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

2. 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”
women, 17 trials
Anthracyclines-based regimens > Non-anthracyclines-based regimens
Absolute 3% to 4.5% improvement in RFS and OS
EBCTCG Lancet 2005

3. Anthracyclines vs Taxanes: few trials
Study HR P
USON 9735: 4 AC v 4 DC (1016 pts)
CALGB 9344: 4 AC v 4 AC→P (3121)
NSABP B-28: 4 AC v 4 AC→4 P (3060)
MD Anderson: 8 FAC v 4 P→4 FAC (524)
ECTO: 4 A→4 CMF v 4 AP→4 CMF (904)
BCIRG 001: 6 FAC v 6 DAC (1491)
PACS 01: 6 FEC v 3 FEC→3 D (1999)
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

4. 4 x DC(75/600) is associated with an OS benefit vs 4 x AC(60/600): 7-years Follow-Up of USON Trial (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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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 % 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+

12. 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

13. 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)

14. 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

15. 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

16. 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

17. 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

18. 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….