HOT TOPICS IN BREAST CANCER11 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 trialsAnthracyclines-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 PUSON 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 HER2ResultsDFS 81% TC vs 75% AC HR, 0.74 P=.033OS 87% TC vs 82% AC HR, 0.69 P=.032

TC > AC in older as well as younger pts, tolerable regimenNo 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+ ptsEfficacy in HER2+/- pts; HR+/- pts; in older and younger pts (?):

unplanned exploratory analysessmall 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.

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 (anthracyclinesvs non anthracyclines-based regimens and efficacy data according toHER2 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< .001HER2- disease: DFS pooled HR, 1 P = .75

OS pooled HR,1.03 P = .6Conclusions

The added benefits of adjuvant CT with anthracyclines appear to beconfined 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

BC cells with TOP2A amplification are more sensitive to anthraciclinesBC 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)

ImplicationsThe degree of responsiveness similar to that observed in pts with HER2 amplifTumors normal forTOP2A and HER2 do not derive benefit from athracyclinesMeasurements of TOP2A alteration/HER2 amplif. have similar value in guiding

LimitationsClose but not complete concordance between TOP2A and HER2

TOP2A protein overexpression not closely correlated to TOP2A amplificationLarger number of pts will be needed to determine which measurement is mostclosely associated with responsiveness to anthracyclines regimens

Predictive Power of TOP2A

Adjuvant Incidence TOP2A Predictive findingsabnormalities

BCIRG005 no TOP2A amplif.cases Improved efficacy of anthra without HER2 amplif. restricted to pts with

BCIRG 006 35% HER2 amplified HER2/TOP2A co-amplificationalso TOP2A amplified

DFS and OS better in both trastuzumab arms vs AC→D

HER2/TOP2A coamplified tumorsAC→D ~ DHCarbo or AC→DH→HHER2+tumors without amplified TOP2ADHCarbo ~ AC→DH→H

Toxicity of AnthracyclinesDC > 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-amplificationalso 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 ptsTOP2 amplif. 23/61 with HER2 amplf. and equally

HER2 amplif.tumors active in HER2 non amplified;

(38%) superiority of anthra may beconfined to HER2/TOP2Acoamplified 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 findingsabnormalities

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

RR36 cases no HER/TOPA2amplification

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 selectivebenefit from anthracyclines remain weak because of small sample size;

Anthracyclines have many mechanisms of action other than TOP2Ainhibition;

Expression and enzymatic activity of TOP2A increase with cellproliferation, indipendent of any gene amplification;

Technical differences in the methods of TOP2A analysis (lack ofcorrelation 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 beevaluated

Priority should be given to prospective trials:sequential anthracyclines/taxane schedules and/or dose denseregimens vs non-anthracyclines containing regimens

Not all pts benefit from anthracycline: genetic assays need to bereliable and validated

A prospective trial, powered for survival, to analyse predictive power ofof a TOP2A assay would help….