Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways.

Immunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%, p = 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage of METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.

The prognostic role of cigarette smoking in Kidney Cancer Survival.

BACKGROUND: The role of cigarette smoking as a prognostic factor for kidney cancer (KC) is unclear. In this population-based study, we analyze cancer-specific survival (CSS) outcomes among KC patients by smoking status at diagnosis in the diverse state of Florida. METHODS: All primary KC cases from the Florida Cancer Registry diagnosed during 2005-2018 were analyzed. Cox proportional regression was conducted to assess the determinants of KC survival, including age, sex, race/ethnicity, socioeconomic status, histology type, cancer stage, and treatment received with a particular focus on smoking status (smokers at diagnosis referred to as current smokers, former smokers, and never smokers). RESULTS: Among all 36,150 KC patients, 18.3% were smokers at diagnosis (n = 6629), 32.9% were former smokers (n = 11,870), and 48.8% were never smokers (n = 17,651). Age-standardized five-year survival for current, former, and never smokers was 65.3 (95% CI: 64.1-66.5), 70.6 (95% CI: 69.7-71.5), and 75.3 (95% CI: 74.6-76.0) respectively. In multivariable analysis, current and former smokers had an estimated 30% and 14% higher risk of KC death compared to never smokers, respectively, after adjusting for potential confounders (HR: 1.30, 95% CI: 1.23-1.40; HR: 1.14, 95% CI: 1.10-1.20). CONCLUSION: Smoking independently contributes to poorer survival, across all KC stages. Clinicians should encourage and facilitate participation in cigarette smoking cessation programs targeted at current smokers. Prospective studies are warranted to assess the role of different types of tobacco use and cessation programs on KC survival.

The soluble guanylyl cyclase pathway is inhibited to evade androgen deprivation-induced senescence and enable progression to castration resistance.

Castration-resistant prostate cancer (CRPC) is fatal and therapeutically under-served. We describe a novel CRPC-restraining role for the vasodilatory soluble guanylyl cyclase (sGC) pathway. We discovered that sGC subunits are dysregulated during CRPC progression and its catalytic product, cyclic GMP (cGMP), is lowered in CRPC patients. Abrogating sGC heterodimer formation in castration-sensitive prostate cancer (CSPC) cells inhibited androgen deprivation (AD)-induced senescence, and promoted castration-resistant tumor growth. We found sGC is oxidatively inactivated in CRPC. Paradoxically, AD restored sGC activity in CRPC cells through redox-protective responses evoked to protect against AD-induced oxidative stress. sGC stimulation via its FDA-approved agonist, riociguat, inhibited castration-resistant growth, and the anti-tumor response correlated with elevated cGMP, indicating on-target sGC activity. Consistent with known sGC function, riociguat improved tumor oxygenation, decreasing the PC stem cell marker, CD44, and enhancing radiation-induced tumor suppression. Our studies thus provide the first evidence for therapeutically targeting sGC via riociguat to treat CRPC. Statement of significance: Prostate cancer is the second highest cancer-related cause of death for American men. Once patients progress to castration-resistant prostate cancer, the incurable and fatal stage, there are few viable treatment options available. Here we identify and characterize a new and clinically actionable target, the soluble guanylyl cyclase complex, in castration-resistant prostate cancer. Notably we find that repurposing the FDA-approved and safely tolerated sGC agonist, riociguat, decreases castration-resistant tumor growth and re-sensitizes these tumors to radiation therapy. Thus our study provides both new biology regarding the origins of castration resistance as well as a new and viable treatment option.

Clinicogenomic characterization of prostate cancer liver metastases.

BACKGROUND: The site of prostate cancer metastasis is an important predictor of oncologic outcomes, however, the clinicogenomic characteristics associated with the site are not well-defined. Herein, we characterize the genomic alterations associated with the metastatic site of prostate cancer. METHODS: We analyzed clinical and genomic data from prostate cancer patients with metastatic disease and known metastatic sites from publicly available targeted sequencing data. RESULTS: Prostate cancer metastasis to the liver versus other sites of metastasis conferred a high hazard for death in patients with metastatic prostate cancer (HR: 3.96, 95% CI: 2.4-6.5, p < 0.0001). Genomic analysis of metastatic tissues of prostate cancer-specific genes demonstrated that liver metastases were more enriched with MYC amplification (29.5% vs. 9.8%, FDR = 0.001), PTEN deletion (42% vs. 20.8%, FDR = 0.005), and PIK3CB amplification (8.2% vs. 0.9, FDR = 0.005) compared to other sites. No point mutations were significantly associated with liver metastasis compared to other metastatic sites. CONCLUSION: Liver metastases in prostate cancer are associated with poor survival and aggressive genomic features, including MYC-amplification, PTEN-deletion, and PIK3CB-amplification. These findings could have prognostic, treatment, and trial implications.

Kidney cancer mortality disparities among Hispanics in the US.

INTRODUCTION: Kidney cancer incidence is increasing among Hispanics but rate differences by distinct group, such as Cuban, Puerto Rican, and Mexican have not been studied. To fill this knowledge gap, we use mortality data, reflecting fatal kidney cancers, to examine patterns by race-ethnicity, including detailed Hispanic groups, and correlate the mortality rates with each group's prevalence of known kidney cancer risk factors: smoking, obesity, hypertension, diabetes, and chronic kidney disease. METHODS: We used individual-level death data for California, Florida, and New York (2008-2018), and population prevalence data from the National Health Interview Surveys (2008-2018). Age-adjusted mortality rates (AAMRs) and regression-derived mortality rate ratios (MRRs) were computed. Pearson correlation analyses assessed the extent to which group-specific risk factor prevalence explained variability in observed AAMRs. RESULTS: US-born Mexican Americans and American Indians had the highest rates and MRRs compared to Whites: 1.44 (95 %CI: 1.35-1.53) and 1.51 (1.38-1.64) for Mexican American men and women, respectively, and 1.54 (95 %CI: 1.25-1.89) and 1.53 (95 %CI: 1.15-2.04) for American Indians. In contrast, non-Mexican Hispanics had lower rates than Whites. Among males, positive correlations between AAMRs and smoking, obesity, and chronic kidney disease prevalence by race-ethnicity were found. CONCLUSION: Mexican Americans and American Indians are high-risk for fatal kidney cancer. Disparities are only partially attributable to higher smoking and obesity prevalence, and more so among men than women. A shared risk factor profile, as well as possible genetic similarities, may explain their disproportionately higher kidney cancer mortality, but further research is warranted.

Survival Disparities in Black Patients With EGFR-mutated Non-small-cell Lung Cancer.

BACKGROUND: Little is known about the difference between black and non-black patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), particularly regarding survival. We thus characterized the EGFR expression profile, clinical characteristics, and survival outcome in these patients. PATIENT AND METHODS: We reviewed the cancer registry and patient charts at a New York-Bronx network (n = 2773) treating a large population of minority patients, for non-squamous NSCLC (n = 1986) diagnosed between 2009 and 2015. Survival was adjusted for smoking, gender, age, weight, and stage. RESULTS: The EGFR mutation rate was 15% (98/652) in tested patients (black, 14%; non-black, 16%). There was no significant difference between the 2 cohorts with respect to age at diagnosis, gender, presenting stages, and socioeconomic status. On the other hand, weight was noted to be heavier in black patients with EGFR-mutated NSCLC than their non-black counterparts (P = .012). After adjusting for gender, age, smoking status, weight, and stage, the multivariate analysis revealed no racial disparity in survival among patients with wild-type EGFR (P = .774); However, among patients with EGFR-mutated NSCLC, black patients had shorter survival in comparison with non-black patients (P = .001), with 2-year survival rates being 33% versus 61%, respectively. Such shorter survival was also observed among EGFR-inhibitor treated patients with common EGFR mutations (P = .040). CONCLUSIONS: To our knowledge, this is the first report of inferior survival among black patients with NSCLC with EGFR mutations, relative to non-black patients. The survival disparities suggest the need of more tailored management for this patient population.

Patient Characteristics at Prostate Cancer Diagnosis in Different Races at an Academic Center Serving a Diverse Population.

BACKGROUND: In the United States, the prostate cancer (PCa) incidence and death rate has been greater in non-Hispanic black (NHB) men than in non-Hispanic white (NHW) men and slightly lower in Hispanic men than in NHW men. We compared the sociodemographic and baseline prognostic factors at the diagnosis of PCa in different races/ethnicities at a large, academic center serving an ethnically diverse population. METHODS: The Montefiore Medical Center Cancer Registry was used to generate a comprehensive list of all patients with PCa diagnosed from 2004 to 2014. The clinical Looking Glass (a proprietary searchable database of patient information) and individual patient medical record review were used to obtain data, including age at diagnosis, socioeconomic status (SES), clinical Gleason score, clinical stage, and prostate-specific antigen level at diagnosis. The patients were classified by self-identified race/ethnicity as Hispanic, NHB, NHW, or other. The χ2 test was used for categorical variables, and analysis of variance or the Kruskal-Wallis test was used for continuous variables. RESULTS: We identified 2352 patients with newly diagnosed PCa during the study period, including 778 Hispanic, 1046 NHB, 486 NHW, and 42 other. The NHW men were significantly older at diagnosis (Hispanic, 63.2 years; NHB, 63.4 years; NHW, 67 years; other, 63.0 years; P < .0001). The mean SES for the Hispanic and NHB men was significantly lower (SES below average: Hispanic, 92.8%; NHB, 91.3%; NHW, 56.6%; other, 75%; P < .0001). The Gleason score at diagnosis differed among these race groups (Gleason score ≤6 PCa: Hispanic, 42.8%; NHB, 39.1%; NHW, 52.2%; other, 50%; Gleason score 8-10: Hispanic, 15.8%; NHB, 17.6%; NHW, 14.3%; other, 16.7%; P = .0005). The proportion of men with metastatic disease at diagnosis also differed significantly among the groups (Hispanic, 7.5%; NHB, 9.0%; NHW, 4.3%; other, 9.5%; P = .0139). Using pairwise comparisons, the odds ratio for a higher Gleason score at presentation between NHB and NHW was 1.592 (P < .001) and was 1.378 for Hispanic versus NHW (P = .0200). The pairwise comparison for metastatic disease at diagnosis showed an odds ratio of 2.186 for NHB versus NHW (P = .0087). After adjusting for SES, the odds ratio for a higher Gleason score comparing NHB and NHW was 1.55 (P = .001). Although the odds of metastatic disease were greater in Hispanic men than in NHW men (odds ratio, 1.784), the differences were not statistically significant (P = .1197). CONCLUSIONS: At our center, the clinical features of men from different racial groups differed significantly at the time of newly diagnosed PCa. Differences included age at diagnosis, SES, Gleason score, and proportion with metastatic disease. Our pairwise comparisons between different ethnic groups suggested that PCa in Hispanic men might be more similar to that in NHB than to that in NHW patients and are generally more aggressive at diagnosis.

Hypersensitivity in ALK-positive lung cancers exposed to ALK inhibitors: a case of successful switch to an alternative ALK inhibitor and systematic review of the literature.

Alectinib can cause rare, but severe hypersensitivity. The cross-reactivity between different ALK inhibitors is unknown and desensitization is the only reported management. We hereby report the first case of severe delayed hypersensitivity developed in a lung cancer patient treated by alectinib, who was successfully managed by switching to brigatinib, another ALK inhibitor. The patient achieved excellent anti-tumor response to brigatinib. Our case provides an alternative and safe strategy in patients with alectinib-related hypersensitivity.

Synchronous Bone Metastasis From Multiple Myeloma and Prostate Adenocarcinoma as Initial Presentation of Coexistent Malignancies.

The radiographic appearance of bone metastases is usually determined by tumor histology and can be osteolytic, osteoblastic, or mixed. We present a patient with coexistent bone metastasis from multiple myeloma and prostate adenocarcinoma who exhibited synchronous bone involvement of both histologies within the same bone lesion, a rare phenomenon that has not been previously reported and led to atypical radiographic findings. The radiograph of a 71-year-old man with thigh swelling and pain demonstrated a lytic femoral lesion. Magnetic resonance imaging (MRI) confirmed a destructive process, but showed coexistent metaphyseal sclerosis. Multiple myeloma was suspected by demonstration of monoclonal gammopathy and confirmed by computed tomography (CT)-guided biopsy. Incidentally, CT demonstrated areas of sclerosis corresponding to T2 hypointensity on MRI. Further studies revealed osteoblastic spinal metastasis, prostate enhancement on CT and prostate-specific antigen (PSA) level of 90 ng/mL, concerning for concomitant prostate neoplasm. After endoprosthetic reconstruction, pathology of the femur identified both plasma cell neoplasm and metastatic prostate adenocarcinoma. An association between prostate cancer and multiple myeloma is hypothesized due to tumor microenvironment similarities and possible common genetic variations, however, coexisting bone metastases have never been reported. This unusual finding explains the discrepant imaging features in our patient and is evidenced that certain clinical situations merit contemplation of atypical presentations of common malignancies even if this leads to additional testing.

Update of systemic immunotherapy for advanced urothelial carcinoma.

PURPOSE: Until recently, therapeutic options for metastatic urothelial carcinoma (UC) were limited to cytotoxic chemotherapy. Cisplatin-based combination chemotherapy has proven benefit in the perioperative settings for muscle-invasive disease and for metastatic disease. A large proportion of patients is cisplatin-ineligible and limited to less effective chemotherapeutic options. However, treatment options have recently expanded with the development of systemic immunotherapy with checkpoint inhibitors (CPIs).Herein we review the clinical trial data supporting the use of CPIs in UC. We also describe ongoing clinical trials that are exploring CPIs in novel combinations and in a variety of disease settings. METHODS: A comprehensive literature review was performed using Medline/Pubmed and clinical trials. RESULTS/CONCLUSIONS: Based on results of the IMvigor 210 clinical trial, the anti-programmed death-ligand1 antibody atezolizumab gained regulatory approval in May 2016 for use in locally advanced and metastatic UC in patients with progression of disease despite prior platinum-based chemotherapy. Since that time, additional CPIs (avelumab, durvalumab, nivolumab, and pembrolizumab) have gained regulatory approval in the postplatinum setting. The approval of pembrolizumab was supported by KEYNOTE-045, the first reported randomized, phase III trial of a CPI in UC. Atezolizumab and pembrolizumab are also approved for first-line therapy for cisplatin-ineligible patients with locally advanced or metastatic disease. The rapid expansion of therapeutic options in UC has shifted the treatment paradigm.

Emerging treatment for ALK-positive lung cancer.

INTRODUCTION: Lung cancer is associated with poor prognosis and limited benefit from chemotherapy. The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the discovery of targetable genetic alterations, including the ALK fusion oncogene. AREAS COVERED: Three drugs have been approved for clinical use in ALK-positive patients - crizotinib, ceritinib and alectinib. Unfortunately, treatment resistance inevitably develops. Several mechanisms of acquired resistance are reported. In this review, we will discuss emerging treatment options in ALK-positive advanced NSCLC and strategies to overcome resistance mechanisms, including newer generation of ALK inhibitors, Hsp90 inhibitors and immunotherapy. EXPERT OPINION: Tremendous advances have been made in the treatment of ALK-positive lung cancers, but management hurdles still exist, including universal development of resistance to ALK inhibitors and limited CNS activity. Given that specific treatment strategies target distinct patterns of resistance, re-biopsy at the time of progression appears necessary to optimize management. However, there remain many issues in routine clinical application including the burden placed on the patients by serial biopsies and the risks of repeat invasive procedures. Future studies are needed to validate the usage of non- or minimally invasive tests and to determine the optimal orders of utilizing different ALK inhibitors.

Medical Treatment in Elderly Patients with Non-Small Cell Lung Cancer.

OPINION STATEMENT: Lung cancer is the leading cause of cancer-related deaths worldwide. In the USA, ≈60 % of lung cancer cases are diagnosed in elderly patients (≥65 years of age). However, elderly patients are underrepresented in clinical studies, leading to a paucity of evidence to guide treatment decisions. Several treatment barriers exist in elderly patients, including comorbidities and poor performance status. In addition, lack of reliable geriatric assessment tools and physician reluctance to treat may contribute to undertreatment in this population. For decades, systemic chemotherapy for elderly patients with advanced non-small cell lung cancer (NSCLC) was either omitted or given as monotherapy, frequently with significant dose reductions, potentially compromising the efficacy of these therapies. Recent analyses of elderly subgroups from multiple clinical trials provide evidence for improved outcomes associated with platinum-based doublet chemotherapies vs monotherapy. Moreover, in the new era of precision medicine, molecularly targeted therapies and more recently immune-targeting therapies (anti-PD-1 and anti-PD-L1 agents) exhibit relatively milder toxicities but superior clinical outcomes in subgroups of patients compared with conventional cytotoxic chemotherapies. Further clinical trials will be needed to confirm similar safety and efficacy profiles of these therapeutic approaches in the elderly compared with their younger counterparts. In this article, we review available evidence from clinical studies and also present expert consensus on the management of NSCLC in the elderly, including treatment in the adjuvant setting and treatment of advanced disease. Screening tools, such as the Comprehensive Geriatric Assessment, that help to identify the right population of elderly patients suitable for systemic treatment are also discussed.