Trials of Adjuvant Trastuzumab in HER2+ Early-Stage Breast Cancer Trial Study Regimen No. of Patients Disease-Free Survival (%) Hazard Ratio P-Value Overall.

Trials of Adjuvant Trastuzumab in HER2+ Trials of Adjuvant Trastuzumab in HER2+ Early-Stage Breast CancerEarly-Stage Breast Cancer

TrialTrial Study RegimenStudy Regimen No. of No. of PatientsPatients

Disease-Free Disease-Free Survival (%)Survival (%)

Hazard Hazard RatioRatio

PP-Value-Value Overall Overall SurvivalSurvival

Hazard Hazard Ratio Ratio (%)(%)

P-P- ValueValue

NSABP B-31 and NSABP B-31 and NCCTG N-9831NCCTG N-9831

Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then paclitaxelthen paclitaxel

16791679 6767 8787

Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then paclitaxel plus trastuzumab, then then paclitaxel plus trastuzumab, then trastuzumabtrastuzumab

16721672 8585 0.480.48 <.001<.001 9191 0.670.67 .02.02

NCCTG N-9831NCCTG N-9831 Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then paclitaxelthen paclitaxel

979979

Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then paclitaxel, then trastuzumabthen paclitaxel, then trastuzumab

985985 0.870.87 .29.29 0.850.85 .48.48

Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then paclitaxel plus trastuzumab, then then paclitaxel plus trastuzumab, then trastuzumabtrastuzumab

840840 0.640.64.48.48

.01.01<.01<.01

0.740.74 .27.27

HERAHERA ObservationObservation 16981698 7474 9090

Trastuzumab for 1 yearTrastuzumab for 1 year 17031703 8181 0.640.64 <.001<.001 9292 0.660.66 .011.011

BCIRG 006BCIRG 006 Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then docetaxelthen docetaxel

10731073 7373 8686

Doxorubicin and cyclophosphamide, Doxorubicin and cyclophosphamide, then docetaxel plus trastuzumab, then then docetaxel plus trastuzumab, then trastuzumabtrastuzumab

10741074 8484 0.490.49 .001.001 9292 0.590.59 .004.004

Docetaxel, carboplatin, and trastuzumabDocetaxel, carboplatin, and trastuzumab 10751075 8080 0.610.61 <.01<.01 9191 0.660.66 .02.02

FinHerFinHer ChemotherapyChemotherapy 116116 7878 9090

Chemotherapy plus trastuzumabChemotherapy plus trastuzumab 116116 8989 0.420.42 .01.01 9696 0.410.41 .07.07

With permission from Hudis CA. N Engl J Med. 2007;357:39-51.

ALTTO ALTTO Formerly Known as APHRODITEFormerly Known as APHRODITE

Randomize

Trastuzumab x 1 year

Lapatinib x 1 year

+ lapatinib x 1 year

Trastuzumab x 1 year

Inclusion Criteria• HER2+ breast cancer• ≥4 cycles anthracycline-based neoadjuvant chemotherapy• LVEF ≥50%

Clinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00490139?term=A.Accessed on: September 15, 2009. ALLTOTRIALS.COM—Trial Overview. Available at: http://www.alttotrials.com/patients.php#5. Accessed on: September 15, 2009.

Trastuzumab x 12 weeks

Break 6 weeks

Lapatanib x 34 weeks

Targeting HER2+ TumorsTargeting HER2+ Tumors

With permission from Burstein HJ. N Engl J Med. 2005;353:1652-1654.

InhibitKinaseActivity

InhibitDimerization

ModerateReceptorExpression

PotentiateDownstreamEffects

RefineAntibodies

Mechanism of Cell Death from Inhibition Mechanism of Cell Death from Inhibition of Polyadenosine Diphosphate-Ribose of Polyadenosine Diphosphate-Ribose

Polymerase 1 (PARP-1)Polymerase 1 (PARP-1)

With permission from Iglehart JD, et al. N Engl J Med. 2009;361:189-191.

Radiologic Evidence of Tumor Radiologic Evidence of Tumor Response to OlaparibResponse to Olaparib

With permission from Fong PC, et al. N Engl J Med. 2009;361:123-134.

Patient 20at Baseline

Patient 41at Baseline

Patient 20at 4 Months

Patient 41at 4 Months

A

BevacizumabBevacizumabSummary of Breast Cancer StudiesSummary of Breast Cancer Studies

Median Progression-Free Survival

Study ChemotherapyChemotherapy +

Bevacizumab P-Value

Miller1 (capecitabine ± bevacizumab)

4.17 months 4.86 months P = .857

AVADO2 (docetaxel ± bevacizumab)

8.0 months

9.0 months with 7.5 mg/kg bevacizumab10.0 months with 15 mg/kg bevacizumab

P = .0164P = .0002

E21003 (paclitaxel ± bevacizumab)

5.9 months 11.8 months P <.001

RIBBON-14

(taxane/anthracycline ± bevacizumab)

8.0 months 9.2 months P <.0001

RIBBON-14 (capecitabine ± bevacizumab)

5.7 months 8.6 months P = .0002

1. Miller KD, et al. J Clin Oncol. 2005;23:792-799. 2. Miles D, et al. 44th ASCO; May 30-June 3, 2008. Abstract LBA1011. 3. Miller K, et al. N Engl J Med. 2007;357:2666-2676. 4. Robert NJ, et al. 45th ASCO; May 29-June 2, 2009. Abstract 1005.

VEGF Signaling Pathway in AngiogenesisVEGF Signaling Pathway in Angiogenesis

With permission from Kerbel RS. N Engl J Med. 2008;358:2039-2049.

NSABP B-20 OutcomeNSABP B-20 Outcomeby Recurrence Scoreby Recurrence Score

With permission from Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

Overall

Intermediate risk: 18–30

Low risk: <18

High risk: >30

Oncotype DX recurrence score tends to correlate Oncotype DX recurrence score tends to correlate with established breast cancer prognostic/with established breast cancer prognostic/predictive factorspredictive factors

– AgeAge

– Tumor gradeTumor grade

– HER2HER2

– Quantitative ER/PR levelsQuantitative ER/PR levels

– Tumor sizeTumor size

The “poor man’s” Oncotype DXThe “poor man’s” Oncotype DX

– TN stage, grade, ER, PR, HER2TN stage, grade, ER, PR, HER2

Oncotype DX, Breast Cancer Assay. Available at: www.oncotypedx.com. Accessed on: September 14, 2009.

Oncotype DX Breast Cancer Assay

Multigene Arrays and Prediction of Multigene Arrays and Prediction of Relapse-Free Survival in Breast CancerRelapse-Free Survival in Breast Cancer

With permission from Fan C, et al. N Engl J Med. 2006;355:560-569.