Faculty Bibliography

Ovarian, endometrial and cervical cancers are the most prevalent gynecologic cancers in the United States and account for significant mortality. Translational research into these cancers has highlighted the distinctive molecular and genomic profiles of these cancers finding that, even within a disease site, the landscapes and drivers of neoplasia are distinctive. Despite this molecular diversity, activation of the phosphatidylinositol-3-kinase (PI3K) pathway appears to be conserved in subsets of these tumors, suggesting that strategies that antagonize mediators in this signaling cascade could offer anti-tumor efficacy. Extensive pre-clinical and clinical data have demonstrated that single agent targeted therapies lead to modest single agent activity of generally limited duration, even in the setting of innate PI3K pathway activation via mutation or amplification. These findings in the laboratory and clinic have prompted investigations into resistance pathways following PI3K pathway inhibition in order to understand escape pathways and restore tumor cell sensitivity. A next generation of clinical trial investigations will focus on novel combinations in order to define how these important therapeutics can be used in the clinic. This review will present preclinical data that supports the role of the PI3K pathway in ovarian, endometrial and cervical cancers, in addition to discussing the reported clinical trial experience with PI3K pathway inhibition. A specific focus will be on the rationale behind ongoing clinical trials utilizing novel agents in concert with PI3K pathway inhibitors to reverse resistance in populations with and without gain of function alterations in this oncogenic signaling cascade.

UNLABELLED:Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually. While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.

Squamous cell carcinomas (SCCs) of the vulva develop through human papilloma virus (HPV)-associated or HPV-independent pathways, but the relationship between pathogenesis, classification, and prognosis of these tumors is controversial. Therefore, we review the morphology, immunophenotype, and select molecular features of a consecutive series of 97 patients with vulvar SCC with a median clinical follow-up of 3.6 years. Tumors were histologically classified as basaloid (13), warty (11), mixed basaloid and warty (1), keratinizing (68), nonkeratinizing (3), and sarcomatoid (1). Diffuse p16 expression was associated with younger age at presentation (P<0.0001), basaloid and warty carcinoma subtypes (P<0.0001), and usual vulvar intraepithelial neoplasia (P<0.0001) and was negatively associated with p53 immunopositivity (P=0.0008). Five keratinizing SCCs showed p16 and p53 coexpression, but only 1 was positive for high-risk HPV by in situ hybridization. Among 8 of 36 tumors with EGFR gene amplification, 4 were p53 positive but none p16 positive. In a Cox regression model, early clinical stage (P<0.006), p16 expression (P=0.002), and absent p53 expression (P=0.02) were independent predictors of improved overall survival. These findings utilize morphologic and immunohistochemical analysis to support HPV-associated and HPV-independent pathogenesis of vulvar SCCs and support p16 and p53 immunohistochemistry as markers of disease biology and clinical outcome.

OBJECTIVES/OBJECTIVE:The objective of this study was to characterize chemotherapy treatment patterns in elderly patients with epithelial ovarian cancer (EOC) and their impact on overall survival (OS). METHODS:We identified patients age ≥65years with stage II-IV EOC who underwent cytoreduction from 2003 to 2011. Relevant clinical variables were extracted and correlated with OS. Statistical analyses were performed using logistic regression, Kaplan-Meier methods, and multivariable Cox proportional hazard models. RESULTS:One hundred and eighty-four patients were included in the analysis. The average age was 73years with American Society of Anesthesiology Physical Status Class 2 or 3. Approximately 78% underwent primary debulking surgery (PDS). OS for the entire cohort was 3.3years. One hundred and fifty-seven patients received adjuvant chemotherapy, of which 70% received initial platinum-based doublet therapy; 67.5% of patients were able to complete the intended six cycles of chemotherapy; of these, 34% experienced a dose reduction and 45% experienced one or more dose delays. Any dose delay was associated with a decrease in overall survival (p=0.02) and remained significant even after controlling for age, stage, and residual disease and number of chemotherapy cycles received (p=0.029). CONCLUSIONS:Elderly EOC patients frequently required chemotherapy dose reductions and delays in chemotherapy administration. Multivariate analysis confirmed that dose delays are an independent factor associated with decreased OS.

OBJECTIVE:To evaluate the mortality outcomes of vaginal sarcomas in a large cohort compared with vaginal squamous cell and adenocarcinomas. METHODS:Women with primary invasive vaginal sarcomas, squamous cell carcinomas, and adenocarcinomas diagnosed between 1988 and 2010 were identified within the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Parametric and nonparametric methods were used to compare the demographic and clinical characteristics of women among the three tumor types as well as between sarcoma histologic subtypes. Overall and cancer-specific mortality outcomes were examined using Kaplan-Meier and multivariable Cox proportional hazards models. RESULTS:The final cohort consisted of 3,121 patients with vaginal squamous cell carcinoma, 720 patients with adenocarcinoma, and 221 patients with sarcoma. Compared with women with squamous cell carcinoma and adenocarcinoma, patients diagnosed with vaginal sarcomas tended to be younger, have larger tumors with less regional extension and lymph node positivity, and be treated primarily with surgery without radiation. In unadjusted analysis, 5-year mortality rates border 30% for all three histologies. After adjusting for other prognostic factors including use of radiation and surgery, patients with vaginal sarcomas had a 69% greater risk of cancer-related mortality compared with patients with squamous cell carcinoma (hazard ratio 1.69, 95% confidence interval 1.26-2.26). Although sarcoma histology failed to associate with mortality risk, age, tumor extension and metastasis, and surgery were poor prognostic factors. CONCLUSION/CONCLUSIONS:Primary vaginal sarcomas are aggressive neoplasms with different presenting characteristics and increased adjusted risk of mortality compared with squamous cell and adenocarcinoma subtypes. LEVEL OF EVIDENCE/METHODS:III.

OBJECTIVE:The aim of this study is to explore the previously unexamined role of the Gynecologic Oncologist as an intraoperative consultant during general gynecologic surgery. METHODS:Demographic and clinical data were collected on 98 major gynecologic surgeries that included both a general Gynecologist and a Gynecologic Oncologist between October 2010 and August 2014. Data were analyzed using XLSTAT-Prov2014.2.02. RESULTS:Of 794 major gynecologic surgeries, 98 (12.3%) cases that involved an intraoperative consultation were identified. There were 36 (37%) planned consults and 62 (63%) unplanned consults. Significantly more planned consults were during laparoscopy (100% v 58%; p<0.01) and significantly more unplanned consults were during laparotomy (42% v 0%; p<0.01). The majority of planned consults were for surgical training (86%) and the most common reasons for unplanned consults were adhesions (40%), bowel injury (19%), inability to identify ureter (19%), and cancer (11%). The most common interventions performed during unplanned consults were identification of anatomy (55%), lysis of adhesions (42%), and retroperitoneal dissection (27%). Average surgeon years in practice were significantly lower for unplanned consults (9 v 15; p<0.01). A total of 25 major adverse events occurred in 15 cases with the majority occurring in cases with unplanned consults (23% v 3%; p<0.01). After controlling for laparotomy, unplanned consultation was not significantly associated with major events (OR=6.67, 95%CI 0.69-64.39; p=0.10). CONCLUSIONS:Gynecologic Oncologists play a pivotal role in the support of generalist colleagues during pelvic surgery. In this series, Gynecologic Oncologists were consulted frequently for complex major benign surgeries. It is important to incorporate the skills required of an intraoperative consultant into Gynecologic Oncology fellowship training.

BACKGROUND:Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa. MATERIALS AND METHODS/METHODS:With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000 and 2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression. RESULTS:We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8RF/mm2 was observed in 53% (n=54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p<0.001). CONCLUSIONS:These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa.

OBJECTIVE:To validate whether Surgical Apgar Score can predict post-operative morbidity in patients undergoing hysterectomies for malignancies. METHODS:We conducted a retrospective cohort study of consecutive hysterectomies performed for cancer at a single academic institution between 2008 and 2010. The Surgical Apgar Score (SAS) was derived as previously reported. Peri-operative complications were as outlined by the American Board for Obstetrics and Gynecology, and then further subdivided into intra-operative and post-operative events. Univariate and multivariate logistic regressions were utilized. RESULTS:A total of 632 patients were identified. Of our cohort, 64% underwent surgery for cancer arising in the uterus, followed by ovary at 28.6% and cervix at 4%. Median patient age was 60 years old with a mean American Society of Anesthesiologists Physical Status Classification System (ASA) score of 2.5 and a median body mass index of 29. Average Surgical Apgar Score was 7.6. As SAS decreased, the risk of peri-operative complications increased (p<0.01). On univariate analysis SAS could predict for both intra-operative and post-operative complications. However, on multivariate analyses SAS could not independently predict for any post-operative complications (OR 1.02, CI 0.47-2.17). In a multivariable model incorporating age, ASA class, SAS <4, disease site, bowel resection and laparotomy, only ASA class and laparotomy were able to predict for postoperative complication events. CONCLUSIONS:Low Surgical Apgar Score significantly associates with morbidity in women undergoing hysterectomy for malignancy, but is unable to predict which patients will have postoperative complications. This renders the SAS less helpful for the creation of peri-operative metrics to guide post-operative care.

PURPOSE/OBJECTIVE:Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts. EXPERIMENTAL DESIGN/METHODS:Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. RESULTS:HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation. CONCLUSIONS:Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation.

Ovarian cancer is the most lethal of all gynecologic malignancies because women commonly present with advanced stage disease and develop chemotherapy refractory tumors. While cytoreductive surgery followed by platinum based chemotherapy are initially effective, ovarian tumors have a high propensity to recur highlighting the distinct need for novel therapeutics to improve outcomes for affected women. The Notch signaling pathway plays an established role in embryologic development and deregulation of this signaling cascade has been linked to many cancers. Recent genomic profiling of serous ovarian carcinoma revealed that Notch pathway alterations are among the most prevalent detected genomic changes. A growing body of scientific literature has confirmed heightened Notch signaling activity in ovarian carcinoma, and has utilized in vitro and in vivo models to suggest that targeting this pathway with gamma secretase inhibitors (GSIs) leads to anti-tumor effects. While it is currently unknown if Notch pathway inhibition can offer clinical benefit to women with ovarian cancer, several GSIs are currently in phase I and II trials across many disease sites including ovary. This review will provide background on Notch pathway function and will focus on the pre-clinical literature that links altered Notch signaling to ovarian cancer progression.