10 jaar Neoadjuvante Studies in het NKI‐AVL Recente Medisch Oncologische Resultaten (met speciale aandacht voor TN tumoren) Sjoerd Rodenhuis, November 2011
Breast Cancer Mortality in the Netherlands
‐30%
1989‐2007: 30% less mortality (= 1.7% p yr)
Verhoging van de effectiviteit van adjuvante therapie • Nieuwe medicamenten • Slimmer gebruik van bestaande medicamenten – Medicatie kiezen op basis van predictieve tests (“Personalized Medicine”) • mRNA microarrays • aCGH • (Proteomics)
– Medicatie aanpassen aan respons • “Respons Monitoring” (Kan alleen als er iets gemonitored kan worden) • Welke mate aan respons is nodig in de (neoadj. setting) ?
Response Prediction & Response Monitoring
BIOPSY Path. DNA RNA Protein
MRI (PET)
3x ddAC
MRI (PET)
CE‐MRI #2: > 25% decrease of late enhancement
3x ddAC PATH pCR ?
CE‐MRI #2: < 25% decrease of late enhancement
3x CapDoc
Verhoging van de effectiviteit van adjuvante therapie • Nieuwe medicamenten • Slimmer gebruik van bestaande medicamenten – Medicatie kiezen op basis van predictieve tests (“Personalized Medicine”) • mRNA microarrays • aCGH • (Proteomics)
– Medicatie aanpassen aan respons • “Respons Monitoring” (Kan alleen als er iets gemonitored kan worden) • Welke mate aan respons is nodig in de (neoadj. setting) ?
NSABP B‐18
pCR after neoadjuvant chemotherapy is associated with a favorable prognosis.
NSABP B‐27
Rastogi et al, J Clin Oncol 26:778‐785, 2008
IHC Subtype and Pathol. CR (ddAC for HER2-; PTC for HER2+ tumors) pCR(breast & axilla) pCR(breast only)
ER+ HER2‐ (N=207) Update Jan 2011
TN (N=92)
HER2+ (N=95)
TN tumors. Initial Regimen = ddAC Event‐Free Survival pCR breast + axila
N = 118 P = 0.09
No pCR
MONTHS
Neoadjuvant Response Index (NRI)
Breast Response Score + Nodal Response Score NRI =
Sum of Maximum Achievable Response Scores
Thus: If NRI = 1: Best Possible Response to Chemotherapy, pCR breast & axilla If NRI = 0: Unresponsive to Employed Chemotherapy Regimen
Ann Oncol 2010, 21: 481‐7
NRI: Neoadjuvant Response Index ER+; HER2‐
ER‐; HER2‐
HER2+; ER‐
HER2+; ER+
Ann Oncol. 2010, 21: 481‐7
NRI in 118 patients with TN Breast Cancer Initial Regimen: ddAC 47 (40%) NRI = 1 (pCR of Breast & Axilla)
Median NRI = 0.67
NRI in 118 patients with TN Breast Cancer Initial Regimen: ddAC BB
B
B
Median NRI = 0.67
B B
Neoadjuvant Response Index (NRI): Ann Oncol. 2010, 21: 481‐7
TN tumors. Initial Regimen = ddAC Event‐Free Survival N = 118 NRI > 0.67 (median)
P = 0.004 NRI < 0.67 (median)
MONTHS
Verhoging van de effectiviteit van adjuvante therapie • Nieuwe medicamenten • Slimmer gebruik van bestaande medicamenten – Medicatie kiezen op basis van predictieve tests (“Personalized Medicine”) • mRNA microarrays • aCGH • (Proteomics)
– Medicatie aanpassen aan respons • “Respons Monitoring” (Kan alleen als er iets gemonitored kan worden) • Welke mate aan respons is nodig in de (neoadj. setting) ?
Which Neoadjuvant Drug Regimen is Best ?
Chemosensitivity Signatures
Bonnefoi et al, Eur J Cancer 2009, 45: 1733‐43
Identificatie van Resistentiegenen
Jorma de Ronde et al (groep Wessels)
Verhoging van de effectiviteit van adjuvante therapie • Nieuwe medicamenten • Slimmer gebruik van bestaande medicamenten – Medicatie kiezen op basis van predictieve tests (“Personalized Medicine”) • mRNA microarrays • aCGH • (Proteomics)
– Medicatie aanpassen aan respons • “Respons Monitoring” (Kan alleen als er iets gemonitored kan worden) • Welke mate aan respons is nodig in de (neoadj. setting) ?
Genes Chromosomes Cancer 2011, 50: 71‐81.
Study Design Dutch Randomized Study N=443
R
Start: August 1993 Closed: July 1999 (10 Dutch Centers)
F F F F F E E E E E C C C C C
N=885
N=442
RT
F F F F E E E E C C C C G‐CSF
Tamoxifen
CTC + PBPC‐Tx
PBPCs
N Engl J Med 349:7‐16, 2003
CTC: cyclophosphamide 6 g/m2 thiotepa 480 mg/m2 carboplatin 1600 mg/m2
Recurrence‐Free Survival (all 885 Patients)
N Engl J Med 349:7‐16, 2003
Intensive Alkylator Therapy in the Adjuvant Treatment of Breast Cancer – Benefit in Triple‐Negative Disease BRCA1‐like aCGH profile
Sporadic‐like aCGH profile
Univariate HR: 0.19 (p<0.01)
Univariate HR: 0.73 (p=0.48)
p‐interaction: 0.03 0
14
0
N = 39 Vollebergh et al, Ann Oncol 22: 1561‐70, 2011
12
N = 38
Findings in TN (Basal‐like) BC • About half of all TN tumors have features of “BRCAness”, defined as a BRCA1‐like aCGH signature (Nederlof/Wessels) – In many of these tumors BRCA1 is silenced, by promoter methylation or otherwise – The BRCA1‐like aCGH signature occurs exclusively in TN tumors – The BRCA1‐like aCGH signature may be associated with alkylator sensitivity (Vollebergh/Linn), but not with higher sensitivity for conventionally dosed AC Lips et al, Ann Oncol 22: 870‐6, 2011
The validation of 2 Discoveries 1. Should intensive chemotherapy with bifunctional alkylators be employed for tumors enriched for a homologous recombination defect (BRCA‐like aCGH) ? 2. Paired CE‐MRI is very good in predicting pCR in TN disease. Should ddAC continue in the presence of a favorable MRI‐response or should every patient have the benefit of a taxane?
Neo‐TN study (Req. 270 patients)
N=118 Required
•Multi‐center study (NL) •First 56 patients entered (1‐11‐11) •Grants from KWF and SK‐Foundation
Lips E, Ladach N, et al., Breast Cancer Res, in press
Lips E, Ladach N, et al., Breast Cancer Res, in press
The validation of 2 Discoveries 1. Should intensive chemotherapy with bifunctional alkylators be employed for tumors enriched for a homologous recombination defect (BRCA‐like aCGH) ? 2. Paired CE‐MRI is very good in predicting pCR in TN disease. Should ddAC continue in the presence of a favorable MRI‐response or should every patient have the benefit of a taxane?
Neo‐TN study (Req. 270 patients)
•Multi‐center study (NL) •First 56 patients entered (1‐11‐11) •Grants from KWF and SK‐Foundation
ACKNOWLEDGEMENTS Clinicians: Sabine Linn, Gabe Sonke, Marjo Holtkamp, Margaret Schot, Ingrid Mandjes. BC Surgeons + NPs, Med Onc + residents + Day Care Facility, Clin. Geneticists etc. etc. Imaging: Claudette Loo, Kenneth Gilhuijs, Bas Koolen, Radiologists, NM Pathology: Jelle Wesseling, Marc van de Vijver Response Prediction: Esther Lips, Jorma de Ronde, Lennart Mulder (CTMM) & Marieke Vollebergh (group Sabine Linn) Mol Path: Petra Nederlof, Lodewyk Wessels, Jelle Wesseling N4‐plus investigators, TNM investigators incl. Alex Imholz (Deventer) Data Center & Methodology: Otilia Dalesio, Andrew Vincent, Harm van Tinteren Central Microarray Facility NKI: Ron Kerkhoven, Wim Brugman
