10 jaar Neoadjuvante Studies in

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 CE MRI #2: < 25% decrease of late enhancement 3x ddac 3x CapDoc PATH pcr?

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) Update Jan 2011 ER+ HER2 (N=207) 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) NRI = Breast Response Score + Nodal Response Score 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 HER2+; ER ER ; HER2 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 B B 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 NRI > 0.67 (median) N = 118 P = 0.004 NRI < 0.67 (median) MONTHS

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)

Genes Chromosomes Cancer 2011, 50: 71 81.

Study Design Dutch Randomized Study N=443 F E C F E C F E C F E C F E C Start: August 1993 Closed: July 1999 (10 Dutch Centers) R N=885 RT Tamoxifen N=442 F E C F E C G CSF F E C F E C PBPCs CTC + PBPC Tx CTC: cyclophosphamide 6 g/m 2 thiotepa 480 mg/m 2 carboplatin 1600 mg/m 2 N Engl J Med 349:7 16, 2003

N Engl J Med 349:7 16, 2003 Recurrence Free Survival (all 885 Patients)

Intensive Alkylator Therapy in the Adjuvant Treatment of Breast Cancer Benefit in Triple Negative Disease BRCA1 like acgh profile Univariate HR: 0.19 (p<0.01) Sporadic like acgh profile Univariate HR: 0.73 (p=0.48) p interaction: 0.03 0 14 0 12 N = 39 N = 38 Vollebergh et al, Ann Oncol 22: 1561 70, 2011

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

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