Treatment Patterns and Attrition With Lines of Therapy for Advanced Urothelial Carcinoma in the US.

Importance: The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents. However, outcomes remain poor, and little is known about current treatment approaches and attrition rates for patients with aUC. Objectives: To delineate evolving treatment patterns and attrition rates in patients with aUC using a US-based patient-level sample. Design, Setting, and Participants: This retrospective cohort study used patient-level data from the nationwide deidentified electronic health record database Flatiron Health, originating from approximately 280 oncology clinics across the US. Patients included in the analysis received treatment for metastatic or local aUC at a participating site from January 1, 2011, to January 31, 2023. Patients receiving treatment for 2 or more different types of cancer or participating in clinical trials were excluded from the analysis. Main Outcomes and Measures: Frequencies and percentages were used to summarize the (1) treatment received in each line (cisplatin-based regimens, carboplatin-based regimens, programmed cell death 1 and/or programmed cell death ligand 1 [PD-1/PD-L1] inhibitors, single-agent nonplatinum chemotherapy, enfortumab vedotin, erdafitinib, sacituzumab govitecan, or others) and (2) attrition of patients with each line of therapy, defined as the percentage of patients not progressing to the next line. Results: Of the 12 157 patients within the dataset, 7260 met the eligibility criteria and were included in the analysis (5364 [73.9%] men; median age at the start of first-line treatment, 73 [IQR, 66-80] years). All patients commenced first-line treatment; of these, only 2714 (37.4%) progressed to receive second-line treatment, and 857 (11.8%) advanced to third-line treatment. The primary regimens used as first-line treatment contained carboplatin (2241 [30.9%]), followed by PD-1/PD-L1 inhibitors (2174 [29.9%]). The PD-1/PD-L1 inhibitors emerged as the predominant choice in the second- and third-line (1412 of 2714 [52.0%] and 258 of 857 [30.1%], respectively) treatments. From 2019 onward, novel therapeutic agents were increasingly used in second- and third-line treatments, including enfortumab vedotin (219 of 2714 [8.1%] and 159 of 857 [18.6%], respectively), erdafitinib (39 of 2714 [1.4%] and 28 of 857 [3.3%], respectively), and sacituzumab govitecan (14 of 2714 [0.5%] and 34 of 857 [4.0%], respectively). Conclusions and Relevance: The findings of this cohort study suggest that approximately two-thirds of patients with aUC did not receive second-line treatment. Most first-line treatments do not include cisplatin-based regimens and instead incorporate carboplatin- or PD-1/PD-L1 inhibitor-based therapies. These data warrant the provision of more effective and tolerable first-line treatments for patients with aUC.

Differences in Tumor Gene Expression Profiles Between De Novo Metastatic Castration-sensitive Prostate Cancer and Metastatic Relapse After Prior Localized Therapy.

BACKGROUND AND OBJECTIVE: It has been reported that patients with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) have worse prognosis and outcomes than those whose cancer relapses after prior local therapy (PLT-mCSPC). Our aim was to interrogate and validate underlying differences in tumor gene expression profiles between dn-mCSPC and PLT-mCSPC. METHODS: The inclusion criteria were histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data for treatment-naïve primary prostate tissue. RNA sequencing was performed by Tempus or Caris Life Sciences, both of which have Clinical Laboratory Improvement Amendments certification. The Tempus cohort was used for interrogation, while the Caris cohort was used for validation. Differential gene expression analysis between the cohorts was conducted using the DEseq2 pipeline. The resulting gene expression profiles were further analyzed using Gene Set Enrichment software to identify pathways with enrichment in each cohort. KEY FINDINGS AND LIMITATIONS: Overall, 128 patients were eligible, of whom 78 were in the Tempus cohort (dn-mCSPC 37, PLT-mCSPC 41) and 50 were in the Caris cohort (dn-mCSPC 30, PLT-mCSPC 20). Tumor tissues from patients with dn-mCSPC had higher expression of genes associated with inflammation pathways, while tissues from patients with PLT-mCSPC had higher expression of genes involved in oxidative phosphorylation, fatty acid metabolism, and androgen response pathways. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study revealed upregulation of distinct genomic pathways in dn-mCSPC in comparison to PLT-mCSPC. These hypothesis-generating data could guide personalized therapy for men with prostate cancer and explain different survival outcomes for dn-mCSPC and PLT-mCSPC. PATIENT SUMMARY: We measured gene expression levels in tumors from patients with metastatic castration-sensitive prostate cancer. In patients with metastatic disease at first diagnosis, inflammatory pathways were upregulated. In patients whose metastasis occurred on relapse after treatment, androgen response pathways were upregulated. These findings could help in personalizing therapy for prostate cancer and explaining differences in survival.

Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting. METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders. RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group. CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

INTRODUCTION: Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. METHODS: Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. RESULTS: Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. CONCLUSION: In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

Real-World Data on Liquid Biopsy Use in Non-Small Cell Lung Cancer in the Community Setting.

Introduction: The yield of adding plasma-based next-generation sequencing (NGS) to tissue NGS for the detection of actionable aberrations (AAs) has been reported; however, additional studies are needed to determine utility in the clinical setting. In this retrospective data review, we present our real world data on the utilization of liquid biopsies in the routine management of NCSLC patients, in a community setting. Methods: We conducted a retrospective review of 279 consecutive patients with non-small cell lung cancer (NSCLC) in the community setting, who had liquid biopsies performed between the years 2014 and 2019 as part of routine clinical management. Results: Over a period of 5 years, 337 liquid biopsy samples, taken from 279 patients were sent for plasma NGS testing. The median age at diagnosis was 73 years (range 36-93 y, SD 10.4 y), 141, (51%) were men and 138 (49%) were women. The majority were White or Caucasian (80% versus 8% Black or African American versus 12% Multiracial or unknown race) and had a history of smoking (79%). Excluding synonymous mutations and variants of unknown significance, 254 AAs were detected in 106 patients. Commonly detected AAs were EGFR (n = 127, 50%), KRAS (n = 61, 24%), BRAF (n = 24, 9.5%), and MET (n = 23, 9%). Tissue NGS detected AAs in 45 patients, with EGFR (n = 28, 57%) and KRAS (n = 10, 20%) being the most common AAs. Concordance agreement between plasma and tissue NGS modalities was detected in 39 of 45, 87% patients and was demonstrated most commonly in EGFR (n = 25) and KRAS (n = 11). In 44 of 106 (42%) of patients, for whom tissue NGS was not performed, additional precision treatment was guided by the AA detected through liquid biopsy. Conclusions: Integration of liquid biopsy into the routine management of patients with non-small cell lung cancer demonstrated AA detection in 44 additional patients, which comprise a 42% increase in AA detection rate, when tissue NGS was not performed.

Lung Adenocarcinoma Presenting as Multiple Thromboembolic Events: A Case Report and Review of the Literature.

Patients with malignancy may present with significant thromboembolic complications including deep vein thrombosis (DVT), pulmonary embolism, arterial thrombosis, nonbacterial thrombotic endocarditis, and stroke due to abnormal coagulation cascades. Although these events are typically recognized later in the disease process, complications of a hypercoagulable state can rarely present as the first manifestation of an occult malignancy. We report a case of a young male who was ultimately found to have an aggressive form of lung adenocarcinoma after the initial presentation of multiple thromboembolic events. DVT and stroke as an initial presentation of an active lung adenocarcinoma in a young patient is extremely rare as patients presenting in a hypercoagulable state usually are older. Though testing for a hypercoagulable state is not recommended for the first unprovoked DVT, clinicians should be prompted to screen for malignancy in the setting of cryptogenic strokes, especially in younger patients with no prior risk factors.

Circulating tumor DNA: Where are we now? A mini review of the literature.

For many years tissue biopsy has been the primary procedure to establish cancer diagnosis and determine further treatment and prognosis. However, this method has multiple drawbacks, including, to mention some, being an invasive procedure carrying significant risk for fragile patients and allowing only for a "snapshot" of the tumor biology in time. The process of liquid biopsy allows for a minimally invasive procedure that provides molecular information about underlying cancer by analyzing circulating tumor DNA (ctDNA) via next-generation sequencing technology and circulating tumor cells. This paper focuses on describing the basis of ctDNA and its current utilities.

Diagnosis and Treatment of Metastatic Disease to the Pancreas.

Introduction: Metastatic disease to the pancreas is a rare entity from all malignant pancreatic masses. Its diagnosis is very challenging, but with the introduction of endoscopic ultrasound (EUS)-fine needle aspiration (FNA), now there is a feasible way to make an accurate histopathological and definitive diagnosis. Materials and Methods: This is a retrospective review of 11 patients with metastasis to the pancreas diagnosed with EUS-FNA in a tertiary referral center over a period of 3 years. We describe our institutional experience in diagnosing metastatic disease to the pancreas through EUS-FNA. Results: Between January 2015 and June 2018, 115 patients were diagnosed with pancreatic malignancy by EUS-FNA and only 11 (10%) with metastatic disease to the pancreas. Most common primary malignancy was renal cell carcinoma, followed by colon carcinoma, squamous/small cell carcinoma of the lung, and urothelial carcinoma. Five of 11 patients presented as a solitary pancreatic mass on initial imaging without any evidence of primary or metastatic disease elsewhere. Conclusions: In our experience, metastatic disease to the pancreas can represent up to 10% of solid pancreatic masses, which is lower compared to the reported incidence in previous literature. Our findings reveal that early identification and diagnosis help patient management and limit surgical morbidity and mortality.

A Rare Case of Light Chain Amyloidosis of the Gastrointestinal Tract.

A 65-year-old Hispanic female presented with a one-year history of anorexia, nausea, early satiety, epigastric discomfort, and a 20 kg weight loss. Computed tomography (CT) demonstrated heterogeneous liver parenchyma. Upper endoscopy revealed large, fungating, infiltrative mass at the lesser gastric curvature incisura, highly suspicious of gastric tumor; however, initial biopsy of the gastric mass was equivocal and an exploratory laparoscopy was performed. Repeated intraoperative biopsies of the gastric mass and of liver parenchyma demonstrated diffuse hyalinized stroma consistent with amyloid deposition, and a bone marrow biopsy confirmed the diagnosis of primary light chain (AL) amyloidosis.

Reactivation of Epstein-Barr Virus Presenting as Massive Splenomegaly after Initiation of Golimumab Treatment.

Epstein-Barr virus infection is most commonly asymptomatic in the acute setting, where the end result of infection is the adoption of a viral latency phenotype. The virus can reactivate later in life leading to the abnormal proliferation of the infected B, T, or NK cells. Hereby, we report a 71-year-old female with seronegative rheumatoid arthritis who presented with massive splenomegaly, pancytopenia, and positivization of antibodies against double-stranded deoxyribonucleic acid (dsDNA) after initiation of the anti-tumor necrosis factor (TNF) golimumab. The diagnosis of EBV-associated lymphoproliferative disorder (LPD) was demonstrated by elevation of the plasmatic EBV viral load. Withdrawal of the anti-TNF and treatment with the anti-CD20 antibody rituximab were able to revert the clinical abnormalities. EBV-associated LPDs are described after initiation of other anti-TNF agents, such as infliximab, but no reports of golimumab-associated EBV LPD are found in the literature. The mechanisms for this occurrence are not clear, but these are known to involve expression of a panel of viral proteins specific to the viral latency phenotypes.

Primary Central Nervous System Lymphoma in an Immunocompetent Patient Presenting as Multiple Cerebellar Lesions: A Case Report and Review of Literature.

Primary central nervous system (CNS) lymphoma (PCNSL) is an uncommon extranodal non-Hodgkin lymphoma often presenting as a single brain lesion within the CNS. On histopathological evaluation of PCNSL a positive CD10, which is frequently observed in systemic diffuse large B-cell lymphoma, is present in approximately 10% of PCNSL. We describe a case of CD10-positive PCNSL presenting with multiple posterior fossa enhancing lesions in an immunocompetent older woman with a history of breast cancer successfully treated by the RTOG 0227 protocol consisting of pre-irradiation chemotherapy with high-dose methotrexate, rituximab, and temozolomide for 6 cycles, followed by low-dose whole-brain radiation and post-irradiation temozolomide.