Erin B. Bailey

Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): Potential clinical implications

Introduction Tumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. Our objective was to assess if GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary. Results When controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When comparing GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways. Materials and Methods Results of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischers exact test was used to compare the incidence of mutations in selected molecular pathways. Conclusions When controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.

Incidence of Immune-Related Adverse Events with Program Death Receptor-1- and Program Death Receptor-1 Ligand-Directed Therapies in Genitourinary Cancers

Program death receptor-1 (PD-1) and program death receptor-1 ligand (PD-L1) inhibitors are increasingly being used in the clinic to treat a growing number of malignancies, including many genitourinary (GU) malignancies. These immune-based therapies have demonstrated a distinct toxicity profile compared to traditional chemotherapy and the targeted therapies directed at the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway. Autoimmune toxicity targeting the skin, gastrointestinal tract, or the endocrine organs are some of the more common adverse events (AEs) noted with these therapies. Here in, we report the results of a systematic review of the incidence of toxicities in GU cancers reported in the phase II or phase III clinical trials using single-agent PD-1 or PD-L1 inhibitors. Overall, the rate of serious (grades 3–4) AEs was noted in approximately 15% of patients. The AEs noted were similar between all the agents tested, highlighting the overall class effect of these therapies. The incidence in GU cancers is similar to those seen in other malignancies. Given the widespread and high volume real-world use of these agents, it is important for oncologists to be familiar with these side effects to minimize the risks for patients while undergoing therapy.

Efficacy of Eplerenone in the Management of Mineralocorticoid Excess in Men With Metastatic Castration-resistant Prostate Cancer Treated With Abiraterone Without Prednisone

Background Abiraterone acetate has been approved for metastatic castration‐resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long‐term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real‐world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy. Patients and Methods The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression‐free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischers exact test or χ2 test, as appropriate. PFS was compared using the Kaplan‐Meier method. Results Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts. Conclusion In a real‐world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation. Micro‐Abstract Prednisone is typically coadministered with abiraterone in the treatment of castrate‐resistant prostate cancer to prevent the toxicities of secondary mineralocorticoid excess. However, many patients do not desire or cannot tolerate chronic glucocorticoid therapy. In the present retrospective study, we report that eplerenone, a mineralocorticoid antagonist, can be safely used with abiraterone, obviating the need for concomitant prednisone in this patient population.

Effect of treatment dose reductions in the setting of hand-foot syndrome on survival outcomes in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor receptor inhibitors

Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.

Targeting Bacteroides in Stool Microbiome and Response to Treatment With First-Line VEGF Tyrosine Kinase Inhibitors in Metastatic Renal-Cell Carcinoma

Micro‐Abstract Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) are a mainstay of treatment for metastatic renal‐cell carcinoma. Stool microbiome composition is predictive of response to immunotherapy and cytotoxic chemotherapy. Antibiotics targeting Bacteroides species are associated with improved progression‐free survival while receiving first‐line VEGF‐TKIs. Background Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for metastatic renal‐cell carcinoma. Stool microbiome composition is predictive of response to immunotherapy and cytotoxic chemotherapy. We sought to investigate whether antibiotics targeting Bacteroides species affect progression‐free survival (PFS) while receiving first‐line VEGF‐TKI therapy. Patients and Methods Using a retrospective cohort of intermediate‐ and poor‐risk metastatic renal‐cell carcinoma patients from the University of Utah, we categorized patients receiving first‐line VEGF‐TKIs by receipt of antibiotics (Bacteroides spp., non‐Bacteroides spp., or none) and assessed PFS by Kaplan‐Meier and Cox proportional hazard models. Results Of 145 patients, 17 received antibiotics with Bacteroides spp. coverage and 32 patients received antibiotics without Bacteroides spp. coverage. When compared to patients not receiving antibiotics, improved PFS was seen with each additional day antibiotics were prescribed with Bacteroides spp. coverage (hazard ratio = 0.92; 95% confidence interval, 0.83‐0.99; P = .04). Conclusion Targeting stool Bacteroides spp. with antibiotics improves PFS in patients receiving first‐line VEGF‐TKIs in a duration‐dependent manner.

Efficacy of eplerenone (Epe) in the management of mineralocorticoid excess (MCE) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (AA) without prednisone (P).

261Background: AA is approved for Mcrpc with co-administration with P to prevent MCE toxicity such as hypertension, hypokalemia and edema. However, use of P is often not desirable by the relatively asymptomatic patients because of potential for detrimental effects of long term corticosteroid therapy. Epe is a non-steroidal mineralocorticoid antagonist demonstrated to abrogate MCE. Here we report real world experience of use of Epe with AA in men with mCRPC who wished to avoid concomitant P. Methods: Incidence and grade (CTCAE v4) of MCE, along with baseline demographics, disease characteristics, and progression free survival (PFS) in men with mCRPC treated with AA (1000 mg daily), not willing to be treated with P (and thus received treatment with Epe 50 mg daily) were collected retrospectively, and compared with those treated with AA + P (10 mg daily) during the same time period (Table). Continuous variables were assessed by Wilcoxon rank sum or student t-test, and categorical variables were assessed by F...