Citations

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]

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy.

Abstract Androgen deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) and chemotherapy for castration-resistant prostate cancer (CRPC) are considered standard of care. However, there are no clinical tests or factors that can reliably predict treatment responses for the advanced prostate cancer patients. Examination of tumor component in circulation, also known as liquid biopsy, has shown promise for predicting treatment outcomes and survival. To capture the tumor-derived genomic alterations and decrease the surrogacy of using PSA measurements as is currently performed, we propose a Plasma Genomic Abnormality (PGA) score and Treatment Efficacy (TEff) index based on copy number variations as estimated by cell free DNA (cfDNA) in plasma. We first performed whole genome and targeted sequencing (NimbleGen comprehensive cancer panel) to examine plasma cfDNA for tumor-associated genetic and genomic aberrations in 10 HSPC patients receiving ADT and 10 CRPC patients receiving chemotherapy. For each patient, we tested plasma from two time points: pre-treatment and 4 months post-treatment. We then calculated the PGA score by summing the most significant genomic abnormalities with higher PGA score indicating greater tumor DNA content in cfDNA. TEff index was derived from comparison of PGA score difference between treatments with higher TEff index reflecting a better treatment response. The sequencing-based copy number analysis revealed locus-specific gains or losses including those previously reported in prostate cancers, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. We found that overall PGA score was significantly higher in CRPC patients than in HSPC patients (p&lt;0.0005), possibly reflecting increased tumor burden during the disease progression. Patients with low TEff index often demonstrated poor response to treatments, and patients with high initial PGA score or low TEff index tended to have poor overall survival. As examples of the PGA-based TEff associations with outcome we presented three CRPC patients including two with neuro-endocrine origin (small cell carcinoma). Comparison of mutational profiles between pre- and post-treatments showed that treatments caused more diverse gene mutations, in particular, in the genes involving androgen biosynthesis, AR activation, DNA repair and chemotherapy resistance, suggesting subclonal evolution of heterogeneous tumor genomes in response to these treatments. Our results strongly support the feasibility of using non-invasive liquid biopsy as a potential powerful tool to study biological mechanisms underlying therapy-specific resistance and monitor disease progression in the advanced prostate cancer. Further studies are needed to develop and validate the genomics-based PGA score and TEff index for clinical applications. Citation Format: Liang Wang, Shu Xia, Meijun Du, Rachel Ditmar, Tiezheng Yuan, Yongchen Guo, Yuan Wang, Adam Lee, Michael Tschannen, Elizabeth Worthey, Howard Jacobs, Chiang-Ching Huang, Manish Kohli. Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2015-5231

AbstractPurpose: A let-7 microRNA-complementary site (LCS6) polymorphism in the 3′ untranslated region of the KRAS gene has been shown to disrupt let-7 binding and upregulate KRAS expression. We evaluated the LCS6 genotype and its association with KRAS mutation status, clinicopathologic features, and disease-free survival (DFS) in patients with stage III colon cancer who enrolled in a phase III clinical trial (NCCTG N0147).Experimental Design: The LCS6 genotype was assayed by real-time PCR in DNA extracted from whole blood (n = 2,834) and compared with paired tumor tissue (n = 977). χ2 and two-sample t tests were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed associations between LCS6 status and DFS, respectively.Results: We identified 432 (15.2%) blood samples and 143 (14.6%) tumor samples heterozygous or homozygous for the LCS6 G-allele, and 2,402 of 2,834 (84.8%) blood samples and 834 of 977 (85.4%) tumor samples homozygous for the LCS6 T-allele. Genotype results were highly concordant (99.8%) in cases with paired blood and tumor tissue (n = 977). G-allele carriers were significantly more frequent in Caucasians versus other races (χ2 test, P &lt; 0.0001). The LCS6 genotype was not associated with KRAS mutation status, clinicopathologic features (all P &gt; 0.2), or DFS (log-rank P = 0.49; HR, 0.929; 95% confidence interval, 0.76–1.14), even after combining LCS6 genotype with KRAS mutation status.Conclusions: In the largest association study investigating the LCS6 polymorphism in colon cancers, the germline LCS6 genotype was not associated with KRAS mutation status or with clinical outcome in patients with stage III tumors. Clin Cancer Res; 20(12); 3319–27. ©2014 AACR.

Abstract Catabolism of fluoropyrimidine drugs such as 5-fluorouracil (5-FU) and its prodrug capecitabine depends on an exclusive enzymatic step, dihydropyrimidine dehydrogenase (DPD), which results in drug inactivation. DPD exhibits wide interindividual variation, with partial to complete DPD deficiency occurring in approximately 3 to 5% of the general population. Patients with less pronounced, but decreased DPD activity may also be unable to efficiently inactivate 5-FU, such that this may contribute to 5-FU toxicity. Though numerous tests have been developed to phenotypically assess the DPD enzyme, they remain labor intensive and time consuming with difficulty in defining threshold values for separating DPD deficient patients from those with normal DPD enzyme activity. To date, attempts to develop genotypic assays have been complicated by the size and complex structure of the gene encoding the DPD enzyme (DPYD). Numerous sequence variants have been reported with varying frequencies across different populations. Unfortunately many DPYD variants have not been examined to determine whether they are associated with loss of function in the DPD enzyme. Current genotypic methods are limited due to the inability to rapidly assess multiple variants in a large number of samples at one time. In the current study, we have developed a rapid, high-throughput genotypic method using 6 multiplexed PCR assays covering 115 DPYD variants analyzed with the Sequenom matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Selected variants included previously identified and functionally characterized SNPs as well as newly identified mutations within the coding region from a previous mutation discovery analysis in Coriell cell lines and patient samples. Due to the potential importance of variants in the untranslated regions (UTRs), we have included known variants from the 5′- and 3′- UTRs (9 and 16 respectively) within our plexes. A total of 95 DNA samples derived from 4 colorectal cancer cell lines, 76 Coriell cell lines (40 Caucasian and 36 African American), and 7 Caucasian patients with clinically observed 5-FU toxicity and/or decreased DPD activity were utilized for initial assay testing. To assess “calling” efficiency and presence of false positives, 8 Coriell DNA samples plated in duplicate and 1 negative control were included. Our results showed that identified variants were 100% in agreement across duplicated samples, and only four variants within the 6 different plexes were removed due to PCR/extension failure. In summary, this method provides a comprehensive and rapid analysis of 111 DPYD variants within 6 different plexes with both sensitive and accurate detection suitable for high-throughput patient screening. Functional studies in a large patient population are underway (CA116964). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5451. doi:10.1158/1538-7445.AM2011-5451

Abstract Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Results: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%–49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking. Cancer Epidemiol Biomarkers Prev; 21(6); 988–92. ©2012 AACR.