the 70-gene profile and chemotherapy benefit in early stage … · 2019. 9. 2. · knauer et al.,...
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Genexpressionsprofile in der Praxis
Jahrestagung Österr. Gesellschaft für Senologie14.10.2010
Michael Knauer
Zertifiziertes Brustzentrum VorarlbergLKH Feldkirch
Netherlands Cancer InstituteAmsterdam
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30 Jahre Fortschritt in der Krebsforschung
1980
Normale Zelle Tumor
?
2010
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Interdisziplinäre Zusammenarbeit
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Wie schlimm ist mein Krebs?Wie schlimm ist mein Krebs? Hilft mir das Medikament?Hilft mir das Medikament?
Individuelle Therapie
Vermeiden von Vermeiden von ÜÜberber-- und Unterbehandlungund Unterbehandlung Individualisierte TherapieIndividualisierte Therapie
Zwei wichtige Fragen
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Kaplan-Meier Survival Curve
Einschätzung des Rezidivrisikos
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• Ähnliche klinisch-pathologische Eigenschaften
• Unterschiedlicher Verlauf
• Adjuvante Therapie auf Basis von Richtlinien
• Alter• Tumorgröße• Grad• Lymphknoten-Status• Hormonrezeptoren• Her2-Status
Einschätzung des Rezidivrisikos
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St. Gallen 2007
• Low risk: T1, N0, Grad 1, Alter > 35, ER/PR +, Her2 -
St. Gallen All Patients: n (%) Highly + Incompletely Responsive, Her2-negative
Low risk 145 (9%) 141 (16%)
Intermediate risk 1287 (76%) 714 (79%)
High risk 190 (11%) 42 (5%)
Not available 74 (4%) 6 (1%)
Total 1696 903/1696 (53)%
Knauer et al., St.Gallen 2009, abstract 72
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• 3.5% profitieren von Chemotherapie• 100% haben Risiko von Nebenwirkungen
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Mikro-skop Micro-array
Neue diagnostische Möglichkeitenvom Mikro-skop zum Micro-array
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Entwicklung Multigen-Assays
Neue Klassifikation: intrinsic subtypes1
Entwicklung von prognostischen Profilen2
Prat, Perou, Nat Med 2009Parker et al., JCO 2009
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Paradigmenwechsel
Weg von vornehmlichstadienbasierter
Risikoabschätzung…
…hin zur Integration vonindividuellen, biologiebasierten
Risikoprofilen
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Entwicklung Multigen-Assays
van t’Veer et al., Nature 2002van de Vijver et al., NEJM 2002
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Wie funktioniert es?
Tumor RNA
Referenz RNA
Gene 1 2 3 4 5 6 7 8
1 2 3 4 5 6 7 8
Über-Expression
Unter-Expression
Gleiche Expression
Aktive Gene mRNA
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Profile beim MammakarzinomProfil Gewebe Technik Evidenzlevel
70-Genprofil (MammaPrint) fresh - frozen DNA
microarray III
21-Gen Recurrence Score (OncotypeDX) FFPE rt-PCR II
HOXB13/IL17BR ratio (Breast Cancer Index) FFPE rt-PCR III
Genomic Grade Index (MapQuant Dx) fresh - frozen DNA
microarray III
Molecular subtypes (PAM50) FFPE rt-PCR III
76-Genprofil (Rotterdam) fresh - frozen DNA
microarray III
Wound-response signature fresh - frozen DNA
microarray III
...
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Entwickelt aus 78 eingefrorenen TumorprobenEntwickelt aus 78 eingefrorenen Tumorproben11
Validiert in 3 unabhValidiert in 3 unabhäängigen Studienngigen Studien22--44
1: van 1: van ‘‘t Veer et al, Nature 2002t Veer et al, Nature 20022: van de Vijver et al, NEJM 20022: van de Vijver et al, NEJM 2002
3: Buyse et al, JNCI 20063: Buyse et al, JNCI 20064: Bueno4: Bueno--dede--Mesquita,BCRT 2008Mesquita,BCRT 2008
70-Genprofil MammaPrint™
-- Stadium I/IIStadium I/II
-- ER+ und ERER+ und ER--
-- N0 uN0 und nd N1N1
-- FDAFDA-- und ISOund ISO--zertifiziertzertifiziert
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PROLIFERATIONKi-67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromolysin 3Cathepsin L2
HER2GRB7HER2
BAG1
GSTM1
REFERENCE
Beta-actinGAPDHRPLPO
GUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category RS (0 – 100)Low risk RS < 18Intermediate risk
RS 18 - 30
High risk RS ≥ 31
Paik et al, NEJM 2004Habel et al, BCRT 2006
21-gene recurrence score – Oncotype Dx™
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Stabilität und Reproduzierbarkeit
Oct-2005 May-2006 Nov-2006 June-2007 Dec-2007 July-2008-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Date
Mam
maP
rint
Inde
x
LRC (n=284HRC (n=284)
Glas et al. BMC Genomics 2006
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Stabilität und Reproduzierbarkeit
Sample 1 Sample 2 Sample 3 Sample 4
IGR (France)
Agendia (Netherlands)
Agilent (USA
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Mam
maP
rin
t O
utc
om
e
Sample 1 Sample 2 Sample 3 Sample 4
IGR (France)
Agendia (Netherlands)
Agilent (USA
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Mam
maP
rin
t O
utc
om
e
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Mam
maP
rin
t O
utc
om
e
Ach et al. BMC Genomics 2007
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21-Genscore: NSABP-B14
Courtesy S. Paik
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Metastasenfreies Überleben (n=369)
0 2 4 6 8 100
20
40
60
80
100
Good prognosis (n=286, 78%)Poor prognosis (n=83, 22%)
Jahre
Proz
ent
Krebsspezifisches Überleben (n=369)
0 2 4 6 8 100
20
40
60
80
100
Good prognosis (n=286, 78%)Poor prognosis (n=83, 22%)
Jahre
Proz
ent
HR 4.4 (2.6-7.3), p<0.001 HR 4.9 (2.5-9.8), p<0.001
Knauer et al, St.Gallen Konsensus 2009
70-Genprofil Rezeptor-positives Karzinom, keine adj. Therapie
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Bueno-de-Mesquita et al., Lancet Oncol. 2007
Machbarkeitsstudie Implementierung MammaPrint 2004 – 2006
16 öffentliche Krankenhäuser in den Niederlanden
427 Patienten
51% low risk, 49% high risk
4 Jahre Nachbeobachtung
Erste prospektive Ergebnisse 2011
Raster Studie
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• 2 prospektiv randomisierte Studien laufen:
TAILORx (USA): 21-Genscore: >10.000 Frauen
MINDACT (Europa): 70-Genprofil: > 6.000 Frauen,
24.9.2010: 4.335 eingeschlossen
• Rekrutierung bis 2012, Ergebnisse noch später
• seit 2004: >100.000 OncotypeDx Tests, jede 8. Patientin
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St. Gallen vs. 70-Genprofil
Mammaprint All Patients: n (%) Highly + Incompletely Responsive, Her2-negative
Low risk 792 (47%) 564 (63%)
High risk 904 (53%) 339 (37%)
Total 1696 903
Knauer et al., St.Gallen 2009, abstract 72Knauer et al., SABCS 2008, abstract 1084
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• Ergebnisse sind logisch und nachvollziehbar
• Unabhängige Information über Prognose
einer einzelnen Patientin
• Überprüft in mehreren unabhängigen Studien
Prognostischer Wert
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Interessant zu wissen
Veränderung dieser (schlechten) Prognose
Vorhersage des Ansprechens auf die Behandlung
Wer profitiert von welcher Therapie?
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Chemotherapie hat wenig Effekt auf späte Rezidive
Kein Effektvon Chemo
Wirkung von Chemotherapie Oxford Overview EBCTCG
Berry, 2006; Ravdin 2008
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Chemotherapie: 21-Genscore• Retrospektive Analyse der randomisierten
SWOG-8814 Studie
• 367 Patientinnen mit nodal-positivem Karzinom
Albain et al., Lancet Oncol 2010
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DDFS
Albain et al., Lancet Oncol 2010
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Albain et al., Lancet Oncol 2010
BCSS
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Chemotherapie: 70-Genprofil
Knauer et al., BCRT 2010
BCSS: MammaPrint LOW RISK(n=252)
0 1 2 3 4 50
20
40
60
80
100
ET (n=174, 69% )ET+CT (n=78, 31% )
99%97%
Time in years
Perc
ent s
urvi
val
BCSS: MammaPrint HIGH RISK(n=289)
0 1 2 3 4 50
20
40
60
80
100
ET (n=141, 49%)ET+CT (n=148, 51%)
94%
81%
Time in years
Perc
ent s
urvi
val
HR 0.58 (0.07‐4.98)p=0.62
HR 0.21 (0.07‐0.59)p<0.01
13% absolute benefit
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Chemotherapie: 70-Genprofil
Knauer et al., BCRT 2010
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Straver et. al., Breast Cancer Res Treat, 2009
Neoadjuvante Chemotherapie
Patientenn = 167
Patientenn = 167
Low RiskSignature
n = 23 (14%)
Low RiskSignature
n = 23 (14%)
pCR (axilla+breast)n = 29 (20%)
pCR (axilla+breast)n = 29 (20%)
High RiskSignature
n = 144 (86%)
High RiskSignature
n = 144 (86%)
pCR (axilla+breast)
n = 0
pCR (axilla+breast)
n = 0p=0.015p=0.015
2 klinische StudienT-Stadium >3 cm und/oder pos. LKUltraschall-StanzbiopsienMRIHistologie
Anthrazyklin-Schema 85Anthrazyklin-Taxan 31Capecitabine 14PTC 37
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Straver et. al., Breast Cancer Res Treat, 2009
Prognose nach neoadjuvanter Chemotherapie
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1. Patientinnen mit “Low Risk” 70-Genprofil haben eine sehr gute Chance, gesund zu bleiben. Die adjuvante Chemotherapie hat nur einen geringen, nicht signifikanten Benefit gegenüber Hormontherapie alleine
2. Patientinnen mit “High Risk” 70-Genprofil haben ein hohes Risiko für Fernmetastasen und zeigen einen signifikanten Benefit von zusätzlicher Chemotherapie
3. MINDACT, die europaweite klinische Studie wird wahrscheinlich diese retrospektiven Analyse bestätigen
Zusammenfassung prädiktiver Wert
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• Präoperative Stanzbiopsie ist Routine: ER, PR, Her2
• Möglichkeit der Genexpressionsanalyse
• Hohe Wahrscheinlichkeit für pCR: genaue Markierung und Responsemonitoring essentiell
• Lokalrezidivrate abhängig von molekularen Subtypen: Optimale Lokaltherapie
Individualisierung der Therapiebeginnt vor der OP
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• Operationsplanung und Logistik• Stanzbiopsie aus dem frischen Tumor gleichzeitig mit
Resektionsrandbeurteilung• Verarbeitung innerhalb einer Stunde:
RNA-Konservierung• 7 Tage bis zur Verarbeitung: Lagerung bei -80°C
Perioperative Veränderungen
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21-Genscore
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Einsatz MammaPrint am LKH FeldkirchJA:Invasiv duktale KarzinomeGrad 1-30-3 positive LymphknotenHormonrezeptoren positivFamiliäre Belastung: BRCA1,2
NEIN:Invasiv lobuläre KarzinomeTriple negative TumorenHer2 positive Tumore DCIS
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(1) If the patient is highly endocrine-responsive, otherwise consider CT
(2) If the patient is highly endocrine-responsive: ET only is an option, no adjuvant therapy is not advised
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St. Gallen 2009Chemo-
EndokrinNicht
zielführendEndokrin
Rezeptoren ER und PR niedrig
ER und PR hoch
Grad Grad 3 Grad 2 Grad 1
Proliferation Hoch Mittel Niedrig
Lymphknoten ≥ 4 1 – 3 0
PVI Extensive PVI
Tumorgröße > 5cm 2,1 – 5 cm ≤ 2cm
Patientenwunsch Alle Therapie-optionen
Vermeidung von NW
Multigensignatur High risk Intermediate Low risk
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Microarray
Chemo-therapie
Prognose schlecht
Hormon-therapie
Target-therapie
Full
gen
om
e ar
ray
Tumor
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Chemo-therapie
Prognose schlecht
Hormon-therapie
Target-therapie
Full
gen
om
e ar
ray
Tumor
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Chemo-therapie
Prognose schlecht
Hormon-therapie
Target-therapie
Full
gen
om
e ar
ray
Tumor
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Chemo-therapie
Prognose schlecht
Hormon-therapie
Target-therapie
Full
gen
om
e ar
ray
Tumor
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Vielen DankNetherlands Cancer Institute:
E. Rutgers, S. Linn, L. van ‘t Veer, S. Mook, V. Retel, J. Bueno-de-Mesquita, M. Kok, W. van Harten, S. Rodenhuis, M. van de Vijver
Österreich:
A. Haid, E. Wenzl, Z. Jasarevic, R. Bartsch, M. Gnant