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