TAILORED ADJUVANT SYSTEMIC THERAPY FOR BREAST CANCER THERAPY FOR BREAST CANCER MYTH OR REALITY? Presented by DR. KATHLEEN I. PRITCHARD Senior Scientist, Sunnybrook Research Institute Sunnybrook Odette Cancer Centre Professor Department of Medicine Professor, Department of Medicine University of Toronto
CMF 6 cycles every 4 weeks • Cyclophosphamide 100 mg/m 2 po R x 14 d A N N • Methotrexate 40 mg/m 2 iv d 1& 8 • Methotrexate 40 mg/m iv d 1& 8 D • 5FU 600 mg/m 2 iv d 1& 8 O NCIC-MA5 M M Pre-menopausal I node positive Z (n=710) (n 710) CEF 6 cycles every 4 weeks CEF 6 cycles every 4 weeks A • Cyclophosphamide 75 mg/m 2 po T x 14d I I • Epirubicin 60 mg/m 2 iv d 1 & 8 O • 5FU 500 mg/m 2 iv d 1 & 8 N Cotrimoxazole or norfloxacin/ciprofloxacin
10 10 84 80 80 MA.5 Disease-Free Survival CMF CEF P=0.005 212 193 193 5 5 Time (years) 351 359 359 0 CMF CMF CEF 100 80 60 40 20 20 0 Percent Risk: At
10 106 106 98 CMF CEF MA.5 Overall Survival P=0.047 269 253 253 5 Time (years) 351 359 359 0 CMF CMF 100 80 60 40 20 CEF 0 Percent Risk: At At
Adverse Events • 4 cases of CHF in the CEF group compared to 1 in the CMF group p g p • 5 patients in the CEF group experience • 5 patients in the CEF group experience acute leukemia (4 myeloid and 1 lymphoid) vs 1 in the CMF group vs 1 in the CMF group
DFS by treatment for those with HER2 amplification HER2 as a HER2 as a predictive factor 100 80 CEF CEF Percentage e 60 CMF 40 DFS by treatment for those 20 HR = 0 52; p=0 003 HR = 0.52; p=0.003 with no HER2 amplification ith no HER2 amplification 0 0.0 5.0 10.0 75 42 19 88 35 12 100 Time (years) # At Risk(CEF) ( ) # At Risk(CMF) # At Ri k(CMF) 80 CEF CMF CEF ercentage 60 CMF 40 e P P HR = 0.91; p=0.49 20 0 0.0 5.0 10.0 237 145 59 228 228 138 138 60 60 Time (years) # At Risk(CEF) # At Risk(CMF) CEF CMF
OS by treatment for those HER2 as a HER2 as a with HER2 amplification ith HER2 lifi ti predictive factor 100 80 CEF ntage OS by treatment for 60 CMF Percen those not HER2 amp 40 HR = 0.65; p=0.060 20 100 0 80 CEF 0.0 5.0 10.0 75 49 20 rcentage CMF 88 47 18 60 Time (years) # At Risk(CEF) # At Risk(CMF) # At Risk(CMF) 40 40 er CEF CMF P HR = 1.06; p=0.91 20 0 0.0 0.0 5.0 5.0 10.0 10.0 237 184 71 228 175 78 Time (years) # At Risk(CEF) # At Risk(CMF) CEF CMF
Adjusted* Hazard Ratios by HER2 Status (CEF vs. CMF) CMF) Disease Free Survival Disease Free Survival Overall Survival Overall Survival HER2 HR 95% CI p p-value HR 95% CI p-value p Amplified 0.52 0.34 - 0.80 0.003 0.65 0.42 – 1.02 0.06 Not Amplified 0.91 0.71 - 1.18 0.49 1.06 0.83 - 1.44 0.68 * adjusted for age, nodal status, grade, ER status, surgical procedure, tumor size Test for interaction: p= 0 02 for DFS; p= 0 01 for OS Test for interaction: p= 0.02 for DFS; p= 0.01 for OS Pritchard et al, NEJM 2006
Her 2-neu amplification/overexpression is predictive of chemotherapy response ANTHRACYCLINE vs NON-ANTHRACYCLINE CONTAINING TRIALS: HER 2-NEU � 10 large studies � Each suggests that HER 2-NEU overexpression is a positive factor for response to anthracycline � Each underpowered to test the question
Her 2-neu amplification/overexpression is Her 2 neu amplification/overexpression is predictive of chemotherapy response • All from published data All support interaction All support interaction � DeLaurentis et al between +Her2/neu status � � Gennari et al Gennari et al and ad antage of and advantage of � Dhesy-Thind et al anthracycline vs non- anthracycline containing regimen
Her 2-neu amplification/overexpression is predictive of chemotherapy response T Topoisomerase 2 A gene (TOP 2A) i 2 A (TOP 2A) � � Located close to Her 2/neu on the 17q L d l H 2/ h 17 chromosome � � Integrally involved in the antitumor action of Integrally involved in the antitumor action of anthracyclines Topoisomerase II α is essential for DNA Topoisomerase II α is essential for DNA � � replication and recombination Anthracyclines target topoisomerase II α enzyme � y g p y
TOPO IIa (not HER2) Amplification as a Predictor of Anthracycline Response in Breast Cancer as a Predictor of Anthrac cline Response in Breast Cancer Since 2002, at least 7 studies have been published demonstrating the association between topo II alpha d t ti th i ti b t t II l h amplification and improved anthracyline response. Study Study Yr Yr N N Park et al. 2006 284 Tanner et al Tanner et al. 2006 2006 525 525 Knoop at al. 2005 805 Park et al. 2003 188 Coon et al. 2002 35 Di Leo et al. 2002 354
TOP2A as a Predictive Factor Knoop et al K l CEF vs CMF � patients with TOP 2A amplification or � ti t ith TOP 2A lifi ti deletion had increased RFS (HR = 0.43; 0.63) and OS (HR = 0.57; HR = 0.56) if treated with and OS (HR 0.57; HR 0.56) if treated with CEF vs CMF � TOP 2A vs treatment interaction was negative g
DFS Non Co-Amplified Topo II by Arm (2nd Interim Analysis) nd 1.0 e isease Free 91% 91% 0.9 90% 85% 83% % D 84% 83% 0.8 81% 78% 71% 0.7 Patients Events Patients Events 0.6 643 146 AC->T 643 87 AC->TH P<0.001 618 92 TCH P<0.001 0.5 0 1 2 3 4 5 Year from randomization
DFS Co-Amplified Topo II by Arm (2nd Interim Analysis) (2nd Interim Analysis) 1.0 95% e isease Free 94% 89% 0.9 92% 87% 87% 85% % D 83% 0.8 83% 0.7 Patients Events Patients Events 0.6 328 42 AC->T 357 35 AC->TH P=0.336 359 42 TCH P=0.648 5 0. 0 1 2 3 4 5 Year from randomization
HER2 and TOPO II HER2 and TOPO II 17 q 12 17 q 12 17 q 21 17 q 21 HER2 Region HER2 Region TOP2A Region TOP2A Region 23 - 50% 23 - 50% 23 - 50% 23 - 50% 13 - 43% Normal Normal Amplified Amplified Deletion Deletion
MA5 Clinical Trial • TMAs constructed – 480 patients (67% entire cohort) – 480 patients (67% entire cohort) • TOP2A gene alterations (FISH) • TOP2A gene alterations (FISH) – FISH results available on 443/480 (92%) (92%)
TOP2A FISH Results • Amplified: p 48 (10.8%) ( ) • Deleted: 27 (6.1%) • Normal: • Normal: 368 (83 2%) 368 (83.2%)
Baseline Characteristics for Patients with TOP2A FISH Measurements TOP2A gene status Characteristic Amplified Deletion Normal (n=368) p* (n=48) (n 48) (n=27) (n 27) HER2/neu Amplified 28 (60%) 18 (67%) 73 (20%) <0.0001 Not amplified 19 (40%) 9 (33%) 288 (80%)
TOP2A norm TOP2A as a prognostic factor OS by TOP2A Status Unadjusted p=0.01 0 46 Adjusted p=0.46 TOP2A amp/ del TOP2A amp/ del t d Adj
DFS by Treatment for patients with TOP2A amplified or deleted tumors p DFS by DFS by CEF CEF Treatment for patients with normal TOP2A normal TOP2A CMF 100 Unadjusted p=0.07 Adjusted p=0.01 80 CEF CEF e r cen t age 60 CMF 40 40 Time (years) Time (years) Pe r TOP2A as a 20 Unadjusted p=0.75 Predictive Adjusted p=0.56 j p 0 0 Factor p= 0.76 0.0 5.0 10.0 172 44 Time (years) 195 49
OS by Treatment for patients with TOP2A amplified or deleted tumors CEF OS by Treatment for patients with normal TOP2A normal TOP2A CMF CMF Unadjusted p=0.06 100 Adjusted p=0.01 CEF 80 80 c en t age 60 Time (years) CMF 40 40 Pe r TOP2A as a 20 predictive factor Unadjusted p=0.41 Adjusted p 0.60 Adjusted p=0 60 0 0 0.0 5.0 10.0 56 Time (years) 186 60 202
Hazard Ratios* by Treatment (CEF vs. CMF) and TOP2A Status DFS S OS OS HR 95%CI P HR 95%CI P Amp/del p 0.42 0.21-0.83 0.01 0.38 0.18-0.80 0.01 Norm 0.93 0.68-1.25 0.56 1.10 0.77-1.56 0.60 *Adjusting for age, nodal status, grade, ER status, surgical procedure, tumor size, HER2 status i HER2 t t Test for interaction: (adjusted) p=0.09 for DFS; p=0.04 for OS
T Topo protein IHC: t i IHC 1. No. positive cells/500; expressed as a percentage 2. Initial analysis used topo protein as a continuous variable 3. Final analysis used y 13% as a cut-off (28.5% over-expression) ( p )
TOPO II Status by FISH and IHC TOPO II Status by FISH and IHC FISH TOP2A gene status IHC Amplified Deleted Normal p-value* Topo protein status (n=44) (n=23) (n=351) Over-expression 13 (30%) 7 (30%) 97 (28%) 0.93 Normal 31 (71%) 16 (70%) 254 (72%) * CHI Square test for association * CHI-Square test for association
Earlier work has also shown that topo protein expression and TOP2A gene amplification status O ge e a p cat o status are not correlated Mueller, Parkes, Andrulis, O’Malley Genes, Chromosomes & Cancer, 2004
PROGNOSIS Disease Free Survival by topo protein expression Disease Free Survival by topo protein expression 100 80 Normal 60 60 Probability Over-expression (%) 40 20 HR= 1 03 95% CI (0 78 1 36) p-value= 0 85 HR= 1.03 95% CI (0.78, 1.36) p-value= 0.85 0 0 0 5 10 # at Risk # at Risk Time (years) Time (years) Over-expression 136 75 27 Normal 342 199 86
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