Role of Cytoreductive Nephrectomy in Metastatic Clear Cell Renal cell Carcinoma in the Era of immunotherapy: An Analysis of the National Cancer Database.

BACKGROUND: The effectiveness of the clinical outcome of CN (Cytoreductive Nephrectomy) in cases of mccRCC (Metastatic Clear Cell Renal cell Carcinoma) is still uncertain despite two trials, SURTIME and CARMENA. These trials, conducted with Sunitinib as the standard treatment, did not provide evidence supporting the use of CN. METHODS: We queried the NCDB for stage IV mccRCC patients between the years of 2004 to 2020, who received (immunotherapy) IO with or without nephrectomy. Overall survival (OS) was calculated among three groups of IO alone, IO followed by CN (IOCN), CN followed by IO (CNIO). Cox models compared OS by treatment group after adjusting for sociodemographic, health, and facility variables. RESULTS: From 1,549,101 renal cancer cases, 7983 clear and nonclear cell renal cell carcinoma cases were identified. After adjusting for sociodemographic and health covariates, patients who received IO followed by CN or CN followed by IO had a respective 64% (adjusted Hazard Ratio [aHR] = 0.36, 95% CI = 0.30-0.43, P = .006] and 47% (aHR = 0.53, 95% CI = 0.49-0.56, P = .001) mortality risk reduction respectively compared to patients who received IO alone. Compared to White adults, individuals who identified as Black exhibited 17% higher risk mortality (aHR = 1.17, 95% CI = 1.06-1.30, P = .002). Patients who received CN prior to IO had a 59% associated mortality risk compared to patients who received IO followed by CN who had a lower risk, 35.7% (P < .001). CONCLUSIONS: Patients receiving CN regardless of sequence with IO did better than IO alone in this national registry-based adjusted analysis for mccRCC. Presently available data indicates that the combination of CN and IO holds promise for enhancing clinical results in patients with mRCC.

Use of UV mutational signatures to distinguish between cutaneous and pulmonary primary squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of presumed lung origin (PLO) is now the second most frequent histologic subtype of non-small cell carcinoma after adenocarcinoma. The use of clinic-genomic correlation provided by comprehensive genomic profiling (CGP) can revise clinicopathologic diagnoses of presumed primary lung SCC (PLO-SCC) to diagnoses of metastatic SCC of cutaneous origin (C-SCC). DESIGN: A total of 10 146 samples of clinically advanced PLO-SCC (84% known Stage IV) passed QC metrics and were designated as PLO-SCCs by review of test requisition forms, clinical notes, and pathology reports. One thousand seven hundred sixty-one cases of known primary C-SCC were also included in this study. All samples underwent hybrid capture-based CGP (Foundation Medicine, Inc.) using a targeted gene panel to evaluate all classes of genomic alterations (GA), determine MSI, TMB, and genomic ancestry status. The mutational signature (MS) of each case was called by the decomposition method using reference signatures in the COSMIC database. PD-L1 tumor cell expression was determined by IHC (22C3; Dako). All results were compared using the Fisher exact method with the false discovery rate corrected with a Benjamini-Hochberg adjustment. RESULTS: A total of 253 of 10 146 (2.5%) PLO-SCC cases featured a UV+ MS; 812 of 1761 C-SCC (46.1%) that also featured a UV radiation exposure MS (UV+) were also included in this study. PLO-SCC UV+ cases used for sequencing included tissue samples from the lung (162), lymph node (34), soft tissue (33), liver (8), head and neck (7), brain (5), and skin thought to be metastatic sites from primary lung SCC (4). The PLO-SCC UV+ patients were 78.7% male and had a median age of 72 years, which was younger and more frequently male gender than both the C-SCC UV+ and C-SCC UV- patients (p < 0.0001). Both the PLO-SCC UV+ and C-SCC UV+ featured greater GA per tumor than the PLO-SCC UV- cases (p < 0.0001). In the PLO-SCC UV- cases, tobacco exposure and APOBEC were the most frequent MSs. For the biomarkers associated with immune checkpoint inhibitor efficacy, when compared with the PLO-SCC UV- cases, the PLO-SCC UV+ cases featured more cases with TMB ≥10 mutations/Mb (88.5% vs. 36.5%; p < 0.0001) and ≥20 mutations/Mb (66.8% vs. 6.8%; p < 0.0001) and a trend for less frequent positive PD-L1 (≥50% TPS) IHC staining (30.2% vs. 39.6%; p = 0.062). Compared to PLO-SCC UV- cases, PLO-SCC UV+ and C-SCC UV+ cases were more likely to harbor clinically-actionable GA in PTCH1 and NOTCH1/2 (p < 0.0001) and less likely to harbor clinically-actionable GA in KRAS, PIK3CA, and PTEN (p < 0.0001). The frequency of PTCH1 GA in PLO-SCC UV+ (32% vs. 0.9% in PLO-SCC UV-) suggested that PLO-SCC UV+ may include a mixture of C-SCC and cutaneous basal cell carcinomas (C-BCC) with squamous differentiation. CONCLUSIONS: When cases of PLO-SCC undergo CGP, a small 2.5% subset of cases that featured a UV MS emerge that indicates that these tumors may actually represent metastatic cutaneous SCC or BCC with squamous differentiation. Given the significant treatment and clinical impact associated with the resolution of the true diagnosis of these cases, the use of genomic sequencing in PLO-SCC may be clinically beneficial.

Neutrophil estimation and prognosis analysis based on existing lung squamous cell carcinoma datasets: the development and validation of a prognosis prediction model.

Background: Notwithstanding the rapid developments in precision medicine in recent years, lung cancer still has a low survival rate, especially lung squamous cell cancer (LUSC). The tumor microenvironment (TME) plays an important role in the progression of lung cancer, in which high neutrophil levels are correlated with poor prognosis, potentially due to their interactions with tumor cells via pro-inflammatory cytokines and chemokines. However, the precise mechanisms of how neutrophils influence lung cancer remain unclear. This study aims to explore these mechanisms and develop a prognosis predictive model in LUSC, addressing the knowledge gap in neutrophil-related cancer pathogenesis. Methods: LUSC datasets from the Xena Hub and Gene Expression Omnibus (GEO) databases were used, comprising 473 tumor samples and 195 tumor samples, respectively. Neutrophil contents in these samples were estimated using CIBERSORT, xCell, and microenvironment cell populations (MCP) counter tools. Differentially expressed genes (DEGs) were identified using DEseq2, and a weighted gene co-expression network analysis (WGCNA) was performed to identify neutrophil-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression model was constructed for prognosis prediction, and the model's accuracy was validated using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC) curves. Additionally, genomic changes, immune correlations, drug sensitivity, and immunotherapy response were analyzed to further validate the model's predictive power. Results: Neutrophil content was significantly higher in adjacent normal tissue compared to LUSC tissue (P<0.001). High neutrophil content was associated with worse overall survival (OS) (P=0.02), disease-free survival (DFS) (P=0.02), and progression-free survival (PFS) (P=0.03) using different software estimates. Nine gene modules were identified, with blue and yellow modules showing strong correlations with neutrophil prognosis (P<0.001). Eight genes were selected for the prognostic model, which accurately predicted 1-, 3-, and 5-year survival in both the training set [area under the curve (AUC) value =0.60, 0.63, 0.66, respectively] and validation set (AUC value =0.58, 0.58, 0.59, respectively), with significant prognosis differences between high- and low-risk groups (P<0.001). The model's independent prognostic factors included risk group, pathologic M stage, and tumor stage (P<0.05). A further molecular mechanism analysis revealed differences between risk groups were revealed in immune checkpoint and human leukocyte antigen (HLA) gene expression, hallmark pathways, drug sensitivity, and immunotherapy responses. Conclusions: This study established a risk-score model that effectively predicts the prognosis of LUSC patients and sheds light on the molecular mechanisms involved. The findings enhance the understanding of neutrophil-tumor interactions, offering potential targets for personalized treatments. However, further experimental validation and clinical studies are required to confirm these findings and address study limitations, including reliance on public databases and focus on a specific lung cancer subtype.

Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Genomic Profiles and Clinical Outcomes of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden.

Importance: Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC). Objective: To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting. Design, Setting, and Participants: In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low (<10 mutations per megabase [mut/Mb]), high (10-19 mut/Mb), or very high (≥20 mut/Mb). Germline status of genetic alterations was predicted using a validated somatic-germline computational method. Clinical outcomes of patients with metastatic PSCC receiving first-line ICI were abstracted using the deidentified nationwide Clinico-Genomic Database (CGDB) from January 1, 2011, through December 31, 2022. Exposure: Comprehensive genomic profiling was performed using FoundationOne and FoundationOne CDx assays from Foundation Medicine Inc. Main outcomes and measures: The spectrum of genetic alterations by TMB level in PSCC, the percentage of germline genetic alterations, and the outcome (overall survival with routine clinical treatment) by TMB of chemotherapy-naive patients with PSCC who received ICI treatment up front were assessed in this descriptive study. Results: Among 397 patients (median [IQR] age, 65 [54-73] years; 266 [67.0%] of European, 83 [20.9%] of admixed American, and 34 [8.5%] of African or other genomic ancestry), the median (IQR) age (eg, 65 [53-73] years for low TMB vs 68 [61-78] years for TMB ≥10 mut/Mb) and genomic ancestry distribution (eg, European 228 of 339 [67.3%] for low TMB vs 38 of 58 [65.5%] for TMB ≥10 mut/Mb) were similar between TMB subgroups. There were 339 PSCC cases (85.4%) with low TMB, 40 cases (10.1%) with high TMB, and 18 cases (4.5%) with very high TMB. Comparisons of TMB of 10 mut/Mb or higher vs low TMB showed an enrichment of genetic alterations in PIK3CA (48.3% vs 18.3%; P < .001) and KMT2D (29.3% vs 7.7%; P < .001) and less frequent genetic alterations in CDKN2A (25.9% vs 45.7%; P = .05). Most genetic alterations did not co-occur. Human papillomavirus identification was more frequent as TMB increased: 28.3% for low TMB, 50.0% for high, and 72.2% for very high. In total, 95 of 1377 genetic alterations (6.9%) were germline. Of 10 patients identified from the CGDB receiving frontline ICIs, median (IQR) follow-up was 9.9 months. Four patients had overall survival with clinical treatment of more than 12 months, including 2 of 3 patients with TMB of 10 mut/Mb or higher. Conclusions and Relevance: In this cohort study of advanced metastatic PSCC based on TMB levels, significant differences were observed for biomarkers in nearly 15% of patients with a TMB of 10 mut/Mb or higher. Germline testing and ICI-based therapy should be integrated into the management of selected PSCC cases.

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.

Introduction: KRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA. Methods: Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed. Results and discussion: Our cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.

Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data.

BACKGROUND: Adjuvant chemotherapy (AC) is indicated for stage II and stage III lung adenocarcinomas (ADC). Using the LACE Bio II database, we analyzed the distribution of various mutations across the subtypes of ADCs and studied the prognostic and predictive roles of PD-L1, TMB, and Tumor Infiltrating Lymphocytes (TILs). MATERIALS AND METHODS: Clinical and genomic data from the LACE Bio II data were extracted. Patients were divided into ADC subtypes, in which the grouping was done based on their known clinical behavior (Lepidic [LEP], Acinar/Papillary [ACI or PAP], Micropapillary/Solid [MIP or SOL], Mucinous [MUC] and Others). Kaplan-Meier (KM) and log-rank test were used to compare survival based on PD-L1, TMB, TILs and combinations of TMB with PD-L1 and TILs. Adjusted Hazard Ratios (HR) were analyzed with Overall Survival (OS), Disease-Free Survival (DFS) and Lung Cancer-Specific Survival (LCSS) as endpoints. RESULTS: A total of 375 ADC patients were identified. MIP/SOL was the subtype most commonly positive for various biomarkers. PD-L1 Negative/high TMB was associated with better outcomes in terms of OS (HR = 0.46 [0.23-0.89], P = .021) and DFS (HR = 0.52 [0.30-0.90], P = .02), relative to PD-L1 Negative/low TMB. High TMB predicted worse outcome with AC use in terms of OS (ratio of hazard ratio rHR = 2.75 [1.07-7.04], P = .035). Marked TILs had better outcome with AC for DFS (rHR = 0.22 [0.06-0.87], P = .031 and LCSS (rHR = 0.08 [0.01-0.66], P = .019) respectively. There was also a beneficial effect of AC among patients with Marked TILs/low TMB in terms of DFS (rHR = 0.06 [0.01-0.53], P = .011). CONCLUSION: High TMB has a prognostic role in resectable lung ADC. The high TMB group had a poor outcome with AC, suggesting that this group may be better served with immune checkpoint therapy.

Does a prior cancer diagnosis impact PSA testing? Results from the National Health Interview Survey.

INTRODUCTION: Prostate-specific antigen (PSA) testing remains a controversial issue. However, most urological guidelines recommend PSA testing in men aged 55-69 through a shared decision-making process with the patient. The impact of prior cancer diagnosis on PSA testing is not well-known. To compare PSA testing in men aged 55-69 years with and without a history of cancer (excluding prostate cancer patients). MATERIALS AND METHODS: Utilizing the National Health Interview Survey (NHIS), a retrospective cross-sectional study during the year 2018 was carried out. Multivariable logistic regression analysis was implemented to demonstrate potential associations with PSA testing and assess the association of cancer history. RESULTS: A total of 2,892 men aged 55-69 years from the NHIS survey who met the inclusion criteria were analyzed. A total of 308 (10.7%) men had a history of cancer (non-prostate). Men with a cancer history had a higher number of PSA tests and more recent testing than men with no previous cancer history. On multivariable analysis, men who were previously diagnosed with cancer had a higher likelihood of undergoing PSA testing compared to men with no history of cancer (OR: 1.87, 95% CI 1.39-2.52, p < 0.0001). CONCLUSIONS: Our data suggest that men aged 55-69 with a history of cancer are more likely to undergo PSA testing than men with no cancer history.

Disparities Associated with Shared Decision-making in Prostate Cancer Screening.

BACKGROUND: Prostate cancer screening guidelines recommend shared decision-making (SDM) regarding prostate-specific antigen (PSA) testing. However, it is unclear who undergoes SDM and whether any disparities exist. OBJECTIVE: To examine sociodemographic differences in participation of SDM and its association with PSA testing in prostate cancer screening. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cross-sectional study was conducted among men aged 45-75 yr undergoing PSA screening, using the 2018 National Health Interview Survey database. The evaluated sociodemographic features included age, race, marital status, sexual orientation, smoking status, working status, financial difficulty, US geographic regions, and cancer history. Questions regarding self-reported PSA testing and whether respondents discussed its advantages and disadvantages with their healthcare provider were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary outcome was to evaluate the possible associations between various sociodemographic factors and undergoing PSA screening and SDM. We used multivariable logistic regression analyses to detect potential associations. RESULTS AND LIMITATIONS: A total of 59596 men were identified, of whom 5605 answered the question regarding PSA testing, with 2288 (40.6%) undergoing PSA testing. Of these men, 39.5% (n = 2226) discussed the advantages and 25.6% (n = 1434) discussed the disadvantages of PSA testing. On a multivariable analysis, older (odds ratio [OR] 1.092; 95% confidence interval [CI] 1.081-1.103, p < 0.001) and married (OR 1.488; 95% CI 1.287-1.720, p < 0.001) men were more likely to undergo PSA testing. Although Black men were more likely to discuss PSA advantages (OR 1.421; 95% CI 1.150-1.756, p = 0.001) and disadvantages (OR 1.554; 95% CI 1.240-1.947, p < 0.001) than White men, this did not correlate with higher rates of PSA screening (OR 1.086; 95% CI 0.865-1.364, p = 0.477). The lack of important clinical data remains a limitation. CONCLUSIONS: Overall, SDM rates were low. Older and married men had an increased likelihood of SDM and PSA testing. Despite higher rates of SDM, Black men had similar rates of PSA testing to White men. PATIENT SUMMARY: We evaluated sociodemographic differences in shared decision-making (SDM) in prostate cancer screening using a large national database. We found that SDM had varying results in different sociodemographic groups.

Urothelial Bladder Cancer: Genomic Alterations in Fibroblast Growth Factor Receptor.

BACKGROUND AND OBJECTIVE: Genomic alterations in fibroblast growth factor receptor (FGFR) genes have been linked to a reduced response to immune checkpoint inhibitors. Some of the immune microenvironment of urothelial bladder cancer (UBC) could be distorted because of the inhibition of interferon signaling pathways. We present a landscape of FGFR genomic alterations in distorted UBC to evaluate the immunogenomic mechanisms of resistance and response. METHODS: There were 4035 UBCs that underwent hybrid, capture-based comprehensive genomic profiling. Tumor mutational burden was determined in up to 1.1 Mbp of sequenced DNA and microsatellite instability was determined in 114 loci. Programmed death ligand expression in tumor cells was assessed by immunohistochemistry (Dako 22C3). RESULTS: The FGFR tyrosine kinases were altered in 894 (22%) UBCs. The highest frequency of alterations was in FGFR genomic alterations with FGFR3 at 17.4% followed by FGFR1 at 3.7% and FGFR2 at 1.1%. No FGFR4 genomic alterations were identified. The age and sex distribution were similar in all groups. Urothelial bladder cancers that featured FGFR3 genomic alterations were associated with lower driver genomic alterations/tumors. 14.7% of the FGFR3 genomic alterations were FGFR3 fusions. Other findings included a significantly higher frequency of ERBB2 amplification in FGFR1/2-altered UBCs compared with FGFR3-altered UBCs. Urothelial bladder cancers with FGFR3 genomic alterations also had the highest frequency of the activating mTOR pathway. FGFR3-altered UBCs also featured significantly higher frequencies of biomarkers associated with a lack of response to immune checkpoint inhibitors including a lower tumor mutational burden, lower programmed death-ligand 1 expression, and higher frequencies of genomic alterations in MDM2. Also linked to IO drug resistance, CDKN2A/B loss and MTAP loss were observed at a higher frequency in FGFR3-driven UBC. CONCLUSIONS: An increased frequency of genomic alterations is observed in UBC FGFR. These have been linked to immune checkpoint inhibitor resistance. Clinical trials are needed to evaluate UBC FGFR-based biomarkers prognostic of an immune checkpoint inhibitor response. Only then can we successfully incorporate novel therapeutic strategies into the evolving landscape of UBC treatment.

Novel synthetic lethality drug target in urothelial bladder cancer based on MTAP genomic loss.

BACKGROUND: When urothelial carcinoma of the bladder (UCB) presents or progresses to chemo-refractory metastatic disease, the search for new therapeutic targets is paramount. Targeting protein arginine methyltransferase 5 accumulation in tumors with methylthioadenosine phosphorylase (MTAP) genomic loss has been proposed as a new anti-tumor strategy. We evaluated the incidence of patients with MTAP loss and correlate to treatment-guiding targets and biomarkers. METHODS: Two thousand six hundred eighty-three cases of advanced UCB underwent hybrid-capture based comprehensive genomic profiling using the FDA-approved F1CDx assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden was determined on at least 0.8 Mbp of sequenced DNA and microsatellite instability was determined on at least 95 loci. RESULTS: 650 (24%) of UCB featured MTAP loss mutations (MTAP-). The gene and age distributions were similar in MTAP intact (MTAP+) and MTAP- UCB. MTAP- UCB contained higher GA/tumor frequency than MTAP+ UCB likely reflecting the frequent co-deletions of cyclin-dependent kinase inhibitor 2A/B. Of potential therapeutic targets, fibroblast growth factor receptor 3, and phosphatase and tensin homolog GA were more frequent in MTAP- UCB. In contrast, biomarkers of immunotherapy response, including higher frequencies of high tumor mutational burden and high programmed death-ligand 1 IHC staining, were observed in the MTAP+ UCB. CONCLUSIONS: When compared with MTAP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potentially targetable alterations but a lower frequency of immunotherapy drug biomarkers. Thus, the genomic landscape in MTAP- UCB may play a role in the design of clinical trials incorporating combination treatment strategies when targeting protein arginine methyltransferase 5 in MTAP- tumors.

Financial Toxicity and Its Association With Prostate and Colon Cancer Screening.

BACKGROUND: The term "financial toxicity" or "hardship" is a patient-reported outcome that results from the material costs of cancer care, the psychological impacts of these costs, and the coping strategies that patients use to deal with the strain that includes delaying or forgoing care. However, little is known about the impact of financial toxicity on cancer screening. We examined the effects of financial toxicity on the use of screening tests for prostate and colon cancer. We hypothesized that greater financial hardship would show an association with decreased prevalence of cancer screening. METHODS: This cross-sectional survey-based US study included men and women aged ≥50 years from the National Health Interview Survey database from January through December 2018. A financial hardship score (FHS) between 0 and 10 was formulated by summarizing the responses from 10 financial toxicity dichotomic questions (yes or no), with a higher score associated with greater financial hardship. Primary outcomes were self-reported occurrence of prostate-specific antigen (PSA) blood testing and colonoscopy for prostate and colon cancer screening, respectively. RESULTS: Overall, 13,439 individual responses were collected. A total of 9,277 (69.03%) people had undergone colonoscopies, and 3,455 (70.94%) men had a PSA test. White, married, working men were more likely to undergo PSA testing and colonoscopy. Individuals who had not had a PSA test or colonoscopy had higher mean FHSs than those who underwent these tests (0.70 and 0.79 vs 0.47 and 0.61, respectively; P≤.001 for both). Multivariable logistic regression models demonstrated that a higher FHS was associated with a decreased odds ratio for having a PSA test (0.916; 95% CI, 0.867-0.967; P=.002) and colonoscopy (0.969; 95% CI, 0.941-0.998; P=.039). CONCLUSIONS: Greater financial hardship is suggested to be associated with a decreased probability of having prostate and colon cancer screening. Healthcare professionals should be aware that financial toxicity can impact not only cancer treatment but also cancer screening.

Older Patients with Lung Cancer: a Summary of Seminal Contributions to Optimal Patient Care.

PURPOSE OF REVIEW: This review aspires to summarize the landmark advancements in the management of the non-small cell lung cancer (NSCLC), both historically and contemporarily with special focus in older adults. RECENT FINDINGS: The past two decades have witnessed remarkable improvements in the diagnosis and management of lung cancer. Screening recommendations now facilitate earlier diagnosis in high-risk individuals, PET/CT scans have improved radiologic accuracy in identifying sites of disease, and surgical management with minimally invasive techniques has rendered surgery safer in those with limited physiologic reserve. Radiation enhancements, especially radiosurgery, have extended the reach and safety of radiation among high-risk populations. Finally, the revolution in precision medicine with identification of numerous actionable mutations, the advent of immunotherapy, and enhanced supportive care have revolutionized the outcomes in patients with advanced lung cancer. Older adults who represent a majority of patients battling lung cancer have not benefitted to the same extent as their younger counterparts. This special population is only expected to grow in coming days. Hence, addressing major gaps in the management of older adults with NSCLC and optimizing the care are much needed.

Acquired Hemophilia as a Paraneoplastic Syndrome in a Patient With Small Cell Lung Carcinoma.

This case report describes a 72-year-old female patient diagnosed with small cell lung carcinoma who was found to have elevated partial thromboplastin time (PTT) after reporting diarrhea and melanotic stool. Further investigations revealed the presence of a factor VIII inhibitor, possibly resulting from a side effect of immunotherapy or of possible paraneoplastic origin. The patient's PTT remained elevated following a course of steroid treatment, raising the likelihood of paraneoplastic etiology. This case represents a rare paraneoplastic syndrome, with a previously unreported presentation of melanotic stool as opposed to an acute bleeding episode.

Diagnosis and Management of Denosumab-Induced Hypocalcemia and Hypophosphatemia in the Setting of Metastatic Prostate Cancer.

Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANK-L) monoclonal antibody used in osteoporosis and various malignancies, has been shown to cause hypocalcemia shortly after initiation of treatment. There have been few case reports of electrolyte abnormalities in patients managed with long-term treatment with this medication. This report presents the case of a 43-year-old male with metastatic prostate cancer who presented with severe hypophosphatemia and hypocalcemia, initially resistant to repletion. After more aggressive and persistent repletion with IV calcium, phosphorus, and vitamin D, as well as time for the denosumab to dissipate, the patient's electrolytes stabilized and he was able to be discharged with oral replacement and close follow-up. Therefore, long-term monitoring of electrolytes for patients on denosumab should be carefully considered.

Association of Race With Cancer-Related Financial Toxicity.

PURPOSE: We investigated the association between race and FT among previous patients with cancer. Studies show that patients with cancer experience financial toxicity (FT) because of their cancer treatment. METHODS: Data on individuals with a cancer history were collected in this cross-sectional study during 2012, 2014, and 2017, from the US Health Information National Trends Survey. This survey is conducted by mail with monetary compensation as an incentive. We specifically assessed responses to two questions: Has cancer hurt you financially? Have you been denied health insurance because of cancer? Multivariable logistic regression analyses were used to assess the associations between these questions and race. RESULTS: Of 10,592 individuals participating, 1,328 men and women (12.5%) with a cancer history were assessed. Compared with Blacks, Whites were found to have a higher rate of insurance (95.4% v 90.0%), were more likely to receive cancer treatment (93.9% v 85%), and had a higher rate of surgical treatment than Blacks (77% v 60%), Hispanics (55%), and others (77%, 60%, 55%, and 74.2%, respectively, P < .001). On multivariable analysis, Blacks were more than five times as likely to be denied insurance (odds ratio, 5.003; 95% CI, 2.451 to 10.213; P < .001) and more than twice as likely to report being hurt financially because of cancer (odds ratio, 2.448; 95% CI, 1.520 to 3.941; P < .001) than Whites. Of all cancer groups analyzed (genitourinary, gynecologic, gastrointestinal, and breast), genitourinary malignancies were the only group in which the rate of reporting being hurt financially varied in a statistically significant manner (Whites 36.7%, Hispanics 62.5%, and Blacks 59.3%, P = .004). CONCLUSION: Our data suggest that race is significantly associated with FT because of cancer. Awareness of racial inequality with regards to FT should be raised among health care workers.