HOT TOPICS IN BREAST CANCER 11 NOVEMBRE 2009 CHIETI Mediterranean School of Oncology Prof Corrado Ficorella Università degli Studi dell’Aquila

Anthracyclines in Early Breast Cancer: Is It the End of an Era? In light of emerging clinical data on : taxanes and biologic agents In light of emerging preclinical/clinical data on : tumor biomarkers (HER2, TOP2A) “Oxford Overview” 15.000 women, 17 trials Anthracyclines-based regimens > Non-anthracyclines-based regimens Absolute 3% to 4.5% improvement in RFS and OS EBCTCG Lancet 2005

Anthracyclines vs Taxanes: few trials Study HR P USON 9735: 4 AC v 4 DC (1016 pts) 0.6 .015 CALGB 9344: 4 AC v 4 AC→P (3121) 0.83 .006 NSABP B-28: 4 AC v 4 AC→4 P (3060) 0.83 .006 MD Anderson: 8 FAC v 4 P→4 FAC (524) 0.66 .09 ECTO: 4 A→4 CMF v 4 AP→4 CMF (904) 0.66 .01 BCIRG 001: 6 FAC v 6 DAC (1491) 0.72 .001 PACS 01: 6 FEC v 3 FEC→3 D (1999) 0.83 .04 NCIC CTG MA21: 4 AC→4 P(arm A) v 6 CEF (arm B) v dd 6 EC→4 P (arm C) 1.49 (A v B) .005 1.68 (A v C) .0006 0.89 (C v B) .46 GEICAM 9906: 4 FEC→8 wP v 6 FEC 0.74 .006

4 x DC(75/600) is associated with an OS benefit vs 4 x AC(60/600): 7-years Follow-Up of USON Trial 9735 (S Jones JCO 2009) 1016 pts, stage I to III, N+/-, HR +/-/unknown, CT-naive 170 pts assessed for HER2 Results DFS 81% TC vs 75% AC HR, 0.74 P=.033 OS 87% TC vs 82% AC HR, 0.69 P=.032 TC > AC in older as well as younger pts, tolerable regimen No interaction of HR status or HER2 status and treatment Older women more febrile neutropenia (TC): 8% vs 4% ,1 toxic death more anemia (AC): G3/4 5% vs < 1% Three late deaths without relapse in AC group: CHF,myelodysplasia,myelofibrosis

4 x DC(75/600) is associated with an OS benefit vs 4 x AC(60/600): 7-years Follow-Up of US Oncology Research Trial 9735 (S Jones JCO 2009) Implication TC effective in various subsets, anthracyclines might not benefit HER2- disease, anthracyclines may be obsolete in early BC. The investigators propose TC for N0,lower risk N+, HER2- Breast Canc Limitations N+ pts (?) : AC is not right comparator/most efficacious regimen AC→P is the standard in N+ pts Efficacy in HER2+/- pts; HR+/- pts; in older and younger pts (?): unplanned exploratory analyses small sample size The trial did not included a combined anthracycline-taxane regimen (HER2- pts → 6x DC vs 6x DAC) My opinion: TC as another option (cardiotoxicity concerns), not as a justification for eliminating other options.

Anthracyclines regimens (vs non Anthracyclines) HER2 Status and Efficacy of Adjuvant Anthracyclines in early BC: A Pooled Analysis of Randomized Trials A Gennari JNCI 2008 Pooled subset analysis within randomized clinical trials (anthracyclines vs non anthracyclines-based regimens and efficacy data according to HER2 status) Eight studies (1536/5354 pts HER2+ BC) Anthracyclines regimens (vs non Anthracyclines) HER2+ disease: DFS pooled HR, 0.71 P< .001 OS pooled HR, 0.73 P< .001 HER2- disease: DFS pooled HR, 1 P = .75 OS pooled HR,1.03 P = .6 Conclusions The added benefits of adjuvant CT with anthracyclines appear to be confined to women who have HER2 overexpressed/amplified BC

HER2 Status and Efficacy of Adjuvant Anthracyclines in early BC: A Pooled Analysis of Randomized Trials A Gennari JNCI 2008 Limitations Reliance on published data; Heterogeneity in the methods and definitions of HER2 positivity; Lack of an indipendent/centralized assessment of HER2 status; More than 50% of pts from NSABP B11 and B15 trials ( examination of predictive role of HER2 was unplanned and retrospective in both); B15 trial evaluated after the positive findings in the B11 trial

Anthracyclines and HER2 Status NSABP B23 (B. Fisher JCO 2001) Pts HER2+ appeared to benefit more from CMF than from AC (HR, 1.27; P= .46) BR9601 trial (J.M.S. Bartlett JCO 2008) Pts with normal HER1, HER2 (FISH), or HER3 levels showed significantly increased RFS ( HR, 0.36; P= .035) and OS ( HR, 0.30; P= .023) when treated with epi-CMF vs CMF

HER2 Status and different dose intensities of adjuvant anthracyclines Studies have shown that the benefits of more intensive anthracyclines based regimens were limited to pts HER2+ Muss HB NEJM 1994; Di Leo Clin Canc Res 2002; Del Mastro Br J Cancer 05 Another study shoved no association between HER2+ tumors and incremental benefit for doses of doxorubicin > 60mg/mq Hayes DF NEJM 2007 A metanalysis of studies of HER2 status and higher-dose vs standard dose of anthracyclines regimens shoved a DFS benefit for higher doses in pts HER2+ but not in pts HER2- (result not statistically significant) Dhesy-Thind B Breast Cancer Res and Trt 2008

Implications Limitations BC cells with TOP2A amplification are more sensitive to anthraciclines BC cells with TOP2A deletions are resistant to anthraciclines (Jarvinen TAH Am J Pathol 2000) TOP2A and Responsiveness of BC to Adjuv.CT (F.P.O’Malley JNCI/09) 438/710 premenopausal pts N+, Rand CEF vs CMF ( MA.5 trial) In pts with TOP2A alteration CEF > CMF in terms of: RFS (HR, 0.35; P= .005) and OS (HR, 0.33; P=.008) Implications The degree of responsiveness similar to that observed in pts with HER2 amplif Tumors normal forTOP2A and HER2 do not derive benefit from athracyclines Measurements of TOP2A alteration/HER2 amplif. have similar value in guiding Limitations Close but not complete concordance between TOP2A and HER2 TOP2A protein overexpression not closely correlated to TOP2A amplification Larger number of pts will be needed to determine which measurement is most closely associated with responsiveness to anthracyclines regimens

Predictive Power of TOP2A Adjuvant Incidence TOP2A Predictive findings abnormalities BCIRG005 no TOP2A amplif.cases Improved efficacy of anthra without HER2 amplif. restricted to pts with BCIRG 006 35% HER2 amplified HER2/TOP2A co-amplification also TOP2A amplified DFS and OS better in both trastuzumab arms vs AC→D HER2/TOP2A coamplified tumors AC→D ~ DHCarbo or AC→DH→H HER2+tumors without amplified TOP2A DHCarbo ~ AC→DH→H Toxicity of Anthracyclines DC > AC (USON 9735) DC → HER2- DHCarbo→ HER2+

Predictive Power of TOP2A Adjuvant Incidence TOP2A Predictive findings abnormalities BCIRG005/006 no TOP2A amplif. Improved efficacy of anthra without HER2 amplif. restricted to pts with 35% HER2 amplified HER2/TOP2A co-amplification also TOP2A amplifed NCIC MA.5 deletions 6.9% TOP2A abnormality predictor for (N,447) amplification 11.9% benefit from CEF vs CMF (OS); normal 81.2% more marked benefit for deletions

Predictive Power of TOP2A Adjuvant Incidence TOP2A Predictive findings abnormalities Di Leo (N,430) HER2 amplif. 21%; Anthra>CMF may be in pts TOP2 amplif. 23/61 with HER2 amplf. and equally HER2 amplif.tumors active in HER2 non amplified; (38%) superiority of anthra may be confined to HER2/TOP2A coamplified subgroup Scandinavian HER2 amplif 32.7% HER2 no predictive of 2 Breast group TOP2A coamplif 37% anthra-based CT regimens; Trial 9401 of HER2 amplif TOP2A amplif may predict the (N,396) efficacy of dose escalated FEC in HER2 coamplified (HR,0.45)

Predictive Power of TOP2A Advanced Incidence TOP2A Predictive findings abnormalities Cardoso no TOPA2 alterations HER2 amplif did not correlate with (Int J Onc 04) without HER2 amplif response to anthracyclines; (N,59/350 screened) TOP2A amplif/overexpr correlated to response to anthracyclines Park 19 cases coaplificated RR to anthra higher with coamplif (EJC 2003) HER2 and TOPA2; lower without coamplification; (N,67) 12 amplif HER alone; HER2 amplif alone intermediate RR 36 cases no HER/TOPA2 amplification

However some studies found: TOP2A amplification in 10 % of cases without HER2 amplification; Deletions rather than amplifications in 50% of HER2 amplified cases; TOP2A deletions and amplifications within individual tumors. Bofin AM Cytopahtol 2003; Olsen KE Acta Oncol 2004;Jarvinen TA GCC 1999 Jarvinen TA Curr Cancer Drug targets 2006 NSABP B23 (B. Fisher JCO 2001) Pts HER2+ appeared to benefit more from CMF than from AC (HR, 1.27; P= .46) In pts without TOP2A protein overexpression no difference in outcame In pts with TOP2A overexpression outcame appeared better with CMF

The role of TOPO2A as a predictive factors for anthracyclines activity still unclear The data from clinical trials linking TOPO2A amplification with selective benefit from anthracyclines remain weak because of small sample size; Anthracyclines have many mechanisms of action other than TOP2A inhibition; Expression and enzymatic activity of TOP2A increase with cell proliferation, indipendent of any gene amplification; Technical differences in the methods of TOP2A analysis (lack of correlation between gene copy number and protein expression); Currently there is not standardized test for TOP2A

Summary Anthracyclines have been shown to be one of most effective agents in Breast Cancer, and changing treatment requires robust evidence Data from a single trial (USO 9735) and from retrospective subgroup analyses are intriguing but require substantiation before…. In HER2+ pts data from BCIRG 006 trial (unpubliblished that only reached interim analysis) should interpreted cautiously (4 published trials support treatment with trastuzumab with anthracyclines ± taxane backbone) Waiting the results of DC vs DAC trial (USO 06090), trials so far support the use of taxanes + anthracyclines in adjuvant therapy

Summary Less cardiotoxic liposomal doxorubicin and schedules should be evaluated Priority should be given to prospective trials: sequential anthracyclines/taxane schedules and/or dose dense regimens vs non-anthracyclines containing regimens Not all pts benefit from anthracycline: genetic assays need to be reliable and validated A prospective trial, powered for survival, to analyse predictive power of of a TOP2A assay would help….