ESMO Supporter 2018

Displaying One Session

Hall B3 - Room 21 Proffered Paper session
Date
20.10.2018
Time
11:00 - 12:30
Location
Hall B3 - Room 21
Chairs
  • Anton Berns (Amsterdam, NL)
  • Therese Sørlie (Oslo, NO)
Proffered paper session - Basic science Proffered Paper session

1891O_PR - Mutational landscape of metastatic cancers discovered from prospective clinical sequencing at community practice cancer program

Presentation Number
1891O_PR
Lecture Time
11:00 - 11:12
Speakers
  • Ricardo H. Alvarez (Newnan, US)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30

Abstract

Background

Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that can be therapeutically targeted. We present an analysis of the results of comprehensive genomic profiling (CGP) from a large series of patients assayed in the setting of a community practice cancer network.

Methods

IRB-approved analysis of pts assayed with CGP using hybrid-capture NGS based CGP assays were performed on 6,177 pts with advanced cancer during the course of clinical care for the purpose of making therapy decisions, with GA suggesting the latter labeled as clinical relevant. Three genomic platforms were utilized, FoundationOne (315 genes, 89% of tests), FoundationOne-Heme (405 genes, 6%) and FoundationAct, (62 genes, 5%)

Results

From 01-2013 to 09-2017, clinical samples from 6,177 pts (6496 CGP assays) with advanced cancer underwent CGP. Median age was 56 years (range, 18-94), 61% of pts were female, 68% were Caucasian. The most common tumor types studies were breast (18%), colorectal (15%), lung (14%), gynecological (11%) and unknown cancer (10%). GA were identified in 94% (5839/6496) of cases, and GA were classified as clinically relevant (47%)/not clinical relevant (52.6%). The most frequent clinically relevant GA were in KRAS(23%) and PIK3CA(15%). The most common genomic alterations were amplification (32%). Treatment history for a large subset of patients (4490) showed that 23% (1169/4490) of pts were ordered a genomically-matched treatment, 57% (662/1169) of which were tied to an FDA approved agent in a different tumor type, and 15% of which (178/1169) were referred to a matched mechanism driven clinical trial. With the access to TAPUR the frequency of matched treatment for clinical trials increased over time from 2013 to 2017.

Conclusions

In a large series of diverse patients assayed with CGP in the community setting, 23% of patients received matched treatment, which was predominantly targeted therapy. The increasing frequency of matching treatment over time and the advent of immunotherapy and matching with PDL1 and tumor mutational burden may further increase the proportion of this population . Future analysis will explore outcomes for this subset of pts.

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Proffered paper session - Basic science Proffered Paper session

1892O - Molecular characterization of epithelioid sarcoma (ES) tumors derived from patients enrolled in a phase 2 study of tazemetostat (NCT02601950)

Presentation Number
1892O
Lecture Time
11:12 - 11:24
Speakers
  • Mrinal Gounder (New York, US)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30

Abstract

Background

Loss of INI1/SMARCB1 protein expression in tumor cells is characteristic of ES and impairs activity of the SWI/SNF chromatin remodeling complex inducing oncogenic dependence on EZH2. Tazemetostat, a potent, selective, orally available EZH2 inhibitor has shown clinical activity in INI1-negative tumors including durable objective responses and disease stabilization. While loss of protein expression is a key characteristic of ES, the molecular basis of loss is poorly understood; here we report genetic characterization results of the largest ES cohort to date.

Methods

DNA was isolated from matched tumor and normal samples from 62 ES cases with confirmed INI1 protein loss by IHC. Sufficient DNA was isolated for WES (N = 43), WGS (N = 37), and DNA methylation analysis (N = 35). WGS and WES were performed on tumor and matched normal samples at 30-200X and 10-50X, respectively.

Results

Interim WES analysis on 19 ES cases established that SMARCB1 was the most frequently altered gene (16/19 cases). Review of 325 cancer specific genes, including all SWI/SNF complex members demonstrated that CTNNA1, LRP1B, and NOTCH1 were the next most commonly mutated genes (3/19 cases each). Additionally, the median mutation burden for ES cases was 25.8 mutations/MB suggesting a greater genetic complexity than other predominantly INI1-negative tumors (e.g. AT/RT and MRT). SMARCB1 alterations were consistent with potential causes of INI1 protein expression loss and included both large and focal chromosomal deletions (n = 13), and SNVs (n = 5). Evidence of SMARCB1 bi-allelic loss occurred in 7/19 ES cases, whereas 9/19 cases only had evidence of monoallelic loss. Analysis of DNA methylation data from cases with either no or monoallelic SMARCB1 loss did not support DNA methylation as a mechanism for SMARCB1 silencing.

Conclusions

Alterations of SMARCB1 were the predominant genetic event observed in ES and is the underlying molecular mechanism leading to loss of INI1 protein expression. Notably, multiple genetic mechanisms leading to protein INI1 loss were detected. Updated genetic characterization data on N = 43 ES cases, including analyses to explore potential genetic associations with clinical outcome will be presented.

Clinical trial identification

NCT02601950.

Legal entity responsible for the study

Epizyme, Inc.

Funding

Epizyme, Inc.

Editorial Acknowledgement

Third-party writing assistance was provided by Rob Steger, PhD, and Andrea Eckhart, PhD, of Ashfield Healthcare Communications (a UDG Healthcare plc company), and supported by Epizyme, Inc.

Disclosure

S. Daigle, A. Clawson, M. Roche, S. Blakemore: Employee, stock owner: Epizyme. P. Schöffski, B.A. van Tine: Honorarium: Epizyme. R. Chugh: Research funding, scientific advisor/consultant: Epizyme. T.W-W. Chen: Research fund, honorarium: Eisai, Novartis T. Jahan: Research funding: Aduro Biotech, Acerta Pharma, Aztrazeneca/MedImmune, Lilly, Boehringer Ingelheim, Kadmon, BMS, Polaris, Epizyme. A. Italiano: Advisory board consulting: Epizyme. M. Agulnik: Consulting/Advisory: Janssen, Eisai, Novartis, Lilly; Speakers' bureau: Eisai, Bristol-Myers Squibb. R.L. Jones: Consultant: Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, PharmaMar, G.D.D. Demetri: Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta, Loxo Oncology, AbbVie, Epizyme, Adaptimmune - Research support: Dana-Farber for GD as PI in clinical trial agreements in DFCI sarcoma unit; Novartis, Pfizer, EMD Serono, Sanofi Oncology, Janssen Oncology, Ignyta, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, Wirb Copernicus Group, ZioPharm, Polaris Pharmaceuticals - consultant/fees; Novartis - patent licensed from Dana-Farber with royalty paid to Dana-Farber; Blueprint Medicines, Merrimack Pharmaceuticals - Member, board of directors, member, scientific advisory board; Blueprint Medicines, Merrimack Pharmaceuticals, G1, Caris Life Sciences, Champions Oncology - consultant advisory board, consulting fees and equity (minor stake, public or non-public); Bessor Pharmaceuticals - consultant, equity (minor stake, non-public). M. Gounder: Paid consultant and board member: Epizyme Medical Advisory Board Karyopharm; Advisory board, honorarium: Daiichi, Tracon; Honorarium: Amgen. All other authors have declared no conflicts of interest.

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Proffered paper session - Basic science Proffered Paper session

LBA11 - Defining the lethal subclone in metastatic lung cancer

Presentation Number
LBA11
Lecture Time
11:24 - 11:36
Speakers
  • Mariam Jamal-Hanjani (London, GB)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30

Abstract

Background

The PEACE study aims to study the genetic and phenotypic relationships between primary and metastatic tumours to establish a model for tumour progression, the metastatic process and potential mechanisms involved in therapeutic resistance and tumour evolution.

Methods

In a cohort of patients initially recruited into the lung TRACERx study (NCT01888601), multiregion sampling was performed at each site of metastasis, DNA was extracted from fresh frozen tissue and deep whole-exome sequencing (WES) was subsequently performed and analysed using bioinformatic tools developed to assess tumour clonal architecture (Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376(22):2109-2121).

Results

Preliminary analysis of the first four TRACERx/PEACE patients has demonstrated the presence of driver events, including mutations and somatic copy number aberrations, in both early and late evolution, continued tumour diversification driving genome instability, and different patterns of metastatic seeding. Using evolutionary phylogenetic analyses, the timing of such events is demonstrated from primary to metastatic disease.

Conclusions

PEACE has the potential to inform our understanding of the metastatic process and to reveal the lethal subclone (s) that are involved in branched tumour evolution. The study has recruited over 100 patients and involved over 50 tissue harvests to date. Data arising from PEACE has already demonstrated implications for tracking disease progression (Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):446-451), the emergence of drug resistance and identifying distinct patterns of metastatic spread with prognostic implications (Turajlic S, Xu H, Litchfield K, et al. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell. 2018;173(3):581–594.e12). WES data from primary and metastatic tumours in this cohort of patients recruited into both TRACERx and PEACE can help decipher the clonal dynamics and evolutionary trajectory of lung cancer. This is a unique study leveraging the true longitudinal sampling in these studies from diagnosis to death.

Clinical trial identification

PEACE (PosthumousEvaluation of Advanced Cancer Environment, NCT03004755)

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Proffered paper session - Basic science Proffered Paper session

Invited Discussant 1891O, 1892O and LBA11

Lecture Time
11:36 - 11:51
Speakers
  • Samra Turajlic (London, GB)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30
Proffered paper session - Basic science Proffered Paper session

1O - KRAS mutant and RAS/BRAF wild type colorectal cancer cells exhibit differences in the rewiring of signal transduction that can impact on future therapeutic strategies

Presentation Number
1O
Lecture Time
11:51 - 12:03
Speakers
  • Alexandros Georgiou (London, GB)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30

Abstract

Background

KRAS mutant (KRAS MT) and RAS/BRAF wild type (RAS WT) colorectal cancer (CRC) responds differently to targeted agents. A better understanding of early effects on signal transduction following exposure to targeted agents may explain this and inform future therapeutic strategies.

Methods

A panel of 25 CRC cell lines (10 KRAS MT, 15 RAS WT) and 13 samples isolated from CRC patients’ (pt) serous effusions were used. Using a multiplex antibody-based platform, simultaneous changes in 60 phosphorylated (p) proteins were quantified following 1-hour exposure to clinically used concentrations of: gefitinib, PI3K inhibitor: pictilisib, AZD5363, everolimus, trametinib and vemurafenib. Statistical analysis included logistic regression, T tests and Spearman’s correlation.

Results

Collectively pMEK was the most commonly upregulated protein in KRAS MT cell lines; 55% KRAS MT vs 18% RAS WT, a difference that was significant (P < 0.05) with pictilisib and gefitinib. Triplicate validation with pictilisib confirmed upregulation of pMEK, as well as pERK, pMSK, pGSK3α in KRAS MT but not RAS WT cell lines. KRAS MT cells had a higher mean pictilisib half maximal inhibitory concentration (P < 0.05), being highest in cells with the greatest pMEK rise. Validation with gefitinib confirmed consistent downregulation of pMEK, pMSK, pGSK3α/β, pPRAS40 and pS6 in sensitive RAS WT but not KRAS MT cells (P < 0.05), despite comparable decrease of pEGFR. Gefitinib sensitivity was related to the degree of downregulation of the aforementioned proteins. In 10 KRAS MT pt samples, pMEK upregulation was most commonly seen with pictilisib (38% of pts). As in cell lines, gefitinib led to upregulation of intracellular effectors in KRAS MT pt samples e.g. mTOR in 40% of pts. In RAS WT cells compensatory activation of receptor tyrosine kinases was the commonest rewiring feature, e.g. pFGFR1 upregulation with gefitinib in 40% of cell lines and 66% of pts.

Conclusions

There are significant differences in the rewiring of signal transduction between KRAS MT and RAS WT CRC cells exposed to clinically relevant concentrations of PI3K and EGFR inhibitors. These differences can help devise/refine future strategies to combine targeted agents in CRC.

Clinical trial identification

NCT00825110, CCR3085.

Legal entity responsible for the study

Royal Marsden NHS Foundation Trust.

Funding

Cancer Research UK.

Disclosure

All authors have declared no conflicts of interest.

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Proffered paper session - Basic science Proffered Paper session

2O - Receptor Tyrosine Kinase dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated colorectal cancer cell lines.

Presentation Number
2O
Lecture Time
12:03 - 12:15
Speakers
  • Pietro Paolo Vitiello (Napoli, IT)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30

Abstract

Background

Previous studies showed that the combination of an anti-Epidermal growth factor receptor (EGFR) and a MEK-inhibitor is active in KRAS-wild type colorectal cancers (CRCs) and reverts anti-EGFR primary resistance in KRAS mutated colorectal cancer cell lines. However, resistance onset is a limit to combination therapies.

Methods

We generated four different KRAS mutated CRC cell lines (HCT15, HCT116, LoVo, SW480) resistant to a combination of cetuximab (anti-EGFR antibody) and refametinib (BAY86-9766, selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. Resistant clones had an IC50 20-100-fold higher than the parental cells. We evaluated by Western Blot (WB) analysis and quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR) the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers. We further analysed by MTT assay the sensitivity of the cetuximab-MEKi resistant (CM-res) cell lines to different kinase knockdown or pharmacologic inhibition. Oncomine comprehensive assay analyses was used for identify new genetic alteration.

Results

We found consistent hyperactivation of the PI3K-AKT pathway coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R in resistant cells when compared to parental cells. Resistant clones exhibit an epithelial phenotype, more pronounced for mesenchymal-like parental cell lines of the CMS4 cluster (HCT116 and SW480). Either selective knockdown of these RTKs or treatment with the pan-HER inhibitor afatinib (BIBW2992) failed to revert the resistance phenotype in our cellular model, while treatment with pictilisib (GDC-0941, selective PI3Kα inhibitor) was able to restore the sensitivity to the drug combination. No new genetic alteration was detected.

Conclusions

Our in vitro preliminary data demonstrate that PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-i in KRAS mutated colorectal cancer cell lines. PI3K activation is achieved through concurrent activation of multiple RTKs such as HER2, HER3 and IGF1R, suggesting a cooperative mechanism.

Legal entity responsible for the study

Department of Precision Medicine - Università della Campania Luigi Vanvitelli.

Funding

Università della Campania Luigi Vanvitelli; Associazione Italiana Ricerca sul Cancro (AIRC).

Disclosure

All authors have declared no conflicts of interest.

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Proffered paper session - Basic science Proffered Paper session

Invited Discussant 1O and 2O

Lecture Time
12:15 - 12:30
Speakers
  • Alberto Bardelli (Candiolo, IT)
Location
Hall B3 - Room 21, ICM München, Munich, Germany
Date
20.10.2018
Time
11:00 - 12:30