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June 22th 2019
Comités de tumores moleculares: experiencia nacional en MD Anderson Cancer Center Madrid
Dr. Gema Moreno-BuenoHead of the Translational Research Laboratory UAM & MDA
PRECISION MEDICINE: Information about the genes, proteins, and other molecular features of a person's cancer todiagnose or treatment. Cancer patients may share a molecular defect although the kind of cancer will be different. Geneticinformation about a particular person's cancer can be used to diagnose or treat its particular disease. Genetic changescharacterization in cancer cells is directed to select a precise treatments.
NIH trials in precision medicine:NCI-MATCHALCHEMISTLung-MAPNCI-MPACTNCI-COG Pediatric MATCHExceptional Responders study
1. Improved in the Cancer Molecular Biology Knowledge2. Advances in the Technology (massive approaches)
NCCN Annual Conference 2018: Updated Guidelines for NSCLC
EGFR mutationsALK fusionsROS1 fusions PD-L1 expression (IHC) BRAF mutations
NCCN 2010: Guidelinesfor NSCLC
EGFR mutationsNCCN 2014: Guidelines for NSCLC
EGFR mutationsALK fusionsROS1 fusions
Advancing in the tumor molecular biology is strictly associated with the need to include more molecular analysis in the tumor diagnosis
The extensive tumor sequencing can identify mutations thatcould enhance clinical decision-making in routine cancer care,potentially improving patient outcomes, at an affordable levelfor healthcare providers.
PLOS Medicine | February 14, 2017
Molecular test by targeted sequencing in the cancer diagnosis
Oncomine Myeloid Research Assay
Lung and colon panel
Extended cancer panel v2
Cancer panel
DNA/RNA sequencing+
IHCImmunoprofiling
Exome versus targeted sequencing for maximizing throughput, coverage depth and cost reduced
Patient Oncologist
Tumourboard
Radiology
Surgery
EndoscopySampling
Targetedtherapies
Results
Cohorts:Clinical Trials
Tumour Registries
Predictivebiomarkers
IHC
NGS
Diagnosis
Pathology Department
Multidisciplinary interactions facilitate personalised oncology treatment
Modified from Conde E, et al. Clin Transl Oncol 2013;15:503–8
Molecular UnitPCR
Molecular screening program:
Trial A Trial DTrial CTrial B
Adapted from Tonellato
Pathologist
Geneticis
Oncologist
Biologist
Clinical trial-ologistNeed to address:- Driver versus passenger mutations (single tumor carries an average of
80 somatic mutations that change the amino acid sequences ofproteins).
- If more than one aberration is present, which one to target first?- How we “validate” the performance of the tumor board- Would decisions be made the same way on different days?
Molecular Tumor Board
• Multidisciplinary-expertise in clinical oncology (early drug development, disease-specific), genomics, signal transduction pathways,
genetic counseling, bioethics, pathology...
• Ad hoc or regularly scheduled meetings/committees
• Tumor heterogeneity, biopsy techniques, low tumor purity (microdissection, cell based enrichment, ploidy based sorting)
• Which aberrations are clinically significant?
• What does the cell percent have a mutation with clinical significance?
• What is the therapy recommended in relation to the mutational profiling?
Aim: To provide an important learning platform for the oncology community about how to effectively use genomicinformation for selection of optimal targeted drugs and/or precise clinical trials.
- Next-generation sequencing assays are widely available and considered to be part of the standard of care inspecific clinical situation.
Challenges for implementing precision medicine: knowledge gaps, privacy, systems barriers, and reimbursementissues.
Molecular tumor boards address gaps in knowledge and clinical utility by providing a forum for individuals withwide-ranging expertise to review patient medical histories and mutation profiles to guide patient-specific treatmentoptions.
Implementation and Clinical Utility of an Integrated Academic-Community Regional Molecular Tumor BoardBurkard et al. 2018 JCO Precision Oncology
Wisconsin PMMTB has a tripartite structure
Recommendations to optimize Molecular Tumor Board (MTB) functioning
1. Global harmonization in cancer sequencing practices and procedures
In comparison to germline genetic testing, somatic testing is relatively new and less evolved. Because of thecurrent variation in cancer sequencing practices and procedures, it is recommend specification of the knowledgebases, bioinformatics pipelines and mutation calling/variant annotation algorithms that were used.
Modified from van der Velden DL et al. Ann Oncol. (2017)
lack of standard molecular testslack of criteria to define actionabilityidentification of VSU mutations (potentiallypathogenic)
2. Minimal member and operational requirements
For an MTB that discusses large-scale sequencing results such as WES and WGS, it is proposed the following minimal member requirements:
• Clinicians, representing all potentially relevant medical specialisms• Pathologists• Clinical (molecular) Biologists• Geneticists, especially when germline testing is included• Bioinformaticians
Several years of experience in and affinity with molecularly targeted cancer treatment is recommended. In addition, consideration should be given tooperational requirements and logistic arrangements such as reporting and feedback systems, access to and experience with knowledge libraries, andchoice of bioinformatics and annotation tools.
3. Appropriate unsolicited findings policy
In the absence of clear legislation on how to handle and return unsolicited findings, it is advised that MTBs predefine how sequencing results will behandled if germ line testing is included (i.e. which unsolicited findings could be reported, who discloses the information to patients and relatives, and arepatients informed by default or can they opt-in or opt-out?).
Precision oncology
Personalized Clinical Decision Making Before and After Implementation of a Molecular Tumor Board:
A MD Anderson Single-Center Experience
2015Real Time
2017Molecular test
relevance/impact study
MD Anderson-Madrid, 2000
2012MDA-Molecular Diagnostic Unit
(PCR, MSI..)2013
Molecular panel basedon NGS
Cancer panel Lung&Colon Panel
(hotspots)
2012First NGS
2016RNA&DNA panel
(Oncomine)2015
Glioma Panel
276 molecular tests
2018Molecular Tumor Board
2017Second NGS
2019Panel mieloide
97 molecular tests
MDA Molecular Diagnostic Unit
2017RNA&DNA panel v2
2013Real Time
2016ctDNA mutation
2019SNP panel
chemotoxicity
Before AfterIMPACT?
MD Anderson-Molecular Tumor Board
MDA-MTB Membership:Multidisciplinary team: oncologists, (surgeons, and radiation oncologists), pathologists,researchers, bioinformatics, molecular biologists/geneticists…(Monthly meeting)
MDA-MTB Process:Patient cases presented by the team.
Genomic tumor findings obtained in the MDA lab (Molecular Diagnosis Unit) or/and by differentCommercial Labs.
Discussion about clinical history, pathological diagnosis, molecular profiling: therapy selection
MTB protocol and clinical steps
PatientBlood sampleTumor biopsy
Archived tumor
Genetic tests:Targeted sequencing(Mut, CNV, fusions)
ValidationMolecular
tumor boardClinician
Follow up
Impact of targeted treatment
Efficacy and toxicity of treatment
Follow up
Treatment decision
Consent and screening
DNA/RNA extracted
Identified alterations
MOLECULAR REPORTbrainstorming
session
PD-L1 and CD8 expressionMSI status
TMB
MDA-Molecular Tumor Board role: Yes or not
Before
MTB implementation
After
Impact in the cancer patient management
The question:• Are the results of identifying therapeutic targets by NGS easily transferred to the clinic?• In how many cases does therapy really change?• What are the reasons in cases where there is no therapeutic change?
MTB implementation
Before
Period 2013-2017:
276 cases with follow up (around 55 per year)
Test: Cancer Panel Hotspot (50 genes) /
Oncomine v1 (35 genes, 19 CNVs, 23 gene fusion)
After
Period 2018-2019:
97 cases with follow up
Test: OM Comprehensive Assay v3,
(87 hotspot, 48 full genes, 43 CNV, 51 gene fusion)
MDA-Molecular Tumor Board role: Yes or Not
NGS molecular diagnosis of cancer patients: analyzing results and their impact on therapeutic decision making
Before AfterPeriod 2013-2017. 276 cases with follow up Period 2018-2019. 97 cases with follow up
MTB
Head & Neck 6%
Uro11%
Breast12%
Sarcoma7%
Lung15%
GI21%
GYN28%
GI25%
GYN13%
Head & Neck7%
Lung32%
Melanoma4%
Other& unkown
5%
Sarcoma7%
Uro
79% (218 cases) of the cases contained at least 1 genetic variant (range 1-5)
87.4% (83 cases) of the cases contained at least 1 genetic variant (range 1-6)
73% (201 cases) of the cases showed targeted alterations
Before After
88% (73 cases) of the cases showed targeted alterations
Genetic alteration classification
MTB
Biological6% Marker
6%
Target88%
Target: Therapeutic markersMarker: Predictive markersBiological markers
In 60% of cases (n= 94) with target mutations, there were no significant therapeutic modifications
In 33% of cases (n= 24) with target mutations, there were no significant therapeutic modifications
Before After
MTB
Treatment45%
no-change33%
NA16%
Awating clinical decision6%
DEC
ISIO
N NA (no data)Awaiting clinical decision (no action yet)Treatment (changed based on the molecular profiling)No change (although targeted therapy is available)
33% : no significant therapeutic modifications
n (79) %SD with other treatments / patients already enrolled in other clinical trials
12 14.9
No trial / Drug not available in Spain 16 17Screening failure 10 10,6No fit/Exitus 29 30.8Lost follow up after diagnosis /NA 12 26.6
Before
After
n (24) %Patient already in response with standard therapy
9 37.5
No trial / Drug not available in Spain 4 16.7Screening failure 2 8.3No fit/Exitus 1 4.2Lost follow up after diagnosis/NA 8 33.3
The treatment was not changed: Why?
60% : no significant therapeutic modifications
Some conclusions…
Only in 30% of patients the treatment was changed.
High patient rate whom treatment was not changed
(60%):
- In a significant fraction of patients, studies are
requested at a too advanced stage of the disease,
which means that patients will not meet inclusion
criteria in most trials.
- Complex and long bureaucracy to get new drugs
out of the approved indications.
- An efficient circuit of enrolling patients in clinical
trials is required, in particular phases I & II.
BeforeIn 45% of patients treatment was changed
Significant reduction in patient rate whom treatment
was not changed (33%):
- Patients are currently in response to standard
treatments (in the case of recurrence new
therapeutic opportunities).
- Test was performed in early disease stages
(facilitating their inclusion in clinical trials in the
case of recurrence).
- No available information about future
therapeutic action (patients only request the
molecular test).
After
MTB
MTB Implications
PRECISION MEDICINE
MTB implementation together with the advance in the knowledge of the role of targeted molecular tests have partiallycontributed in:
- Designing of novel molecular tests which are based on the needs of the current oncology.
- Learning to whom, when, and what kind of samples sample should be used for the molecular test.
- Getting that the molecular test reachs to the clinical practice
- Keep learning in multidisciplinary committees for advancing in the precision medicine.
- Much remains to be learned: early disease?
MDA-Molecular Tumour Board team:
Oncology Department (E Grande, MD)
Pathology Department (A Teijo, MD)
Molecular Diagnosis Unit
ACKNOWLEDGEMENTS
PRECISION MEDICINE
M Lopez-Colomer
S Palacios Zambrano, PhD
G Moreno-Bueno, PhD
Modalities of molecular selection for biology-driven trials.
Andre et al. 2011 JCO 29:1236
Conventional modality: asses a single target when the patient presents a progressive. This scenario is associated with a high rate of screen failure.
Molecular selection at any time during disease course. This modality is associated with a lower rate of screen failure, but requires the set up of multiple bioassays and allows selection for a limited number of targeted therapies.
A molecular enrichment based on clinical characteristics. This modality of selection is associated with a high number of patients exposed to a drug although not presenting the target.
Modalities of molecular selection for biology-driven trials.
Andre et al. 2011 JCO 29:1236
Molecular selection performed at any time during disease course, on the basis of high-throughput technologies. This modality allows detection of a higher number of targets as compared to the modality described in Figure 1B