Faculty Bibliography

The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti-Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.

OBJECTIVE:To determine the prevalence of sexual harassment and perceptions of gender disparities affecting the careers of physicians in gynecologic oncology. METHODS:We conducted a survey of US physician members of the Society of Gynecologic Oncology. Participants were queried about demographics, sexual harassment experiences during training/practice, and perceptions of gender disparities in compensation and career advancement. Responses were categorized as "never" versus "ever" and compared using Fisher's exact test. RESULTS:The survey was sent to 1566 members-405 (255 females, 147 males, 3 other) responded (response rate 26%). Sixty-four percent reported having experienced sexual harassment during training/practice. Sexual harassment was experienced by 71% of females and 51% of males. Of these respondents, only 14.5% reported it. Reasons for not reporting included: "incident did not seem important enough" (40%); "did not think anything would be done about it" (37%); and "fear of reprisal" (34%). Female respondents were more likely to report gender affected their career advancement (34% vs. 10%; p ≤ .001) and compensation (64% vs. 19%; p ≤ .001); males were more likely to report no gender income disparity (91% vs. 57%; p ≤ .001). CONCLUSIONS:Sexual harassment during training/practice appears common among male and female gynecologic oncologists. Although most are aware of how to report an incident, few do so, mostly for fear of reprisal or concern nothing will be done. Despite practicing in a field defined by caring for women, female physicians more often perceive gender influences their compensation and career advancement. Awareness of these issues can lead to their elimination from our specialty.

Objective: The aim of this study was to describe the clinical impact of major diagnostic discrepancies in pathology reports of gynecologic malignancies for patients presenting for second opinion to a comprehensive cancer center.
Method(s): All cases of gynecologic malignancy submitted for second opinion review by gynecologic pathologists between 2010 and 2016 were evaluated. Cases with major discrepancies (deemed to have potential clinical impact) with outside diagnoses were self-identified by the specialized gynecologic pathologists. Cases were grouped according to pathologic disagreement with no impact on care and pathologic disagreement with clinical impact. Clinical impact was based on National Comprehensive Cancer Network (NCCN) guidelines and gynecologic oncologist expert opinion.
Result(s): Of the 8,475 gynecologic cases reviewed, 1,265 (15%) discrepancies with outside hospital diagnoses were identified. Of these, 198 (16%) were deemed to be major discrepancies. There were 77 (39%) endometrial cancers, 42 (21%) ovarian cancers, 32 (16%) sarcomas, 30 (15%) cervical cancers, and 18 (9%) other malignancies. Most cases (n = 78, 39%) resulted in change in histology, while 32 (16%) cases noted a different site of origin of disease compared to original diagnosis. Forty-three (22%) cases were downgraded from malignant to benign, and 33 (17%) upgraded from benign to malignant. There were 123 (62%) cases that were deemed to have a pathologic disagreement that had clinical sequelae (change in treatment). Of these, 53 (43%) were surgical (recommend for or against), and 70 (57%) were nonsurgical. Review of uterine sarcoma cases, although considered major discrepancies by expert pathology, had no clinical impact in 60% (n = 18) of cases.
Conclusion(s): Pathologic review of outside cases by specialized gynecologic pathologists identified a group of cases across all gynecologic tumor types that led to changes in clinical management. The impact on patient outcomes should be further explored.
Copyright

OBJECTIVE:Despite good prognosis for patients with low-risk endometrial cancer, a small subset of women with low-grade/low-stage endometrial cancer experience disease recurrence and death. The aim of this study was to characterize clinical features and mutational profiles of recurrent, low-grade, non-myoinvasive, 'ultra-low risk' endometrioid endometrial adenocarcinomas. METHODS:We retrospectively identified patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrioid endometrial cancers who underwent primary surgery at our institution, between January 2009 and February 2017, with follow-up of ≥12 months. 'Ultra-low risk' was defined as FIGO tumor grade 1, non-myoinvasive, and lacking lymphovascular space invasion. Tumor-normal profiling using massively parallel sequencing targeting 468 genes was performed. Microsatellite instability was assessed using MSIsensor. DNA mismatch repair (MMR) protein proficiency was determined by immunohistochemistry. RESULTS:hotspot mutations were found in 4/9 (44%) recurrent and 8/27 (30%) non-recurrent (p=0.44). CONCLUSIONS:Patients diagnosed with ultra-low risk endometrioid endometrial cancers have an overall excellent prognosis. However, in our study, 2.9% of patients with no identifiable clinical or pathologic risk factors developed recurrence. Further work is warranted to elucidate the mechanism for recurrence in this population.

Ovarian cancer is known for its aggressive pathological features, including the capacity to undergo epithelial to mesenchymal transition, promoting angiogenesis, metastatic potential, chemoresistance, inhibiting apoptosis, immunosuppression and promoting stem-like features. Galectins, a family of glycan-binding proteins defined by a conserved carbohydrate recognition domain, can modulate many of these processes, enabling them to contribute to the pathology of ovarian cancer. Our goal herein was to review specific galectin members identified in the context of ovarian cancer, with emphasis on their association with clinical and pathological features, implied functions, diagnostic or prognostic potential and strategies being developed to disrupt their negative actions.

OBJECTIVES/OBJECTIVE:Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). METHODS:Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. RESULTS:Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. CONCLUSIONS:Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.

PURPOSE/OBJECTIVE: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:p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION/CONCLUSIONS:) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.

OBJECTIVE:To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM). METHODS:Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used. RESULTS:Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis. CONCLUSION/CONCLUSIONS:This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted.

Primary fallopian tube carcinoma is a rare and difficult to cure disease. It is often grouped under the epithelial ovarian cancer umbrella, together with primary ovarian and peritoneal carcinomas. More recent evidence has suggested that epithelial ovarian cancers originate from a fallopian tube precursor. The mainstay of treatment is surgical cytoreduction and platinum-based chemotherapy. There is much debate over the best timing for surgery and the best approach to delivering the chemotherapy: traditional intravenous once every 3 weeks regimen, versus intraperitoneal, versus dose-dense intravenous regimens. Although these debates continue, novel targeted therapies, including bevacizumab and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, have emerged. PARP inhibitors are particularly efficacious in patients with BRCA1/2 gene mutations, and their use has been shown to prolong patient survival. This article reviews the pathologic etiology; describes the heredity, treatment challenges, and controversies; and summarizes novel therapies in primary fallopian tube carcinoma.

Objective/UNASSIGNED:To report characteristics of patients with low-grade endometrioid endometrial carcinoma (EC) who develop brain metastases. Methods/UNASSIGNED:We retrospectively identified all patients treated at our institution for FIGO grades 1/2 EC from 1/2000-12/2016, who developed brain metastases. Electronic medical records were reviewed, data abstracted. Overall survival (OS) was determined from time of brain metastases to death or last follow-up. Appropriate statistical tests were used. Results/UNASSIGNED: = .04) for best supportive care. Conclusion/UNASSIGNED:Brain metastases in low-grade EC is rare, prognosis generally poor. Compared to supportive care only, any treatment results in more favorable outcomes.