Browsing Over 167 Presentations
2O - Pan-genome cfDNA methylation analysis of metastatic prostate cancer
- Anjui Wu, Taipei City, Taiwan, National Taiwan University College of Medicine
Abstract
Background
Tumour DNA circulates in the plasma of cancer patients admixed with DNA from non-cancerous cells. The genomic landscape of plasma tumour DNA has been characterised in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome in mCRPC has not been extensively explored.
Methods
mCRPC plasma samples collected from three different centres were concurrently subject to targeted genomic and pan-genome methylation profiling. The treatment courses and outcomes were also obtained. Tumour fraction of each plasma sample was estimated based on heterogyzous SNPs located in two truncal genomic deletions (8q21 and 21q22). Targeted methylome was performed using pre-designed capture panel followed by deep sequencing. We integrated genomic information with methylation data to extract methylation signatures associated with genomically-determined tumour fraction or private to individual’s tumour.
Results
Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically-determined tumour fraction (r=-0.96; P < 10-9), characterised by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the top PC1 correlated segments revealed that these segments comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual’s cancer, we then focused on an orthogonal methylation signature which revealed enrichment for androgen receptor (AR) binding sequences and where hypomethylation of these segments associated with AR copy number gain. Individuals harbouring this methylation pattern had a more aggressive clinical course, including a significantly shorter overall survival (HR = 8.18, 95% CI = 1.93–34.76, P = 0.0044).
Conclusions
Plasma methylome analysis can accurately quantitate tumour fraction and identify distinct biologically-relevant mCRPC phenotypes associated with worse clinical outcome.
Clinical trial identification
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (REC 2192/2013) Royal Marsden, London, UK (REC 04/Q0801/6) PREMIERE trial (EudraCT: 2014-003192-28, NCT02288936).
Legal entity responsible for the study
The authors.
Funding
Cancer Research UK (CRUK), Prostate Cancer Foundation (PCF).
Disclosure
V. Conteduca: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. E. Gonzalez-Billalebeita: Honoraria (self): Astellas; Honoraria (self): Janssen-Cilag; Honoraria (self): Sanofi-Aventis. U.D. Giorgi: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag,; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. G. Attard: Honoraria (self): Institute of Cancer Research; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Arno. All other authors have declared no conflicts of interest.
Tweaking DNA repair pathways to improve cancer immune surveillance
- Alberto Bardelli, Candiolo, Italy, Istituto di Candiolo - FPO - IRCCS
Clonal evolution of metastatic disease
- Samra Turajlic, London, United Kingdom, Royal Marsden Hospital NHS Foundation Trust
Tracking evolution in prostate cancer with cfDNA profiling
- Gerhardt Attard, London, United Kingdom, University College London Cancer Institute
3O - Temporal dissection of altered pathways during the evolution of cancer
- Johanne Ahrenfeldt, Aarhus, Denmark, Institute of Clinical Medicine, Aarhus University Hospital Skejby
Abstract
Background
Cancer arise as normal cells acquire insults to the genome through both mutations and gross copy number alterations. Our current understanding of the molecular makeup of cancer is based on a snap-shot, a biopsy taken at a single time point. Large-scale studies have shown an abundance of genomic alterations, but few are shared across samples which makes interpretation of effect difficult, particularly as different processes may be dominant at different time points in the development of cancer. Here, we have performed pathway analysis on timed mutational driver events to investigate if specific pathways are preferentially affected at different time points during the life-history of cancer.
Methods
We analyzed mutation data and copy number information from bladder cancer acquired from The Cancer Genome Atlas, to time the mutations as early and late relative to copy number events affecting the same genomic location (McGranahan et al., 2015). The mutations were annotated to genes and potential driver mutations were annotated (Jamal-Hanjani et al., 2017). Timed driver events across each cohort were combined into early and late, and subjected to pathway analysis using Reactome (Fabregat et al., 2017).
Results
Focusing on bladder cancer, 28% of the timed mutations are early and 72% are late. The most frequent early driver mutations are TP53 (12%), MUC4 (8%), and PIK3CA (5%), while in late they are PABPC1 (21%), KMT2C (16%), HLA-A (9%). Pathway analysis on early drivers showed how events that affects cell cycle and proliferation dominates, while late drivers are particularly enriched in pathways associated with the immune system.
Conclusions
Our results demonstrate a clear time-separated preference for specific events. These indicates that selection in early cancer development may be primarily focused on genomic alterations that increase proliferation. Conversely, late cancer development enriches in events targeting pathways associated with the immune response, consistent with increased immune pressure as the cancer develops. These results show how timing of events may provide novel insights into how cancer develops, and may help determine the evolutionary developmental stage of cancer with potential implications for improved prognostics and differential therapy.
Legal entity responsible for the study
The authors.
Funding
The Lundbeck Foundation.
Disclosure
All authors have declared no conflicts of interest.
4O - Tumour cells mirror embryonic developmental programs to acquire invasive and metastatic capabilities
- Sadegh Saghafinia, Lausanne, Switzerland, EPFL - Swiss Institute for Experimental Cancer Research (ISREC)
Abstract
Background
Pancreatic Neuroendocrine Tumours (PanNETs) are the second most common form of pancreatic cancer. We previously identified two principal subtypes of PanNET: insulinomas (islet tumors; IT) and metastasis-like primaries (MLP), corresponding to the low- and high-grade classification of human PanNETs. This study describes the mechanisms by which PanNETs progress from IT to more aggressive MLP tumors and eventually metastasize.
Methods
We profiled single cell transcriptomes, bulk mRNA and miRNA transcriptomes and the proteomes of primary and metastasis specimens from the genetically engineered mouse model of PanNETs (Rip1 Tag2).
Results
We found that the IT tumours maintained the expression of mature ß cell markers. In contrast, the MLP tumours expressed pancreatic progenitor markers. By integrating the data on ß-cell differentiation from pancreatic progenitors to mature ß cells, we demonstrated that the tumour progression from IT to MLP follows the reverse embryonic and postnatal developmental path. Furthermore, we identified Hmgb3 and miR-181cd cluster as the MLP master regulators. Over-expression of the miR-181cd cluster in IT-like cancer cell-lines resulted in the acquisition of the MLP gene signature and MLP morphologic phenotypes, in addition to activation Hmgb3 expression. This suggested a central role for Hmgb3 in initiating the MLP program. Furthermore, inhibiting the expression of Hmgb3 in MLP-like cancer cell-lines resulted in a significant growth decrease, demonstrating the importance of Hmgb3 in the maintenance of MLP-like cell state in vitro. Using transcriptomic data from human patients, we evaluated the relevance of the MLP program in human tumours. We established that aggressive human PanNET tumours also follow the same reverse developmental trajectory of dedifferentiation. Notably, patients with high MLP genes expression had a worse prognosis.
Conclusions
These data demonstrate dedifferentiation as a mechanism by which malignant neuroendocrine cancer cells acquire progenitor-like features, enabling them to become more aggressive and metastatic. In addition, miR-181cd cluster and Hmgb3 act as the core regulators in the initiation of dedifferentiation and maintenance of progenitor-like features in tumour cells.
Legal entity responsible for the study
CMSO Group at ISREC, EPFL.
Funding
Swiss National Science Foundation.
Disclosure
All authors have declared no conflicts of interest.
Taking action: Using TRK inhibitors to treat TRK fusion cancer
- Philip Quirke, Leeds, United Kingdom, Leeds University
Interactive case session
- Philip Quirke, Leeds, United Kingdom, Leeds University
- Fernando Lopez-Rios Moreno, Madrid, Spain, Hospital Madrid Norte San Chinarro - Centro Integral Oncologico Clara Campal
Welcome and Introduction
- Philip Quirke, Leeds, United Kingdom, Leeds University
Q&A and Meeting Close
- Philip Quirke, Leeds, United Kingdom, Leeds University
Maximising therapeutic impact: Detection algorithms for NTRK gene fusions
- Fernando Lopez-Rios Moreno, Madrid, Spain, Hospital Madrid Norte San Chinarro - Centro Integral Oncologico Clara Campal
9P - Plasma gene conversions after one cycle (C) abiraterone acetate (AA) for metastatic castration-resistant prostate cancer (mCRPC): A biomarker analysis of a multi-centre, international trial
- Anuradha K. Jayaram, London, United Kingdom, The Institute of Cancer Research (ICR)
Abstract
Background
A number of genomic alterations detected in plasma DNA have been associated with worse outcome in mCRPC (Jayaram et al Cancer Discov). We hypothesized that patients (pts) who harbored a genomic alteration that decreased after 1C of treatment derive treatment benefit and this would distinguish them from truly resistant pts.
Methods
Plasma DNA (128 C1 day (D) 1,134 C2 D1, and 41 progression [PD] from chemotherapy-naïve mCRPC pts in a phase 2 study of AA (NCT01867710), recently reported (Attard et al, Jama Onc) were subjected to custom targeted-capture NGS. Assay was optimised and validated to detect pathogenic point mutations (PM), deletions and copy number alterations (CNA) inAR, TP53, RB1, PIK3CA and DNA repair deficient genes (DRD): BRCA1, BRCA2, FANCA, ATM, CHEK2, HDAC2, BRIP1, and PALB2. Pts were followed up for overall survival (OS) and radiographic progression-free survival (rPFS) (48 months).
Results
Pts were classified into 4 groups based on whether a gene alteration was detectable (+) or not (-) at C1D1 and C2D1 respectively. At C1D1, 49 pts (37.5%) had + alterations. Pts who converted from + to - (+/-) had similar outcomes as pts who remained - (-/-) and those that did not convert had worst outcomes (+/+) (Table). In matched C1D1 and PD samples pts with ARgain (G) at C1D1 were more ARG at PD (p = <0.01) while ARPM were only detected in PD samples that were ARnormal (N) at C1D1. DRD + pts at C1D1 were more likely DRD + at PD (p = <0.1).Gene conversion (N) C2 conversion (%) rPFS OS p HR 95.0% CI p HR 95.0% CI C1D1 + vs - <0.01 2.0 1.23 3.30 <0.01 2.5 1.51 4.27 TP53 -/- (85) vs +/- (16) 60.7 0.23 1.4 0.74 2.77 0.7 1.2 0.55 2.51 +/ + (8) vs +/- 0.07 2.2 0.73 6.7 <0.01 4.2 1.10 16.44 AR -/-(88) vs +/-(16) 69.6 0.46 1.3 0.61 2.7 0.09 1.8 0.79 3.91 +/ + (7) vs +/- <0.01 3.3 0.9 11.4 0.07 2.5 0.65 9.84 RB1 -/-(92) vs +/- (12) 66.67 0.79 1.1 0.5 2.4 0.37 1.4 0.60 3.27 +/+6) vs +/- <0.01 5.7 1.11 29.1 <0.01 5.6 0.92 34.26 DRD -/-(96) vs +/-(10) 73.3 0.85 0.9 0.44 2.0 1.0 1.0 0.43 2.36 +/ + (4) vs +/- 0.03 4.4 0.29 69.1 <0.01 4.7 0.72 30.39 PIK3CA +/ + (100) vs +/-(5) 50 0.02 2.7 0.65 11.37 0.06 2.6 0.54 12.33 +/ + (5) vs +/- 0.29 1.9 0.51 6.85 0.7 1.3 0.32 5.2
Conclusions
These findings suggest that tracking gene aberrations in plasma DNA could be an early marker of treatment efficacy.
Clinical trial identification
NCT01867710.
Legal entity responsible for the study
The authors.
Funding
Janssen Pharmaceuticals.
Disclosure
D. Shen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Research and Development. A. Wingate: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Janssens. C. Sternberg: Honoraria (self): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Medscape; Advisory / Consultancy: UroToday; Advisory / Consultancy: Genentech; Advisory / Consultancy: Medivation; Research grant / Funding (institution): Exelixis. R. Jones: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self): BMS; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Exelixis; Honoraria (self): Sanofi; Honoraria (self): Genentech; Honoraria (self): Eusa Pharma; Honoraria (self): Pharmacyclics. A. Berruti: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Travel / Accommodation / Expenses: Sanofi. F. Lefresne: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Johnson & Johnson. M. Lahaye: Honoraria (self), Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen-Cilag. S. Thomas: Leadership role, Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Janssen Research and Development. S. Joshi: Honoraria (self), Travel / Accommodation / Expenses, Full / Part-time employment: Janssen Research and Development. M. Gormley: Travel / Accommodation / Expenses, Licensing / Royalties, Full / Part-time employment: Janssen Research and Development. B. Tombal: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ferring; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Takeda; Advisory / Consultancy: Steba Biotech; Honoraria (self): Myovant Sciences. A. Merseburger: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self): Eisai; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): Novartis; Research grant / Funding (institution): Clovis Oncology. D. Ricci: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Janssen. G. Attard: Honoraria (self), Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas Pharma; Advisory / Consultancy: Janssen-Cilag; Research grant / Funding (institution): Innocrin; Research grant / Funding (institution): Arno; Advisory / Consultancy, Travel / Accommodation / Expenses: Ventana Medical Systems; Travel / Accommodation / Expenses: Abbott Laboratories; Licensing / Royalties: ICR Rewards to Inventors; Honoraria (self), Travel / Accommodation / Expenses: Abbott; Advisory / Consultancy, Travel / Accommodation / Expenses: ESSA; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.