Zhang, Ben Yiming

494 Background: Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both rhabdoid and sarcomatoid differentiation are classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We sought to determine the prognostic value of rhabdoid differentiation in comparison to RCC with sarcomatoid differentiation, grade 4 RCC without rhabdoid or sarcomatoid differentiation, and grade 3 RCC. Methods: Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1,758 patients with grade 3 RCC. A urologic pathologist reviewed all specimens to determine the presence of both rhabdoid and sarcomatoid differentiation. Associations of clinical and pathologic features with death from RCC were evaluated using Cox models. Results: Among the 406 grade 4 RCC tumors, 111 (27%) had rhabdoid differentiation and 189 (47%) had sarcomatoid differentiation, although only 28 (7%) demonstrated both rhabdoid and sarcomatoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (HR 0.95, p=0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR 1.63, p<0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than patients with grade 3 RCC (HR 2.45, p<0.001) and grade 3 RCC with necrosis (HR 1.62; p<0.001). Conclusions: This study confirms that RCC with rhabdoid differentiation is appropriately classified as grade 4. However, unlike sarcomatoid differentiation, the presence of rhabdoid differentiation in grade 4 RCC is not associated with an increased risk of death from RCC. Therefore, rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC.

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]

209 Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]

313 Background: We evaluated variation in candidate genes implicated in either initiation or progression of prostate cancer with survival in CRPC stage. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of > 5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model using Cox regression adjusted for age at CRCP and Gleason score (GS) were used. Results: Two hundred and forty five CRPC patients who met the criteria of having adequate DNA were genotyped (14 genes, 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS = 7 and 13% with GS < 7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level JAK2 was detected to be associated with OS. Six of 18 JAK2 SNPs were associated with OS after adjustment for age and GS as well as pruning of SNPs in high linkage disequilibrium with each other (see table). In our multivariate model including age, GS, rs2149556, and rs4372063, the adjusted HRs for rs2149556 and rs4372063 were 0.67 (95% CI 0.38-1.18) and 2.17 (95% CI 1.25-3.76), respectively. The protective effect of rs2149556 appears after adjusting for the presence of minor alleles for rs4372063 in this dataset. Conclusions: Germline variation in the JAK2gene is associated with survival in CRPC stage and warrants further validation as a potential prognostic biomarker. [Table: see text]