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Objective: This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as second-line therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes., Methods: An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinum-based chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle., Results: There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR., Conclusions: Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies., Competing Interests: Declaration of competing interest Ignace Vergote: Personal fees from Advaxis, Inc., Eisai, Inc., F. Hoffman-La Roche Ltd., Millennium Pharmaceuticals, Oncoinvent AS, Sotio, and MSD Belgium; personal fees and nonfinancial support from Roche NV, Genmab, PharmaMar, Clovis Oncology, AstraZeneca NV, Tesaro, and Immunogen Inc. Grants from Amgen, Roche, and Stichting tegen Kanker. Other (contracted research) support from Oncoinvent AS, Genmab. Nonfinancial support (accommodations and travel) from Takeda Oncology. All outside the submitted work. Matthew A. Powell: Personal fees from Tesaro, Merck, Roche/Genentech, Clovis Oncology, AstraZeneca, Johnson & Johnson, Eisai. All outside the submitted work. Michael G. Teneriello: Nothing to disclose. David S. Miller: Consultancy with Tesaro, Eisai, Incyte, Karyopharm, Genentech, and Merck. Grants (grants pending) from nVision Medical, Advenchen, Forty Seven, Merck, and Syros. Agustin A. Garcia: Advisory board participation for GlaxoSmithKline. Grants and personal fees (regional advisory board) from Eisai, during the conduct of the study. Olga N. Mikheeva: Nothing to disclose. Mariusz Bidzinski: Nothing to disclose. Cristina Ligia Cebotaru: Advisory board participation for Boehringer-Ingelheim, Novartis, Pfizer, Merck. Lecture fees from AstraZeneca, BMS, Bayer, Ipsen, and Astellas. Travel grants from Alvogen, Merck, and Boehringer-Ingelheim. Educational grants from AstraZeneca. Corina E. Dutcus: Employee of Eisai during the conduct of the study. Min Ren: Employee of Eisai during the conduct of the study. Tadashi Kadowaki: Personal fees from Eisai Co., Ltd., during the conduct of the study. Yasuhiro Funahashi: Employee of Eisai during the conduct of the study, and a related patent (WO2002032872A1) issued. Richard T. Penson: Grants and personal fees from Eisai Inc., and from Merck & Co., Inc., during the conduct of the study., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined., Patients and Methods: Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups., Results: The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806)., Conclusion: Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

Purpose: This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC)., Patients and Methods: Patients with platinum-sensitive ROC (recurrence ≥ 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety., Results: Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective response rate (78.5% v 57.4%; P < .0001) and DOR (10.4 v 7.4 months; HR, 0.534; 95% CI, 0.408 to 0.698) were significantly improved with the addition of BV. No new safety concerns were noted. Grade 3 or higher hypertension (17.4% v < 1%) and proteinuria (8.5% v < 1%) occurred more frequently in the BV arm. The rates of neutropenia and febrile neutropenia were similar in both arms. Two patients in the BV arm experienced GI perforation after study treatment discontinuation., Conclusion: GC plus BV followed by BV until progression resulted in a statistically significant improvement in PFS compared with GC plus PL in platinum-sensitive ROC.

Uterine sarcomas are unusual neoplasms of the female genital tract whose molecular etiology is largely unknown. We examined 20 leiomyomas as well as 23 uterine leiomyosarcomas for the presence of mutations in the Ki-ras and p53 genes, and overexpression of the MDM2 gene. Codons 12, 13, and 61 from the Ki-ras gene were characterized for the presence of mutations by restriction enzyme polymorphisms using mismatched primers and nucleic acid sequencing as appropriate. Activated Ki-ras genes were identified in 3/20 leiomyomas and 0/23 leiomyosarcomas. The p53 gene was analyzed by SSCP, nucleic acid sequencing, and immunohistochemical staining. None of 20 leiomyomas and 6/23 leiomyosarcomas exhibited p53 abnormalities. The SSCP/sequencing results did not consistently correlate with the IHC staining. MDM2 overexpression occurred in 0/20 leiomyomas and 3/23 sarcomas. Clinical correlation suggested that tumors with p53 mutations have a higher histologic grade or stage at presentation. We conclude that leiomyomas and leiomyosarcomas have different patterns of molecular alterations and are separate biologic entities. In addition, p53 and MDM2 overexpression may play a role in the development of a subset of leiomyosarcomas.

We analyzed the expression of the retinoblastoma (Rb) gene in a group of ovarian neoplasms previously characterized for mutations in the p53 suppressor gene and the Ki-ras oncogene. Using immunohistochemical techniques, a total of 59 ovarian neoplasms spanning the histiologic spectrum from benign to malignant were examined for the expression of the Rb protein. All benign cystic adenomas and low malignant potential tumors exhibited normal expression of the Rb protein. Abnormalities in Rb protein staining were noted in 3 of 22 (14%) ovarian carcinomas. The staining patterns included tumors that were totally or focally negative for Rb protein. One tumor focally expressed Rb. This tumor demonstrated a direct juxtaposition of sections of Rb expressing and nonexpressing malignant epithelial cells. Two of the three tumors with abnormal Rb expression also had p53 mutations and staining on serial sections demonstrated that selected ovarian cancer cells possessed mutations in both oncogenes. These data suggest that the loss of Rb gene expression may play a role in the pathogenesis of a small number of invasive ovarian malignancies, but not in noninvasive ovarian neoplasms.

Ovarian cancer meets the criteria of a disease for which screening can be justified. The disease is most often diagnosed in advanced stages, when chances for long-term survival are poor. Yet effective treatment exists for early-stage disease, such that early detection can increase long-term survival. However, screening for early-stage ovarian cancer with the high specificity necessary for this low-prevalence disease has proven to be a challenge. This article reviews the issues of early detection of ovarian cancer, including pathology, statistical considerations, diagnostic modalities, and results of the major clinical studies undertaken.

Gynecologic malignancies, representing 13% of all cancers affecting women, have a major impact on women's health. Cervical, endometrial, and ovarian cancers comprise the majority of these tumors and contribute significant morbidity and mortality to the female population. While cervical and endometrial cancers can be detected early in their development, sadly, many patients present with advanced disease, as do the majority of patients with ovarian cancer. Unfortunately, advanced cases of these malignancies are usually lethal despite modern therapeutic modalities. In order to impact upon these grim statistics, gynecologic researchers have turned to molecular biology in an attempt to elucidate the etiology of these cancers. Recent research describing dominant oncogene and tumor suppressor gene mutations common to these malignancies is providing a basis for the molecular genesis of these cancers. This information should offer new avenues for the development of early detection and chemoprevention, as well as novel treatment strategies.

In an effort to define the pathogenic relationship between ovarian neoplasms spanning the clinicopathological spectrum from benign to malignant, the incidence of Ki-ras and p53 mutations was determined in 20 ovarian cystadenomas, 20 low malignant potential (LMP) tumors of the ovary, and 23 ovarian carcinomas. Using DNA extracted from paraffin embedded tissue, polymerase chain reaction amplification, designed restriction fragment length polymorphism analysis, and DNA sequencing, 1 cystadenoma (5%), 6 LMP tumors (30%), and 1 ovarian carcinoma (4%) demonstrated an activated Ki-ras gene. All of the Ki-ras mutations identified except one were GGT to GAT transversions at codon 12. One LMP tumor demonstrated a CAA to CAC transversion at codon 61. Using polymerase chain reaction/single strand conformational polymorphism, DNA sequencing, and immunohistochemistry, 11 ovarian carcinomas (48%) demonstrated a p53 mutation. These mutations included 5 missense, 2 nonsense, and 1 frameshift mutation located within exons 6-8 and 3 mutations that were identified only by immunohistochemical staining. No p53 mutations could be identified in cystadenomas or LMP tumors. Clinically, the presence of either a Ki-ras or p53 mutation was associated with advanced stage disease. The pattern of Ki-ras and p53 mutations appears to distinguish LMP tumors from invasive carcinomas and suggests that they may be separate biological entities.