Faculty Bibliography

Sexual and gender minorities (SGM) include persons identifying as lesbian, gay, bisexual, transgender/non-binary, and queer experience a greater cancer burden than their heterosexual or cisgender counterparts. Access to cancer care includes prevention and early detection, however despite known increased risk for various malignancies among SGM individuals, cancer screening rates remain low. This commentary outlines disparities in cancer screening for SGM individuals and provides the current evidence-based screening guidelines for these patients.

Transgender, non-binary, and gender non-conforming people, also referred to as gender minorities, have unique cancer prevention, treatment, and care needs and experience cancer health disparities compared to the cisgender population. We present four composite cases of the cancer care challenges experienced by gender minorities.

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.
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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.