Recently, Vigil showed significant clinical benefit with improvement in relapse free (RFS) and overall survival (OS) in pre-planned subgroup analysis in stage III/IV newly diagnosed ovarian cancer ...patients with BRCA wild type (BRCA-wt) molecular profile. Here we analyze homologous recombination (HR) status of patients enrolled in the Phase 2b VITAL study and determine clinical benefit of Vigil in HR proficient (P) patients.
Patients were previously enrolled in a Phase 2b, double-blind, placebo-controlled trial. All were in complete response with Stage III/IV high grade serious, endometroid or clear cell ovarian cancer. HR status was determined using MyChoice®CDx score (<42 = HRP) (Myriad Genetics, Inc., UT). Post-hoc analyses were carried out using Kaplan Meier and restricted mean survival time (RMST) analysis to evaluate RFS and OS based on HR deficiency (D) status.
RFS was improved with Vigil (n = 25) in HRP patients compared to placebo (n = 20) (HR = 0.386; 90% CI 0.199–0.750; p = 0.007), results were verified by RMST (p = 0.017). Similarly, OS benefit was observed in Vigil group compared to placebo (HR = 0.342; 90% CI 0.141–0.832; p = 0.019). Results with OS were also verified with RMST (p = 0.008).
Vigil exhibited clinical benefit in HRP molecular profile patients.
•Limited treatment options exist for homologous recombination proficient ovarian cancer.•Vigil is an anticancer immuno-therapeutic.•Vigil provides neoantigen education, GMCSF activation and TGFβ suppression reversal.•Vigil vs. placebo shows benefit of RFS and OS (HR = 0.386, p = 0.007; HR = 0.342, p = 0.019).•Vigil demonstrated no Grade 3/4 toxicity compared to placebo.
Abstract Objective Uterine sarcomas are aggressive cancers, often not recognized prior to surgical exploration. The goal of this study was to determine the utility of endometrial sampling in ...detecting uterine sarcomas and to examine factors associated with diagnostic inaccuracy. Methods All uterine tumors identified at hysterectomy from 1990 to 2006 were reviewed. Included patients underwent preoperative endometrial sampling reviewed at our center. Pathologic data was documented through review of hospital records. Statistical analysis was performed using Chi square test. Results 938 patients were identified. Preoperative sampling was available for review in 730 (78%) subjects. Uterine sarcomas occurred in 142 patients; 72 (51%) underwent preoperative sampling. Overall, endometrial sampling identified an invasive tumor in 84% (600/713), and the correct histology in 79% (564/713). Among women with sarcomas, preoperative sampling suggested an invasive tumor in 86% (62/72) and predicted the correct histologic diagnosis in 64% (46/72). The rate of detection of an invasive cancer by preoperative sampling was not statistically different among sarcomas and epithelial tumors (86% vs. 84%, p = 0.76). Preoperative sampling was significantly less reliable in predicting the correct histology for uterine sarcomas (64% vs. 81%, p < 0.0001). Similar trends were seen when sarcoma patients were compared to low-grade and high-grade epithelial cancers. Both biopsy and curettage had similar accuracy in diagnosing sarcomas ( p = 0.84). Conclusions Endometrial sampling has a significantly lower predictive value in diagnosing uterine sarcomas compared to epithelial uterine malignancies. Biopsy and curettage have similar accuracy. Novel diagnostic techniques are needed to accurately identify uterine sarcomas preoperatively.
This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC).
Black and White ...patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes.
Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88–3.97)) and OS (HR 2.20 (95% CI 1.77–2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22–3.32)) and OS (HR 1.61 (95% CI 1.18–2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race.
Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.
•Black patients are more likely to have TP53-mutated and p53-abnormal EC compared to White patients.•Patients with TP53-mut and p53-abn EC have a 2.2 and 1.6-fold greater risk of death than those with TP53- and p53-wt EC.•White and Black patients with TP53-mutated and p53-abnormal EC have similar progression-free and overall survival outcomes.•Concordance between TP53 NGS and p53 expression IHC tumor testing was 84.3%.
A first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease was conducted. The primary objective of this study was to ...assess the safety of rAAV1-CMV-hGAA vector delivered to the diaphragm muscle of Pompe disease subjects with ventilatory insufficiency. Safety was assessed by measurement of change in serum chemistries and hematology, urinalysis, and immune response to GAA and AAV, as well as change in level of health. The data demonstrate that the AAV treatment was safe and there were no adverse events related to the study agent. Adverse events related to the study procedure were observed in subjects with lower baseline neuromuscular function. All adverse events were resolved before the end of the study, except for one severe adverse event determined not to be related to either the study agent or the study procedure. In addition, an anti-capsid and anti-transgene antibody response was observed in all subjects who received rAAV1-CMV-hGAA, except for subjects who received concomitant immunomodulation to manage reaction to enzyme replacement therapy, as per their standard of care. This observation is significant for future gene therapy studies and serves to establish a clinically relevant approach to blocking immune responses to both the AAV capsid protein and transgene product.
Identification of persons at risk for hereditary syndromes through genetic testing prior to cancer diagnosis may proactively reduce the cancer burden morbidity and mortality. Using a framework of ...health equity, this study characterizes the global landscape of publication and reference to
genetic testing guidelines (GTG).
This study used a systematic literature search supplemented by an International Gynecologic Cancer Society (IGCS) informal survey and cross referenced with Myriad Genetics records, to identify published GTG, their country of origin, and countries referencing them.
Of 1011 identified publications, 166 met the inclusion criteria, from which 46 unique guidelines were identified, published by 18 countries and two regions (Europe and the UK). Authorship from the USA accounted for 63% of publications on GTG. Systematic mapping reviews revealed 34 countries with published and/or referenced guidelines, the IGCS survey revealed 22 additional countries, and coordination with Myriad Genetics revealed additional information for two countries and primary information for one country. Of the 57 countries evaluated, 33% published their own guidelines and reference guidelines from another country/region, 5% published their own guidelines without referencing another country/region, and 61% only referenced a guideline from another country/region. No data were available for 138 of 195 countries, disproportionately from Africa, the Middle East, Eastern Europe, and Southeast Asia.
Global geographic disparities in the publication and referencing of GTG exist, with a large emphasis on North American and European guidelines in the published literature. These disparities highlight a need for uniform
GTG to improve global health equity.
To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated (“Lynch-like”) endometrial tumors and determine whether their ...molecular profiles can elucidate the differential outcomes.
1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves.
The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity.
Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.
•MLH1 hypermethylated patients display discrepant survival and immunotherapy outcomes compared to MLH1 mutated patients.•MLH1 hypermethylated tumors have an altered mutational profile compared to MLH1 mutated tumors.•MLH1 hypermethylated tumors display a more immune cold phenotype than MLH1 mutated tumors.•MLH1 tumors have greater estrogen receptor and progesterone receptor positivity than MLH1 mutated tumors.•The MLH1 hypermethylated cohort may benefit from multiple targeted agents rather than sole checkpoint inhibition.
Abstract Aim Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol ...2010;28:3107–14). Methods Women, stratified by performance status (0–1 versus 2) and platinum sensitivity (platinum-free interval PFI <6 versus ⩾6 months), were randomly assigned to receive PLD 30 mg/m2 IV followed by a 3-h infusion of trabectedin 1.1 mg/m2 every 3 weeks or PLD 50 mg/m2 every 4 weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred. Results After a median follow-up of 47.4 months, there were 522 deaths among 672 subjects. The median OS for trabectedin + PLD and PLD arms was 22.2 and 18.9 months, respectively (hazard ratio HR = 0.86; 95% confidence interval CI: 0.72–1.02; p = 0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD = 13.3 months, trabectedin + PLD = 10.6 months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin + PLD arm (HR = 0.82; 95% CI: 0.69–0.98; p = 0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6–12 months had the largest difference in OS (HR = 0.64; 95% CI: 0.47–0.86; p = 0.0027). Conclusions The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.
There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery.
We applied ...glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues.
We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues.
Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.
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