Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a...

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Routine Molecular Diagnosis of Cancer in Clinical Oncology

Transcript of Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a...

Page 1: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Routine Molecular Diagnosis of Cancer in Clinical Oncology

Page 2: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

“I’m afraid you’ve got cows, Mr. Farnsworth.”

Page 3: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

Page 4: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

1. To provide reproducible, quantitative diagnoses for all cancer patients.

Page 5: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

1. To provide reproducible, quantitative diagnoses for all cancer patients.

2. To clarify diagnostic distinctions that are problematic using current methods.

Page 6: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

1. To provide reproducible, quantitative diagnoses for all cancer patients.

2. To clarify diagnostic distinctions that are problematic using current methods.

3. To deliver newly defined molecular diagnoses that influence treatment choice and/or prognosis.

Page 7: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

1. To provide reproducible, quantitative diagnoses for all cancer patients.

2. To clarify diagnostic distinctions that are problematic using current methods.

3. To deliver newly defined molecular diagnoses that influence treatment choice and/or prognosis.

4. To translate insights from therapeutic trials that incorporate molecular profiling.

Page 8: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

1. To provide reproducible, quantitative diagnoses for all cancer patients.

2. To clarify diagnostic distinctions that are problematic using current methods.

3. To deliver newly defined molecular diagnoses that influence treatment choice and/or prognosis.

4. To translate insights from therapeutic trials that incorporate molecular profiling.

5. To promote excellence in clinical science.

Page 9: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 10: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 11: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 12: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 13: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 14: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 15: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Diversity of Human Lymphomas

Page 16: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Lymphoma Subtype Diagnosis Alters Treatment Choice

Diffuse Large B Cell Yes CHOP chemotherapy + RituximabLymphoma

Primary Mediastinal Yes CHOP chemotherapy + RituximabB Cell Lymphoma +/-radiation

Burkitt Lymphoma Yes High dose chemotherapyCNS prophylaxis

Follicular Lymphoma No Watchful waitingRituximabSymptomatic chemotherapy

Mantle Cell Lymphoma No Watchful waitingSymptomatic chemotherapyResponsive to:--Bortezomib--rapamycin analogues

Lymphoma subtype Curable? Therapy

Page 17: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Goals: --Establish a molecular classification of humanlymphoid malignancies.

--Define molecular correlates of clinicalparameters that are useful in prognosis andin the choice of optimal therapy.

Collaborating InstitutionsUniv. of Nebraska Medical Center Univ. of WürzburgBritish Columbia Cancer Agency Univ. of BarcelonaSouthwest Oncology Group Univ. of ArizonaCleveland Clinic Univ. of RochesterNorwegian Radium Hospital St. Bart’s Hospital

National Cancer Institute Center for Cancer Research

Page 18: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Improving the Accuracy andReproducibility of Diagnosis

Using Gene Expression Profiling

Page 19: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

ClassicBurkitt Lymphoma

AtypicalBurkitt Lymphoma

Diffuse LargeB Cell Lymphoma

RecommendedTreatment

Intensivechemotherapy

Intensivechemotherapy

CHOP-likechemotherapy

Diagnosis of Burkitt Lymphoma vs. Diffuse Large B Cell LymphomaAlters Treatment Choice

Page 20: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 21: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 22: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 23: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Burkitt lymphoma“discrepant”

cases

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Effect of Treatment on Overall Survival in Burkitt Lymphoma

CHOPCNOP

BFMCODOX-M/IVAC

Regimens requiringautologous stem cell

rescue

Classification of Treatments

Intensive CHOP-Like

Page 25: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 26: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 27: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Burkitt lymphomacases potentiallyundertreated by

CHOP-like therapy

Page 28: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Conclusions

• Burkitt lymphoma has a distinct molecular profile that can reliably distinguish it from all forms of diffuse large B-cell lymphoma.

• Current means used for the diagnosis of Burkitt lymphoma disagree with the molecular diagnosis of Burkitt lymphoma in 17% of cases.

• The distinction between Burkitt lymphoma and DLBCL is critical because of significant differences in treatment.

=>Molecular diagnosis of Burkitt lymphoma will improve patient outcome.

Page 29: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Defining New Molecular Subgroupsof Cancer

by Gene Expression Profiling

Page 30: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Diffuse large B cell lymphoma

40% of Non-Hodgkin lymphomas

~23,000 new diagnoses/yr

~40% cure rate

~10,000 deaths/yr

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PMBLGCBDLBCLABCDLBCL

64%59%

30%

5-yearsurvival

Page 33: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 34: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 35: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 36: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Molecular Predictors of OutcomeIn Cancer

Using Gene Expression Profiling

Page 37: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 38: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 39: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why Can Gene Expression ProfilingPredict Outcome in Cancer?

1. Heterogeneity in cell of origin.2. Heterogeneity in oncogenic pathways.3. Heterogeneity in common cellular

functions e.g. proliferation, survival,cell-cell interactions.

Within a current diagnostic category, gene expression profiling can identify:

This heterogeneity is present in the tumor at the time of diagnosis.

Page 40: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Routine Molecular Diagnosis of Cancer in Clinical Oncology:

Development of a Lymphoma Diagnostic Microarray

Page 41: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The LymphDx Project Team

• Metabolism Branch, CCR, NCI– George Wright– Sandeep Dave– Bruce Tan– Andreas Rosenwald– Michael Chiorazzi– Hong Zhao– Liming Yang– Louis Staudt

• Members of the LLMPP• Affymetrix

– John Palma– Janet Warrington

Page 42: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Gene Expression-based Diagnosis of Lymphoma

Page 43: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Gene Expression-based Diagnosis of Lymphoma

Page 44: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Gene Expression-based Diagnosis of Lymphoma

Page 45: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The LymphDx Custom DNA Microarray

~2643 human genes:

Lymphoma diagnostic genes

Lymphoma prognostic genes

EBV, HHV8, HTLV1viral genes

Genes encoding all humankinasescytokines

chemokinescytokine receptors

chemokine receptors

Invariantly expressedcontrol genes

Page 46: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

LymphDx: The One-stop Shopping Approach toLymphoma Diagnosis

Molecular Diagnosis

Molecular Prognosis

DLBCLMantle CellLymphoma

FollicularLymphomaLymphDx

microarray

Page 47: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

GOAL: Implementation of a gene expression-based moleculardiagnosis of lymphoma in routine clinical practice.

Collaborating LLMPP InstitutionsUniv. of Nebraska Medical Center Univ. of WürzburgBritish Columbia Cancer Center Univ. of BarcelonaSouthwest Oncology Group Univ. of ArizonaCleveland Clinic Univ. of RochesterNorwegian Radium Hospital St. Bart’s Hospital

National Cancer Institute Center for Cancer Research

Page 48: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

PHASE 1Affymetrix whole genome profiles of retrospectively ascertained lymph node biopsies

(non-Hodgkin and Hodgkin lymphoma, other cancers, benign conditions)(n= 2000)

Design custom diagnostic microarray

Page 49: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

PHASE 1Affymetrix whole genome profiles of retrospectively ascertained lymph node biopsies

(non-Hodgkin and Hodgkin lymphoma, other cancers, benign conditions)(n= 2000)

Design custom diagnostic microarray

PHASE 2Diagnostic microarray profiles of prospectively ascertained lymph node biopsies

(n= 2000)

Generate data for regulatory approval

Page 50: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Evolving Molecular DiagnosisTo Match Changes in

Cancer Treatment

Page 51: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

The Molecular Diagnosis Cycle

ClinicalTrial

RxArm A

RxArm B

Genomic-scalegene

expressionprofiling

Build amolecularpredictor

ofresponse

Create adiagnostic

test forroutine

clinical use

New Therapy

Page 52: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Phase III Randomized Clinical Trial ofCHOP-Rituximab

vs. Dose-adjusted EPOCH-Rituximabwith Gene Expression Profiling Analysis

in Untreated Diffuse Large B cell Lymphoma

CALGB Study 50303Opened for accrual: May 2005

Study Chairs:Wyndham H. Wilson, Center for Cancer Research, NCI

Bruce Cheson, CALGB Lymphoma Committee Andrew D. Zelenetz, CALGB Lymphoma CommitteeRichard Fisher, Chair, SWOG Lymphoma CommitteeLouis M. Staudt, Center for Cancer Research, NCI

Page 53: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Phase III Randomized DLBCL Trial DesignCALGB Study 50303

Untreated DLBCL patients(n= 430)

CHOP-R(n= 215)

DA-EPOCH-R(n= 215)

Test previous survivalpredictors:

ABC vs GCB DLBCLGC B cell Signature

Proliferation SignatureLymph Node SignatureMHC Class II Signature

Createnew

survivalpredictor

Test previous survivalpredictors:

ABC vs GCB DLBCLGC B cell Signature

Proliferation SignatureLymph Node SignatureMHC Class II Signature

Createnew

survivalpredictor

Page 54: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Why We Need Gene Expression Profiling forAll Cancer Patients

1. To provide reproducible, quantitative diagnoses for all cancer patients.

2. To clarify diagnostic distinctions that are problematic using current methods.

3. To deliver newly defined molecular diagnoses that influence treatment choice and/or prognosis.

4. To translate insights from therapeutic trials that incorporate molecular profiling.

5. To promote excellence in clinical science.

Page 55: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of
Page 56: Routine Molecular Diagnosis of Cancer in Clinical Oncology · Therapy. Goals: --Establish a molecular classification of human lymphoid malignancies.--Define molecular correlates of

Collaborating InstitutionUniv. of Nebraska Medical Center John ChanBritish Columbia Cancer Agency Randy GascoyneSouthwest Oncology Group Rich Fisher Univ. of Würzburg Konrad Muller-HermelinkUniv. of Barcelona Elias CampoNorwegian Radium Hospital Erlend SmelandSt. Bart’s Hospital, London Andrew Lister

Center for Cancer Research, Lou StaudtNational Cancer Institute Sandeep Dave

George Wright


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