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DR. R. RAJKUMAR III YR POST GRADUATE DEPARTMENT OF MEDICAL ONCOLOGY
JOURNAL CLUB
13/09/2012
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Question 1
• Important prognostic factors in breast cancer include:– A. Lymph node status, hormone receptor
status, and TNM stage– B. Histologic subtype– C. Family History– D. Age at diagnosis
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Question 2
• Genomic Analysis:– A. Determines familial breast cancer risk– B. Oncotype DX technology is useful in
ER+ and ER- breast cancers– C. Helps determine the best adjuvant
chemotherapy regimen– D. Has been validated in retrospective
studies
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Question 3
HORMONAL THERAPY FOR ER+ PR – BREAST CANCER
• 1.TAMOXIFEN• 2.AROMATASE INHIBITORS• 3.NOVEL TARGETED AGENTS• 4.DONT KNOW
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Copyright © American Society of Clinical Oncology
Outcomes of Adjuvant Chemotherapy in Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
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Lum A Lum B Basal Her2
claudin low
Changing Portraits
Concept evolution
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Adjuvant Systemic Therapy for Breast Cancer: Decision Making
· Prognostic Factors– Estimate outcome independent of systemic
treatment– Reflect tumor biology: Who should be treated?
· Predictive Factors– Reflect a relative resistance or sensitivity to
specific therapy– What specific treatment(s) should be offered to
an individual?
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Breast Cancer Prognostic Factors· Accepted
– TNM Stage– Axillary Nodal Status– Tumor Size– Tumor Grade– ER Content– Oncotype DX (?)
· Investigational– Gene expression arrays– Proteomics– Pharmacogenetics– Novel imaging– Other
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Breast Cancer Predictive Factors· Accepted
– ER status– Grade – HER 2 overexpression– Oncotype DX (?)
· Investigational– Gene expression arrays– Proteomics– Pharmacogenetics– Novel imaging– Other
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11Sotiriou, C. et al. NEJM, 2009.
Luminal ALuminal B
HER2+Basal-like
Intrinsic Breast CancerSubtypes described by
Perou et al.
Express ↑ amountsOf luminal cyto-Keratins & geneticMarkers of luminalEpithelial cells ofNormal tissue
Express ↑ levels of EGFR, c-kit, & growth factors like hepatocyte growth factor and IGF
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Figure 1a.
Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-23, 2003
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St. Gallen 2007
Highly Endocrine Responsive
Non–endocrine Responsive
Incompletely Endocrine Responsive
High ER and PgR and
ER and PgR both absent
Low ER and PgR or
No HER2 overexpression
and
PgR absent or
Low Ki-67 HER2 overexpressionor
High Ki-67
ER = estrogen receptor; PgR = progesterone receptor.Goldhirsch et al. Ann Oncol. 2007;18:1133.
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St. Gallen – Endocrine Responsiveness “Practical” Clinical Subgroups
ER and PR absent ER and PR low/intand/or any of these
Both receptorshigh levels
• PgR absent• UPA/PAI-1 high• HER-2 overexpressed• Increased proliferation• High grade
NoNoNoNoNo
Chemo only options Chemo adds to hormonal
Chemo doesn’t work
Absent
Endocrine-responsiveness
Uncertain Sure
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The Level of ER Expression Is Predictive
· The higher the level of expression, the greater the benefit from endocrine treatment
· The higher the level of expression, the lesser the added benefit of chemotherapy
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Added Value of PgR Status in Assessing Endocrine Responsiveness
Estrogens ER
Estrogen-responsive elements
Cell cycle PgR synthesis
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Added Value of PgR Status Assessment
· Quality control of ER status assessment– ER-/PgR+ tumors do not exist (almost!)– ER 10%/PgR 90% is very unusual (and likely related to poor
sensitivity of ER staining)
· Prognosis (among ER+ tumors)
· Effectiveness of endocrine therapies (and chemotherapyin premenopausal patients)
· Response to AI?
AI = aromatase inhibitor.Viale et al. J Clin Oncol. 2007;25:3846.
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0
20
40
60
80
100
0 9910 30 40 50 60 75 90
4-y
DF
S (
%)
Subpopulation by PgR%
TamoxifenLetrozole
STEPP for Central PgR (ER-Expressing) in the BIG 1-98 Trial
STEPP = subpopulation treatment effect pattern plot.
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Is ER/PgR Status Assayed Well in Clinical Practice?
· Inconsistent allocation to “ER/PgR-negative”– No immunoreactive cells?– Less than 10% immunoreactive cells?– Less than 20% immunoreactive cells?– A different threshold for different clinical questions/settings?
· Conflicting results– >15% disagreement between different laboratories (false negative)
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False-Positive Assays?
Local Central
N % N %
ER+/PgR+3124 71.0 3330 75.7
ER+/PgR-965 21.9 832 18.9
ER+/PgR?220 5.0 48 1.1
ER-/PgR+80 1.8 13 0.3
ER-/PgR- 50.1 103 2.3
ER-/PgR? 0 0 1<0.1
ER?/PgR+ 2<0.1 23 0.5
ER?/PgR- 0 0 70.2
ER?/PgR? 3<0.1 42 1.0
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Oncotype DX 21-Gene Recurrence Score (RS) Assay
PROLIFERATIONKi-67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromelysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
REFERENCEBeta-actinGAPDHRPLPO
GUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category RS (0-100)Low risk RS <18
Int risk RS ≥18 and <31
High risk RS ≥31
Paik et al. N Engl J Med. 2004;351:2817-2826.
RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score + 0.05 x CD68- 0.08 x GSTM1- 0.07 x BAG1
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Recurrence Score in N-, ER+ patients
Standardized Quantitative Oncotype DX Assay
0%
5%
10%
15%
20%
25%
30%
35%
40%
0 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Dis
tan
t R
ecu
rren
ce a
t 10
Yea
rs
Low Risk Group High Risk Group Intermediate Risk Group
1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006 3) Paik et al JCO 2006, 4) Gianni et al JCO 2005
Lower RS’s•Lower likelihood of recurrence•Greater magnitude of TAM benefit•Minimal, if any, chemotherapy benefit
Higher RS’s•Greater likelihood of recurrence•Lower magnitude of TAM benefit•Clear chemotherapy benefit
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Oncotype DX Extensively Studied:Study Experience in >3700 Patients
Study Type No. Pts
Providence Exploratory 136
Rush* Exploratory 78
NSABP B-20 Exploratory 233
NSABP B-14* Prospective 668
MD Anderson* Prospective 149
Kaiser Permanente* Prospective Case-Control 790 Cases/Controls
NSABP B-14 Prospective Placebo vs Tam 645
Milan* Exploratory 89
NSABP B-20* Prospective Tam vs Tam+Chemo 651
ECOG 2197* Exploratory and Prospective 776
SWOG 8814 Prospective Tam vs Tam+Chemo 367
*Published studies
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Schema: TAILORx
Node-Neg, ER-Pos Breast CancerNode-Neg, ER-Pos Breast Cancer
RS <10HormoneTherapyRegistry
RS <10HormoneTherapyRegistry
RS 11-25Randomize
Hormone Rxvs
Chemotherapy + Hormone Rx
RS 11-25Randomize
Hormone Rxvs
Chemotherapy + Hormone Rx
RS >25Chemotherapy
+Hormone Rx
RS >25Chemotherapy
+Hormone Rx
Oncotype DX AssayOncotype DX AssayRegister
Specimen banking
Primary study group
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Mammaprint: Development of the 70-Gene Signature
· DNA microarray analysis of 78 breast primary tumors (untreated)– Pts were <55 years of age with T1-2/N0 disease– Pts selected based on outcome: Distant metastases within 5
years
· Statistical analysis, “supervised classification,” identified 231 genes correlated with disease outcome Top 70 genes selected
· Genes that regulate cell cycle, invasion, metastasis, & angiogenesis
· Patients categorized as “good prognosis” or “poor prognosis.”
· Found to be a better predictor of distant metastases within 5 years than all clinical variables in this study
· Odds ratio (distant metastases): poor to good prognosis groups = 15
Van ’t Veer, L. Nature, 2002.
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EORTC-BIG MINDACT TRIAL DESIGN6,000 Node negative women
Dr Martine Piccart-Gephart JBI, Brussels
Evaluate Clinical-Pathological risk and 70-gene signature risk
Clinical-pathological and 70-gene both
HIGH risk
Discordant cases
Clin-Path HIGH70-gene LOW
Clinical-pathological and 70-gene both
LOW risk
Use Clin-Path risk to decide Chemo or not
Use 70-gene risk to decide Chemo or not
AdjuvantChemotherapy
(+ endocrine Tx if ER+)
N=3300 (55%) N=600 (10%)
Adjuvant Endocrinetherapy only
N=2100 (35%)
Clin-Path LOW70-gene HIGH
Randomize
The goal of this trial is to show that MammaPrint can spare 20-30% of patients from adjuvant chemo
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70-gene Signature
21-geneSignature
2-GeneRatio
IntrinsicSubtypes
AnalysisApproach
Supervised Supervised Supervised Unsupervised
Tissue Type Fresh or FrozenFormalin-Fixed,
Parafin-embedded
Formalin-Fixed, Parafin-
embedded
Formalin-Fixed, Parafin-
embedded
Technique DNA microarrays Q-RT-PCR Q-RT-PCR Q-RT-PCR
Prognostic Untreated pts age<60, T1-2, LN-
Untreated & TAM-treated ER+/LN-
TAM-treated, ER+/LN- untreated
TAM-treated
PredictiveNO
Benefit to TAM +/- CMF/MF
Response to TAMNO
Validation Retrospective Retrospective Retrospective Retrospective
ProspectiveTrials MINDACT TAILORX NONE NONE
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Reading: Handbook of cell signaling, Ed RA Bradshaw and EA Dennis, 2003. Chapter 275
Cheskis, BJ, 2004. Regulation of cell signaling cascades by steroid hormones
Steroid Hormone Receptor Signaling
Steroid hormones are produced by endocrine glands
Essential regulators of: reproduction, secondary sex characteristics
Development, differentiation
Glucose metabolism
Response to stress and salt balance
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Nuclear Receptor Superfamily
large family of structurally related ligand-inducible transcription factors, including: steroid receptors (SRs), thyroid/retinoids receptors (TR, RARs and RXRs),
vitamin D receptors (VDR), estrogen receptors (ERa and ERb), and orphan receptors for which no ligand has
been yet identified. While having in common a modular structure, they
are activated by distinct lipophilic small molecules such as glucocorticoids, progesterone, estrogens, retinoids, and fatty acid derivatives
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Estrogen Receptors ER-a
Uterus, testis, pituitary, ovary, epididymis, and adrenal gland.
ER-b (Kuiper et al. 1996) brain, kidney, prostrate, ovary, lung, bladder, intestine,
and epididymis. 88% identity with rat ER-b;
47% identity with human ER-a
Both ERs are localized to membrane, cytosol, and nucleus.
ERa and b differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain.
Estrogen-related orphan receptors (ERR) , , a b g
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Estrogen Receptors
http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime
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Estrogen Receptor
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ER effects on different cell types
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Steroid receptor coactivators and ER-dependent gene transcription
TATA
ERE
Estradiol-bound ERTranscription
HistoneAcetylaseActivity
P/CAFCBP
SRCFamily AIB1
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Estradiol
CoactivatorAF1
ERE
EE+
AF1 + AF2
ACTIVE
Receptordimerization
Nuclear localization offully active ER
to ERE
Coactivator
ERE RNAPOLII
FULLY ACTIVATEDTRANSCRIPTION(tumor cell division)
AF1 and AF2recruit
coactivators
E
AF2
AF1
E
Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.
Mode of Action of Estradiol
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Fig.15-12
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HREs are short cis-acting sequences located within the promoters or enhancers of target genes.
HREs: inverted repeats of AGGTCA (ER and ERRs)
inverted repeats of AGAACA (for GR, MR, PR, and AR)
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J. Biol. Chem., Vol. 276, Issue 40, 36869-36872, October 5, 2001
Hall et al.
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Genomic versus Non-genomic
changes in gene expression
delayed (hrs-days)
requires nuclear receptor
prevented by transcription and translation inhibitors
changes in existing enzyme activity and/or protein structure
rapid (sec-min)
unknown cytosolic mechanisms
not affected by transcription and translation inhibitors
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Cross-talk between signal transduction and endocrine pathways
Adapted from Johnston 2005
SOSRAS
RAF
Basaltranscriptionmachineryp160
ERE ER target gene transcription
ER CBPPP P P
ER
Pp90RSK
AktP
MAPKP
Cellsurvival
Cytoplasm
Nucleus
ER
PI3-KP
P
PPP
P
Cellgrowth
MEKP
Plasmamembrane
AI
HER2
IGFRGrowth factorEstrogen
Trastuzumab
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P
Ras
p8
5
p110 ERE
E
ERE
P
P
P
Transcription
ErbB ErbB
ER-Responsive Element
P
MAPKAkt
Ligand
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CHARACTERISTICS OF ER+ PR- BREAST CANCER
• MORE AGGRESSIVE PHENOTYPE• LARGER IN SIZE• OLDER PATIENTS >60 YRS• HIGHER BMI• HIGHER S PHASE FRACTION• GREATER GENOMIC INSTABILITY• HIGHER LEVELS OF EGFR & HER1 HER2• TAMOXIFEN RESISTANCE
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ER+/PR tumors are resistant to tamoxifen (ATAC)
From Cui et al. JCO 23:7721, 2005
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ER+/PR+
ER+/PR+
Negative PR is a marker of high HER1/HER2levels and tamoxifen resistance
Arpino et al. JNCI 97:1254, 2005
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ER+/PR+
ER+/PR+
ER+/PR
ER+/PR
Negative PR is a marker of high HER1/HER2levels and tamoxifen resistance
Arpino et al. JNCI 97:1254, 2005
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The Molecular Portrait Hypothesis
You can recognize theMona Lisa by her smile
and her nose and her eyes and even her hands – if you are really good,but not the sky or the trees
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Tamoxifen
ChemotherapyAnth, Taxane,
Platimun
Postmenopausal Women with HR+
breast Cancer
Aromatase Inhibitor
Biologic agentsHer2, EGFR, VEGF, Parp
The Promise of Personalized Medicine in Breast Cancer
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Question 1
• Important prognostic factor in breast cancer include lymph node status, hormone receptor status, and TNM staging– Histologic subtype and family history have
not been independently validated prognostically, and age at diagnosis is neither prognostic nor predictive
Stearns et.al., BCRT 1998; 52: 239-259Harris, L et.al., J Clin Oncol 2007 Nov 20; 25 (83) 5287-312
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Question 2
• Genomic analysis has been validated in retrospective studies– Available genomic analytic assays
(Oncotype DX, Mammaprint) do not determine familial risk. Oncotype DX has been validated only in ER+ breast cancers. Neither assay determines type of adjuvant chemotherapy.
Paik, S et.al., N Eng J Med 2004 Dec 30; 351(27): 2817-26Paik, S et.al., J Clin Oncol 2006 Aug 10; 24(23): 3726-34Albain, K et.al., SABCS 2007 abstr #10
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Question 3
• HORMONAL THERAPY FOR ER+ PR – BREAST CANCER
1. AI - 52% lower risk for recurrence 2. EGFR INHIBITORS , m TOR INHIBITORS,
PI3K INHIBITORS, IGF INHIBITORS anastrozole plus gefinitib- 49% clinical benefit.