Faculty Bibliography
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302
SPL-108 mediates metastasis and chemoresistance in high-grade serous tubo-ovarian carcinoma [Meeting Abstract]
ISI:000687070800520
ISSN: 0090-8258
CID: 4990732
Integrated Multi-Tumor Radio-Genomic Marker of Outcomes in Patients with High Serous Ovarian Carcinoma
Purpose: Develop an integrated intra-site and inter-site radiomics-clinical-genomic marker of high grade serous ovarian cancer (HGSOC) outcomes and explore the biological basis of radiomics with respect to molecular signaling pathways and the tumor microenvironment (TME). Method: Seventy-five stage III-IV HGSOC patients from internal (N = 40) and external factors via the Cancer Imaging Archive (TCGA) (N = 35) with pre-operative contrast enhanced CT, attempted primary cytoreduction, at least two disease sites, and molecular analysis performed within TCGA were retrospectively analyzed. An intra-site and inter-site radiomics (cluDiss) measure was combined with clinical-genomic variables (iRCG) and compared against conventional (volume and number of sites) and average radiomics (N = 75) for prognosticating progression-free survival (PFS) and platinum resistance. Correlation with molecular signaling and TME derived using a single sample gene set enrichment that was measured. Results: The iRCG model had the best platinum resistance classification accuracy (AUROC of 0.78 [95% CI 0.77 to 0.80]). CluDiss was associated with PFS (HR 1.03 [95% CI: 1.01 to 1.05], p = 0.002), negatively correlated with Wnt signaling, and positively to immune TME. Conclusions: CluDiss and the iRCG prognosticated HGSOC outcomes better than conventional and average radiomic measures and could better stratify patient outcomes if validated on larger multi-center trials.
PMID: 33212885
ISSN: 2072-6694
CID: 4672972
State of the science: Uterine sarcomas: From pathology to practice [Editorial]
PMID: 32839026
ISSN: 1095-6859
CID: 4615132
Why do patients decline cascade testing in families with an identified mutation associated with hereditary gynecologic cancers? [Meeting Abstract]
Objective: We sought to prospectively evaluate the feasibility of obtaining genetic testing for at least 1 first- or second-degree family member of a proband known to have actionable germline mutation associated with endometrial and/or ovarian cancer through a coordinated referral system. We also identified barriers to genetic assessment in family members. Here we report initial probands screened and their reasons for declining cascade testing.
Method(s): Patients with a diagnosed pathogenic or suspected pathogenic mutation associated with ovarian and/or endometrial cancer were identified from the gynecologic oncology and genetics clinics. If patients did not consent to the study, their reasons for declining participation were documented. Patients who provided consent were asked to contact their first- and/or second-degree relatives to disclose their genetic testing results and advise them to contact our center for a referral to a genetic counselor. The number of relatives per proband who contacted us for a genetic counseling referral was recorded. In addition to providing the referral, we followed up with relatives to determine whether they attended their genetic counseling appointment, received genetic testing, or took any cancer risk-reducing measures based on their results.
Result(s): This study opened in March 2019. To date, we have screened 71 patients and enrolled 26 (37%). Among the 45 patients who were screened but not enrolled, 48.9% (n = 22) reported that their reason for declining participation in the study was that their family members had already received genetic testing. Other common reasons for declining participation were family members refusing testing (17.8%, n = 8) or no eligible family members (17.8%, n = 8) (Table 1).
Conclusion(s): The majority of probands declined participation in this facilitated cascade testing protocol. The most common reason for lack of participation was family members already having genetic testing or not having eligible family members. Patients who declined participation because family members refused testing could benefit from counseling on how to best to communicate with their relatives. Genetic testing for both patients and their relatives is critical to provision of appropriate cancer screening and prevention services. Knowledge of these barriers is important to further improve cascade testing among family members.
Copyright
Method(s): Patients with a diagnosed pathogenic or suspected pathogenic mutation associated with ovarian and/or endometrial cancer were identified from the gynecologic oncology and genetics clinics. If patients did not consent to the study, their reasons for declining participation were documented. Patients who provided consent were asked to contact their first- and/or second-degree relatives to disclose their genetic testing results and advise them to contact our center for a referral to a genetic counselor. The number of relatives per proband who contacted us for a genetic counseling referral was recorded. In addition to providing the referral, we followed up with relatives to determine whether they attended their genetic counseling appointment, received genetic testing, or took any cancer risk-reducing measures based on their results.
Result(s): This study opened in March 2019. To date, we have screened 71 patients and enrolled 26 (37%). Among the 45 patients who were screened but not enrolled, 48.9% (n = 22) reported that their reason for declining participation in the study was that their family members had already received genetic testing. Other common reasons for declining participation were family members refusing testing (17.8%, n = 8) or no eligible family members (17.8%, n = 8) (Table 1).
Conclusion(s): The majority of probands declined participation in this facilitated cascade testing protocol. The most common reason for lack of participation was family members already having genetic testing or not having eligible family members. Patients who declined participation because family members refused testing could benefit from counseling on how to best to communicate with their relatives. Genetic testing for both patients and their relatives is critical to provision of appropriate cancer screening and prevention services. Knowledge of these barriers is important to further improve cascade testing among family members.
Copyright
EMBASE:2008347296
ISSN: 0090-8258
CID: 4638392
Small Cell Carcinoma of the Ovary, Hypercalcaemic Type - genetics, new treatment targets and current management guidelines
Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets and propose management guidelines for this challenging cancer.
PMID: 32156746
ISSN: 1078-0432
CID: 4349732
Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline
PURPOSE/OBJECTIVE:To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus. METHODS:A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence. RESULTS:The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs. RECOMMENDATIONS/CONCLUSIONS:genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.
PMID: 31986064
ISSN: 1527-7755
CID: 4386252
Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of genetic counseling and testing and impact on patient-reported stress, anxiety and depression
BACKGROUND:Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. METHODS:Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. RESULTS:From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10-189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). CONCLUSIONS:Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.
PMID: 32057464
ISSN: 1095-6859
CID: 4304652
Proteogenomic Characterization of Endometrial Carcinoma
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
PMID: 32059776
ISSN: 1097-4172
CID: 4304672
Pan-cancer analysis of whole genomes
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658Â whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5Â driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.
PMID: 32025007
ISSN: 1476-4687
CID: 5018742
BRCA 1/2 Somatic Mutations in Patients with Advanced or Recurrent Endometrial Cancer [Meeting Abstract]
ISI:000542994200036
ISSN: 0090-8258
CID: 4525902
