A Common Cell of Origin for Inflammatory Myofibroblastic Tumor and Lung Adenocarcinoma with ALK rearrangement.

This case signifies the importance of obtaining tumor comprehensive genomic profiling (CGP) as it has utility in cancer type classification and helping in diagnosing recurrence/metastasis or separately occurring primary tumors. CGP can also help guiding treatment as in this case separately occurring Inflammatory Myofibroblastic Tumor had ALK fusion and responded to crizotinib. As treatment progresses, new biopsies should be obtained and CGP used to evaluate for appearance of any new genomic alterations, in order to guide further therapy.

Tumor Mutational Burden as a Predictor of First-Line Immune Checkpoint Inhibitor Versus Carboplatin Benefit in Cisplatin-Unfit Patients With Urothelial Carcinoma.

PURPOSE: In real-world settings, patients with metastatic urothelial carcinoma (mUC) are often more frail than clinical trials, underscoring an unmet need to identify patients who might be spared first-line chemotherapy. We sought to determine whether tumor mutational burden (TMB) identifies patients with comparable or superior clinical benefit of first-line single-agent immune checkpoint inhibitors (ICPI) in real-world patients deemed cisplatin-unfit. METHODS: Patients with mUC treated in first-line advanced setting (N = 401) received ICPI (n = 245) or carboplatin regiment without ICPI (n = 156) at physician's discretion in standard-of-care settings across approximately 280 US academic or community-based cancer clinics between March 2014 and July 2021. Deidentified data were captured into a real-world clinicogenomic database. All patients underwent testing using Foundation Medicine assays. Progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) comparing ICPI versus chemotherapy were adjusted for known treatment assignment imbalances using propensity scores. RESULTS: TMB ≥ 10 was detected in 122 of 401 (30.4%) patients. Among patients receiving ICPI, those with TMB ≥ 10 had more favorable PFS (HR, 0.59; 95% CI, 0.41 to 0.85), TTNT (HR, 0.59; 95% CI, 0.43 to 0.83), and OS (HR, 0.47; 95% CI, 0.32 to 0.68). Comparing ICPI versus carboplatin, adjusting for imbalances, patients with TMB ≥ 10 had more favorable PFS (HR, 0.51; 95% CI, 0.32 to 0.82), TTNT (HR, 0.56; 95% CI, 0.35 to 0.91), and OS (HR, 0.56; 95% CI, 0.29 to 1.08) on ICPI versus chemotherapy, but not TMB < 10. Comparisons unadjusted for imbalances had similar associations. CONCLUSIONS: In real-world settings, mUC patients with TMB ≥ 10 have more favorable outcomes on first-line single-agent ICPI than carboplatin, adding clinical validity to TMB assessed by an existing US Food and Drug Administration-approved platform.

Clinical and pathological features associated with circulating tumor DNA content in real-world patients with metastatic prostate cancer.

BACKGROUND: Liquid biopsy is a powerful tool that can enable treatment decisions for metastatic prostate cancer patients with difficult-to-biopsy tumors. However, the detection of genomic alterations via liquid biopsy is limited by the fraction (tumor fraction [TF]) of circulating tumor DNA (ctDNA) within the total cell-free DNA content. While prior work has preliminarily correlated TF with clinical features of prostate cancer, we sought to validate and provide additional resolution, such that a clinical practitioner might anticipate the probability of successful liquid biopsy profiling leveraging commonly assessed clinical and laboratory features. METHODS: A total of 813 liquid biopsy specimens were assessable, with 545 associated with a PSA prostate specific antigen measurement, collected in standard-of-care settings across approximately 280 US academic or community-based cancer clinics from September 2018 to July 2021. Deidentified data were captured into a real-world clinico-genomic database (CGDB). Comprehensive genomic profiling (CGP) was performed on extracted cell-free DNA from liquid biopsy samples. RESULTS: In multivariable models, higher PSA level, lower hemoglobin, lower albumin, higher alkaline phosphatase (all p < 0.001), and collection of liquid biopsy blood draw within 60 days of new treatment initiation (p = 0.002) were the most strongly associated features with higher TF. At PSA levels of <5 ng/ml, 43% of patients had a TF of <1% indicating an increased likelihood of unevaluable results. Conversely, at PSA levels of >5 ng/ml, 78% of patients had a TF of at least 1% and 46% had a TF of ≥10%, suggesting improved sensitivity for detection of targetable alterations. CONCLUSIONS: Universal genomic profiling of prostate cancers will require complementary use of liquid biopsy and tumor tissue profiling for suitable patients. The likelihood of adequate ctDNA shedding into plasma is one consideration when deciding whether to pursue CGP via liquid biopsy versus tumor profiling. Our real-world data suggest that PSA < 5 ng/ml is associated with lower ctDNA yield on liquid biopsy, potentially increasing the incidence of negative results or a need for confirmation with tissue testing.

ERBB2 Copy Number as a Quantitative Biomarker for Real-World Outcomes to Anti-Human Epidermal Growth Factor Receptor 2 Therapy in Advanced Gastroesophageal Adenocarcinoma.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression or amplification (ERBB2amp) are biomarkers for approved anti-HER2 therapies. ERBB2amp may better predict response compared with immunohistochemistry or in situ hybridization, and quantitative copy number (CN) may further stratify patients. We characterized ERBB2amp in advanced gastroesophageal adenocarcinomas (GEA) and hypothesized that increased CN was associated with better outcome to trastuzumab. METHODS: Comprehensive genomic profiling, including assessment of ERBB2amp, was performed for 12,905 GEA tissue cases. Clinical outcomes were assessed using a clinicogenomic database linking deidentified electronic health record-derived clinical data to genomic data. Multivariable Cox proportional hazard models were used for real-world progression-free survival (rwPFS) comparisons. RESULTS: ERBB2amp (CN ≥ 5) was detected in 15% (1,934 of 12,905) of GEA; median CN 22 (interquartile range 9-73). Median ERBB2 amplicon size was 0.27 megabase (interquartile range 0.13-0.95), and smaller amplicons were associated with higher CN (P < .001). In the clinicogenomic database, of 101 evaluable first-line trastuzumab-treated patients, ERBB2 CN was a significant predictor of rwPFS as a continuous variable (adjusted hazard ratio = 0.73; 95% CI, 0.60 to 0.89; P = .002), whereas ERBB2 CN was not predictive of rwPFS on chemotherapy (adjusted hazard ratio = 0.93; 95% CI, 0.73 to 1.20; P = .59). Among trastuzumab-treated patients, no significant associations with ERBB2 CN were observed for disease site, age, stage at advanced diagnosis, or most selected coalterations. CONCLUSION: ERBB2amp was detected in 15% of GEA tissue samples, with significant diversity in ERBB2 CN and amplicon focality. ERBB2 CN was predictive of rwPFS as a continuous variable for patients treated with trastuzumab. Further studies exploring the clinical utility of quantitative ERBB2 CN, particularly in the setting of the evolving anti-HER2 landscape and combination therapies, are warranted.

Patient with Lobular Carcinoma of the Breast and Activating AKT1 E17K Variant.

OBJECTIVE: To present the characteristics of the AKT1E117K gene variant and a description of the clinical application in a patient with metastatic breast cancer. RESULTS: 63 y/o woman with Stage IV Invasive lobular carcinoma at diagnosis was treated with Palbociclib and aromatase inhibitors (AI). At progression, tissue was sent for comprehensive genomic profiling to Foundation Medicine (FM) which revealed AKT1E17K mutation. In lieu of available clinical data within the patient's tumor type (HR+ HER2- breast cancer), extrapolated data from the Flatiron Health-FM (FH-FMI) Clinico-genomic Database (CGDB) was discussed at our Molecular Tumor Board (MTB). After multidisciplinary discussion, the consensus recommendation was to start treatment with the combination of mTOR inhibitor everolimus, and AI, exemestane. Patient tolerated treatment without major side effects. By the second clinical visit the patient's breast showed signs of improvement. PET/CT showed diminished left axillary uptake, decreased right paratracheal lymph node PET avidity, and stable bone disease consistent with a partial response. The most recent office visit in January 2021, breast exam revealed a normal-appearing skin with only faint erythema. All other skin lesions have resolved. Although, the role of AKT1 variant described here is not well defined and therapeutic significance of M-Tor inhibitors not established in metastatic breast cancers, comprehensive approach to this case unraveled new and successful therapeutic option in this patient. CONCLUSION: This demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.

tRNA Genes Affect Chromosome Structure and Function via Local Effects.

The genome is packaged and organized in an ordered, nonrandom manner, and specific chromatin segments contact nuclear substructures to mediate this organization. tRNA genes (tDNAs) are binding sites for transcription factors and architectural proteins and are thought to play an important role in the organization of the genome. In this study, we investigate the roles of tDNAs in genomic organization and chromosome function by editing a chromosome so that it lacked any tDNAs. Surprisingly our analyses of this tDNA-less chromosome show that loss of tDNAs does not grossly affect chromatin architecture or chromosome tethering and mobility. However, loss of tDNAs affects local nucleosome positioning and the binding of SMC proteins at these loci. The absence of tDNAs also leads to changes in centromere clustering and a reduction in the frequency of long-range HML-HMR heterochromatin clustering with concomitant effects on gene silencing. We propose that the tDNAs primarily affect local chromatin structure, which results in effects on long-range chromosome architecture.

Methods to Study the Atypical Roles of DNA Repair and SMC Proteins in Gene Silencing.

Silenced heterochromatin influences all nuclear processes including chromosome structure, nuclear organization, transcription, replication, and repair. Proteins that mediate silencing affect all of these nuclear processes. Similarly proteins involved in replication, repair, and chromosome structure play a role in the formation and maintenance of silenced heterochromatin. In this chapter we describe a handful of simple tools and methods that can be used to study the atypical role of proteins in gene silencing.

Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis.

Condensin is enriched in the pericentromere of budding yeast chromosomes where it is constrained to the spindle axis in metaphase. Pericentric condensin contributes to chromatin compaction, resistance to microtubule-based spindle forces, and spindle length and variance regulation. Condensin is clustered along the spindle axis in a heterogeneous fashion. We demonstrate that pericentric enrichment of condensin is mediated by interactions with transfer ribonucleic acid (tRNA) genes and their regulatory factors. This recruitment is important for generating axial tension on the pericentromere and coordinating movement between pericentromeres from different chromosomes. The interaction between condensin and tRNA genes in the pericentromere reveals a feature of yeast centromeres that has profound implications for the function and evolution of mitotic segregation mechanisms.