Background
An estimated 5–10% of breast and ovarian cancers are due to hereditary causes such as hereditary breast and ovarian cancer (HBOC) syndrome. Medicare, the third-party payer that covers 44 ...million patients in the United States, has implemented a set of clinical criteria to determine coverage for the testing of the
BRCA1
and
BRCA2
genes. These criteria, developed to identify carriers of
BRCA1/2
variants, have not been evaluated in the panel testing era. This study investigated a series of Medicare patients undergoing genetic testing for HBOC to determine the efficacy of genetic testing criteria in identifying patients with hereditary risk.
Methods
This study retrospectively examined de-identified data from a consecutive series of Medicare patients undergoing genetic testing based on personal and family history of breast and gynecologic cancer. Ordering clinicians indicated whether patients did or did not meet established criteria for
BRCA1/2
genetic testing. The genetic test results were compared between the group that met the criteria and the group that did not. Patients in families with known pathogenic (P) or likely pathogenic (LP) variants were excluded from the primary analysis.
Results
Among 4196 unique Medicare patients, the rate of P/LP variants for the patients who met the criteria for genetic testing was 10.5%, and for those who did not, the rate was 9% (
p
= 0.26).
Conclusions
The results of this study indicate that a substantial number of Medicare patients with clinically actionable genetic variants are being missed by current testing criteria and suggest the need for significant expansion and simplification of the testing criteria for HBOC.
Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their ...intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown.
One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3.
High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival (n=70, CXCL9: HR 0.41; P=0.006; CXCL10: HR 0.46; P=0.010) which was confirmed in an independent validation set (n=114; CXCL9: HR 0.60; P=0.019; CXCL10: HR 0.52; P=0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF-κB activation and inhibited chemokine release.
Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies.
The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole‐exome sequencing (WES) was performed in the germline DNA of 52 non‐BRCA1/BRCA2/TP53 mutation ...carrier women at high‐risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer‐related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high‐risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.
The current study aimed to identify new breast and/or ovarian cancer predisposition genes. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer‐related genes such as DROSHA and SLC34A2. This is the largest Brazilian WES study involving families at high‐risk for hereditary breast and ovarian cancer which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.
Population-based BRCA1/BRCA2 testing has been found to be cost-effective compared with family history–based testing in Ashkenazi-Jewish women were >30 years old with 4 Ashkenazi-Jewish grandparents. ...However, individuals may have 1, 2, or 3 Ashkenazi-Jewish grandparents, and cost-effectiveness data are lacking at these lower BRCA prevalence estimates. We present an updated cost-effectiveness analysis of population BRCA1/BRCA2 testing for women with 1, 2, and 3 Ashkenazi-Jewish grandparents.
Decision analysis model.
Lifetime costs and effects of population and family history–based testing were compared with the use of a decision analysis model. 56% BRCA carriers are missed by family history criteria alone. Analyses were conducted for United Kingdom and United States populations. Model parameters were obtained from the Genetic Cancer Prediction through Population Screening trial and published literature. Model parameters and BRCA population prevalence for individuals with 3, 2, or 1 Ashkenazi-Jewish grandparent were adjusted for the relative frequency of BRCA mutations in the Ashkenazi-Jewish and general populations. Incremental cost-effectiveness ratios were calculated for all Ashkenazi-Jewish grandparent scenarios. Costs, along with outcomes, were discounted at 3.5%. The time horizon of the analysis is “life-time,” and perspective is “payer.” Probabilistic sensitivity analysis evaluated model uncertainty.
Population testing for BRCA mutations is cost-saving in Ashkenazi-Jewish women with 2, 3, or 4 grandparents (22-33 days life-gained) in the United Kingdom and 1, 2, 3, or 4 grandparents (12-26 days life-gained) in the United States populations, respectively. It is also extremely cost-effective in women in the United Kingdom with just 1 Ashkenazi-Jewish grandparent with an incremental cost-effectiveness ratio of £863 per quality-adjusted life-years and 15 days life gained. Results show that population-testing remains cost-effective at the £20,000–30000 per quality-adjusted life-years and $100,000 per quality-adjusted life-years willingness-to-pay thresholds for all 4 Ashkenazi-Jewish grandparent scenarios, with ≥95% simulations found to be cost-effective on probabilistic sensitivity analysis. Population-testing remains cost-effective in the absence of reduction in breast cancer risk from oophorectomy and at lower risk-reducing mastectomy (13%) or risk-reducing salpingo-oophorectomy (20%) rates.
Population testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States. These results support population testing in Ashkenazi-Jewish women with 1-4 Ashkenazi-Jewish grandparent ancestry.
Epithelial ovarian cancer has become the most frequent cause of deaths from among gynecologic malignancies. Our study elucidates the diagnostic performance of ROMA, HE4 and CA-125. Objective of the ...study was to compare the diagnostic accuracy of ROMA, HE4 and CA-125 in the early diagnosis and screening of Epithelial Ovarian Cancer. Search strategy-Literature search in electronic databases. Selection criteria-Studies that evaluated the diagnostic measures of ROMA, HE4 and CA-125 by using CLIA or ECLIA as index tests. Data collection and analysis-24 studies (6,704 women) were included in our meta-analysis .We calculated AUC by SROC, pooled estimated like sensitivity, specificity, likelihood ratio, diagnostic odds ratio, Tau square, Cochran Q through random effect analysis and meta-regression. Data was retrieved from 24 studies. The pooled estimates of the three markers were sensitivity : ROMA(0.86, 95% CI 0.84-0.88)> CA-125(0.84, 95% CI 0.82-0.85)> HE4 (0.73, 95% CI 0.82-0.85) specificity: HE4 (0.91, 95% CI 0.90-0.91) > ROMA (0.76, 95% CI 0.95-0.99) > CA125 (0.71, 95%CI 0.69-0.72) AUC(SE): ROMA (0.93((0.036)) > HE4 (0.906(0.017)) > CA125 (0.846(0.019) through bivariate random effects model considering the heterogeneity. Our study found ROMA as the best marker to differentiate EOC from benign pelvic masses with high diagnostic accuracy (AUC- 0.913) as compared to HE4 (0.906) and CA-125 (0.846) with highest pooled sensitivity as compared to other markers. Specificity for ROMA (0.76) was also higher than CA-125. The AUC (0.93) and sensitivity (0.88) for ROMA was highest for postmenopausal women suggesting it as promising predictor of Epithelial ovarian cancer in this group however its utilization requires further exploration.
•This ESMO Clinical Practice Guideline provides key recommendations for managing epithelial ovarian cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, ...treatment and follow-up.•Treatment and management algorithms for early and advanced disease, as well as recurrent disease, are provided.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices including targeted therapies.•The multidisciplinary expert author group stems from different institutions and countries in Europe, Asia and the USA.
Abstract
BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we ...performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.
•Cytoreduction to no visible disease predicts survival in serous, mucinous and clear cell ovarian cancer.•Prognostic significance of residual disease does not differ by histologic type.•Association ...of residual disease and survival is independent of chemoresponsiveness.
Surgical cytoreduction has been postulated to affect survival by increasing the efficacy of chemotherapy in ovarian cancer. We hypothesized that women with high-grade serous ovarian cancer, which usually responds to chemotherapy, would derive greater benefit from complete cytoreduction than those with histologic subtypes that are less responsive to chemotherapy, such as mucinous and clear cell carcinoma.
We conducted a retrospective cohort study of patients who underwent primary cytoreductive surgery and adjuvant chemotherapy for stage IIIC or IV epithelial ovarian cancer from 2011 to 2013 using data from the National Cancer Database. We constructed multivariable models to quantify the magnitude of associations between residual disease status (no residual disease, ≤1cm, or >1cm) and all-cause mortality by histologic type among women with clear cell, mucinous, and high-grade serous ovarian cancer. Because 26% of the sample had unknown residual disease status, we used multiple imputations in the primary analysis.
We identified 6,013 women with stage IIIC and IV high-grade serous, 307 with clear cell, and 140 with mucinous histology. The association between residual disease status and mortality hazard did not differ significantly among histologic subtypes of ovarian cancer (p for interaction=0.32). In covariate adjusted models, compared to suboptimal cytoreduction, cytoreduction to no gross disease was associated with a hazard reduction of 42% in high-grade serous carcinoma (hazard ratio HR=0.58, 95% confidence interval CI=0.49–0.68), 61% in clear cell carcinoma (HR=0.39, 95% CI=0.22–0.69), and 54% in mucinous carcinoma (HR=0.46, 95% CI=0.22–0.99).
We found no evidence that surgical cytoreduction was of greater prognostic importance in high-grade serous carcinomas than in histologies that are less responsive to chemotherapy.
•Diaphragmatic stripping is associated with acceptable postoperative morbidity.•The procedure offers significant advantage on patients‘ survival.•The survival benefit seems to be independent of the ...stage at diagnosis or adequacy of tumor debulking.
Diaphragmatic stripping is a standard procedure that is performed in a significant proportion of patients undergoing surgical cytoreduction for advanced ovarian cancer. The objective of the present study is to evaluate morbidity and survival outcomes among patients offered diaphragmatic surgery for primary diagnosed optimally resected ovarian cancer.
We conducted a retrospective cohort study, identifying patients that were offered surgery between 2016 and 2021 for primary diagnosis of ovarian cancer. Cases that had diaphragmatic stripping or partial diaphragmatic resection were selected and compared to cases that did not require this procedure. Kaplan-Meier and Cox-regression analyses were applied to evaluate survival outcomes.
Overall, 61 patients that had diaphragmatic stripping were identified. Severe postoperative complications (Clavien-Dindo 3 + ) were noted in 19 patients (31 %). Survival analyses denoted that the stage of the disease at the time of diagnosis, as well as the timing of the surgical procedure (PDS vs IDS) and the completion of tumor debulking were factors that significantly affected the recurrence free and overall survival of patients. Severe postoperative morbidity was a significant predictor of the overall survival. Multivariate cox-regression analysis that was adjusted for the stage of the disease revealed that preoperative pleural effusion, optimal (compared to complete) tumor resection and the occurrence of postoperative complications significantly affected the overall survival of patients. Compared to patients that did not have diaphragmatic surgery, patients submitted to diaphragmatic stripping or resection had improved progression free and overall survival rates, irrespective of the stage of the disease at diagnosis or the adequacy of resection status.
Diaphragmatic surgery is feasible in advanced ovarian cancer patients with acceptable morbidity that mainly refers to postoperative pleural effusion. Its positive impact on patients‘ survival requires further investigation.
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