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![Page 1: Expression profiles for prognosis and prediction Laura J. Van ‘t Veer The Netherlands Cancer Institute, Amsterdam.](https://reader034.fdocuments.net/reader034/viewer/2022051019/56649d205503460f949f4a51/html5/thumbnails/1.jpg)
Expression profilesfor prognosis and prediction
Laura J. Van ‘t VeerThe Netherlands Cancer Institute, Amsterdam
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Breast Cancer - Survival premenopausal patients, lymph node negative
time (years)
surv
ival
~30% die of breast cancer
~70% survive breast cancer
Kaplan-Meier Survival Curves
1) Who to treat2) How to treat
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61 y-old, fit,61 y-old, fit,postmenopausalpostmenopausalNode negativeNode negativepT = 0.9 cm pT = 0.9 cm ductal cancerductal cancerER and PR ER and PR negativenegativeHER2 negativeHER2 negativeGrade 2Grade 2
HOW SHOULD ONE TREAT HOW SHOULD ONE TREAT A SMALL (<1CM) BREAST TUMOR ?A SMALL (<1CM) BREAST TUMOR ?
FA(E)C x 6
0
10
20
30
40
50
NONE CMFx6 ACx4 TAM OTHER
%
4848
2525
151544
88
Choices of 40 experts worldwideChoices of 40 experts worldwide
Courtesy of Martine PiccartCourtesy of Martine Piccart
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Gene expression profiling to improve prediction of clinical
outcome• aim
-to identify patients at risk to develop distant metastases and die of cancer
-to accurately select for adjuvant therapy
-to predict treatment response
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Cy3-dUTPgreen fluorescent
reverse transcriptase,T7 RNA polymerase
Cy5-dUTPred fluorescent
cRNA
sample 2(reference)
RNAcDNA
sample 1(tumortissue)
RNAcDNA
cRNA
RNA extraction and labelingto determine expression level
sample of interestcompared tostandard reference
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Scanned image of flexjet25K human oligonucleotide
microarray
Hybridized with mixture of ‘red’-labeled cRNA of a tumor sample and ‘green’-labeled reference cRNA (pool of tumor samples)
Determine:• fluorescence intensities• fluorescence ratio’s
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2010: Outcome for Prognosis
Micro-array
Treatment 2
Prognosis poor
Treatment 1
Treatment 3
Classifier
• Tumor
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Response for treatment 1
Micro-array
Treatment 2
Prognosispoor
Treatment 1 resistant
Treatment 3
Classifier
• Tumor
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• Tumor
Micro-array
Treatment 2sensitive
Prognosispoor
Treatment 1resistant
Treatment 3
Response for treatment 2
Classifier
• Tumor
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Response for treatment 3
• Tumor
Micro-array
ClassifierTreatment 2sensitive
Prognosispoor
Treatment 1resistant
Treatment 3sensitive
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78 breast tumors (‘83-’94)patients < 55 yearstumor size < 5 cm
lymph node negative (LN0)no adjuvant therapy
no distant metastasesin at least 5 years (n=44)
distant metastases< 5 years (n=34)
Prognosis Reporter Genes
Who to treat?Retrospective series –
TissuebankNo adjuvant treatment
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Classification Prognosis7
8 t
um
ors
goodsignature
poorsignature
threshold
threshold set with 10% false negatives91 % sensitivity, 73% specificity
metastases
(white = +)
70 significant prognosis genes
Nature 415, p530-536, 2002
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Breast Cancer - Metastases riskby profiling
time (years) 151 patients, <53, LN010 year survival curve
Distinguish in: 40% good profile, 60% poor profile
meta
stase
s-fr
ee good profile:
~13% develop metastases~87% disease-free
poor profile:~56% develop metastases~44% disease-free
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Implementation of Profiling
Breast cancer patients, lymph node negative:
~20-30% reduction of unnecessary treatmentand avoidance of 2-3% undertreatment
Who to treat
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70 genes
Prospective NKI - Raster trial - work in progress
Good signatureLow risk
Poor signatureHigh risk
• accrual 75 patients• microarray 40 patients
24 low, 16 high risk
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- biopsy of primary tumor - upfront chemotherapy
- response of primary tumor by imaging
determine therapy response profiles in biospy
How to treatNeo-adjuvant trials
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Chang et al, Lancet 2003
Neo-adjuvant docetaxol response
92 differentially expressed genesdifferentiate sensitive andResistant breast tumors.Confirmed in ‘6’ sensitive tumors
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• identification of predictive factors to neoadjuvant chemotherapy using gene expression profiling
• comparison of two different drug combinations:– AC (adriamycine/cyclophosphamide)– AD (adriamycine/docetaxel)
Neo-adjuvant response profile
NKI/AVL study locally advanced breast cancer
S. Rodenhuis, M. van de Vijver
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Why these drugs ?
• standard drug combination for neoadjuvant chemotherapy: AC– but: resistance against anthracyclines can
exist or develop under primary therapy
• good responses observed with docetaxel containing combinations– high activity also in anthracycline-resistant
disease– but: very toxic agent
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Study design (NOODCD)
• prospective phase III trial within the NKI/AvL
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Patients included
• first 62 patients included into the study• enough RNA obtained from 49 patients:
50% tumour cells– 46 biopsies, 18 tumours
CT-arm biopsy/tumour
pairs biopsies
only tumours
only total amount of patients
AC 7 15 3 25
AD 8 16 0 24
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Patients response
CR: complete remission
PR: partial remission
MR: minor remission
SD: stable disease
PD: progressive disease
CT-arm (almost) CR PR MR/SD/PD NA total
AC 7 (28 %) 9 (36 %) 8 (32 %) 1 (4 %)* 25
AD 5 (21 %) 11 (46 %) 8 (33 %) 0 (0 %) 24
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Interim Conclusions NOODCD
• Thus far, no major differences in gene expression between tumours from patients with a CR compared to all other patients– (work in progress)
• significant differences in gene expression in tumour specimens before and after treatment
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Neo-adjuvant or Metastatic response relevant for Adjuvant?
Are gene activities similar or different when comparing the primary tumor and metastasis
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Expression profiling of matched pairs
Primary tumors – lymph node metastasesPrimary tumors – distant metastases
microarrays
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ER- positive
ER- negative
15 primary breast tumors and lymph node metastases of the same patient
Hierarchical clustering
Primary breast tumors – lymph node metastases
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Hierarchical clustering
Primary breast tumors – distant metastases
8 primary breast tumors and distant metastases of the same patient
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How to treatNeo-adjuvant therapy response profiles
similarity of primary/metastasis profile implies:therapy recommendations based on expression profileof the primary tumor are a rational approach towards preventing the outgrowth of micrometastases
- biopsy of primary tumor profiled - upfront chemotherapy
- response of primary tumor by imaging
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Who to treat:• Prognosis profile as diagnostic tool
-> improvement of accurate selection for adjuvant therapy (less under- and overtreatment)
• Prognosis profile implemented in clinical trials-> reduction in number of patients & costs (select only patients that are at metastases risk)
Therapeutic implications
How to treat:•Predictive profile for drug response
-> selection of patients who benefit