[Show abstract][Hide abstract] ABSTRACT: Adrenocortical carcinoma (ACC) is a rare tumor in which prognostic factors are still not well established. Programmed Death Ligand-1 (PD-L1) expression in ACC and its association with clinico-pathological features and survival outcomes are unknown.
Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 28 patients with ACC. PD-L1 expression was evaluated by immunohistochemistry (IHC) in both tumor cell membrane and tumor infiltrating mononuclear cells (TIMC). PD-L1 positivity on tumor cells was defined as ≥5% tumor cell membrane staining. TIMC were evaluated by IHC using a CD45 monoclonal antibody. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrates and percentage of positive cells was developed. Any score greater that zero was considered PD-L1 positive. Baseline clinico-pathological characteristics and follow up data were retrospectively collected. Comparisons between PD-L1 expression and clinico-pathological features were evaluated using unpaired t-test and Fisher's exact test. Kaplan-Meier method and log-rank test were used to assess association between PD-L1 expression and 5-year overall survival (OS).
Among 28 patients with surgically treated ACC, 3 (10.7%) were considered PD-L1 positive on tumor cell membrane. On the other hand, PD-L1 expression in TIMC was performed in 27 specimens and PD-L1 positive staining was observed in 19 (70.4%) patients. PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS.
PD-L1 expression can exist in ACC in both tumor cell membrane and TIMC with no relationship to clinico-pathologic parameters or survival.
[Show abstract][Hide abstract] ABSTRACT: Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.
SIGNIFICANCE: Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.
Cancer Discovery 09/2015; DOI:10.1158/2159-8290.CD-15-0369 · 19.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. Methods We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. Results Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. Conclusions Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747 .).
New England Journal of Medicine 09/2015; DOI:10.1056/NEJMoa1510016 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Methods A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. Results The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). Conclusions Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784 .).
New England Journal of Medicine 09/2015; DOI:10.1056/NEJMoa1510665 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.
PLoS ONE 09/2015; 10(9):e0139267. DOI:10.1371/journal.pone.0139267 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To identify contemporary, clinically low-risk patients with ≥50% cores positive and compare the risk of upgrading at prostatectomy to other low- or intermediate-risk patients.
We studied 14,902 patients with prostate cancer in the Surveillance, Epidemiology, and End Results database in 2010-2011 with prostatectomy. Patients were categorized by NCCN clinical risk-groups, separating low-risk patients by percent positive biopsy cores (PBC). We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and multivariable logistic regression (MVA) was used to determine if patients with clinical low-risk disease and ≥50% PBC were similar to other low- or intermediate-risk patients. This analysis was repeated with favorable- and unfavorable-intermediate risk.
At prostatectomy, 9.2% of clinically low-risk and <50%PBC, 18.6% of clinically low-risk and ≥50%PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease (p<0.001). On MVA low-risk with ≥50%PBC were more likely than low-risk with <50%PBC to have pathologic high-risk disease (Adjusted odds ratio [AOR] 2.28, 95%CI 1.90-2.73, p<0.001), had similar risk to favorable-intermediate disease overall (AOR 1.09, 0.91-1.31, p=0.33), and had higher risk than favorable-intermediate among men over 60 (AOR 1.28, 1.00-1.64, p=0.04). Low-risk and ≥50%PBC had a mean tumor size similar to unfavorable-intermediate risk (21.3 vs. 21.0mm, p=0.82).
Nearly one in five clinically low-risk prostate cancer patients with ≥50% positive biopsy cores harbor occult pT3a-T4 or Gleason 8-10, suggesting that national guidelines should not classify low-risk with ≥50% cores positive as "low-risk" and patients should be made aware of this excess risk if considering active surveillance.
[Show abstract][Hide abstract] ABSTRACT: Background:
In clinical trials, the use of intermediate time to event endpoints (TEE) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for endpoint definitions.
Material and methods:
A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the non-metastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each endpoint. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent endpoints and the associated events.
Thirty-four experts scored 121 events for 9 endpoints. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds respectively. In the NM setting: Disease-Free Survival (contralateral renal cell cancer, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), Metastasis-Free Survival (appearance of metastases, regional recurrence, death from RCC); and Local Regional Free-Survival (local or regional recurrence, death from RCC). In the MA setting: Kidney Cancer Specific Survival (death from RCC or protocol treatment) and Progression-Free Survival (death from RCC, Local, regional, or metastatic progression).
The consensus method revealed that intermediate endpoints have not been well defined, since all of the selected endpoints had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.
Annals of Oncology 09/2015; DOI:10.1093/annonc/mdv380 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-clear cell renal cell carcinomas (RCCs) represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the second in a 2-part series) reviews the current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC. Ultimately, enhanced understanding of genetic triggers and the development of more tailored treatments remain imperative to improve outcomes in non-clear cell RCC.
Clinical advances in hematology & oncology: H&O 09/2015; 13(6):383-391.
[Show abstract][Hide abstract] ABSTRACT: Non-clear cell renal cell carcinomas (RCCs) represent up to 20% of all RCCs. Despite often being clustered as a single entity, these tumors represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the first in a 2-part series) reviews the histology of RCC, whereas the second article reviews current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC.
Clinical advances in hematology & oncology: H&O 09/2015; 13(5):308-313.
[Show abstract][Hide abstract] ABSTRACT: Background:
Monoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown.
Medical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT.
Of 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1months (range: 0.2, 30.6months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6months (range: 0.2+, 23.0). 1-year and 2year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41-72%) and 36% (95% CI: 18-54%), respectively.
Both VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade.
European journal of cancer (Oxford, England: 1990) 09/2015; DOI:10.1016/j.ejca.2015.08.017 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To examine racial disparities in end-of-life (EOL) care among black and white patients dying of prostate cancer (PCa).
Relying on the SEER-Medicare database, 3789 patients who died of metastatic PCa between 1999 and 2009 were identified. Information was assessed regarding diagnostic care, therapeutic interventions, hospitalizations, intensive care unit (ICU) admissions, and emergency department visits in the last 12 months, 3 months, and 1 month of life. Logistic regression tested the relationship between race and the receipt of diagnostic care, therapeutic interventions, and high-intensity EOL care.
Overall, 729 patients (19.24%) were black. In the 12-months preceding death, laboratory tests (odds ratio [OR], 0.51; 95% CI, 0.36-0.72), prostate-specific antigen test (OR, 0.54; 95% CI, 0.43-0.67), cystourethroscopy (OR, 0.71; 95% CI, 0.56-0.90), imaging procedure (OR, 0.58; 95% CI, 0.41-0.81), hormonal therapy (OR, 0.53; 95% CI, 0.44-0.65), chemotherapy (OR, 0.59; 95% CI, 0.48-0.72), radiotherapy (OR, 0.74; 95% CI, 0.61-0.90), and office visit (OR, 0.38; 95% CI, 0.28-0.50) were less frequent in black versus white patients. Conversely, high-intensity EOL care, such as ICU admission (OR, 1.27; 95% CI, 1.04-1.58), inpatient admission (OR, 1.49; 95% CI, 1.09-2.05), and cardiopulmonary resuscitation (OR, 1.72; 95% CI, 1.40-2.11), was more frequent in black versus white patients. Similar trends for EOL care were observed at 3-month and 1-month end points.
Although diagnostic and therapeutic interventions are less frequent in black patients with end-stage PCa, the rate of high-intensity and aggressive EOL care is higher in these individuals. These disparities may indicate that race plays an important role in the quality of care for men with end-stage PCa.
Journal of the National Comprehensive Cancer Network: JNCCN 09/2015; 13(9):1131-1138. · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IntroductionPatients with cancer are at increased risk of suicide. Further, evidence suggests a relationship between suicides and deaths due to accidents and externally caused injuries. We sought to determine if American men with prostate cancer (PCa) are at increased risk of suicide/accidental death compared to other cancers, and if the receipt of definitive treatment alters this association.Material & Methods
Demographic, socio-economic and tumor characteristics of men with PCa and men with other solid malignancies were extracted from the Surveillance, Epidemiology and End Results (1988-2010). Poisson regression models were fitted to compare the incidence of suicidal and accidental deaths in PCa vs. other solid cancers. Multivariate Cox regression was used to determine if receipt of definitive primary treatment impacted the risk of suicide or accidental death in men with localized/regional PCa.ResultsRisk of suicidal and accidental death was significantly lower in men with PCa [1165 (0.2%) and 3,199 (0.6%)] than men with other cancers [2,232 (0.2%) and 4,501 (0.5%) respectively], except within the first year of diagnosis (adjusted relative risk [ARR]=3.98 [95%CI 3.02-5.23] and ARR=4.22 [95%CI 3.24-5.51] respectively, 0-3 months after diagnosis). Men with non-metastatic PCa who were white, uninsured, or recommended but did not receive treatment (HR vs. treated=1.44, 95% CI 1.20-1.72, and 1.44, 95% CI 1.30-1.59, both p<0.001) were at increased risk of suicidal and accidental mortality, respectively. Absence of data regarding previous co-morbidities and drug addictions in the SEER dataset was an important limitation.Conclusions
Relative to other cancers, men with PCa were at increased risk of suicide and accidental deaths within the first year of diagnosis and when definitive treatment was recommended but not received, suggesting the need for close monitoring and coordination with mental health professionals in at-risk men with potentially curable disease.This article is protected by copyright. All rights reserved.
BJU International 08/2015; DOI:10.1111/bju.13257 · 3.53 Impact Factor