Teresa Rutledge

Epidermal growth factor receptor as a biomarker for cervical cancer

This review focuses on the different modes of expression of the epidermal growth factor receptor (EGFR). All methods used to assess EGFR expression are critically analyzed and insights into the use of inhibitors of EGFR for treatment of cervical cancer are discussed. Currently, expression of EGFR as a biomarker for prognosis or for treatment of cervical cancer is not defined for clinical use.

Pelvic floor disorders and sexual function in gynecologic cancer survivors: a cohort study

OBJECTIVE The purpose of this study was to assess the prevalence of pelvic floor disorders and sexual function in survivors of gynecologic cancer. STUDY DESIGN We surveyed survivors of gynecologic cancer (survivors) and women seeking gynecologic care (control patients) who were >30 years old. All survivors were disease- and treatment-free for ≥1 year. Validated questionnaires were used to evaluate pelvic floor disorders. RESULTS One hundred eight control patient and 260 survivor questionnaires were completed. A high prevalence of pelvic floor disorders was observed in both groups; 56% of control subjects and 70% of survivors reported moderate to severe urinary incontinence (P > .05). Survivors were more likely to experience fecal incontinence (42% vs 32%; P = .02). Survivors reported less sexual desire (P = .04) and less ability to climax (P = .04), despite no difference in dyspareunia. CONCLUSION Fecal incontinence and sexual dysfunction are significant problems in survivors of gynecologic cancer.

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion, and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high-throughput screening and computational shape homology approaches, we identified R-ketorolac as a Cdc42 and Rac1 inhibitor, distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip) and primary patient-derived ovarian cancer cells show that R-ketorolac is a robust inhibitor of growth factor or serum-dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small-molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration, and invasion. In summary, we provide evidence for R-ketorolac as a direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiologic responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA-approved drug, racemic ketorolac, that can be used in humans. Mol Cancer Ther; 14(10); 2215–27. ©2015 AACR.

Extraperitoneal para-aortic lymph node evaluation for cervical cancer via pfannenstiel incision: Technique and peri-operative outcomes

OBJECTIVE To examine surgico-pathologic outcomes following extraperitoneal para-aortic lymph node dissection (EPLND) via pfannenstiel compared to paramedian incision prior to radiation in patients with cervical cancer. METHODS At our institution, patients with locally advanced cervical cancer undergo, EPLND. From 1990 to 2000, EPLND was performed via paramedian incision (PM) primarily to identify positive para-aortic lymph nodes (PALN). From 2000 to present, a complete pelvic and para-aortic lymphadenectomy was performed via pfannenstiel incision (PF). Records for all patients undergoing EPLND were reviewed. Pathologic findings, post-operative complications, and time to initiation of radiation (TRT) were abstracted. RESULTS 93 patients underwent EPLND, 48 via PF and 45 via PM incision. The mean age and body mass index did not differ between the two groups. Stage distribution was similar: IB2 8 vs. 0%; IIB 44 vs. 44%; IIIA/B 35 vs. 44%; IVA 13 vs. 11%, respectively. Positive PALN were identified in 44% of PF patients and 29% of PM patients (p=ns). TRT was not significantly different at 36.4 vs. 28.8 days, respectively. There were more complications among the PF group including cellulitis and lymphocyst formation. Pre-treatment computed tomography (CT) scan had positive and negative predictive values of only 86 and 66% for evaluation of PALN involvement. CONCLUSIONS We present an extraperitoneal method for removal of the pelvic and para-aortic lymph nodes with acceptable complications and no significant delay to initiate chemoradiation. Accurate assessment of lymphatic metastases results in modification of the radiation field, which, along with surgical debulking, may impact overall survival.

A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients

Purpose: We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes. Experimental Design: Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer–specific survival in ovarian cancer cases. Results: Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the R-enantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11–0.88). Conclusions: Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac. Clin Cancer Res; 21(22); 5064–72. ©2015 AACR.

Randomized phase IIB evaluation of weekly paclitaxel versus weekly paclitaxel with oncolytic reovirus (Reolysin®) in recurrent ovarian, tubal, or peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

OBJECTIVE To assess whether the addition of oncolytic reovirus (Reolysin®) to weekly paclitaxel prolonged progression-free survival (PFS) in the treatment of women with recurrent or persistent ovarian, tubal or primary peritoneal cancer. PATIENTS AND METHODS Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to paclitaxel (80mg/m2 intravenously days 1, 8, and 15 every 4weeks) or the combination of paclitaxel (80mg/m2 intravenously days 1, 8, and 15) plus reovirus 3×1010TCID50/day intravenously on days 1-5, both every 4weeks until disease progression or toxicity. The primary end point was PFS. The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS The study accrued 108 patients, 100 of whom were evaluable for toxicity. Median PFS was 4.3months for paclitaxel and 4.4months for paclitaxel plus reovirus (hazard ratio, 1.11; 90% two-sided CI, 0.78 to 1.59; one-sided P=0.687). The proportion responding (overall response rate) to paclitaxel was 20% among 45 patients with measurable disease receiving paclitaxel alone, and 17.4% among the 46 patients treated with the combination. The asymptotic relative probability of responding was 0.87 (90% CI, 0.42 to 1.79). Severe adverse events were more common in the combination regimen than in paclitaxel arm for severe neutropenia (grade≥4, 12% versus 0%), and severe respiratory adverse events (grade≥3, 25% versus 2%). No deaths were considered treatment related. CONCLUSION The addition of reovirus to weekly paclitaxel in the treatment of women with recurrent or persistent ovarian, tubal or peritoneal cancer did not sufficiently reduce the hazard of progression or death to warrant further investigation.

Optimizing endometrial cancer follow-up and survivorship care for rural and other underserved women: Patient and provider perspectives

OBJECTIVES This study describes patient and provider attitudes on transitioning cancer surveillance visits and treatment of comorbid conditions to the primary care setting in a rural patient population as a strategy for minimizing financial and travel related barriers for patients while simultaneously enhancing quality and availability of health care options. METHODS Focus group discussions and telephone interviews were conducted with endometrial cancer (EC) survivors and primary care providers (PCPs) to provide insights into post-treatment follow-up practices and the acceptability of transitioning follow-up to primary care setting utilizing a cancer survivorship care plan model. RESULTS EC survivors expressed high levels of satisfaction with their oncology care and suggested that transitioning to PCPs for follow-up care would be convenient yet challenging. Challenges cited include: 1) patient perceptions of deficits in PCPs understandings of cancer surveillance; 2) inability to identify a personal PCP; and 3) lack of communication between oncologists and PCPs. PCP participants similarly identified the need for extensive EC training and effective communication strategies with oncologists as necessary factors for accepting responsibility for EC follow-up care. Both groups offered strategies to create a more team based approach to EC survivorship care. CONCLUSIONS Increasing the role of the PCP in the ongoing care of EC survivors was generally considered acceptable by both patients and providers in both rural and urban women. Successful coordination of care between cancer survivors, oncologists and PCPs will be a critical step in improving the cancer care delivery of our rural patient and provider population.

Abstract 4044: R-ketorolac targets Cdc42 and Rac1 GTPases and alters ovarian tumor cell behaviors critical for invasion and metastasis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Ovarian cancer (OvCa) is the 5th leading cause of cancer death in women in the US with a 5-year survival rate of 44.6%. About 70% patients are diagnosed at advanced stages with intraperitoneal dissemination, therefore identifying intracellular targets and developing effective molecules to reduce tumor metastasis have great significance for ovarian cancer therapy. Cdc42 and Rac1 are small Rho GTPase and function as molecular switches of actin reorganization which are crucial to tumor cell adhesion, migration and invasion. In previous work, our group found Cdc42 and the constitutively active Rac1b are overexpressed in primary ovarian tumor tissues and ovarian cancer cell lines. Lead identification through a high-throughput screen combined with a computational shape homology approach, identified R-ketorolac as a Cdc42 and Rac1 regulator, an activity that is distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. RhoA was unaffected by R-ketorolac. A bead-based flow cytometry assay identified R-ketorolac reduced Cdc42 and Rac1 GTPase nucleotide binding in vitro and inhibition was an allosteric mechanism of action. In cell-based assays, using Skov3ip cells, and in ascites-derived ovarian tumor cells, R-ketorolac was found to inhibit the activities of Cdc42 and Rac1 and their direct downstream effectors, the phosphorylation of p21-activated kinases (PAKs). R-ketorolac, but not S-ketorolac impeded Cdc42 mediated filopodia formation, measured based on both the length and numbers of filopodia in Skov3ip and primary OvCa cells. Cell behavior assays showed that R-ketorolac but not S-ketorolac strikingly inhibited cell adhesion, migration and invasion. In a xenograft mouse model a 50% reduction in tumor cell number and decreased total tumor burden was observed with R-ketorolac as compared to S-ketorolac treatment. Finally, in a ‘phase 0′ clinical study we found Cdc42 and Rac1 activities were reduced in a time-dependent manner after a single IV dose of racemic ketorolac treatment. In sum, we established R-ketorolac inhibition on Cdc42 and Rac1 activities and subsequent physiological consequences which are critical to tumor metastasis. Our findings provide the first demonstration of selective inhibition of Cdc42 and Rac1 GTPases by an FDA approved drug in humans. Citation Format: Yuna Guo, S. Ray Kenney, Larry A. Sklar, Tione Buranda, Tudor I. Oprea, Oleg Ursu, Sarah F. Adams, Teresa Rutledge, Carolyn Muller, Lesley Lomo, Laurie G. Hudson, Angela Wandinger-Ness. R-ketorolac targets Cdc42 and Rac1 GTPases and alters ovarian tumor cell behaviors critical for invasion and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4044. doi:10.1158/1538-7445.AM2015-4044

Advances in Surgical Care

The numerous advances in the surgical care of gynecologic oncology patients are allowing clinicians to offer improved quality of life while maintaining excellent cancer outcomes. Advances in technology and disease understanding will only enhance our surgical abilities beyond what can be imagined today. Surgeons have a responsibility to evaluate new technology critically and incorporate the technology into patient care safely and efficiently.

Abstract B20: Optimizing endometrial cancer follow-up and survivorship care for rural and other underserved women: Patient and provider perspectives

BACKGROUND The number of women diagnosed with gynecologic cancers in the U.S. is increasing rapidly. The American Society of Clinical Oncology predicts a 48% increase in the number of people developing cancer by the year 2020. Yet the numbers of oncologists and available services are rising much more slowly; data indicates an increase in the workforce of only 14% by 2020. This workforce shortage may lead to challenging conditions for optimal survivorship care, particularly in rural and other underserved areas. Although endometrial cancer survivors (EC) often receive favorable prognoses, they remain vulnerable as many suffer health challenges due to comorbidities that can be more life threatening than the cancer itself. Adequate treatment for these comorbid conditions requires regular clinician oversight, yet many rural EC survivors travel hours for follow-up care in oncology settings, and comorbidities are often unaddressed. Although transition from oncology specialty care to primary care seems an obvious solution, acceptance of this transition by EC survivors and primary care providers (PCPs) has not been well studied. METHODS We conducted a qualitative study with 53 EC survivors and 16 PCPs to identify barriers and facilitators to optimal EC survivorship care. Between October 2014 and September 2015, we conducted 9 focus groups with EC survivors in rural and urban communities, and 3 focus groups with PCPs from across New Mexico. Focus groups were designed to elicit information specific to routine cancer follow-up care from patient and provider perspectives as well as to ascertain patient willingness to, and provider readiness for, transition of EC survivors from oncology clinics to primary care practices for post-treatment cancer care. Focus groups were digitally recorded and iteratively reviewed for development of initial coding structures. The transcripts were reviewed by the research team and a thematic analysis was performed. Transcripts were imported into NVivo 10, a qualitative data analysis program, for final coding and data analysis. RESULTS Twenty-one (40%) of the EC survivor participants were Hispanic origin and 55% resided in rural communities. 37.5% of the provider participants served rural regions. EC survivors expressed high levels of satisfaction with their oncology care and suggested that transitioning to PCPs for follow-up care would be convenient yet challenging. Challenges cited include: 1) patient perceptions of deficits in PCP9s understandings of cancer surveillance; 2) inability to identify a personal PCP; and 3) lack of communication between oncologists and PCPs. PCP participants similarly identified the need for more extensive EC training and more effective communication strategies with oncologists as necessary factors for accepting responsibility for EC follow-up care. Both EC patients and PCPs offered strategies to improve the coordination of care and create a more team based approach to EC survivorship care. Strategies discussed include: 1) develop survivorship care plans to improve communication for both patients and provides; 2) ensure easy access back to oncologist; and 3) provide supportive care services. CONCLUSIONS The transition from cancer treatment to cancer survivor care is a complex time for the patient. Increasing the role of the PCP in the ongoing care of EC survivors was generally considered acceptable by both patients and providers in both rural and urban women. Findings from our study did inform strategies to facilitate this transition. Successful coordination of care between cancer survivors, oncologists and PCPs will be a critical step in improving the cancer care delivery of our rural patient and provider population. Citation Format: Teresa Rutledge, Miria Kano, Dolores Guest, Andrew Sussman, Anita Kinney. Optimizing endometrial cancer follow-up and survivorship care for rural and other underserved women: Patient and provider perspectives. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B20.