Current concepts in Breast Cancer- Beyond TNM
Professor Ravi KantFRCS (England), FRCS (Ireland), FRCS (Edinburgh),
FRCS(Glasgow), MS, DNB, FAMS, FACS, FICS, Professor of Surgery
Applications of Genes Assay in CA Breast
• To subclassify breast cancer• To estimate prognosis• To predict response to therapy
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Applications of Genes Assay in CA Breast
• To subclassify breast cancer• To estimate prognosis• To predict response to therapy
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Gene Expression Patterns of Breast Carcinomas Distinguish Tumor Subclasses With Clinical
Implications
PNAS 2001;98;10869-10874
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Molecular classification & Prognosis:
• Luminal A= Best prognosis• Luminal B• Luminal C• Normal breast like• Her 2+• Basal like= Worst= Triple Negative
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SubtypeType ImportanceLuminal A ER +, Best overall
survival, Best DFS
Luminal B ER,Her2+,Intermediate
Her 2 +ve ER-, Intermediate
Basal like ER-,PR-, Her2 - Worst 7
Tumor based Gene assayTest # of Genes Tissue
Mammaprint(Amsterdam)
70 Fresh
Oncotype Dx 21 Fixed
76 gene 76 Fresh
Wound response Fresh
Two gene ratio 2 Fixed
Intrinsic subtype Fresh9
Tumor based Gene assayTest Aim
Mammaprint 70 To predict risk of distant mets in N-, To identify who will benefit from Chemo
Oncotype Dx 21 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
76 gene 76 To predict DFS & OS in N-, early stage
Wound response To predict risk of mets & death
Two gene ratio 2 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
Intrinsic subtype To predict clinical outcome
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Tumor based Gene assayTest Aim
Mammaprint 70 To predict risk of distant mets in N-, To identify who will benefit from Chemo
Oncotype Dx 21 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
76 gene 76 To predict DFS & OS in N-, early stage
Wound response To predict risk of mets & death
Two gene ratio 2 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
Intrinsic subtype To predict clinical outcome
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• 70 gene classifier developed further by the company Agendia (www.agendia.com) under the name MammaPrint.
• MammaPrint was approved by the FDA in February 2007 for node negative women under 61 years of age and with a tumor < 5cm.
Tumor based Gene assayTest Aim
Mammaprint 70 To predict risk of distant mets in N-, To identify who will benefit from Chemo
Oncotype Dx 21 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
76 gene 76 To predict DFS & OS in N-, early stage
Wound response To predict risk of mets & death
Two gene ratio 2 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
Intrinsic subtype To predict clinical outcome
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Tumor based Gene assayTest Aim
Mammaprint 70 To predict risk of distant mets in N-, To identify who will benefit from Chemo
Oncotype Dx 21 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
76 gene 76 To predict DFS & OS in N-, early stage
Wound response
To predict risk of mets & death
Two gene ratio 2 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
Intrinsic subtype To predict clinical outcome
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Tumor based Gene assayTest Aim
Mammaprint 70 To predict risk of distant mets in N-, To identify who will benefit from Chemo
Oncotype Dx 21 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
76 gene 76 To predict DFS & OS in N-, early stage
Wound response To predict risk of mets & death
Two gene ratio
2 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
Intrinsic subtype To predict clinical outcome
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Tumor based Gene assayTest Aim
Mammaprint 70 To predict risk of distant mets in N-, To identify who will benefit from Chemo
Oncotype Dx 21 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
76 gene 76 To predict DFS & OS in N-, early stage
Wound response To predict risk of mets & death
Two gene ratio 2 To identify N-, ER+ who will benefit by addition of Chemo to Tamoxifen
Intrinsic subtype
To predict clinical outcome
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Applications of Genes Assay in CA Breast
• To subclassify breast cancer• To estimate prognosis/
prediction• To predict response to therapy
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Conventional classification
• Convential Classification assumes that women with a tumor bigger than 2 cm have a high risk to develop distant metastasis.
Size is an insufficient indiactor of metastasis risk
• Molecular studies shows that size alone is not an indicator of high or low metastasis risk.
• Small and large tumors can be either low or high risk as determined by Molecular studies
Molecularclassification
Molecular studies provides additional data to assess the risk of distant
metastasis
Molecular studiesclassification
Patients re-characterized as Low-RiskMammaPrint: 34%
MammaPrint Discovers 34% Low Risk MammaPrint Discovers 34% Low Risk Patients in Adjuvant! High-Risk GroupPatients in Adjuvant! High-Risk Group
Buyse et al., Journal of the National Cancer Institute. 2006;98(17):1183-92.
Adjuvant! High Risk
MammaPrint Low Risk
MammaPrint High Riskn = 20987%
n = 13766%
n = 7234%
N = 209
Gene Assay prediction > Adjuvant Online
• Buyse M. Validation and clinical utility of 70 gene prognostic signatures for women with node negative breast cancer.
• J Natl Cancer Inst 2006;98:1183-92.
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Different proportion of low and high risk patients
• MammaPrint profiles accurately 40% as low risk compared to only 15% with St. Gallen criteria.
MammaPrint identifies correctly
MammaPrint identifies correctly
• 40% of patients with low risk in comparison to the 15% that are identified with conventional methods, thus preventing many unnecessary chemotherapies.
• More precise in predicting the outcome of disease than St. Gallen when comparing survival rates.
Mets free / Survival
LN + or -
Gene Expression vs. Clinical
St Gallen vs NIH
TRANSBIG Validation:302 Patients, Node-Neg, T1/2, Age <
61
Buyse et al., Journal of the National Cancer Institute. 2006;98(17):1183-92.
RNA
Target n=400
Achieved n=307
High or Low Gene
Signature Risk
<<local>> pathological dataClinical Data
Tissue Samples
UK (Guy’s, Oxford)1984 – 1996
France (IGR, CRH)1978 – 1998
Sweden (Karolinska)1980 – 1990
Node negative, untreated
<60 years > 5 years follow-up T1, T2 Tumor cell % > 50%
Tissue Samples
UK (Guy’s, Oxford)1984 – 1996
France (IGR, CRH)1978 – 1998
Sweden (Karolinska)1980 – 1990
Node negative, untreated
<60 years > 5 years follow-up T1, T2 Tumor cell % > 50%
BrusselsComparison of
clinicalv gene signature assessment ofprognostic risk
EndpointsTime to Distant MetastasisOverall SurvivalDistant Metastasis-Free Survival, Disease-Free Survival
BrusselsComparison of
clinicalv gene signature assessment ofprognostic risk
EndpointsTime to Distant MetastasisOverall SurvivalDistant Metastasis-Free Survival, Disease-Free Survival
AmsterdamGene expression profiling
Agilent platform70-gene prognostic custom designed chip
AmsterdamGene expression profiling
Agilent platform70-gene prognostic custom designed chip
Audited clinical
data
Centrally reviewed path data (Milan)
Agendia 70-gene
prognostic signatureN=78
N=151
Level 5 and 4Level 5 and 4
IndependentIndependentvalidation study on validation study on archival materialarchival material
NN300• The signature isThe signature is robustrobust• The technology is The technology is reproducible reproducible
Level 2-3Level 2-3
Levels of evidence for biomarkers studiesLevels of evidence for biomarkers studies
Prospective clinical trial specifically addressing the
gene signature’s utility
N6000
Level 1Level 1
Three step validation strategyThree step validation strategy
Buyse et al., Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer, Journal of the National Cancer Institute, Vol 98, No. 17, 2006
MammaPrint® identifies early metastases risk with highest accuracy
29%39%
50%62%
75%83%
96% 100%
4.52
7.54
4.683.24 3.5
9.14
2.132.33
2 3 4 5 7 10 15 none
Censoring time (in years)
0.1
1
10
Adjusted hazard ratio for gene signature
Cumulative
proportion of events
Time to distant metastasis
HR: all endpoints strongest in first 5 years after diagnosis
FDA Clearance of MammaPrint® Study Purpose Details Comments
1NatureDevelopment 70-gene profile
200278 patients, LN0, <55yrs6.4% adjuvant treatment
Within 5 year metastasis risk by profile multivariate OR 18
2NEJM Validation 70-gene profile
2002151 patients5.2% adjuvant treatment
Metastasis-free at 10 yrs: low risk 87%,high risk: 44%5 yrs: low risk 93%,high risk 56%
3MammaPrintDevelopment MammaPrint
2006reproducibility of (1) and (2) on MammaPrint
Highly reproducible MammaPrint as a diagnostic tool
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TRANSBIGIndependent European validation
2006302 patientsno adjuvant treatment
Metastasis-free at 10 yrs: low risk 88%,high risk: 71%5 yrs: low risk 96%,high risk 83%
TRANSBIG, the Translational Research Network of the Breast International Group (BIG), conducted anindependent validation study of both the Amsterdam and Rotterdam gene signatures in a series of 302 patients
TRANSBIG, the Translational Research Network of the Breast International Group (BIG), conducted anindependent validation study of both the Amsterdam and Rotterdam gene signatures in a series of 302 patients
Although there was only a 3-gene overlap between the two signatures, both were validated on the same patient cohort
So time to learn basics again
Catabolism and tumorhypoxia related metabolism
Cell cycle and cytoskeleton related biogenesis
Extracellular matrixadhesion and remodeling
General signal transductionand intracellular transport
Growth factor
Immune response
Cellular mobility or actin filament related
MammaPrint interrogates all of the criticalgenomic pathways associated with tumor
progression and the metastatic cascade
MammaPrint interrogates critical genomic pathways
Applications of Genes Assay in CA Breast
• To subclassify breast cancer• To estimate prognosis/
prediction• To predict response to therapy
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71 Gene assay predictive value
• Van de Vijver MJ,He YD, van’t Veer IJ, et al. A gene expression signature as predictor of survival in breast cancer. Amsterdam
• N Engl J Med 2002; 347:1999-2009
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Oncotype Dx-21 gene predictive value
• Palk S, Tang G, Shak S et al. Gene expression and benefit of chemotherapy in women with node negative, ER + breast cancer. J Clin Oncol 2006;24:3726-34.
• Can be done on fixed tissue.
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21 gene analysis-Oncotype Dx
• Independent of –Tumor size–AgePark S. NEMJ 2004;351:2817-26.
• > Accurate than Adjuvant OnlineGoldstein RP. Abstract #63. San Antonio 2007
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21 gene analysis can predict
• breast cancer related mortalityHabel LA. Breast Cancer Res 2006
• NSABP- B14 trial
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21 gene Predictive value
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Newer prognostic Indicators
• Wound response gene– risk of mets and death
• 2 gene recurrence score –adding chemotherapy to tamoxifen in ER+ ve, N- ve
• Chang HY . Gene signature of fibroblast serum predicts cancer progression:similAarities between tumors and wound.
PloS Biol 2004; 2:206-14.
Wound response gene expression profile• Activation of fibroblasts• Active wound healing predicts ▲ risk of
–metastases–Death
( in Breast, Lung & Gastric cancer)– Cong HY. PLoS Biol 2004;2:206-14
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2 gene expression profile
• 60, ER+, Early stage (MaXJ.Cancer Cell 2004)
• Expression of–Homeobox 13–IL-17B
• ▲ ratio= poor outcome• ≡Tamoxifen alone will not do in such
patients50
Six models
• All are different• Great concordance in five out of six gene
expression profile models• 21 gene (Oncotype Dx) and 70 gene
(Mammaprint) are popular• 81% concordance between 21 & 70 gene.
• Perou, Fan C. NEMJ 2006
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Courtesy: Martine Piccart
Breast Cancer: The Treatment Dilemma
Choices of 40 experts world-wide
61 y-old, fit,postmenopausal
Node negativepT = 0.9 cm ductal cancerER and PR negativeHER2 negativeGrade 2
Of 100 women with breast cancer
Only 25% will develop distant metastases
But we treat over 75% of all patientswith chemotherapy
Which means that 50% of all breast cancer patients get a toxic chemotherapy that they did not need!
Applications of Genes Assay in CA Breast
• To subclassify breast cancer• To estimate prognosis• To predict response to therapy
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To predict response to therapy
• Selection of the therapy based on attributes of the –Tumor–Host
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21 gene analysis can predict
• Responsiveness to Chemo/ Hormone Gianni L. J Clin Oncol.2005Palk S. J Clin Oncol 2006;24:3726-34
• NSABP- B14 trial
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TAILORx=
Trial Assigning Individualized Options for Treatment
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TAILORx trial
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ASSESS clinical RISK AND MammaPrint RISKASSESS clinical RISK AND MammaPrint RISK(adjuvant!online & MammaPrint)(adjuvant!online & MammaPrint)
BOTH HIGH BOTH HIGH RISKRISK
DISCORDANTDISCORDANTRISKRISK
BOTH LOW BOTH LOW RISKRISK
RANDOMIZERANDOMIZEdecision-makingdecision-making
ChemotherapyChemotherapy No chemotherapyNo chemotherapy
Use MammaPrintUse MammaPrintUse clinical riskUse clinical risk
MINDACT study designMINDACT study design
6000 patients, <70 YRS, 1-3 POS NODES6000 patients, <70 YRS, 1-3 POS NODES
highhigh low
low
55% 35% 10%
MINDACTMicroarray in Node Negative Disease
may avoid Chemo
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Her2 positive MammaPrint low risk patients have an excellent survival
Knauer SABCC 2008
Knauer et al, 2008 unpublished
HR 0.28 (0.14- 0.56; p=0<0.001)
88% Endocrine & Chemo (n= 265)
69% Endocrine (n=184)
Distant metastasis-free survival (years)
MammaPrint low risk (n=126)
HR 1.99 (0.00- 6.3; p=non significant)
Median Follow-up 5.2 years
benefit
Benefit of adjuvant chemotherapy Benefit of adjuvant chemotherapy in MammaPrint high risk patientsin MammaPrint high risk patients
To predict response to therapy
• Selection of the therapy based on attributes of the –Tumor–Host
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To predict response to therapy based on attributes of the host
• Drugs metabolized by–CYP450 encoded enzymes
• CYP 2• CYP 3• CYP2D6• CYP2C19
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To predict response to therapy based on attributes of the host
• Drugs metabolized–AmpliChip CYP450 by Roche
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Prognostic Signature and Clinical Benefit-the chemotherapy choice-
MammaPrint prognosis signature
• Assigns patients to risk categories with high specificity and sensitivity
(low risk vs high risk for recurrence)
• Low risk sufficiently low to forego chemotherapy
• High risk identifies patients with early relapseand shows chemo benefit (predictiveness)
Who to treat:• Prognosis profiles as diagnostic tool
-> improved selection for adjuvant therapy
How to treat:• Predictive profiles for drug response -> selection of patients who will benefit most
Clinical applications of microarrays
WHO WHO NEEDS NEEDS
THERAPY?THERAPY?
WHICH WHICH THERAPY WILL WORK THERAPY WILL WORK
BEST?BEST?
Prognostic factorsPrognostic factors Predictive factorsPredictive factors
What does “low risk” mean? • MammaPrint® “Low Risk”: 90% metastasis-
free without any adjuvant treatment over the following 10 years (NEJM 2002/JNCI 2006)
• Most of the “Low Risk” patients are ER+• With ER+ patients receiving hormonal therapy,
a further 50% risk reduction can be achieved in the “Low Risk” group, thus MammaPrint “Low Risk” means >95% 10 year metastasis-free survival
Summary : Poor risk
• Basal like• Luminal B• HER2+/ER-• Poor 70 gene profile• High 21 gene recurrence score• Activated wound response
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Summary : New Decision aid
• 21 gene (Oncotype Dx) & 70 gene (Mammaprint) is better than Adjuvant Online
• Personalised treatment• Less toxicity, less cost
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Contrast of Appearance vs.Contrast of Appearance vs.Expression PhenotypingExpression Phenotyping
Microarray Low Risk High Risk
Microscope Low Grade High GradeTreatment
Advice
Triple Negative
• ER-, PR-, and HER2 –• Basal like on gene profiling• Adverse prognosis• → new Rx
Thanks
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