Targeted Therapies and Gut Microbiome in Renal Cell Carcinoma (RCC) Nazli Dizman, MD Postdoctoral Fellow Department of Medical oncology & Experimental Therapeutics City of Hope Comprehensive Center December 15 th, 2017
None Disclosures
Advances in RCC treatment 2005 vs 2017 Cohen, Herbert T., and Francis J. McGovern. "Renal-cell carcinoma." New England Journal of Medicine 353, no. 23 (2005): 2477-2490 Choueiri, T.K. and Motzer, R.J., 2017. Systemic therapy for metastatic renal-cell carcinoma. New England Journal of Medicine, 376(4), pp.354-366.
Systemic treatment options in metastatic RCC Choueiri, T.K. and Motzer, R.J., 2017. Systemic therapy for metastatic renal-cell carcinoma. New England Journal of Medicine, 376(4), pp.354-366.
Question marks Which patient will respond to treatment? Which patient will develop side effect? Can stool microbiota composition provide us a marker for prediction of response or side effect development?
Stool microbiome and VEGF-TKI induced diarrhea Hypothesis: The composition of the stool microbiome might be associated with presence or absence of vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) induced diarrhea Eligibility -RCC diagnosis -Distant metastatic disease -Current Treatment with VEGF-TKIs (sunitinib, sorafenib, pazopanib, axitinib) Specimen collection A random stool specimen was collected by the patient placed in a sealed plastic container immediately then shipped to City of Hope Assessment of gut microbiota composition Microbial DNA was extracted, 16s RNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina)
Stool microbiome and VEGF-TKI induced diarrhea Patient characteristics
Results Patients with diarrhea had Higher levels of Bacteroides spp. Lower levels of Prevotella spp. Patients in our cohort had Less relative abundance of Bifidobacterium spp. When compared with previous reports based on healthy subjects
Hypothesis: The composition of the stool microbiome might be associated with presence or absence of vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) induced diarrhea Conclusion: This is the first study to characterize the stool bacteriomic profile of patients with mrcc receiving VEGF-TKIs This study demonstrates an interplay between microbiota and VEGF-TKI induced diarrhea Further efforts with larger sample size is warranted
Stool microbiome and response to sunitinib Hypothesis: The composition of the stool microbiome might be associated with response to sunitinib Eligibility -RCC diagnosis -Distant metastatic disease -Planned treatment with sunitinib Specimen collection Stool sample collection at baseline, week 2, 3, 4 and 12 of treatment Assessment of gut microbiota composition Microbial DNA was extracted, 16s RNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina) Response assessment Using RECIST 1.1 criteria after 3 months of sunitinib (R: complete/partial response and stable disease) and non-responders (P: primary progression)
Stool microbiome and response to sunitinib Results Patient characteristics
Stool microbiome and response to sunitinib Results Stool bacteriomic profiling shows that 25,304 OTUs were attributed to 165 genera from 8 phyla. PCo analysis reveals that first two PCo s can explain 51.5% of data set variation. Subsequent k-means clustering confirms the difference of microbiota in R and P groups (ANOSIM analysis p=0.005)
Stool microbiome and response to sunitinib Results The analysis of microbiota composition in P and R groups revealed 14 differentially abundant taxonomic units at the genus level, with 5 present at more than 1% abundance Name Mean (Group R) Mean (Group P) p value q value
Stool microbiome and response to sunitinib Results The analysis of microbiota membership in P and R groups differentially abundant 5 taxonomic units of genus level were observed with an abundance level of more than 1% Group R had elevated levels of Bacteroides, Barnesiellavere, Phascolarctobacterium (p<0.01) Group P had elevated levels of Bifidobacterium and Dorea in (p<0.01)
Conclusion Hypothesis: The composition of the stool microbiome might be associated with response to sunitinib We report the first in-human study suggesting a link between microbiota and response to sunitinib Although limited by sample size, we identify a significant discrepancy in stool bacteriomic distribution between P and R
Conclusion Study is still recruiting patients We anticipate publication of full data by 2019
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