225 Background: Metastatic, castration-resistant prostate cancer (mCRPC) is commonly the deadly form of PC. Among these, a subset of tumors are androgen-indifferent with the most aggressive often manifesting variant histology, including neuroendocrine or small cell changes. Neuroendocrine PC can be de novo (NEPC) or develop in response to therapy as treatment emergent (CRPC-NE). Currently effective durable treatments for NEPC are lacking. Hence, we sought to identify additional targets in CRPC/NEPC using an integrative platform of whole genome (WGS) and transcriptome sequencing (RNAseq). Methods: WGS was performed on55 tumor/normal pairs (CRPC-Ad, n= 32; CRPC-NE, n=13; de novo NEPC, n=7; metastatic hormone naïve, PC n=3) from 48 patients. RNAseq data was available in a subset of 21 samples. We employed the Isabl GxT analytic platform and manually curated single base substitution (SBS, COSMIC v3) molecular signatures and structural variants (SV) that involved tumor suppressor genes and oncogenes. Results: We observed 184 events in cancer-associated genes and targets in 38 cases. Non-canonical ETS fusions were identified in 2 CRPC-Ad patients ( MSMB-ERG and YWHAE-ETV4). Other rare events included SVs affecting ALK ( SLC45A3-ALK) and FGFR1 amplification in 1 patient each. Pathogenic germline alterations in 15% of patients with equal frequency in each clinicopathological state. These variants included genes such as BRCA1, BRCA2, and ATM, and other genes of uncertain relevance for prostate cancer ( e.g., PPM1D and MUTYH). SBS genomic signatures associated with homologous recombination deficiency (HRD) were observed in 15% of the patients (7 cases): 3 harbored germline BRCA1/2mutations, 2 with somatic BRCA2 mutations, and 2 without alteration in BRCA1/2 (1 of these CRPC-Ad had a complex SV disrupting RAD51B) without apparent enrichment for any histology, and a majority of both histologies were enriched in Mismatch repair (MMR)-associated SBS. One subject CRPC-NE and amphicrine character, which displayed a complete response to immune checkpoint blockade, harbored driver mutations in AR and CTNNB1, and homozygous loss of MSH2/6. Further, molecular signatures of potential clinical relevance were detected at varying contributions and included CDK12-type genomic instability (CRPC-Ad, n=2) (4%) and MMR deficiency with POLD1 proofreading (CRPC-Ad) who also experienced a durable response to pembrolizumab. Conclusions: WGS/RNAseq in CRPC and NEPC elucidates genomic signatures associated with HRD and MMR, complex SVs in oncogenes, and non-canonical ETS fusions. Expansion of our analysis is underway with enhanced integration of clinical metadata and RNAseq for rational trial design for aggressive variant CRPC and NEPC.
Background:There is a paucity of outcome data to guide the surgical treatment of posterolateral corner knee injuries. Purpose: To systematically review the literature to compare clinical outcomes of the treatment PLC injuries. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review of the literature including PubMed was performed. The following search terms were used: "posterolateral corner", "chronic PLC injuries" "acute PLC injuries" and "repair of PLC injuries", "reconstruction of PLC". Inclusion criteria were: Human examinations and treatment, measures of functional and clinical outcome included, exclusion criteria were: Non English papers, Non-human trials, Articles with no clinical data. Results: Eighteen studies with a total of 559 patients were included. When time to surgery was performed within 6 weeks it is considered acute injury while on the other hand more than that was considered chronic injury. Surgical treatment varied between repair and reconstruction there was an overall success rate of repair 75% and failure rate of 25% and overall success rate of reconstruction was 91% and 9% failure rate. Surgical techniques: 83 patients underwent repair for the PLC while 476 patients underwent reconstruction for the PLC, surgical techniques varied among studies, between repair and reconstruction techniques which was different between studies, including fibular sling using one femoral tunnel or two femoral tunnels, posterolateral capsular shift trying to increase rotational stability, anatomic PLC reconstruction, biceps tenodesis and isometric reconstruction of the FCL and the popliteus with a single graft. Conclusion:The repair of acute PLC injuries and staged treatment of combined cruciate injuries were associated with a substantially higher postoperative PLC failure rate than reconstruction. Further research is required to identify the reconstruction technique that provides optimal subjective and objective outcomes.
Whole genome sequencing (WGS) has emerged as a tool to characterize the entire genomic landscape of cancer and capture potential new targets and predictive biomarkers. Using state-of-the-art whole-genome and transcriptome sequencing (WGTS) analysis we interrogated a pan cancer cohort to nominate new treatment options. WGS was performed on 414 tumor/germline pairs from our pan cancer cohort of 355 patients, of which 103 had results of other commercial NGS assays. RNAseq data was available in 96 samples. We employed the Isabl GxT analytic platform and manually curated single base substitution (COSMIC v3) mutational signatures and structural variants (SVs). WGTS results were correlated with available clinico-pathologic data. High throughput drug screening that included PARP inhibitors and functional validation were performed in 61 matched patient-derived tumor organoids (PDTO). We found 5,129 SVs affecting at least one cancer gene in 88% of cases. High-confidence homologous recombination deficiency (HRD), determined by curation of mutational signatures and mutations/SVs affecting oncogenes and tumor suppressor genes, was detected in 8.3% of solid tumors (e.g., prostate, pancreas, ovarian, uterine, breast, gallbladder, and stomach carcinomas). HRD status included tumors with BRCA1/2 wildtype and SVs impacting BRCA1/2, RAD51, ATM and other HRD genes. CDK12-loss associated genomic instability was detected in 7 cases including 3 cases of prostate adenocarcinoma. 93 gene fusions involving cancer genes were detected including known and novel fusions of potential significance (e.g., SLC45A3::ALK in metastatic prostate adenocarcinoma, TMEM106A::BRCA1 in serious ovarian carcinoma, ESR1::EP300 in metastatic breast cancer). Some tumor cohorts demonstrated enrichment of drivers e.g., FGFR1 amplification in male breast cancer, rearrangements at the TERT locus in adrenocortical carcinoma, enrichment for repeat-mediated deletion attributed to mismatch repair (MMR) in gynecological carcinosarcoma, and SVs affecting FHIT in gastric adenocarcinoma. Drug screening of PDTO and functional testing with RAD51 immunofluorescence assay validated high-confidence HRD annotation. One example is a BRCA1/2 wildtype pancreatic adenocarcinoma with increased tandem duplications and SV (inversion) impacting BRCA2, and high-confidence HRD by our novel WGS classifier. Drug screening of the corresponding PDTO showed an enhanced response to Olaparib, in contrast to cases without HRD that did not. We have used state-of-the-art analysis of WGTS to improve the detection of targets and significant biomarkers in a pan cancer cohort, including HRD, CDK12-type genomic instability, pathogenic germline mutations and potential targetable novel fusions. A robust and clinically relevant ex vivo preclinical model allowed us to validate a WGS-based classifier that detects HRD even in cancers with wildtype BRCA1/2. Citation Format: Majd Al Assaad, Hui-Hsuan Kuo, Jones Nauseef, Max F. Levine, Gunes Gundem, Juan S. Medina-Martínez, Jyothi Manohar, Michael Sigouros, Ahmed Elsaeed, David Wilkes, Elli Papaemmanuil, Eloise Chapman, Scott T. Tagawa, Allyson Ocean, Cora N. Sternberg, Eleni Andreopoulou, Manish Shah, Andrea Sboner, Kevin Holcomb, David Nanus, Laura Martin, Olivier Elemento, Juan Miguel Mosquera. Whole genome and transcriptome sequencing of a pan cancer cohort unearths novel therapeutic avenues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3437.
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