cancer genomics and personalised medicine in oncologymanagement of rectal cancer major challenges...
TRANSCRIPT
![Page 1: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/1.jpg)
Cancer Genomics and Personalised Medicine in Oncology
Anamaria A. Camargo Molecular Oncology Center
Hospital Sírio Libanês São Paulo SP Brazil
CERCA/ FAPESP Week Barcelona May 2015
![Page 2: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/2.jpg)
Cancer is a genetic disease
Endogenous andexogenous mutagens
DNA replication errors
Caused by the accumulation of genetic and epigenetic alterations in DNA of normal somatic cells
3,000 point mutations hundreds chromosomal aberrations
![Page 3: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/3.jpg)
Alterations in gene expression and cell reprogramming
Genes are switched on and off !!!
![Page 4: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/4.jpg)
The hallmarks of cancer
Sustainingproliferative signal
Evading growthsuppressors
Resisting cell death
Enabling replicativeimmortality
Inducing angiogenesis
Activating invasion and metastasis
Hanahan & Weinberg Cell, 2011
![Page 5: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/5.jpg)
Basic Cancer Research in São Paulo
Public Universities
![Page 6: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/6.jpg)
Translational Cancer Research in São Paulo Brazil
Dedicated Research Institutes in Public and Private Hospitals
![Page 7: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/7.jpg)
Molecular Oncology Center at Hospital Sírio-Libanês
Expertise: Genome-wide methodologies (NGS) and bioinformatics for:
- gene expression analysis- germline polymorphisms (CNV, SNPs)- somatic alterations (genetic, epigenetic)
- tumor biobank linked to clinical information - breast and colon tumours
- 4 Principal Investigators- 4 Associate Investigators- 4 Technicians- 1 IT support- Post Doc, PhD and Ms Students
![Page 8: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/8.jpg)
Sequencing Tumor Genomes
HCC1954BL HCC1954
Comprehensive Characterisation of Somatic Genetic Alterations Present in Tumor Genomes
![Page 9: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/9.jpg)
Somatic Alterations
Why search for genetic alterations in tumor genomes?
Understand Tumor Biology
Identify Key Cancer Genes
![Page 10: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/10.jpg)
Understand Tumor Biology - ADAM23
![Page 11: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/11.jpg)
Understand Tumor Biology - ADAM23
A23posA23neg
![Page 12: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/12.jpg)
Genetic Alterations
Determine tumor characteristics
Predict disease outcome
Predict treatment response
Specific for tumor cells
Development of alternative therapies
Monitor presence oftumor cells
Genetic alterations can also be used to improve patient care
![Page 13: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/13.jpg)
Personalized Medicine in Oncology
https://pct.mdanderson.org/
The use of tumor genetic profile to define patient treatment and follow up
![Page 14: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/14.jpg)
Genetic Alterations
Determine tumor characteristics
Predict disease outcome
Specific for tumor cells
Genetic alterations can also be used to improve patient care
![Page 15: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/15.jpg)
Predict Disease Outcome - ADAM23
Silencing occurs during tumor progression and is more frequently observed in late stage tumours!
ADAM23 methylation analysis in primary breast tumours
![Page 16: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/16.jpg)
Predict Disease Outcome - ADAM23
91.0
74.1
37.5
93.1
92.4
50.0
Metastasis-free survival Overall survival
p<0.001 p<0.001
ADAM23 methylation can be used to
determine the risk of developing metastasis
![Page 17: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/17.jpg)
Genetic Alterations
Determine tumor characteristics
Predict disease outcome
Predict treatment response
Specific for tumor cells
Monitor presence oftumor cells
Genetic alterations can also be used to improve patient care
![Page 18: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/18.jpg)
middle
low
7cm
Treatment response and monitoring in rectal cancer patients
~ 40,000 cases/yr US
anal dentate line
Adenocarcinomas
Rectal Tumors
![Page 19: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/19.jpg)
6 weeks 8 weeks
RT – 5040cGy – 3 fields
CT – 5FU (425mg/m2) + leucovorin (20mg/m2)
Stag
ing
Re-s
tagi
ng
3 days
Rest
3 days
Management of Rectal Cancer Neoadjuvant therapy followed by surgery
![Page 20: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/20.jpg)
Complete Response
ypT0
No Response
Near Complete
Management of Rectal Cancer Variable clinical response
Despite the response rate all patients are submitted to
radical surgery
![Page 21: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/21.jpg)
Management of Rectal Cancer Why search for Alternatives to Radical Surgery?
Overall Morbidity 38% Mortality 2-3% Urinary Dysfunction 20% Sexual Dysfunction 15% Anorectal Dysfunction 20% Recurrence Rates 8-40%
![Page 22: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/22.jpg)
Complete Response
ypT0
No immediate surgery Close follow up
Radical Surgery No Response
Management of Rectal Cancer Major Challenges
#1 Can we avoid the unnecessary toxic effects of QRT in patients with no clinical evidence of response to therapy?
#2 Can we avoid the unnecessary surgery and comorbidities in patients with complete clinical response to therapy?
![Page 23: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/23.jpg)
Management of Rectal Cancer Major Challenges
Next Generation Sequencing
#1 Avoid unnecessary CRT toxic effects
#2 Avoid unnecessary surgery and morbidity
Develop a predictive marker for therapeutic
response
RNA-seq Gene expression signatures
Develop a biomarker for detection of residual disease and monitoring
Paired-end gDNA-seq Chromosomal rearrangements
![Page 24: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/24.jpg)
MUC17
Incomplete Response
Complete Response
Gene expression signature to predict response to therapy
Global gene expression analysis in 25 pré-treatment biopsies
![Page 25: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/25.jpg)
We identified 27 genes whose expression patterns can be used
to discriminate patients with complete and incomplete
response to therapy
Gene expression signature to predict response to therapy
![Page 26: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/26.jpg)
Genetic Alterations
Determine tumor characteristics
Predict disease outcome
Predict treatment response
Specific for tumor cells
Monitor presence oftumor cells
Genetic alterations can also be used to improve patient care
![Page 27: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/27.jpg)
Circulating tumour DNA and liquid biopsies
J Clin Oncol 32:579-586. © 2014 by American Society of Clinical Oncology
![Page 28: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/28.jpg)
Identification of personalised biomarkers for response assessment and disease monitoring
Patient # 1
Unpublished results
![Page 29: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/29.jpg)
Identification of personalised biomarkers for response assessment and disease monitoring
Unpublished results
Patient with complete pathological responseFree of disease after surgery
![Page 30: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/30.jpg)
Identification of personalised biomarkers for response assessment and disease monitoring
Unpublished results
Patient with incomplete responseFree of disease after surgery
![Page 31: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/31.jpg)
Identification of personalised biomarkers for response assessment and disease monitoring
Unpublished results
Patient with complete pathological responseWho developed metastasis after surgery
![Page 32: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/32.jpg)
Genetic Alterations
Determine tumor characteristics
Predict disease outcome
Predict treatment response
Specific for tumor cells
Development of alternative therapies
Genetic alterations can also be used to improve patient care
Indirect detection oftumor cells
![Page 33: Cancer Genomics and Personalised Medicine in OncologyManagement of Rectal Cancer Major Challenges Next Generation Sequencing #1 Avoid unnecessary CRT toxic effects #2 Avoid unnecessary](https://reader035.vdocuments.net/reader035/viewer/2022071517/613bed8ef8f21c0c8269469a/html5/thumbnails/33.jpg)
Identify new therapeutic targets