Anthracyclines for Breast Cancer? Are Adjuvant Anthracyclines Dispensible? Needs to be Answered in a Large Prospective Trial Joanne L. Blum, MD, PhD Baylor-Sammons Cancer Dallas, TX
Early Breast Cancer Trialists Collaborative Group (EBCTCG) Anthracyclines reduced risk of recurrence by 11% Reduced risk of death by 16% Absolute difference: 3% at 5 years and 4% at 10 years Lancet 2005; 365: 1687 1717
But at what cost? CHF within 5 years of treatment: 0.5-1.5% Sub-clinical cardiac dysfunction: 10-15% Leukemia and myelodysplasia within 5-10years: 0.4-1.7%
Two Studies: AC versus TC: Jones et al 2007 and 2009 BCIRG 006: Her2 + SABCS 2009
Jones SA, et al. J Clin Oncol 27:1177-1183, 2009 Disease Free Survival Proportion DFS 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 P = 0.033 HR =.74 0.60 0 12 24 36 48 60 72 84 96 Months TC AC 81% 75%
Overall Survival 1.00 0.95 0.90 TC 87% 0.85 0.80 P = 0.032 HR =.69 AC 82% 0.75 Proportion Surv 0.70 0.65 0.60 0 12 24 36 48 60 72 84 96 Months Jones SA, et al. J Clin Oncol 27:1177-1183, 2009
Limitations: Is AC x 4 the best comparator? Is duration of treatment important: Is longer better? NSABP B30: OS: AC-Docetaxel (8 cycles): 8 yr OS 83% compared with AT 79%, HR 0.83; P=0.03, compared with TAC x 4 79%, HR 0.86, P =0.09 Swain, SM N Eng J Med 2010 362: 2053-65
TC versus TAC: USOR 06090/NSABP B46-I/07132 TC x 6 versus TAC x 6 in Her2 negative Early Stage Breast Cancer Original goal: 2000 pts (superiority) Combined forces with the NSABP to add third arm: TC with Bevacizumab 3900 pts Drop in enrollment with uncertainty about Bevacizumab Return to the original TC versus TAC question (total of 3500 pts), non-inferiority Tissue obtained on first 2000 Stay Tuned
Can we Define a Group of Patients who Might Benefit from Anthracyclines: Her2 positive DFS OS Gennari, A JNCI 2008; 100:14-20
Can We Omit Anthracyclines in Her2+ BC? Slamon D, SABCS 2009, abstract 62
Slamon D, SABCS 2009, abstract 62
Slamon D, SABCS 2009, abstract 62
Considerations in Anthracycline Efficacy Oakman C et al. Breast Cancer Res and Treat 2010 123:171-5
A HER2- MA.5 Trial A HER2+ B B Pritchard KI, et al. N Engl J Med. 2006;354:2103-11
MA 5 RFS OS CEF CMF-------- A Amplified or Deleted TOP2A B Normal TOP2A O Malley FP, et al. J Natl Cancer Inst 101:644-650, 2009
MA 5 O Malley, FP et al. Breast Cancer Res Treat 2011; 128:401-409
Conclusions from MA 5 CEF >CMF Her2 Positive TOP2A Amplified or Deleted topo2α Overexpressed But amplification at DNA level doesn t correlate with protein expression
Effects of Doxorubicin on Topoisomerase 2Α Doxorubicin binds to DNA, blocking the progression of TOPO 2α which unwinds DNA for transcription Doxorubicin stabilizes the TOPO 2α complex after it has broken the DNA chain for replication Doxorubicin prevents the DNA double helix from being resealed, interrupting the process of replication Action of Doxorubicin is dependent on the amount of TOPO 2α in the cell
Correlation Between TOP2A Expression and Response to Doxorubicin and Docetaxel: Pre-operative Treatment with Either Dox 75 mg/m2 x 4 or Doc 100 mg/m2 x 4: 204 pts Predictors of sensitivity to Dox: low TOP2A expression, ER- Predictors of sensitivity to Doc: small size and ER- Triple Negative: resistance to Dox Martin M, et al Breast Cancer Res and Treat 2011; 128:127-136
TOP2A Overexpression: Prognostic Information: 1681 Breast Tumors Rody A et al. Breast Cancer Res and Treat 2009; 113:457-466
TOP2A Expression and Risk of Recurrence Sparano et al: E2197 AC vs AT Expression by RT PCR Overall: AC or AT, no difference in recurrence However, in HR + Her2-, TOP2A expression was associated with increased risk of recurrence: p = 0.01 This was complimentary to RS Trend to better outcome with AT if high TOP2A expression Sparano JA Clin Cancer Res 2009; 15:7693-700
TOP2A: 782 pts with Node Neg BC, No Adjuvant Therapy and 80 pts treated with neo-adjuvant EC High TOP2A RNA levels associated with worse metastasis free interval (MFI) in ER +, p< 0.001 or Her2 negative, p < 0.001 Brase JC et al. Clin Cancer Res 2010; 16:2391-2401
Neoadjuvant Trial of Principle: TOP Trial Goal: To identify molecular markers that predict response/resistance to anthracyclines ER negative pts treated with Epirubicin 139 evaluable for response prediction analysis Primary Endpoint: pcr: 14% TOP2A gene amplification but not protein expression: associated with pcr in the Her2+pts and with pcr in Her+/ER- pts (additional validation series) Desmedt C, et al. J Clin Oncol 2011 29:1578-1586
So What to Make of TOP2A? High TOP2A expression and high topo2α protein: benefit of anthracyclines But what about triple negative.if too much topo2α, can overcome effect of anthracyclines ER+, TOP2A high, poor prognosis What is the optimal way to study? Protein by IHC or RNA expression? Can we use this yet to identify sub-types who require anthracyclines? Hope to answer with the TC/TAC adjuvant trial
So are we ready to abandon Anthracyclines? Not yet TC/TAC should be definitive Look to subsets to help clarify Need large numbers of high risk patients with aggressive biology to answer