Molecular landscape of ERBB2/HER2 gene amplification among patients with gynecologic malignancies; clinical implications and future directions.

OBJECTIVE: Investigate the prevalence of ERBB2/HER2 gene amplification among patients with gynecologic malignancies. METHODS: The American Association of Cancer Research (AACR) Genomics Evidence of Neoplasia Information Exchange (GENIE) (version 13.1) database was accessed and patients with endometrial, ovarian, and cervical cancer were identified. Patients with available data on the presence of copy-number gene alterations were selected for further analysis. Incidence of ERBB2 amplification following stratification by tumor site and histology was evaluated. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine presence of pathogenic genomic alterations. RESULTS: A total of 6961 patients who met the inclusion criteria were identified: 49.1% with ovarian cancer, 45.2% with endometrial cancer and 5.7% with cervical cancer respectively. Overall incidence of ERBB2 amplification was 3.8%. Highest incidence of ERBB2 amplification was observed among patients with mucinous ovarian (14.4%), uterine serous (13.2%), uterine clear cell (9.4%), and uterine carcinosarcoma (7.9%). ERBB2 amplification was rare among patients with TP53 wild-type endometrioid endometrial cancer (0.4%). High incidence of mutations in genes of the PI3K pathway was observed among patients with ERBB2 amplified tumors. CONCLUSION: ERBB2 amplification is frequently encountered among patients with uterine serous carcinoma, and mucinous ovarian carcinoma. In addition, a high incidence was also observed among those with uterine clear cell carcinoma, and uterine carcinosarcoma. For patients with endometrioid endometrial carcinoma, incidence of ERBB2 amplification is low, especially in the absence of TP53 mutations.

Disparities in clinical trial participation in ovarian cancer: A real-world analysis.

BACKGROUND: Significant disparities exist in clinical trial participation in non-gynecologic cancers, but little is known about disparities in ovarian cancer trial participation. Our objective was to examine patient, sociodemographic (race/ethnicity, insurance), cancer, and health system factors associated with clinical trial participation in ovarian cancer. METHODS: We conducted a retrospective cohort study of patients with epithelial ovarian cancer diagnosed from 2011 to 2021, using a real-world electronic health record derived database, representing around 800 sites of care in US academic and community practices. We used multivariable Poisson regression modeling to analyze the association of ever participating in an ovarian cancer clinical drug trial with patient, sociodemographic, health system, and cancer factors. RESULTS: Of the 7540 patients with ovarian cancer, 5.0% (95% CI 4.5-5.5) ever participated in a clinical drug trial. Patients of Hispanic or Latino ethnicity were 71% less likely to participate in clinical trials (RR 0.29, 95% CI 0.13-0.61) than non-Hispanic patients, and patients whose race was unknown or other than Black or White were 40% less likely to participate in clinical trials (RR 0.68, 95% CI 0.52-0.89). Patients who had Medicaid insurance were 51% less likely (RR 0.49, 95% CI 0.28-0.87) and those with Medicare were 32% (RR 0.48-0.97) less likely to participate in clinical trials than privately-insured patients. CONCLUSION: In this national cohort study, only 5% of patients with ovarian cancer participated in clinical drug trials. Interventions are needed to decrease race, ethnicity, and insurance disparities in clinical trial participation.

Telehealth utilization in gynecologic oncology clinical trials.

OBJECTIVE: Prior to the COVID-19 pandemic, telehealth visits and remote clinical trial operations (such as local collection of laboratory tests or imaging studies) were underutilized in gynecologic oncology clinical trials. Current literature on these operational changes provides anecdotal experience and expert opinion with few studies describing patient-level safety data. We aimed to evaluate the safety and feasibility of telehealth and remote clinical trial operations during the COVID-19 Pandemic. METHODS: Gynecologic oncology patients enrolled and actively receiving treatment on a clinical trial at a single, academic institution during the designated pre-Telehealth and Telehealth periods were identified. Patients with at least 1 provider or research coordinator telehealth visit were included. Patient demographics, health system encounters, adverse events, and protocol deviations were collected. Pairwise comparisons were performed between the pre-Telehealth and Telehealth period with each patient serving as their own control. RESULTS: Thirty-one patients met inclusion criteria. Virtual provider visits and off-site laboratory testing increased during the Telehealth period. Delays in provider visits, imaging, and laboratory testing did not differ between time periods. Total and minor protocol deviations increased in incidence during the Telehealth period and were due to documentation of telehealth and deferment of non-therapeutic testing. Major protocol deviations, emergency department visits, admissions, and severe adverse events were of low incidence and did not differ between time periods. CONCLUSIONS: Telehealth and remote clinical trial operations appeared safe and did not compromise clinical trial protocols in a small, single institutional study. Larger scale evaluations of such trial adaptations should be performed to determine continued utility following the Pandemic.

The spectrum of MAPK-ERK pathway genomic alterations in gynecologic malignancies: Opportunities for novel therapeutic approaches.

OBJECTIVE: To investigate the incidence of MAPK/ERK pathway genomic alterations among patients with gynecologic malignancies. METHODS: We accessed the American Association of Cancer Research Genomics Evidence of Neoplasia Information Exchange publicly available dataset (v13.0). Patients with malignant tumors of the ovary, uterus, and cervix were identified. Following stratification by tumor site and histology, we examined the prevalence of MAPK/ERK pathway gene alterations (somatic mutation, and/or structural chromosome alterations). We included the following RAS-MAPK pathway genes known to be implicated in the dysregulation of the pathway; KRAS, NRAS, BRAF, HRAS, MAP2K1, RAF1, PTPN11, NF1, and ARAF. Data from the OncoKB database, as provided by cBioPortal, were utilized to determine pathogenic gene alterations. RESULTS: We identified a total of 10,233 patients with gynecologic malignancies; 48.2% (n = 4937) with ovarian, 45.2% (n = 4621) with uterine and 6.6% (n = 675) with cervical cancer respectively. The overall incidence of MAPK pathway gene alterations was 21%; the most commonly altered gene was KRAS (13%), followed by NF1 (7%), NRAS (1.3%), and BRAF (1.2%). The highest incidence was observed among patients with mucinous ovarian (71%), low-grade serous ovarian (48%), endometrioid ovarian (37%), and endometrioid endometrial carcinoma (34%). CONCLUSIONS: Approximately 1 in 5 patients with a gynecologic tumor harbor a MAPK/ERK pathway genomic alteration. Novel treatment strategies capitalizing on these alterations are warranted.

Facility level variation in the utilization of neoadjuvant chemotherapy is associated with higher surgical morbidity for patients with advanced stage epithelial ovarian carcinoma.

OBJECTIVE: Investigate outcomes for advanced stage epithelial ovarian cancer (EOC) patients based on facility-level utilization of neoadjuvant chemotherapy (NACT). METHODS: Stage III-IV EOC patients diagnosed between 2010 and 2016 were identified in the National Cancer Database. Percentage of patients managed with NACT was calculated for facilities, reporting ≥120 patients. Facilities with lowest and highest quartile of NACT rate comprised the low and high-utilizing groups. Clinico-pathological characteristics were collected, and appropriate statistical analysis performed. RESULTS: High- and low-utilizing facilities managed on average 54.1% and 25.4% of patients with NACT respectively. Patients managed at high-utilizing facilities were significantly more likely to be >65 (p = 0.029), have stage IV disease (p < 0.001) and comorbidities (p < 0.001). Patients managed with primary debulking surgery (PDS) at low-utilizing facilities were significantly more likely to be >65, have stage IV disease, and have comorbidities (all, p < 0.001). Patients undergoing PDS at low-utilizing facilities were significantly less likely to achieve complete gross resection (p < 0.001), and were significantly more likely to experience 90-day mortality (p < 0.001), and unplanned 30-day readmission (p < 0.001). After controlling for age, comorbidities, race, insurance status, stage, grade and histology, high-utilizing facilities trended towards better overall survival (OS) (HR: 0.92, 95% CI: 0.85-0.99). Overall, patients undergoing PDS had better OS compared to those who had NACT (median 42 vs 27 months, p < 0.001). CONCLUSIONS: Despite treating an EOC population with more advanced disease and comorbidities, high-utilizing facilities have lower surgical morbidity and mortality with no detrimental impact on long-term survival. Careful patient selection to minimize the morbidity and mortality associated with PDS is pivotal.

Next generation sequencing reveals a high prevalence of pathogenic mutations in homologous recombination DNA damage repair genes among patients with uterine sarcoma.

OBJECTIVE: Investigate the incidence of homologous recombination DNA damage response (HR-DDR) genomic alterations among patients with uterine sarcoma. METHODS: The American Association for Cancer Research GENIE v13.0 database was accessed and patients with uterine leiomyosarcoma, adenosarcoma, undifferentiated uterine sarcoma, high-grade endometrial stromal sarcoma, low-grade endometrial stromal sarcoma, and endometrial stromal sarcoma not otherwise specified were identified. We determined the incidence of pathogenic alterations in the following genes involved in HR-DDR: ATM, ARID1A, ATRX, BAP1, BARD1, BLM, BRCA2, BRCA1, BRIP1, CHEK2, CHEK1, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine the presence of pathogenic genomic alterations. RESULTS: A total of 509 patients contributing with 525 samples were identified. Median patient age at sample collection was 56 years while the majority were White (80.7%). The most common histologic subtype was leiomyosarcoma (63.8%) followed by adenosarcoma (12.3%). The overall incidence of HR-DDR genomic alterations was 28.2%. The most commonly altered genes were ATRX (18.2%), BRCA2 (4%), and RAD51B (2.6%). The highest incidence of HR-DDR genomic alterations was observed among patients with leiomyosarcoma (35.4%), adenosarcoma (27%) and undifferentiated uterine sarcoma (30%), while those with low-grade endometrial stromal sarcoma had the lowest (2.9%) incidence. CONCLUSIONS: Approximately 1 in 3 patients with uterine sarcoma harbor a pathogenic alteration in HR-DDR genes. Incidence is high among patients with uterine leiomyosarcoma and adenosarcoma.

Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer.

The DNA damage response (DDR) results in activation of a series of key target kinases that respond to different DNA damage insults. DDR inhibitors such as PARP inhibitors lead to the accumulation of DNA damage in tumor cells and ultimately apoptosis. However, responses to DDRi monotherapy in the clinic are not durable and resistance ultimately develops. DDRi-DDRi combinations such as PARPi-ATRi, PAPRi-WEE1i and PARPi-AsiDNA can overcome multiple resistance mechanisms to PARP inhibition. In addition, DDRi-DDRi combinations can provide viable treatment options for patients with platinum-resistant disease. In the present chapter we discuss rationale of DDRi-DDRi strategies that capitalize on genomic alterations found in ovarian cancer and other solid tumors and may provide in the near future new treatment options for these patients.

Impact of adjuvant chemotherapy on the overall survival of patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery.

OBJECTIVE: To investigate the use and outcomes of adjuvant chemotherapy for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery. METHODS: Patients diagnosed between 2010 and 2015 with International Federation of Gynecology and Obstetrics stage II-IV low-grade serous ovarian carcinoma who underwent primary debulking surgery with known residual disease status and had at least 1 month of follow-up were identified in the National Cancer Database. Adjuvant chemotherapy was defined as receipt of chemotherapy within 6 months of surgery. Overall survival was evaluated using the Kaplan-Meier method and compared with the log-rank test. A Cox model was constructed to control for a priori-selected confounders. A systematic review of the literature was also performed. RESULTS: In total, 618 patients with stage II-IV low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery were identified; 501 (81.1%) patients received adjuvant chemotherapy, while 117 (18.9%) patients did not. The median follow-up of the present cohort was 47.97 months. There was no difference in overall survival between patients who did and did not receive adjuvant chemotherapy (p=0.78; 4-year overall survival rates were 77.5% and 76.1%, respectively). After controlling for patient age, medical co-morbidities, disease stage, and residual disease status, administration of adjuvant chemotherapy was not associated with better overall survival (HR=0.87, 95% CI 0.55 to 1.38). Based on data from three retrospective studies, omission of adjuvant chemotherapy following cytoreductive surgery was not associated with worse progression-free survival benefit (HR=1.25, 95% CI 0.80 to 1.95) for patients with stage III-V low-grade serous ovarian carcinoma. CONCLUSIONS: Adjuvant chemotherapy may not be associated with an overall survival benefit for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery.

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis.

OBJECTIVE: Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non­platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. METHODS: In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. RESULTS: Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. CONCLUSIONS: Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer.

BACKGROUND: Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. METHODS: Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses. RESULTS: NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. CONCLUSIONS: NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary-Clinical significance of BRCA2 gene variants in genomically stable tumors.

OBJECTIVE: The mutational spectra of low-grade serous carcinomas (LGSCs) and serous borderline tumors (SBTs) of the ovary are poorly characterized. We present 17 cases of advanced or recurrent LGSC/SBT patients who underwent molecular profiling. METHODS: Thirteen LGSCs and four SBTs underwent targeted gene panel testing by massively parallel sequencing. Microsatellite stability and tumor mutation burdens (TMBs) were determined based on panel sequencing data. RESULTS: The mean TMB was 5.2 mutations/megabase (range 3-10) in 14 cases. Twelve of twelve (12/12) cases were microsatellite stable. Clear driver mutations were identified in 11 cases, namely KRAS (5/17), BRAF (2/17), NRAS (2/17) and ERBB2 (2/17). Five cases harbored BRCA2 alterations (allele fractions: 44-51%), including two classified as likely benign/benign variants, and three classified as variants of uncertain significance (VUSs), with two variants being confirmed to be germline. The three BRCA2 VUSs were missense variants that were assessed to be of unlikely clinical significance, based on family cancer history and expected impact on protein function. Two patients received PARP inhibitors during their disease course, with neither of the patients demonstrating appreciable response. CONCLUSIONS: The mutational spectra in 17 clinically aggressive SBT/LGSC cases demonstrate genomically stable tumors, frequently driven by the RTK/RAS/MAPK pathway. While BRCA2 variants were identified, our data demonstrate BRCA2 gene variants are at most VUSs and of dubious clinical significance, in contrast to disease-associated BRCA1/2 variants that may be identified in high-grade serous carcinoma. Germline testing and PARP inhibitors are thus expected to provide limited benefit to patients with LGSC/SBTs.

Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer.

OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.

CAR T Cells Targeting MISIIR for the Treatment of Ovarian Cancer and Other Gynecologic Malignancies.

The prognosis of patients diagnosed with advanced ovarian or endometrial cancer remains poor, and effective therapeutic strategies are limited. The Müllerian inhibiting substance type 2 receptor (MISIIR) is a transforming growth factor ß (TGF-ß) receptor family member, overexpressed by most ovarian and endometrial cancers while absent in most normal tissues. Restricted tissue expression, coupled with an understanding that MISIIR ligation transmits apoptotic signals to cancer cells, makes MISIIR an attractive target for tumor-directed therapeutics. However, the development of clinical MISIIR-targeted agents has been challenging. Prompted by the responses achieved in patients with blood malignancies using chimeric antigen receptor (CAR) T cell therapy, we hypothesized that MISIIR targeting may be achieved using a CAR T cell approach. Herein, we describe the development and evaluation of a CAR that targets MISIIR. T cells expressing the MISIIR-specific CAR demonstrated antigen-specific reactivity in vitro and eliminated MISIIR-overexpressing tumors in vivo. MISIIR CAR T cells also recognized a panel of human ovarian and endometrial cancer cell lines, and they lysed a battery of patient-derived tumor specimens in vitro, without mediating cytotoxicity of a panel of normal primary human cells. In conclusion, these results indicate that MISIIR targeting for the treatment of ovarian cancer and other gynecologic malignancies is achievable using CAR technology.

Adjuvant chemotherapy for early stage endometrioid ovarian carcinoma: An analysis of the National Cancer Data Base.

INTRODUCTION: The benefit of adjuvant chemotherapy for Stage IC grade 1 and stage IA/IB grade 2 endometrioid ovarian adenocarcinoma (EOOC) remains unclear as the NCCN guidelines recommend either observation only or adjuvant chemotherapy. Therefore, we sought to determine whether patients with stage I EOOC had improved overall survival (OS) following receipt of adjuvant chemotherapy. METHODS: Patients with pathological stage I ovarian endometrioid adenocarcinoma diagnosed between 2004 and 2014 were identified from the National Cancer Database. Demographics, pathologic factors including tumor grade, and treatment information including receipt of adjuvant chemotherapy were collected. The impact of chemotherapy on OS was evaluated with Kaplan-Meier curves, and compared with log-rank tests. Multivariate Cox analysis was performed to control for confounders. RESULTS: A total of 4538 patients were identified and the median age was 55 years The rate of adjuvant chemotherapy use was 50.9%. Higher rates were noted among patients with stage IC and grade 3 tumors. Following stratification by tumor grade, substage and extent of lymphadenectomy, adjuvant chemotherapy was associated with a survival benefit for patients with grade 2 tumors who did not undergo (stage IA/IB: 95.7% vs 83%, p = 0.038; stage IC: 84.5% vs 84.8%, p = 0.39) or had limited lymphadenectomy (stage IA/IB: 96% vs 89.5%, p = 0.03; stage IC: 97.2% vs 83.9%, p = 0.001). A survival difference was also seen for patients with grade 3 tumors who did not undergo lymphadenectomy but did not reach statistical significance. CONCLUSION: Adjuvant chemotherapy was associated with an overall survival benefit for patients with inadequately-staged, grade 2 stage I ovarian endometrioid adenocarcinoma. A possible benefit for inadequately-staged patients with grade 3 tumors cannot be excluded.

An autologous humanized patient-derived-xenograft platform to evaluate immunotherapy in ovarian cancer.

OBJECTIVE: The aim of this study was to "humanize" ovarian cancer patient-derived xenograft (PDX) models by autologous transfer of patient-matched tumor infiltrating lymphocytes (TILs) to evaluate immunotherapies. METHODS: Orthotopic high-grade serous ovarian cancer (HGSOC) PDX models were established from three patient donors. Models were molecularly and histologically validated by immunohistochemistry. TILs were expanded from donor tumors using a rapid expansion protocol. Ex vivo TIL and tumor co-cultures were performed to validate TIL reactivity against patient-matched autologous tumor cells. Expression of TIL activation markers and cytokine secretion was quantitated by flow cytometry and ELISA. As proof of concept, the efficacy of anti-PD-1 monotherapy was tested in autologous TIL/tumor HGSOC PDX models. RESULTS: Evaluation of T-cell activation in autologous TIL/tumor co-cultures resulted in an increase in HLA-dependent IFNγ production and T-cell activation. In response to increased IFNγ production, tumor cell expression of PD-L1 was increased. Addition of anti-PD-1 antibody to TIL/tumor co-cultures increased autologous tumor lysis in a CCNE1 amplified model. Orthotopic HGSOC PDX models from parallel patient-matched tumors maintained their original morphology and molecular marker profile. Autologous tumor-reactive TIL administration in patient-matched PDX models resulted in reduced tumor burden and increased survival, in groups that also received anti-PD-1 therapy. CONCLUSIONS: This study validates a novel, clinically relevant model system for in vivo testing of immunomodulating therapeutic strategies for ovarian cancer, and provides a unique platform for assessing patient-specific T-cell response to immunotherapy.

Combining novel agents with radiotherapy for gynecologic malignancies: beyond the era of cisplatin.

Therapeutic strategies combining radiation therapy with novel agents have become an area of intense research focus in oncology and are actively being investigated for a wide range of solid tumors. The mechanism of action of these systemic agents can be stratified into three general categories: (1) enhancement or alteration of the immune system; (2) disruption of DNA damage response mechanisms; and (3) impediment of cellular signaling pathways involving growth, angiogenesis, and hypoxia. Pre-clinical data suggest that radiation therapy has immunogenic qualities and may optimize response to immuno-oncology therapies by priming the immune system, whereas other novel systemic agents can enhance radiosensitivity through augmentation of genomic instability and alteration of central signaling pathways related to growth and survival. Gynecologic cancers in particular have the potential for synergistic response to combination approaches incorporating radiation therapy and novel systemic therapies. Several clinical trials have been proposed to elucidate the efficacy and safety of such approaches. Here we discuss the mechanisms of novel therapies and the rationale for these combination strategies, reviewing the relevant pre-clinical and clinical data. We explore their optimal use with respect to indications, interactions, and potential synergy in combination with radiation therapy and review ongoing trials and active areas of investigation.

Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors.

OBJECTIVES: Cancer-testis (CT) antigens have been proposed as potential targets for cancer immunotherapy. Our objective was to evaluate the expression of a panel of CT antigens in epithelial ovarian cancer (EOC) tumor specimens, and to determine if antigen sharing occurs between tumors. METHODS: RNA was isolated from EOC tumor specimens, EOC cell lines and benign ovarian tissue specimens. Real time-PCR analysis was performed to determine the expression level of 20 CT antigens. RESULTS: A total of 62 EOC specimens, 8 ovarian cancer cell lines and 3 benign ovarian tissues were evaluated for CT antigen expression. The majority of the specimens were: high grade (62%), serous (68%) and advanced stage (74%). 58 (95%) of the EOC tumors analyzed expressed at least one of the CT antigens evaluated. The mean number of CT antigen expressed was 4.5 (0-17). The most frequently expressed CT antigen was MAGE A4 (65%). Antigen sharing analysis showed the following: 9 tumors shared only one antigen with 62% of the evaluated specimens, while 37 tumors shared 4 or more antigens with 82%. 5 tumors expressed over 10 CT antigens, which were shared with 90% of the tumor panel. CONCLUSION: CT antigens are expressed in 95% of EOC tumor specimens. However, not a single antigen was universally expressed across all samples. The degree of antigen sharing between tumors increased with the total number of antigens expressed. These data suggest a multi-epitope approach for development of immunotherapy for ovarian cancer treatment.

Paclitaxel, Carboplatin, and Bevacizumab in Advanced and Recurrent Endometrial Carcinoma.

OBJECTIVE: The aim of this study was to evaluate the efficacy of adding bevacizumab to paclitaxel and carboplatin and as maintenance in a larger cohort of patients with advanced or recurrent endometrial carcinoma. METHODS: We retrospectively identified endometrial cancer patients treated with paclitaxel (175 mg/m per 3 hours), carboplatin (area under the curve, 5) and bevacizumab (15 mg/kg) and maintenance bevacizumab treated in a post-protocol treatment cohort and evaluated them with our previously published phase 2 trial of this regimen. RESULTS: Twenty-seven additional patients were identified; 19 received the regimen as first-line therapy, and 8 received the regimen as second-line therapy after prior paclitaxel and carboplatin. The 19 patients who received first-line therapy were analyzed alone and with the 15 patients enrolled on protocol. The 2 cohorts were similar with respect to risk factors. Overall survival curves were not statistically different between the protocol and the postprotocol patients (log-rank test; P > 0.1). Collectively, a total of 266 courses (median, 6 courses; range, 1-20 courses) of carboplatin, paclitaxel, and bevacizumab combination therapy and 305 courses (median, 16 courses; range, 0-45courses) of bevacizumab maintenance therapy were administered as first-line therapy. Collectively, the median progression-free survival was 20 months, and median overall survival was 56 months. Among 29 patients with measurable disease, the response rate was 82.8% (95% confidence interval, 69.0%-96.5%; 15 complete responses and 9 partial responses). Among the 8 patients who received paclitaxel and carboplatin and bevacizumab as second-line therapy after paclitaxel and carboplatin, the response rate was 87.5% (6 complete responses, 1 partial response). Their median progression-free survival and median overall survival were not reached after a median follow-up of 23.5 months. CONCLUSIONS: Although there are inherent limitations to small retrospective studies, this second analysis confirms the high response rate, progression-free survival, and overall survival in the bevacizumab, paclitaxel, and carboplatin regimen as first-line therapy in advanced and recurrent endometrial carcinoma.

Race-based disparities in loss of functional independence after hysterectomy for uterine cancer.

PURPOSE: Racial disparities in uterine cancer-related outcomes have been reported. The goal of this study was to determine if race, pre-operative body mass index (BMI), and medical comorbidities are predictors of loss of functional independence after hysterectomy for uterine cancer. METHODS: Loss of independence was defined as a change from pre-operative functional independence, to a post-operative requirement of discharge to a post-care facility, or death within the first 30 days following uterine cancer surgery. Demographic factors, comorbidities, BMI, intra-operative and post-operative outcomes, and discharge status were abstracted from the 2011 and 2012 American College of Surgeons National Surgical Quality Improvement Program (NSQIP). Statistical analyses included multivariable logistic regression and Wald tests for interaction. RESULTS: A total of 4005 patients had uterine cancer and were functionally independent pre-operatively. After adjusting for clinical features and comorbidities, Black women were not significantly more likely to lose functional independence than non-Black women. However, a significant interaction (OR = 1.17, p < 0.001) was found between race and BMI for loss of functional independence. Interaction plots revealed worsening functional outcomes for Black women with BMI >40 but not in non-Blacks. CONCLUSIONS: The interaction suggests a 17 % increased odds of losing independence for each unit of BMI difference for Black uterine cancer patients, or 170 % increased odds of losing independence for a 10-point increase in BMI, given a linear association. To reduce the likelihood of losing post-operative functional independence, Black, high-BMI patients with or at risk for uterine cancer may especially benefit from weight loss or interventions to optimize physical function.

A phase II trial of paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma (EMCA).

OBJECTIVE: To evaluate the effect of adding bevacizumab to adjuvant paclitaxel and carboplatin and as maintenance on progression-free survival (PFS) in advanced or recurrent endometrial carcinoma (EMCA). METHODS: A phase II trial was conducted in patients with measurable disease. Paclitaxel (175mg/m(2)/3h), carboplatin (AUC 5) and bevacizumab (15mg/kg) were administered q 21 days. Patients with a complete response after 6-8cycles received maintenance therapy with bevacizumab 15mg/kg q 21 days for 16cycles. Based on GOG 177 which had a 6-month PFS rate of 59%, an increase in 6-month PFS to 72% with the treatment regimen was considered of clinical interest. RESULTS: 15 patients were enrolled on protocol when accrual to the study was discontinued due to the initiation of a national randomized phase II trial. A total of 127 courses (median 8, range 1-20) of carboplatin, paclitaxel, and bevacizumab combination therapy were administered. One patient suffered a bowel perforation after her first course of therapy and was inevaluable for response. Fourteen of the 15 patients (93%, 95% CI: 82-100) were progression free at 6months. The median follow-up was 36months (7-58+). The median PFS was 18months (CI: 11-25). Five complete responses and 6 partial responses were seen for an overall response rate of 73% (CI: 45-91). The median overall survival was 58months (CI: 48-68). CONCLUSIONS: The bevacizumab, paclitaxel, and carboplatin regimen is active and tolerable in advanced and recurrent EMCA. Its impact awaits results of the recently completed randomized phase II trial.