Increasing grade of endometrioid endometrial cancer (EEC) is associated with aggressive behavior and poor prognosis. The traditional classification system is limited in its ability to guide treatment ...planning and prognostication. We identify distinct immune biomarker phenotypes using known markers of immunogenicity to identify patients who may benefit from immune therapy (IT).
621 tumors were analyzed by multiplatform profiling. NextGen sequencing was performed on 592 genes. Tumor mutational burden (TMB) was defined as high (H) ≥10mutations/megabase. Microsatellite Instability (MSI) by NGS was ≥46 loci. PD-L1 positivity was ≥2+, >5% by IHC. Chi-square tests were used.
Overall, MSI-H was found in 33% of EECs, most frequent in grade 3 (G3), followed by grade 2 (G2) and grade 1 (G1) tumors (G3: 37%, G2: 32%, G1: 22%, p = 0.007).
TMB-H was identified in 25% of EECs. TMB-H was most common in G3, followed by G2 and G1 tumors (G3: 34%, G2: 23%, G1: 13%, p = 0.006).
Overall, PD-L1 expression was found in 5.5% of EECs. G3 EECs had the most frequent PD-L1 expression, followed by G2 and G1 tumors (G3: 12%, G2: 3.0%, G1: 0.9%, p < 0.0001). We identified POLE mutations in 4.5% (28/618). All POLE mutated tumors harbored TMB-H phenotypes but MSI-H and PD-L1 were only present in 10.7% and 14.8% of tumors respectively, suggesting upregulation of T-cell immune response in only a fraction of POLE mutated EECs.
Triple negative (TN) biomarker phenotype (ER-/PR-/Her2-) was evaluated as a potential surrogate marker of tumor immunogenicity. We identified TN phenotype in 4% of G1 EEC compared with 9% in G2 and 33% in G3, suggesting loss of hormone expression and possible greater immunogenicity with increasing tumor grade.
High grade tumors appear to be more immunogenic than low grade tumors and may preferentially benefit from IT.
•Our analysis of over 600 EECs suggests that high grade tumors appear to be more immunogenic than low grade tumors•High grade tumors may preferentially benefit from immune therapy•We found no differences in immunogenic markers between primary and metastatic tumors•Tumors with a TN phenotype were more common in G3 tumors and appeared to be more immunogenic than low grade tumors•Rational, pathway driven immune therapies may offer alternative strategies to treat patients with endometrial cancer
The presence of polyethylene terephthalate (PET) oligomers in food contact materials (FCMs) is well-documented. Consumers are exposed through their migration into foods and beverages; however, there ...is no specific guidance for their safety evaluation.
This systematic evidence map (SEM) aims to identify and organize existing knowledge and associated gaps in hazard and exposure information on 34 PET oligomers to support regulatory decision-making.
The methodology for this SEM was recently registered. A systematic search in bibliographic and gray literature sources was conducted and studies evaluated for inclusion according to the Populations, Exposures, Comparators, Outcomes, and Study type (PECOS) framework. Inclusion criteria were designed to record hazard and exposure information for all 34 PET oligomers and coded into the following evidence streams: human, animal, organism (non-animal), ex vivo, in vitro, in silico, migration, hydrolysis, and absorption, distribution, metabolism, excretion/toxicokinetics/pharmacokinetics (ADME/TK/PK) studies. Relevant information was extracted from eligible studies and synthesized according to the protocol.
Literature searches yielded 7445 unique records, of which 96 were included. Data comprised migration (560 entries), ADME/TK/PK-related (253 entries), health/bioactivity (98 entries) and very few hydrolysis studies (7 entries). Cyclic oligomers were studied more frequently than linear PET oligomers. In vitro results indicated that hydrolysis of cyclic oligomers generated a mixture of linear oligomers, but not monomers, potentially allowing their absorption in the gastrointestinal tract. Cyclic dimers, linear trimers and the respective smaller oligomers exhibit physico-chemical properties making oral absorption more likely. Information on health/bioactivity effects of oligomers was almost non-existent, except for limited data on mutagenicity.
This SEM revealed substantial deficiencies in the available evidence on ADME/TK/PK, hydrolysis, and health/bioactivity effects of PET oligomers, currently preventing appropriate risk assessment. It is essential to develop more systematic and tiered approaches to address the identified research needs and assess the risks of PET oligomers.
Objective We sought to determine the association between tumor responses in vitro to platinum therapy by using the ChemoFx drug response marker and overall survival (OS) after first-line ...platinum-based chemotherapy in patients with advanced-stage primary ovarian cancer (POC). Study Design Chemosensitivity testing was performed in vitro on tumors from 192 POC patients. Tumors were classified as responsive, intermediately responsive, and nonresponsive to chemotherapy. Physicians made all management decisions. Survival status was retrieved from the Social Security Death Index. OS was modeled using Cox proportional hazard regression analysis. Results Median OS was 72.5 months for patients with tumors categorized as responsive, 48.6 months for intermediately responsive, and 28.2 months for nonresponsive ( P = .03; hazard ratio, 0.70; 95% confidence interval, 0.50–0.97). The ChemoFx prediction of responses to platinum agents was an independent predictor of OS. Conclusion Results of chemosensitivity testing with a drug response marker for therapy was predictive of OS in POC patients.
Introduction: The majority of women with epithelial ovarian cancer present with advanced stage disease and there is a critical need for novel drugs and treatment strategies to improve outcomes. ...Trabectedin is a unique cytotoxic agent with a complex mechanism of action. It binds to guanines in the N2 position in the minor groove of DNA and its cytotoxicity involves DNA repair pathways and transcription regulation. Trabectedin's activity is also related to the drug-induced changes of the tumor microenvironment. It has been shown to improve progression-free survival in combination with pegylated liposomal doxorubicin in patients with platinum-sensitive relapsed ovarian cancer. The most common adverse events experienced with trabectedin are nausea, vomiting, fatigue, neutropenia and transaminitis. Studies of biomarkers that are predictors of trabectedin benefit are underway.
Areas covered: This review covers trabectedin's mechanism of action and pharmacology, the clinical development of the drug in ovarian cancer, ongoing trials, and the use of biomarkers to predict efficacy to trabectedin.
Expert opinion: Ongoing phase III trials with biomarker studies will help to elucidate the patient population that will best benefit from trabectedin and pave the way for personalized treatment decisions and potential future approval of trabectedin in the United States.
Ovarian cancer is the leading cause of gynecologic cancer–related death in the United States. Historically, studies have demonstrated that ovarian cancer is a heterogeneous disease with several ...patient and oncologic characteristics, including BRCA status and residual disease at surgery, known to be predictive of clinical outcomes. However, during the last decade, the discovery and approval of bevacizumab and poly(adenosine diphosphate-ribose) polymerase inhibitors have moved the frontline treatment paradigm beyond platinum-doublet therapy for women with advanced ovarian cancer. Subsequently, investigators have sought to assess the therapeutic efficacy of these agents in women who are considered “high” risk and “low” risk to determine which patients may benefit the most from aggressive therapy and in whom additional treatment may be avoided.
We reviewed historic and contemporary definitions of “high-risk” and “low-risk” ovarian cancer and how this has been incorporated into the subset analyses of randomized, clinical trials of therapeutic agents, including bevacizumab and poly(adenosine diphosphate-ribose) polymerase inhibitors. Next, we provided an in-depth discussion of landmark trials for frontline maintenance therapy with bevacizumab and/or poly(adenosine diphosphate-ribose) polymerase inhibitors, focusing on the impact of treatment efficacy according to a “high-risk” and “low-risk” paradigm. Furthermore, we highlighted that recent data have challenged this dichotomous classification, notably from the Gynecologic Oncology Group-0218, ICON7, SOLO-1, and PAOLA-1 trials. Although some studies have suggested that certain populations of women with advanced ovarian cancer may have a more favorable prognosis and be considered “low risk,” the risk of progression and death remains unacceptably high in all women. Furthermore, in many cases, those considered the lowest risk have the most treatment benefit from maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors and/or bevacizumab. From these data, we have advocated that virtually all women with advanced ovarian cancer are high risk and that the use of our most effective therapies in the frontline setting holds promise for potentially curing more patients. Lastly, we critically discuss the practice of using subanalyses in clinical trials, with emphasis that although this practice is important for hypothesis generation, caution must be taken before accepting findings from subanalyses as actual treatment effects.
This phase 3 study aimed to compare overall survival (OS) of women with platinum-sensitive, recurrent ovarian cancer (ROC) treated with third-line trabectedin (T) + pegylated liposomal doxorubicin ...(PLD) vs. PLD monotherapy.
Women with advanced-relapsed epithelial ovarian cancer were randomly assigned 1: 1 to intravenous infusions of either T + PLD (trabectedin 1.1 mg/m2 for 3 h; PLD 30 mg/m2 for 1.5 h, every 3 weeks) or PLD (50 mg/m2 for 1.5 h, every 4 weeks). Primary endpoint was OS. Secondary endpoints included investigator-assessed progression free survival (PFS) and objective response rates (ORR). At randomization, patients were stratified by time from last dose of first-line platinum therapy to disease progression, ECOG grade 0 or 1, BRCA1/2 germline mutational status, and prior PLD therapy. Exploratory endpoints included OS, PFS, and ORR in the stratified subgroups (PFI, ECOG, BRCA1/2 status, and prior PLD therapy). This trial is registered with ClinicalTrials.gov, number NCT01846611.
576 patients were randomized (T + PLD, n = 289; PLD, n = 287). Median OS was 23.8 months with T + PLD vs. 22.2 months with PLD (HR:0.92, 95%CI:0.73–1.18; p = 0.52). Median PFS was 7.52 vs. 7.26 months (HR:0.93, 95%CI:0.76–1.15; p = 0.52); ORR was 46% vs. 35.9% (OR:1.52, 95%CI:1.07–2.16; p = 0.01). Patients with BRCA1/2 mutations had median OS of 34.2 months with T + PLD vs. 20.9 months with PLD (HR:0.54, 95%CI:0.33–0.90; p = 0.016). Patients with BRCA1/2 mutations had median PFS of 10.1 months with T + PLD vs. 7.6 months with PLD (HR:0.72, 95%CI:0.48–1.08; p = 0.039). Patients with BRCA1/2 mutations and a 6–12 months platinum-free interval (PFI), median OS was 31.5 vs. 14.9 months, respectively (HR:0.37, 95%CI:0.17–0.82; p = 0.011). Grade 3–4 AEs were higher in T + PLD (79%) vs. PLD (54%).
Combination of T and PLD did not show favorable OS benefit nor safety; however, patients with germline BRCA1/2 mutations and/or a PFI of 6–12 months appear to have clinically relevant survival benefit with T + PLD. No new safety signals were identified.
•Survival benefit and safety of T + PLD evaluated in third-line setting in platinum-sensitive patients with ROC•Combined T + PLD did not show improvement in OS in the overall population.•T + PLD may have clinical benefits for patients with partially platinum-sensitive ROC and germline BRCA1/2 mutation.
•KN A-18 led to approval of pembrolizumab plus chemotherapy and radiation in treating locally advanced cervical cancer.•Only a subset of those enrolled in the study were included in the indication ...statement.•Regulatory approvals should focus on primary objectives and sound statistical endpoints.
Purpose of Review
The treatment of patients with advanced gynecologic malignancies remains challenging. Advancements in genomics have led to recognition and development of individualized therapeutic ...targets. This article reviews the current trends in precision medicine for treatment of gynecologic cancers.
Recent Findings
With the identification of the molecular aberrations inherent to gynecologic malignancies, we have discovered targetable mutations. Specific to ovarian, endometrial and cervical cancers, potential therapeutic targets that have been identified and shown to have benefit include: hormonal therapies, anti-angiogenic agents, poly-ADP-ribose polymerase inhibitors (PARPi), and immunotherapy.
Summary
The adoption of targeted therapeutics for the treatment of gynecologic cancers has been gradual, but we have started to see the rapid employment of novel targeted agents into clinical trial development, leading to new treatment approvals. However, there are challenges to the universal precision medicine implementation, and future studies need to identify, discover, and validate robust biomarkers with strong prognostic/predictive capabilities.
The definition of “platinum-resistant ovarian cancer” has evolved; it now also reflects cancers for which platinum treatment is no longer an option. Standard of care for platinum-resistant ovarian ...cancer is single-agent, non-platinum chemotherapy with or without bevacizumab, which produces modest response rates, with the greatest benefits achieved using weekly paclitaxel. Several recent phase 3 trials of pretreated patients with prior bevacizumab exposure failed to meet their primary efficacy endpoints, highlighting the challenge in improving clinical outcomes among these patients. Combination treatment with antiangiogenics has improved outcomes, whereas combination strategies with immune checkpoint inhibitors have yielded modest results. Despite extensive translational research, there has been a lack of reliable and established biomarkers that predict treatment response in platinum-resistant ovarian cancer. Additionally, in the platinum-resistant setting, implications for the time between the penultimate dose of platinum therapy and platinum retreatment remain an area of debate. Addressing the unmet need for an effective treatment in the platinum-resistant setting requires thoughtful clinical trial design based on a growing understanding of the disease. Recent cancer drug approvals highlight the value of incorporating molecular phenotypes to better define patients who are more likely to respond to novel therapies. Clinical trials designed per the Gynecologic Cancer InterGroup recommendations—which advocate against relying solely upon the platinum-free interval—will help advance our understanding of recurrent ovarian cancer response where platinum rechallenge in the platinum-resistant setting may be considered. The inclusion of biomarkers in clinical trials will improve patient stratification and potentially demonstrate correlations with biomarker expression and duration of response. With the efficacy of antibody-drug conjugates shown for the treatment of some solid and hematologic cancers, current trials are evaluating the use of various novel conjugates in the setting of platinum-resistant ovarian cancer. Emerging novel treatments coupled with combination trials and biomarker explorations offer encouraging results for potential strategies to improve response rates and prolong progression-free survival in this population with high unmet need. This review outlines existing data from contemporary clinical trials of patients with platinum-resistant ovarian cancer and suggests historical synthetic benchmarks for non-randomized trials.
Psychiatric comorbidity is common in eating disorders (EDs) and associated with poor outcomes, including increased risk for relapse and premature death. Yet little is known about comorbidity ...following ED recovery.
We examined two common comorbidities, major depressive disorder (MDD) and substance use disorder (SUD), in adult women with intake diagnoses of anorexia nervosa and bulimia nervosa who participated in a 22-year longitudinal study. One hundred and seventy-six of 228 surviving participants (77.2%) were interviewed 22 years after study entry using the Eating Disorders Longitudinal Interval Follow-up Evaluation to assess ED recovery status. Sixty-four percent (n = 113) were recovered from their ED. The Structured Clinical Interview for DSM-IV was used to assess MDD and SUD at 22 years.
At 22-year follow-up, 28% (n = 49) met criteria for MDD, and 6% (n = 11) met criteria for SUD. Those who recovered from their ED were 2.17 times more likely not to have MDD at 22-year follow-up (95% CI 1.10, 4.26, p = .023) and 5.33 times more likely not to have a SUD at 22-year follow-up than those who had not recovered from their ED (95% CI 1.36, 20.90, p = .008).
Compared to those who had not fully recovered from their ED, those who had recovered were twice as likely not to be diagnosed with MDD in the past year and five times as likely not to be diagnosed with SUDs in the past year. These findings provide evidence that long-term recovery from EDs is associated with recovery from or absence of these common major comorbidities. Because comorbidity in EDs can predict poor outcomes, including greater risk for relapse and premature death, our findings of reduced risk for psychiatric comorbidity following recovery at long-term follow-up is cause for optimism.
•ED recovery was associated with absence of MDD and SUDs at 22-year follow-up.•Those recovered from their EDs were twice as likely not to be diagnosed with MDD.•Those recovered from EDs were five times as likely not to be diagnosed with SUDs.
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