Citations

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<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

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

Abstract Massively parallel next generation sequencing data (NGS) has proved to be useful in identification of rare Mendelian disorders. Efforts are on-going to use NGS for discovery of novel rare variants in common disease etiology. Distinguishing rare private mutations from causal variants remains a major challenge in complex disorders. With decreasing cost, investigators are generating NGS data for common cancers. However, power and other considerations suggest that a consortia approach of pooling data is more likely to succeed where individual efforts fail. Combining data within such consortia brings its own level of challenges. We enumerate these challenges and suggest recommendations based on our experience of combining and harmonizing NGS data on 358 breast cancer samples from four centers; (City of Hope n=8, Mayo Clinic n=221, MSKCC n=96 and University of Pennsylvania n=33). Major concerns were ability of individual datasets to discover known and novel variations, depth of coverage across the exome, and quality of variants. Using pre- and post-processed data, we demonstrate an increased power for detecting variants when using a joint-calling method, quality control (QC) and quality assurance pre- and post-merge, as well as the advantages of combined annotations and filtering procedures. To generate a filtered list of high confident calls, we subset the data on Depth per Allele (DP), Genotyping Quality (GQ), Allele balance, Phred likelihood score (PL) as well as using frequency filters on the alternate allele both within the data and comparing against convenience control summaries. We describe general principles and QC measures to be adopted when NGS data is used from diverse sources, specifically applicable to large consortia. Note: This abstract was not presented at the meeting. Citation Format: Joseph Vijai, Steven Hart, Tinu Thomas, Bradley Wubbenhorst, Lucia Guidugli, Kasmintan Schrader, Kara Maxwell, Lauren Jacobs, Danylo Villano, Robert Klein, Steven Lipkin, Susan Neuhausen, Jeffrey Weitzel, David Altshuler, Fergus Couch, Kenneth Offit, Katherine Nathanson. Harmonization of next generation sequencing data within consortia for gene discovery in familial breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2378. doi:10.1158/1538-7445.AM2014-2378

AbstractObjectives:Data suggest physicians poorly assess disease‐specific literacy and transition readiness in pediatric patients with inflammatory bowel disease (IBD). We piloted an electronic, interactive iPad quiz game that could be used in a clinical setting, with the aims of measuring IBD‐related knowledge, and concomitant mood and quality of life (QOL) in a pediatric population.Methods:Two pediatric IBD clinics developed and tested 2 versions of “Emma.” Patients between 10 and 18 years of age played Emma during an office visit. Each patient answered 12 randomly selected disease‐related questions and 4 mood‐related questions.Results:Sites 1 and 2 tested Emma v1 between May and August 2013. Emma v2 was tested from November 2013 to January 2014 and from September 2013 to January 2014. A total of 56 patients played Emma v1, whereas 60 played Emma v2. In Emma v2, 73.1% of questions were answered correctly. Patients recognized signs of IBD (88%), causes of diarrhea in addition to IBD (79.4%), and could define lactose intolerance (95.8%), but fewer patients understood serological testing used for disease monitoring (68%) or knew that magnetic resonance enterography did not involve radiation (22.9%). Patients tended to report good functioning in the areas of energy, mood, anxiety, and school‐related QOL. Patients with Crohn disease, however, reported higher stress levels compared with patients with ulcerative colitis; older patients reported lower energy levels, and postsurgical patients reported lower QOL.Conclusions:The Emma iPad game has the potential to evaluate gaps in IBD knowledge, assess emotional functioning, and increase patient engagement as a transition tool in the clinical setting.

Abstract Background: To better understand colorectal cancer etiology and prognosis, archived surgical tissues were collected from Cancer Prevention Study II (CPS-II) Nutrition Cohort participants who were diagnosed with colorectal cancer. Herein, the methodology for this collection is described to help inform other efforts to collect tissues. Methods: The main components to accruing tissue were: (i) obtaining consent from participants or next-of-kin; (ii) contacting hospitals to request materials; and (iii) pathology review and laboratory processing. Results: In CPS-II, we identified 3,643 participants diagnosed with colorectal cancer between 1992/1993 and 2009. Of these, tissue could not be sought from cases verified through state cancer registry linkage (N = 1,622), because of insufficient information on tissue location. We sought tissue from the 2,021 cases verified using medical records, and received tissue from 882. When hospitals were contacted within 10 years of diagnosis, we received 87% of tissue materials; beyond that 10-year mark, we received 32%. Compared with the 2,761 colorectal cancer cases without tissue, the 882 cases with tissue were more likely to be alive, diagnosed more recently during follow-up, and had less-advanced staged disease. Cases with and without tissues were similar with respect to age at diagnosis, smoking, body mass index, physical activity, and other epidemiologic factors. Conclusions: Some of the most important elements in forming a tissue repository included having the cases' hospital contact and surgical accession information as well as contacting patients/next-of-kin and hospitals within 10 years of surgery. Impact: This tissue repository will serve as an important resource for colorectal cancer studies. See all the articles in this CEBP Focus section, “Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology.” Cancer Epidemiol Biomarkers Prev; 23(12); 2694–702. ©2014 AACR.

Summary Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8+ T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

Abstract Background: Genetic and environmental factors influence colorectal cancer (CRC) risk. Previous studies have provided additional etiologic insight by examining multiplicative gene-environment interactions for individual susceptibility loci. However, individual loci confer only modest risks, which may limit statistical power and clinical significance. A genetic risk score comprising known CRC loci may provide a more comprehensive assessment of risk. Further, there is a paucity of data on the role of additive gene-environment interactions, which may have greater public health implications than multiplicative interactions. We thus evaluated both additive and multiplicative interactions between a genetic risk score and 15 key environmental factors on risk of CRC. Methods: We conducted an analysis of 10,491 CRC cases and 10,725 controls of European ancestry in 7 cohort and 6 case-control studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or Colon Cancer Family Registry (CCFR). To provide a global measure of genetic predisposition, information across multiple risk variants was combined by calculating a genetic risk score based on 24 polymorphisms near 21 genetic loci identified in previous genome-wide association studies. For the genetic score and environmental factors, the reference category corresponded to that associated with lower CRC risk. We tested for additive interactions by estimating relative excess risk due to interactions (RERIs) using logistic regression; for multiplicative interactions we used an empirical-Bayes approach. Nominal P values ≤ 0.05 were considered statistically significant. Results: After adjustment for age, sex, center, study, principal components, and total energy, as appropriate, we observed super-additive gene-environment interactions for CRC risk between the genetic risk score and body mass index (RERI=0.15; 95% CI: 0.00-0.31), ever smoking (RERI=0.14; 95% CI: 0.00-0.28), pack-years of smoking (RERI=0.23; 95% CI: 0.05-0.41), postmenopausal hormone therapy use (RERI=0.38; 95% CI: 0.17-0.59), and intake of processed meat (RERI=0.23; 95% CI: 0.06-0.40). Of the 15 environmental risk factors, 12 showed RERIs > 0 – suggesting an overall trend toward super-additive interactions for these factors. In addition, we observed evidence of sub-multiplicative interactions for use of aspirin and non-steroidal anti-inflammatory drugs. There were no other statistically significant multiplicative interactions. Conclusions: We observed evidence for super-additive effects of genetic predisposition and environmental risk factors on risk of CRC. Our findings suggest that certain environmental risk factors have stronger effects on absolute risk among individuals with higher genetic risk of CRC. If confirmed in future studies, these results may have implications for targeted prevention strategies. Citation Format: Mengmeng Du, Sonja I. Berndt, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew Chan, Jenny Chang-Claude, Stephen J. Chanock, Nilanjan Chatterjee, David V. Conti, David Duggan, Jane C. Figueiredo, Steven Gallinger, Jian Gong, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, John L. Hopper, Li Hsu, Thomas J. Hudson, Carolyn M. Hutter, Eric J. Jacobs, Mark A. Jenkins, Shuo Jiao, Laurence N. Kolonel, Peter Kraft, Loic Le Marchand, Mathieu Lemire, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Aung Ko Win, Emily White, Brent W. Zanke, Ulrike Peters. Additive and multiplicative gene-environment interactions for colorectal cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4831. doi:10.1158/1538-7445.AM2013-4831

Abstract Background: Retrospective studies suggest that primary breast surgery is associated with improved overall survival (OS) in Stage IV breast cancer. TBCRC 013 is a multi-center prospective registry study evaluating the role of surgery for the primary tumor in Stage IV disease. Methods: From 7/09 - 4/12, 128 eligible pts from 14 sites were enrolled in two cohorts (A: Stage IV with intact primary tumor (n = 112); B: metastases (mets) within 3 months of primary surgery (n = 16)). Baseline patient and tumor characteristics, and surgery of the primary were correlated with 2yr overall survival (OS) using log rank, Kaplan Meier and Cox regression for all patients. Comparisons were also made between cohorts A and B and within cohort A stratified by response to systemic therapy. Responders included those with any response (partial,complete) or stable disease at distant sites. Results: Median pt age was 52yrs(21-79) and median primary tumor size 3.2cm(0.7-15). Phenotypes were ER+ 106 (83%), HER2neg 91(71%), and triple neg 10(8%). 60(47%) had bone-only mets. The only significant baseline difference between cohorts A and B was the presence of palpable nodes (A:62% vs B:0%, p<0.001). There were no differences in age, tumor size, ECOG scores, ER or HER2 status, number or sites of mets between cohorts A and B. At a median follow-up of 25 mo (95%CI, 23-31), 2yr OS for all pts is 86% (80-92) and is superior in cohort B as compared to A, (100% vs 84%, p = 0.03). On multivariate analysis (MVA) including all pts, only surgery, ER and HER2 positivity were associated with improved OS (table). Among 112 pts with an intact primary (Arm A), 17(15%) were non-responsive (NR) to systemic therapy, 3(18%) of whom required palliative surgery at a median time of 10.4mos. 2yr OS among NR was 33% (15-69) as compared to 94% (88-99) in Arm A responders (R) (p<0.001). ER positivity was the only baseline difference between NR (65%) and R (88%) within Arm A (p = 0.02). Among 94(85%) Arm A responders, 39(41%) had elective surgery (median 8.4 mos, 95%CI:6.9-10.3) and only 1 of the remaining 47(2%) required palliation. When limited to Arm A responders, elective surgery was not associated with improved 2yr OS (surgery vs not: 94% vs 92%, p = 0.5). Median time to progression following elective surgery was 12 mos (95%CI,8-19mos). When cohort B (n = 16) and cohort A surgery groups (n = 39) are combined, surgery of the primary tumor is associated with improved 2yr OS (96% vs 74%, p = 0.002). Conclusions: In this prospective registry study, patients diagnosed with mets within 3 months of primary breast surgery have an improved 2yr OS. When all pts having surgery (A + B) are examined, surgery is associated with improved OS on MVA, but when limited to Arm A responders, elective surgery does not improve OS. Given that the number of Arm A responders is small, results from the prospective randomized trial will be needed to address this question. These data also demonstrate that the need for surgical palliation of the primary tumor is uncommon in the modern era. Multivariate Analysis for OSN = 128HR Death (95%CI)pvalueSurgery0.28 (0.10-0.74)0.01ER positivity0.28 (0.10-0.72)0.01HER2 positivity0.21 (0.06-0.74)0.01MVA included: age, tumor size, ECOG, ER, PR, HER2, met sites, and surgery Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-09.