The adherence to the American Association for the Study of Liver Diseases 2018 guidelines in the management of hepatocellular carcinoma and its impact on survival.

Introduction: In two Korean and Italian studies, the adherence rate (AR) to ASSLD 2005 guidelines in the management of hepatocellular carcinoma (HCC) was 60%. In a US study, the AR to American Association for the Study of Liver Disease (AASLD) 2005 guidelines was 73.3%, 26.8%, 25.3%, and 58.8% for patients with Barcelona Clinic Liver Cancer (BCLC) Stage A, B, C, and D, respectively, and nonadherence to guidelines was associated with longer overall survival (OS) in patients with BCLC Stage D. Here, we explored the AR to AASLD 2018 guidelines and its impact on OS. Methods: Between 2017 and 2019, 148 unique treatment-naïve patients with HCC were identified. Patients were staged according to the BCLC staging system and their AR to AASLD 2018 guidelines was noted. OS was estimated using Kaplan-Meier method. Survivals among patients from different groups was compared using Log-rank test. Results: The overall AR to AASLD 2018 guidelines was 83%. The AR for BCLC Stages 0, A, B, C, and D were 100%, 97%, 77%, 77%, and 38%, respectively. In patients with BCLC Stage D, the OS of patients treated with modalities adherent versus nonadherent to AASLD 2018 guidelines was 0.03 vs. 5.2 months (P = 0.0005). Otherwise, adherence versus nonadherence to AASLD 2018 guidelines showed no statistically significant differences in OS for patients with BCLC Stages 0, A, B, and C. Conclusion: The overall AR to AASLD 2018 guidelines was 83%. Nonadherence to AASLD 2018 guidelines in patients with BCLC Stage D translated into better OS.

Recent adventive soft scale insects (Hemiptera: Coccomorpha: Coccidae) and mealybugs (Hemiptera: Coccomorpha: Pseudococcidae) in India.

Four species of soft scale insect [Hemiptera: Coccidae: Fistulococcus pokfulamensis Hodgson & Martin, Kilifia deltoides De Lotto, Maacoccus piperis (Green) and Paralecanium machili Takahashi] and two species of mealybug [Hemiptera: Pseudococcidae: Antonina thaiensis Takahashi and Formicococcus simplicior (Green)] are recorded in India for the first time. Each of the six species is comprehensively diagnosed based on Indian material, and compared with earlier descriptions. Keys to the Indian species in their respective genera are provided to facilitate identification. Ecological information on host plants, associated ants and natural enemies is also given.

The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer.

BACKGROUND: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. METHODS: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. RESULTS: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). CONCLUSION: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.

Occurrence and spread of Ceroplastes cirripediformis Comstock (Hemiptera: Coccomorpha: Coccidae) in India.

The notoriously destructive and invasive soft scale, Ceroplastes cirripediformis Comstock (Hemiptera: Coccomorpha: Coccidae), is recorded for the first time from India. The scale is redescribed to facilitate its identification and information on its host range, natural enemies and distribution is provided. An identification key to the Indian species in this genus is given. Management options in the event of an outbreak are discussed briefly. The establishment of this scale insect warrants special attention in India as it is a potentially damaging plant pest and has a broad host range across many plant families.

Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research.

We have witnessed noteworthy progress in our understanding of prostate cancer over the past decades. This basic knowledge has been translated into efficient diagnostic and treatment approaches leading to the improvement in patient survival. However, the molecular pathogenesis of prostate cancer appears to be complex, and histological findings often do not provide an accurate assessment of disease aggressiveness and future course. Moreover, we also witness tremendous racial disparity in prostate cancer incidence and clinical outcomes necessitating a deeper understanding of molecular and mechanistic bases of prostate cancer. Biological research heavily relies on model systems that can be easily manipulated and tested under a controlled experimental environment. Over the years, several cancer cell lines have been developed representing diverse molecular subtypes of prostate cancer. In addition, several animal models have been developed to demonstrate the etiological molecular basis of the prostate cancer. In recent years, patient-derived xenograft and 3-D culture models have also been created and utilized in preclinical research. This review is an attempt to succinctly discuss existing information on the cellular and molecular progression of prostate cancer. We also discuss available model systems and their tested and potential utility in basic and preclinical prostate cancer research.

The cassava mealybug, Phenacoccus manihoti Matile-Ferrero (Hemiptera: Coccomorpha: Pseudococcidae) arrives in India.

Invasive species threaten the ecological and economic wellbeing of a country (Pimentel et al. 2001). In the last decade, several mealybugs and soft scale insects have been accidentally introduced to India, of which some have become serious pests (e.g., Phenacoccus solenopsis Tinsley, Paracoccus marginatus Williams Granara de Willink, Phenacoccus madeirensis Green and Pseudococcus jackbeardsleyi Gimpel Miller); others are widening their host ranges and spreading rapidly. Kilifia acuminata (Signoret) and Protopulvinaria longivalvata Green seem relatively harmless but Trijuba oculata (Brain) and Pulvinaria urbicola Cockerell cause economic damage (Joshi Rameshkumar 2013; Joshi 2017).

Symptomatic hypocalcemia in primary hyperaldosteronism: a case report.

The metabolic alterations caused by hyperaldosteronism are being increasingly recognized and have generated considerable interest among the medical fraternity. Hyperaldosteronism is suspected to have a pivotal role in the patho-physiology of congestive cardiac failure where it has been studied extensively. But its effects on calcium metabolism, parathyroid metabolism and renal handling of calcium are less well described. Recent experimental models have shed light into the roles played by previously unknown mechanisms in causing these metabolic alterations. We hereby report a case of primary hyperaldosteronism due to adrenal adenoma (Conn's syndrome) who presented with a myriad of clinical features including symptomatic hypocalcemia, significant weight loss along with uncontrolled hypertension for a prolonged period before eventually detected to have primary hyperaldosteronism. Surgical removal of the causative tumor resulted in prompt disappearance of all the symptoms and signs and regain of lost weight.

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope.

Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the men of European origin. Since androgens play an important role in the growth of normal prostate and prostate tumors, targeting of androgen signaling has remained a mainstay for the treatment of aggressive prostate cancer. Over the years, multiple approaches have been evaluated to effectively target the androgen signaling pathway that include direct targeting of the androgens, androgen receptor (AR), AR co-regulators or other alternate mechanisms that impact the outcome of androgen signaling. Several of these approaches are currently in clinical practice, while some are still pending further development and clinical evaluation. This remarkable progress has resulted from extensive laboratory, pre-clinical and clinical efforts, and mechanistic learnings from the therapeutic success and failures. In this review, we describe the importance of androgen signaling in prostate cancer biology and advances made over the years to effectively target this signaling pathway. We also discuss emerging data on the resistance pathways associated with the failure of various androgen signaling- targeted therapies and potential of this knowledge for translation into future therapies for prostate cancer.

The Prevalence of DPYD*9A(c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis.

INTRODUCTION: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation. PATIENTS AND METHODS: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis. RESULTS: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275). CONCLUSION: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

Exosomal markers (CD63 and CD9) expression and their prognostic significance using immunohistochemistry in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Exosomes are important mediators of intercellular communications and play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are widely accepted exosomal markers. In patients with pancreatic ductal adenocarcinoma (PDAC), positive correlation between CD9 expression and overall survival (OS) was reported. CD63 expression was conserved in all patients with no reported prognostic significance. This study explored the prognostic significance of CD63 and CD9 expression using immunohistochemistry (IHC) in patients with PDAC of mixed racial background. METHODS: Between 2012 and 2016, 49 patients with PDAC had available tissues for CD63 and CD9 staining using IHC. Two pathologists independently scored the CD63 and CD9 expression. Staining intensity was graded from 1-3 and staining percentage was estimated in 10% increments. Mean Quick-score (Q-score) (Intensity X Percentage of staining) was calculated. RESULTS: The mean Q-score for CD63 and CD9 are higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites (185 vs. 102, P=0.0002) and (48 vs. 20, P=0.0418) respectively. We fitted Cox proportion hazard regression models to investigate the impact of the covariates CD63 and CD9 on progression free survival (PFS) and OS. CD63 has significant impact on PFS (P=0.0135) and OS (P=0.003). The higher the CD63 Q-score, the longer the PFS and OS. CD9 doesn't have significant impact on PFS (P=0.5734) or OS (P=0.2682). The mean CD63 and CD9 Q-scores are slightly higher in African American (AA) compared to Caucasians (157 vs. 149, P=0.76) and (45 vs. 29, P=0.43) respectively. CONCLUSIONS: CD63 and CD9 expression is higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites. There is correlation between CD63 expression (but not CD9 in this cohort) and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC. A trend of higher expression of CD63 and CD9 among AA compared to Caucasians was also noticed.

Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition.

We are developing the fluoropyrimidine polymer F10 to overcome limitations of 5-fluorouracil (5-FU) that result from inefficient metabolism to 5-fluoro-2'-deoxyuridine-5'-mono- and tri-phosphate, the deoxyribonucleotide metabolites that are responsible for 5-FU's anticancer activity. F10 is much more cytotoxic than 5-FU to colorectal cancer (CRC) cells; however, the mechanism of enhanced F10 cytotoxicity remains incompletely characterized. Using DNA fiber analysis, we establish that F10 decreases replication fork velocity and causes replication fork collapse, while 1000-fold excess of 5-FU is required to achieve similar endpoints. Treatment of HCT-116 cells with F10 results in Chk1 phosphorylation and activation of intra-S-phase checkpoint. Combining F10 with pharmacological inhibition of Chk1 with either PF-477736 or prexasertib in CRC cells enhanced DNA damage relative to single-agent treatment as assessed by γH2AX intensity and COMET assay. PF-477736 or prexasertib co-treatment also inhibited upregulation of Rad51 levels in response to F10, resulting in reduced homologous repair. siRNA knockdown of Chk1 also increased F10-induced DNA damage assessed and sensitized CRC cells to F10. However, Chk1 knockdown did not inhibit Rad51 upregulation by F10, indicating that the scaffolding activity of Chk1 imparts activity in DNA repair distinct from Chk1 enzymatic activity. Our results indicate that F10 is cytotoxic to CRC cells in part through DNA damage subsequent to replication fork collapse. F10 is ~1000-fold more potent than 5-FU at inducing replication-mediated DNA damage which correlates with the increased overall potency of F10 relative to 5-FU. F10 efficacy can be enhanced by pharmacological inhibition of Chk1.

Correlation of tumor mutational burden and treatment outcomes in patients with colorectal cancer.

BACKGROUND: The Cancer Genome Atlas (TCGA) showed that 16% of colorectal cancers (CRCs) display DNA repair mechanisms and high tumor mutational burden (TMB). Although, there is accumulating evidence of greater benefit of immunotherapy in tumors with high-TMB, its impact on response to chemotherapy is unknown. METHODS: In this retrospective cohort study, we investigated the impact of TMB on progression-free survival (PFS) of CRC patients treated at tertiary care oncology clinics who had their tumors profiled by next-generation sequencing (NGS). Low TMB (TMB-L) and intermediate/high TMB (TMB-I/H) were defined as ≤5 mutations per base (MB) or ≥6 MB, respectively. RESULTS: Seventy-four CRC patients (61 colon and 13 rectal cancers) were identified from the database. In the TMB-L cohort, irinotecan-based chemotherapy treated patients had improved PFS compared to oxaliplatin-based chemotherapy treated patients (11.9 vs. 6.5 months, P<0.001). No difference in PFS was observed between the two treatment cohorts in TMB-I/H group. There was also no difference in time to recurrence in the TMB-L and TMB-I/H arms in patients treated with oxaliplatin-based therapy in perioperative setting. CONCLUSIONS: TMB-L may be a predictive biomarker in a subset of CRC patients treated with chemotherapy but these results need to confirmed in larger studies.

Wnt/beta-catenin pathway: modulating anticancer immune response.

Wnt/ß-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of ß-catenin in signal transduction. ß-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/ß-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/ß-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/ß-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials.

PURPOSE: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. METHODS: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. RESULTS: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. CONCLUSION: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.

Novel therapeutic agents in the treatment of metastatic colorectal cancer.

Over the past couple of decades considerable progress has been made in the management of metastatic colorectal cancers (mCRC) leading to a significant improvement in five-year survival. Although part of this success has been rightly attributed to aggressive surgical management and advances in other adjunct treatments, our understanding of the pathogenesis of cancer and emergence of newer molecular targets for colon cancer has created a powerful impact. In this review article we will discuss various targeted therapies in the management of mCRC. Newer agents on the horizon soon to be incorporated in clinical practice will be briefly reviewed as well.

FGFR3-TACC3 fusion in solid tumors: mini review.

Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies. FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies. The recently described FGFR3-TACC3 fusion protein has a constitutively active tyrosine kinase domain and promotes aneuploidy. We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors.

Spotlight on lenvatinib in the treatment of thyroid cancer: patient selection and perspectives.

Thyroid cancer is the most common endocrine malignancy, with over 60,000 cases reported per year in the US alone. The incidence of thyroid cancer has increased in the last several years. Patients with metastatic differentiated thyroid cancer (DTC) generally have a good prognosis. Metastatic DTC can often be treated in a targeted manner with radioactive iodine, but the ability to accumulate iodine is lost with decreasing differentiation. Until recently, chemotherapy was the only treatment in patients with advanced thyroid cancer, which is no longer amenable to therapy with radioactive iodine. The modest efficacy and significant toxicity of chemotherapy necessitated the need for urgent advances in the medical field. New insights in thyroid cancer biology propelled the development of targeted therapies for this disease, including the tyrosine kinase inhibitor sorafenib as salvage treatment for DTC. In 2015, the US Food and Drug Administration approved a second tyrosine kinase inhibitor, lenvatinib, for the treatment of radioiodine-refractory thyroid cancer. Although associated with a significant progression-free survival improvement as compared to placebo in a large Phase III study (median progression-free survival 18.2 vs 3.6 months; hazard ratio 0.21; 99% confidence interval 0.14-0.31; P<0.001), the benefit of lenvatinib needs to be proved in the context of associated moderate to severe toxicities that require frequent dose reduction and delays. This article reviews the evidence supporting the use of lenvatinib as salvage therapy for radioactive iodine-refractory thyroid cancer, with a focus on the toxicity profile of this new therapy.

The challenge of developmental therapeutics for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of only 0.7 new cases per million per year. Approximately 30-70% of the patients present with advanced disease with very poor prognosis and without effective therapeutic options. In the recent years, unprecedented progresses in cancer biology and genomics have fostered the development of numerous targeted therapies for various malignancies. Immunotherapy has also transformed the treatment landscape of malignancies such as melanoma, among others. However, these advances have not brought meaningful benefits for patients with ACC. Extensive genomic analyses of ACC have revealed numerous signal transduction pathway aberrations (e.g., insulin growth factor receptor and Wnt/ß-catenin pathways) that play a central role in pathophysiology. These molecular alterations have been explored as potential therapeutic targets for drug development. This manuscript summarizes recent discoveries in ACC biology, reviews the results of early clinical studies with targeted therapies, and provides the rationale for emerging treatment strategies such as immunotherapy.

Genomic characterization of high-risk non-muscle invasive bladder cancer.

The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors"). Fifteen patients had no progression ("non-progressors"). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. We found no difference in frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of deletions of CDKN2A/B was identified in tumors at progression (37%) compared to non-progressors (6%) (p = 0.10). We found a significant decrease in total mutational burden (TMB) that has been associated with immunotherapy response comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p = 0.02). This association suggests more advanced tumors have decreased neoantigen burden and may explain the mechanism of BCG response in non-progressors. We found no novel genetic drivers in progressors and HR-NMIBC had many genetic features similar to metastatic BC. Loss of CDKN2A/B may occur late during invasion of BC and may represent an important step in progression. Further research is necessary to evaluate TMB and loss of CDKN2A/B locus as a biomarker for progression of NMIBC.