No abstract

The recurrence of breast cancer (BC) is a serious therapeutic problem, and the risk factors for recurrence urgently need to be identified. In this study, we examined the functional pathways in tumor and normal tissues to more comprehensively identify biomarkers for the risk of BC recurrence. We collected tumor and normal tissue gene expression profiles of recurrent BC patients and non-recurrent BC patients from the TCGA database.We derived an expression interval (mean ± 1.96SD) based on non-recurrent patients rather than a single value, such as a mean or median. If the expression of a gene was significantly different from its normal expression interval, it was considered a differentially expressed gene. Eight pathways that significantly distinguished recurrent and non-recurrent BC patients were obtained based on 65% accuracy, and these pathways were all associated with the immune response and sensitivity to drugs. The genes in these eight pathways were also used to analyze survival, and the significance level reached 0.003 in an independent dataset (p = 0.02 in tumor and p = 0.03 in normal tissue). Our results reveal that the integration of tumor and normal tissue functional analyses can comprehensively enhance the understanding of BC prognosis.

The genomic landscape of metastatic renal cell carcinoma (RCC) is not well understood, and currently available data suggest that it is functionally distinct from that of localized tumors. Additionally, the large number of approved and trial agents used to treat metastatic RCC likely cause selective adaptations in the tumors. Circulating tumor DNA (ctDNA) is a platform to non-invasively determine the genomic profiles of these tumors. The objectives of the present study were to corroborate previous ctDNA studies in metastatic RCC, to identify novel mutations in metastatic RCC, and to compare ctDNA profiles obtained from plasma and urine in patients with metastatic RCC. ctDNA sequencing using the plasma and urine of 50 patients with metastatic RCC who received ctDNA profiling as part of routine clinical care at a single institution was performed using an investigational 120-gene panel. Genomic alterations (GAs) were identified in all 50 patients. The genes with the most GAs were GNAS, PTEN, MYC, MET and HNF1A and novel mutations in additional genes were identified. A significant correlation between the number of GAs detected in matched urine and plasma samples was also identified, but only 28.1% of GAs detected in plasma samples were also detected in matched urine samples. The results of the present study were consistent with those of the largest previous study of ctDNA from patients with metastatic RCC and may help identify additional potential targets for the treatment of such patients.

e17100 Background: Despite extensive work to characterize genomic alterations (GAs) in metastatic renal cell carcinoma (mRCC), GAs are not currently used for treatment sequencing or selection. Circulating tumor DNA (ctDNA) in both blood and urine may elucidate potential mRCC biomarkers through a minimally invasive approach. We aimed to validate previous blood-based ctDNA studies (Pal et al Eur Urol 2017) and compare detection rates of clinically relevant GAs in plasma and urine. Methods: From a single institution, patients (pts) with mRCC were recruited to provide a plasma and urine specimen. ctDNA next-generation sequencing was performed using an investigational 120-gene panel, and we limited our assessment to 7 GAs with biological relevance in RCC ( VHL, MTOR, PIK3CA, TSC2, MET, AKT1, TSC1). Further, only pathogenic alterations previously recognized in RCC and cited in the Catalogue of Somatic Mutations in Cancer (COSMIC) database were considered. Clinicopathologic variables, treatment type and response to therapy were collected from an institutional mRCC patient database. Concordance analysis was performed at the gene level between blood and urine using previously published approaches (Chae et al Oncotarget 2016). Results: 50 pts (40M:10F) were enrolled with a median age of 65. 40 pts (80%) had clear cell histology, while the remainder were papillary (12%), chromophobe (4%) or other (4%). Pts received a median of 1 line of therapy (range, 0-7). GAs were identified in 45 pts (90%) in blood and in 45 pts (90%) in urine . Applying the above criteria, the most frequently observed GAs in blood specimens were TSC2 (9%), MTOR (4%), and VHL (2%). The most frequently observed GAs in urine were VHL (4%) and MTOR (2%). The rate of concordance between blood- and urine-detected GAs was 93%. Of pts bearing mTOR pathway alterations in blood or urine, 3 received everolimus-based therapy. All 3 pts remain on therapy at 10.4, 13.8 and 14.0 months, respectively. Conclusions: Biologically relevant GAs can be detected in pts with mRCC using blood and urine. Our methodology showed high concordance between both platforms. Consistent with prior reports, ctDNA assessment of pts with pretreated mRCC shows a higher frequency of TOR pathway alterations and a lower frequency of VHL mutation.