NRG-GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer.

Purpose: This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer.

Methods: This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2.

A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas.

Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer.

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC.

Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC.

Design, Settings, And Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US.

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer.

BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens.

A randomized phase II trial of everolimus and letrozole or hormonal therapy in women with advanced, persistent or recurrent endometrial carcinoma: A GOG Foundation study.

Background: Blocking the PI3K/AKT/mTOR pathway decreases resistance to hormonal therapy in endometrial carcinoma (EC).

Objective: In this study, the aim was to assess the efficacy and tolerability of everolimus(E)/letrozole (L) or medroxyprogesterone acetate(M)/tamoxifen(T) in the treatment of metastatic EC.

Study Design: This single stage, open-label two arm randomized phase II trial accrued women with advanced/persistent/recurrent EC.

Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors.

Purpose: CD137 agonism and CSF1R blockade augment stereotactic body radiotherapy (SBRT) and anti-programmed death-1 in preclinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF1R inhibitor).

Patients And Methods: This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies.

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial.

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).

Patients And Methods: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.

Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer: A Phase Ib Study.

Purpose: Atezolizumab has shown antitumor activity in patients with ovarian cancer. Dual blockade of programmed death-ligand 1 (PD-L1) and VEGF enhances anticancer immunity and augments antitumor activity in several cancers. The safety and efficacy of atezolizumab plus bevacizumab were evaluated in patients with ovarian cancer.

Immune checkpoint inhibitors in women with gynecologic cancers: Practical considerations.

Immune checkpoint inhibitors are an exciting new class of cancer therapeutics. Recently, a PD-1 inhibitor has been approved by the Food and Drug Administration for several indications that are relevant to patients with gynecologic malignancies. In this review, we explore the clinical considerations for the use of checkpoint inhibitor therapy in this population.

Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma.

Importance: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited.

Objective: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma.

Design, Setting, And Participants: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status.

Current recommendations and recent progress in endometrial cancer.

Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite-instable, metastatic disease, anti- programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.

Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors.

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden.

Potential role of radiation therapy in augmenting the activity of immunotherapy for gynecologic cancers.

Immune checkpoint inhibitors have become an area of intense interest in oncology and are actively being studied in a variety of cancer types with a wide range of success. In vitro data suggest mechanisms by which radiation can activate the immune system, and ongoing studies are exploring the potential interaction of checkpoint inhibitors with radiotherapy in both preclinical and clinical settings. Gynecologic malignancies are a heterogeneous group of tumors with varying prognoses, intrinsic immunogenicity, and potential for response to immune-based therapies.

Ovarian Sertoli-Leydig Cell Tumor with Elevated Inhibin B as a Cause of Secondary Amenorrhea in an Adolescent with Germ Line DICER1 Mutation.

Background: Ovarian tumors, although uncommon in children, can retain endocrine function that disrupts normal feedback mechanisms leading to amenorrhea. Inheritance of germline DICER1 mutations can lead to increased risk for development of ovarian Sertoli-Leydig cell tumors (SLCTs).

Case: We report, to our knowledge, the first case of secondary amenorrhea due to elevated inhibin B levels in a female adolescent with an ovarian SLCT.

Robotic surgical staging for cervical cancer diagnosed during pregnancy: Immediate versus delayed definitive treatment.

•Definitive treatment of cervical cancer in pregnancy poses a dilemma for patients desiring to continue gestation.•Robotic surgical staging of cervical cancer diagnosed during pregnancy is feasible.•Robotic surgical staging improves the prognostic assessment for pregnant patients when making a decision between immediate versus delayed treatment.

Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity.

Purpose: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines.

Experimental Design: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types.

A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies.

Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates.

PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.

Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore, tumors from patients referred to the phase I program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20.

Phase I clinical trials in 85 patients with gynecologic cancer: the M. D. Anderson Cancer Center experience.

Objective: Disseminated gynecologic cancers are usually fatal due to chemoresistance. Recently, rationally developed, targeted agents are entering the early clinical trials setting. We assessed patients with metastatic gynecologic cancers in a dedicated phase I clinical trials clinic in order to determine their outcome.

Aflibercept in epithelial ovarian carcinoma.

Angiogenesis is a hallmark of malignant transformation. With improved understanding of angiogenic signaling in both the normal and malignant state, there have been a number of agents developed that target VEGF signaling. These targeted agents can affect downstream VEGF signal transduction via unique mechanisms at different cellular and extracellular locations.

Laparoscopy training in gynecologic oncology fellowship programs.

Objective: To assess the adequacy of laparoscopic surgical training as perceived by gynecologic oncology fellows-in-training and to compare current opinions to those on a 2003 survey.

Study Design: Fellows were surveyed via mail or an internet website.

Results: Seventy-eight (64%) of 121 fellows responded.

Common gynecologic problems in geriatric-aged women.

Gynecologic concerns in postmenopausal women are common. Although various conditions may affect all women in this age group, the prevalence of certain disorders, and also diagnostic approaches and treatment options, may vary significantly when considering very elderly women compared with those early in the sixth decade. The focus of this chapter is to address several commonly encountered gynecologic issues in postmenopausal women, with particular attention given to aspects that must be considered when caring for women in the geriatric age group.