Biomarkers: the next therapeutic hurdle in metastatic renal cell carcinoma

Despite recent advances, metastatic renal cell carcinoma remains largely an incurable disease. Vascular endothelial growth factor and mammalian target of rapamycin inhibitors have provided improvements in clinical outcomes. High-dose interleukin 2 remains an option for highly selected patients and is associated with durable remissions in a small minority of patients. The toxicity profiles of specific agents and patient characteristics and comorbidities and costs have an important role in the current choice of therapy. Major challenges encountered in developing molecular biomarkers to guide therapy are tumour heterogeneity and standardisation of tissue collection and analysis. Although biomarkers are in their infancy of development, they should be a priority in early preclinical and clinical development in order to guide rational tailored development of emerging agents

Pan-urologic cancer genomic subtypes that transcend tissue of origin

AbstractUrologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes—reflecting in part tumor microenvironmental influences—driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways—including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint—can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.</jats:p

Disparities in selective referral for cancer surgeries: implications for the current healthcare delivery system

Objectives: Among considerable efforts to improve quality of surgical care, expedited measures such as a selective referral to high-volume institutions have been advocated. Our objective was to examine whether racial, insurance and/or socioeconomic disparities exist in the use of high-volume hospitals for complex surgical oncological procedures within the USA. Design, setting and participants Patients undergoing colectomy, cystectomy, oesophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy or prostatectomy were identified retrospectively, using the Nationwide Inpatient Sample, between years 1999 and 2009. This resulted in a weighted estimate of 2 508 916 patients. Primary outcome measures Distribution of patients according to race, insurance and income characteristics was examined according to low-volume and high-volume hospitals (highest 20% of patients according to the procedure-specific mean annual volume). Generalised linear regression models for prediction of access to high-volume hospitals were performed. Results: Insurance providers and county income levels varied differently according to patients’ race. Most Caucasians resided in wealthier counties, regardless of insurance types (private/Medicare), while most African Americans resided in less wealthy counties (≤$24 999), despite being privately insured. In general, Caucasians, privately insured, and those residing in wealthier counties (≥$45 000) were more likely to receive surgery at high-volume hospitals, even after adjustment for all other patient-specific characteristics. Depending on the procedure, some disparities were more prominent, but the overall trend suggests a collinear effect for race, insurance type and county income levels. Conclusions: Prevailing disparities exist according to several patient and sociodemographic characteristics for utilisation of high-volume hospitals. Efforts should be made to directly reduce such disparities and ensure equal healthcare delivery

Assessing population diversity in phase III trials of cancer drugs supporting Food and Drug Administration approval in solid tumors

Our study aimed to assess inequities in the clinical trial participation for the selected patient groups. We searched the Food and Drug Administration (FDA) database and extracted phase-III clinical trial data from MEDLINE for each approved drug by the FDA between January 1, 2006, and June 30, 2020. We analyzed the inclusion/exclusion criteria, participation according to gender, ethnic group, performance score, the positivity of HBV and HCV, and HIV, having comorbidities and brain metastasis. We compared the findings with that of the general population by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We identified 142 phase III pivotal oncology trials that enrolled 105 397 patients. The proportion of female patients in trials was lower than their relative prevalence in the general population from SEER region (36% vs 49.6%, P < .001). The rates of black patients included were lower than their relative prevalence from SEER region (2.1% vs 9.8%, P < .001). 1.3% and 0.8% of patients had HBV and HCV infections, respectively. The patients' numbers with organ dysfunction were not established due to insufficient data from clinical trials. 1.6% of all patients had controlled brain metastasis. Black patients, women and patients with brain metastasis or with HBV and HCV were underrepresented. Our study underscores the importance of expanding the inclusion/exclusion criteria of pivotal oncology trials to be more representative of patients seen in clinical practice

Genomic investigation of etiologic heterogeneity: methodologic challenges

Background: The etiologic heterogeneity of cancer has traditionally been investigated by comparing risk factor frequencies within candidate sub-types, defined for example by histology or by distinct tumor markers of interest. Increasingly tumors are being profiled for molecular features much more extensively. This greatly expands the opportunities for defining distinct sub-types. In this article we describe an exploratory analysis of the etiologic heterogeneity of clear cell kidney cancer. Data are available on the primary known risk factors for kidney cancer, while the tumors are characterized on a genome-wide basis using expression, methylation, copy number and mutational profiles. Methods: We use a novel clustering strategy to identify sub-types. This is accomplished independently for the expression, methylation and copy number profiles. The goals are to identify tumor sub-types that are etiologically distinct, to identify the risk factors that define specific sub-types, and to endeavor to characterize the key genes that appear to represent the principal features of the distinct sub-types. Results: The analysis reveals strong evidence that gender represents an important factor that distinguishes disease sub-types. The sub-types defined using expression data and methylation data demonstrate considerable congruence and are also clearly correlated with mutations in important cancer genes. These sub-types are also strongly correlated with survival. The complexity of the data presents many analytical challenges including, prominently, the risk of false discovery. Conclusions: Genomic profiling of tumors offers the opportunity to identify etiologically distinct sub-types, paving the way for a more refined understanding of cancer etiology. Electronic supplementary material The online version of this article (doi:10.1186/1471-2288-14-138) contains supplementary material, which is available to authorized users

Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series

Background: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. Case presentation: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens. Conclusions: Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

This randomised phase III trial compared standard of care Everolimus with the anti-PD1 monoclonal antibody Nivolumab in previously treated patients with locally advanced inoperable or metastatic clear cell renal cancer. 810 patients were randomised to receive either Everolimus 10 mg orally daily or 3 mg/kg of Nivolumab intravenously every two weeks. Patients were treated until unacceptable toxicity or disease progression. Patients could be treated beyond progression if the investigator believed that the patient was gaining clinical benefit. The primary endpoint was overall survival. The median survival was 25 months for Nivolumab and 19.8 months for Everolimus (p=0.002). The objective response rate was higher for Nivolumab (25 versus 5%; p=&#60;0.001).The median progression free survivals were 4.6 & 4.4 months (p=0.11). Grade 3 & 4 treatment related toxicities were observed in 19 & 37% of patients on Nivolumab or Everolimus respectively. In patients with previously treated renal cell carcinoma Nivolumab produced superior survival and more tolerable treatment than Everolimus

Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma

Altres ajuts: We thank the patients, their families, the investigators and site staff, and the study teams who participated in the METEOR trial. This study was funded by Exelixis, Inc. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Editorial support was provided by Fishawack Communications (Conshohocken, PA, USA) and funded by Exelixis.In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC), after prior antiangiogenic therapy. Outcomes were evaluated for subgroups defined by prior therapy with sunitinib or pazopanib as the only prior VEGFR inhibitor, or prior anti-PD-1/PD-L1 therapy. For the prior sunitinib subgroup (N = 267), median PFS for cabozantinib versus everolimus was 9.1 versus 3.7 months (HR 0.43, 95% CI 0.32-0.59), ORR was 16% versus 3%, and median OS was 21.4 versus 16.5 months (HR 0.66, 95% CI 0.47-0.93). For the prior pazopanib subgroup (N = 171), median PFS for cabozantinib versus everolimus was 7.4 versus 5.1 months (HR 0.67, 95% CI 0.45-0.99), ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR 0.66, 95% CI 0.42-1.04). For prior anti-PD-1/PD-L1 therapy (N = 32), median PFS was not reached for cabozantinib versus 4.1 months for everolimus (HR 0.22, 95% CI 0.07-0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR 0.56, 95% CI 0.21-1.52). Cabozantinib was associated with improved clinical outcomes versus everolimus in patients with advanced RCC, irrespective of prior therapy, including checkpoint inhibitor therapy

FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder

While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon