0.53). Median follow-up for the entire cohort was 30 months (range 0.4-121). Two-year progression-free survival rates were 52.8% (SE±8.4) in the open group and 58.5% (SE±5.1) in the minimally invasive group (p=0.7). Two-year disease-specific survival rates were 66.1% (SE±8.0) and 81.4% (SE±4.1), respectively (p=0.8).

Conclusions: In patients with clinical stage I endometrial carcinosarcoma, minimally invasive compared with open surgery was not associated with poor oncologic outcomes, but with a shorter length of hospital stay and a lower rate of overall complications.
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http://dx.doi.org/10.1136/ijgc-2020-001573DOI Listing
August 2020

Mutant FOXL2 Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors.

Cancer Res 2020 09 8;80(17):3466-3479. Epub 2020 Jul 8.

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark.

The mutant protein FOXL2 is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2 contributes to tumorigenesis is not known. Here, we show that mutant FOXL2 acquires the ability to bind SMAD4, forming a FOXL2/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2 mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2 also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2 binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2 and its interaction with SMAD4 as potential therapeutic targets to this condition. SIGNIFICANCE: FOXL2 hijacks SMAD4 and leads to the expression of genes involved in EMT, stemness, and oncogenesis in AGCT, making FOXL2 and the TGFβ pathway therapeutic targets in this condition. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3466/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0259DOI Listing
September 2020

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

Gynecol Oncol 2020 Sep 6;158(3):608-613. Epub 2020 Jun 6.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Obstetrics & Gynecology, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Objective: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT).

Methods: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score.

Results: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS.

Conclusions: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.
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http://dx.doi.org/10.1016/j.ygyno.2020.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487016PMC
September 2020

NCCN Guidelines Insights: Cervical Cancer, Version 1.2020.

J Natl Compr Canc Netw 2020 06;18(6):660-666

29National Comprehensive Cancer Network.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.
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http://dx.doi.org/10.6004/jnccn.2020.0027DOI Listing
June 2020