ASCO 2005 Adjuvant Breast Cancer Update Lori J
ASCO 2005 Adjuvant Breast Cancer Update Lori J. Goldstein, MD Director, Breast Evaluation Center Leader, Breast Cancer Research Program Fox Chase Cancer Center Philadelphia, PA
ASCO 2005 Breast Cancer Update Abstract #/ Session 512 513 Mo. AB Ed Title/ Subject E 2197: Adjuvant AT vs. AC ECTO: A->CMF vs AT->CMF N 9831/ NSABP B 31 Joint Analysis – Adjuvant Trastuzumab N 9831 – Adjuvant Trastuzumab HERA: Adjuvant Trastuzumab Mo. AB Ed E 2100: T +/- bevacizumab MBC
E 2197: Phase III AT vs. AC in the Adjuvant Treatment of Node Positive and High Risk Node Negative Breast Cancer Goldstein LJ, O’Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE.
E 2197 Rationale Phase II Studies Anthracyline + Taxane Study A/Por D mg/m 2 RR % CHF % Gianni/ 60/P 200 80 -90 20 50/P 150 60/P 200 47 57 9. 8 6 60/D 60 50/D 75 57 63 81 6 10 0 Dombernowsky Sledge E 1193 Sparano E 4195 Sparano E 1196 Cresta Misset
E 2197 Rationale Phase III Studies: Anthracyline + Docetaxel Phase III Studies: MBC AT (50/75) RR% 60 TTPwk 37. 1 CHF % 2 FN% 33 No difference OS AC (60/600) 47 p=. 012 31. 9 p=. 015 4 10 Nabholtz JCO 2003 TAC vs. FAC MBC Mackey ASCO 2002 Increase RR with TAC; no difference in TTP or OS TAC vs. FAC Adjuvant: Nabholtz ASCO 2002 TAC increase DFS/ OS
E 2197: Schema T 1 -3 N 0 -1 M 0 No then T> 1. 0 cm R A N D O M I Z E Adriamycin 60 mg/m 2 Docetaxel (T) 60 mg/m 2 IV q 3 wk x 4 Cipro 500 mg po. bid D 8 x 10 d Adriamycin 60 mg/m 2 IV q 3 wk x 4 2 Cyclophosphamide 600 mg/m Tamoxifen 20 mg daily x 5 years post chemotherapy for ER and/or PR positive tumor *G-CSF per ASCO guidelines Stratified: • Nodal Status • HR Status (ER+PR+, ER+PR-, ER-PR+, ER- PR-, ER/PR unknown) • Menopausal Status
E 2197: Objectives • To determine whether AT will improve DFS and OS • To compare toxicity of AT vs. AC No difference in LVEF between AT and AC reported ASCO 2003.
E 2197: Study Design • Primary endpoint: DFS-recurrences, new breast primaries, or death without recurrence whichever comes first. • Design: 83% power to detect a 25% reduction of the DFS failure hazard rate (5% absolute improvement in 5 yr DFS from 78% to 83% by using AT) • Sample size: 2778 including an estimated 10% ineligible • Primary Analysis: Intent-to-treat analysis on eligible patients.
E 2197: Results • Opened 7/30/98; closed 1/21/00 • 2952 entered through the collaborative effort of ECOG, CALGB, NCCTG, SWOG and EPP. • 3% Ineligibility rate • 2885 eligible and analyzable
E 2197: Patient Characteristics • Balanced for age, HR, menopause, nodes, surgery, grade and size • Age range 24 -85 yo, Median age 51 • 64% ER + • 65% LN • Grade: 10% low, 38% int. , 46% high • Size: 0. 1 – 12. 5 cm; Median – 2. 0 cm
E 2197: Toxicity Summary Feb/Infxn/N AML/MDS Lethal Events Related Unrelated AT 28% 7 AC 10% 7 4 2 2
E 2197 Cardiac Safety Grade 3 AT 4 5 CHF 15 2 1 AC 3 4 10 Total 18 10 %. 01. 006 No statistically significant difference
E 2197: DFS • Fall 2004 DMC (409/ 420 DFS failures) • O’Brien-Fleming boundary had not been crossed, there was not enough evidence to suggest a significant difference • April 2005 - Median follow-up = 59 months • 432/ 2885 (15%) recurred, developed second breast cancer or died.
E 2197: DFS/OS Hazard Ratio HR > 1 favors AT HR (adjusted) DFS 1. 03 (0. 86 -1. 25), p=0. 70 OS 1. 09 (0. 85 -1. 40), p=0. 49 As of 4/4/05, 242 deaths
E 2197 Disease-Free Survival 100 90 80 Percent 70 60 50 40 30 20 10 0 0 12 24 AT AC 36 Months N Events 1444 213 1441 219 48 60 4 -Yr % (S. E. ) 87 (1) 72
E 2197 Overall Survival 100 90 80 Percent 70 60 50 40 30 20 10 0 0 12 24 AT AC 36 Months N Events 1444 117 1441 125 48 60 4 -Yr % (S. E. ) 94 (1) 93 (1) 72
E 2197: DFS Subgroup Analysis No significant effect within any of the following subgroups : • Nodes • Size • Age • Menopausal Status • Grade • Type of Surgery • Race
E 2197 Disease-Free Survival: ER-/PR- E 2197 Disease-Free Survival: ER-/PR+ 90 90 80 80 70 70 60 60 Percent 100 50 40 30 30 20 20 10 10 0 12 24 36 N 454 463 AT AC 48 Months Events 85 109 60 72 0 4 -Yr % (S. E. ) 83 (2) 79 (2) 90 80 80 70 70 60 60 Percent 90 Percent 100 50 40 20 20 10 10 AT AC 36 N 162 164 Months Events 22 34 48 60 4 -Yr % (S. E. ) 90 (2) 83 (3) 81 Months Events 14 3 60 72 4 -Yr % (S. E. ) 77 (6) 95 (4) 40 30 24 N 52 38 48 50 30 12 36 E 2197 Disease-Free Survival: ER+/PR+ 100 0 24 AT AC E 2197 Disease-Free Survival: ER+/PR- 0 12 72 0 0 12 24 AT AC 36 N 767 770 Months Events 91 73 48 60 4 -Yr % (S. E. ) 90 (1) 92 (1) 72
Disease Free Survival ER-/PR- 1. 30 (0. 96, 1. 70) ER-/PR+ 0. 30 (0. 10, 0. 95) ER+/PR- 1. 64 (0. 96, 2. 80) ER+/PR+ 0. 79 (0. 58, 1. 10) 0. 1 0. 2 Favors AC 0. 5 1 2 Favors AT 5
E 2197 Conclusions • These results show a better than expected outcome for both regimens. 87%(obs) vs 78% (expected for AC) DFS at 4 yrs. • At 59 mo median follow-up, there is no difference in DFS or OS between AT and AC. • Prespecified stratifications at randomization: LN, menopause, ER/PR – no significant difference between the 2 treatment arms. • In PR negative tumors, a potential benefit to AT may be suggested.
E 2197: Issues for Discussion Would longer f/u change these results? Unlikely Observed DFS = 87% at 4 yrs. Expected DFS = 78% at 4 yrs. Aromatase Inhibitor Affect: 60% on Tam; Median 41 mo; AI info collected; future analysis Subset analysis of prespecified ER/PR stratifications: Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies. Central review of ER/PR/Her 2 pending Genomic Health/ Sanofi-Aventis Analysis: Oncotype Genomic profiling Use as training set for validation with E 1199 Pharmacogenomics PACCT- 1 Trial
Thank You Patients Data managers/ CRA’s CALGB, NCCTG, SWOG, EPP Anne O’Neill, Deborah Namande, Eric Ross
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