Browsing Over 167 Presentations
7O - Contrasting the drivers of response to immunotherapy across solid tumour types: Results from analysis of > 1000 cases
- Kevin Litchfield, London, United Kingdom, The Francis Crick Institute
Abstract
Background
Multiple genomic and transciptomic biomarkers have been associated with response to immune checkpoint inhibitor (CPI) therapy. Emerging evidence suggests that each solid tumour type has a unique mix of factors determining CPI response, reflecting the subtle differences in antigen repertoire and immune microenvironment across histologies. Compiling large-scale sequencing datasets of patients treated with CPI therapy, from a range of solid tumour types, allows detailed comparison of the contrasting immune drivers per histology. Understanding these differences enhances our understanding of the pathways influencing CPI response, which may be of utility for therapeutic and biomarker development.
Methods
We compiled data from 13 CPI treated cohorts, across 6 solid tumour types, encompassing 1,453 patients (n = 1,453 with exome data, n = 674 with RNAseq data). All raw data was accessed, and reprocessed through a standardised state of the art bioinformatics pipeline. A comphrehensive range of genomic & transcriptomic biomarker metrics were derived across the cohort. A combined predictive model was constructred encompassing all biomarkers, & the importance weighting was calculated for each biomarker, in each tumour type.
Results
TMB was found to be a universal predictor of response across all tumour types, except for renal cell carcinoma (RCC). Instead CPI response in RCC appears to be strongly driven by expression of human endogeneuos retroviruses (hERV). In malignant melanoma, while TMB (nsSNVs) was associated with CPI response, the number of expressed indel mutations was found to be a stronger predictor. Shared antigen expression also demonstrated tumour specific predictive patterns. A signature of high immune inflitatation was found to be another universal predictor of response across multiple tumour types, however differences in the varying importance of immune cell subsets across histologies was observed. The rate of HLA LOH, and other immune evasion mechanisms also varied dramatically by cancer type.
Conclusions
The determinants of immunotherapy response vary across solid tumour types, offering unique insight into both tumour intrinsic and extrinsic drivers of immunogenicity.
Legal entity responsible for the study
The Francis Crick Institute.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Predictive biomarkers for the efficacy of IO: which biomarkers to use for daily use?
- John B. Haanen, Amsterdam, Netherlands, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital (NKI-AVL)
Predictive biomarkers for the efficacy of IO: What’s in the pipeline
- Daniela S. Thommen, Amsterdam, Netherlands, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL)
Discussion
6O - Comprehensive genomic profiling and outcomes among metastatic melanoma patients (pts) treated with first-line cancer immunotherapy (CIT) in a real-world setting
- Yibing Yan, South San Francisco, CA, United States of America, Genentech Inc. - Roche - USA
Abstract
Background
Distinctive genomic subtypes (BRAF-mutated [BRAFmut], NRASmut, NF1mut, and triple wild type [wt]) have been identified in melanoma, but little is known about their distribution and association with outcomes outside of clinical trials. By linking longitudinal electronic health records (EHR) and comprehensive genomic profiling we aim to describe characteristics and outcomes among CIT-treated pts in a real-world setting.
Methods
Metastatic melanoma pts in the de-identified Flatiron Health (FH)-Foundation Medicine (FMI) Clinico-Genomic Database (CGDB), in which EHR-derived data from FH are linked to genomic data from FMI, who received first-line pembrolizumab (pembro), nivolumab (nivo), ipilimumab (ipi), or ipi + nivo between Jan 1, 2011, and Nov 30, 2018, were analyzed. Median OS was calculated from the start of first-line therapy and was evaluated according to BRAF status and genomic subtypes.
Results
Of 656 melanoma pts in CGDB, 236 received first-line CIT. The majority of pts (69%, n = 165) were BRAFwt and the rest (31%, n = 71) were BRAFmut. Median age was 62.9 yrs (57.3 yrs for BRAFmut pts and 65.6 yrs for BRAFwt pts), 89% were white, and 97% were treated in community clinics. Among BRAFwt pts, 40% (n = 66) were NRASmut, 32% (n = 53) were NF1mut, and 28% (n = 46) were triple wt. Pembro was used in 36% of pts, followed by ipi + nivo (25%), nivo (20%), and ipi (18%). Almost half (47%) of the pts received subsequent therapy; of these pts, 53% (n = 59) received CIT, 23% (n = 26) received targeted therapy, and 24% (n = 27) received other therapies. Median OS for BRAFwt and BRAFmut pts after first-line CIT was 38.6 mo (95% CI 20.2–not estimable [NE]) and 28.9 mo (95% CI 23.3–NE), respectively. Among BRAFwt pts, median OS was 44.9 mo (95% CI 28.9–NE) for NRASmut pts, 27.1 mo (95% CI 19.4–NE) for NF1mut pts, and 19.8 mo (95% CI 11.8-NE) for triple wt pts.
Conclusions
Our study demonstrated that outcomes among melanoma pts receiving first-line CIT in real-world setting vary based on genomic subtypes and revealed, for the first time, differences in outcomes of major genomic subtypes in BRAFwt pts. Continued investigation of the association between specific genomic subtypes and survival in a real-world setting is needed.
Editorial acknowledgement
Melanie Sweetlove, MSc (ApotheCom, Yardley, PA, USA).
Legal entity responsible for the study
Genentech, a member of the Roche Group.
Funding
Genentech, a member of the Roche Group.
Disclosure
N. Sadetsky: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. P. Lambert: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. C. Julian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. J. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group. Y. Yan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech, a member of the Roche Group.
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.
Tracking evolution in prostate cancer with cfDNA profiling
- Gerhardt Attard, London, United Kingdom, University College London Cancer Institute
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
Interpretation of germline variation in cancer susceptibility genes: Pitfalls and challenges
- Clare Turnbull, London, United Kingdom, The Institute of Cancer Research (ICR)
Emerging management paradigms in syndromes of high penetrance susceptibility: TP53 as an exemplar case
- Helen Hanson, London, United Kingdom, St George's Hospital NHS Trust