julie r. gralow, m.d. director, breast medical oncology, seattle cancer care alliance
DESCRIPTION
Breast Cancer Systemic Therapy for Early Stage Disease. Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle Cancer Care Alliance Professor, Medical Oncology, University of Washington School of Medicine Member, Clinical Division, Fred Hutchinson Cancer Research Center. - PowerPoint PPT PresentationTRANSCRIPT
Julie R. Gralow, M.D.Julie R. Gralow, M.D.
Director, Breast Medical Oncology, Seattle Cancer Care AllianceDirector, Breast Medical Oncology, Seattle Cancer Care Alliance
Professor, Medical Oncology, University of Washington School of Professor, Medical Oncology, University of Washington School of MedicineMedicine
Member, Clinical Division, Fred Hutchinson Cancer Research CenterMember, Clinical Division, Fred Hutchinson Cancer Research Center
Breast CancerBreast CancerSystemic Therapy for Early Systemic Therapy for Early
Stage DiseaseStage Disease
Adjuvant Systemic Treatment Adjuvant Systemic Treatment of Breast Cancerof Breast Cancer
• Breast cancer is most often curable when Breast cancer is most often curable when detected in early stagesdetected in early stages
• Micrometastases exist at the time of Micrometastases exist at the time of diagnosis in many patients, leading to diagnosis in many patients, leading to eventual recurrenceeventual recurrence
• Adjuvant systemic therapy has been found Adjuvant systemic therapy has been found to prolong both overall and disease-free to prolong both overall and disease-free survival in breast cancer patientssurvival in breast cancer patients
Systemic Therapy for Breast CancerSystemic Therapy for Breast Cancer
Endocrine TherapyEndocrine Therapy
ChemotherapyChemotherapy
Biologically-targeted TherapyBiologically-targeted Therapy
New Strategies: Individualizing treatment New Strategies: Individualizing treatment to the cancer and the patientto the cancer and the patient
Systemic Treatment of Early Stage Breast Systemic Treatment of Early Stage Breast CancerCancer
• THE PAST THE PAST (2000 NCI Consensus Development (2000 NCI Consensus Development Conference on Adjuvant Breast Cancer)Conference on Adjuvant Breast Cancer)
– Chemotherapy should be offered to the majority of Chemotherapy should be offered to the majority of women with early stage breast cancer regardless of women with early stage breast cancer regardless of size, lymph node, menopausal or hormone receptor size, lymph node, menopausal or hormone receptor statusstatus
• THE PRESENT AND FUTURETHE PRESENT AND FUTURE
– Individualizing estimates of recurrence risk and Individualizing estimates of recurrence risk and chemotherapy benefit using genomic/molecular chemotherapy benefit using genomic/molecular profilingprofiling
– Many patients don’t need chemotherapyMany patients don’t need chemotherapy
normal cell
atypical cell cancer cell
The Genomic EraThe Genomic EraUnderstanding the Genetic Changes in Each Understanding the Genetic Changes in Each
Individual TumorIndividual Tumor
Testing the Testing the acquiredacquired genetic makeup of genetic makeup of the tumorthe tumor can lead to more effective treatment strategiescan lead to more effective treatment strategies
Genetic change Genetic change
Genomics of Breast Cancer: Genomics of Breast Cancer: Breast Cancer is NOT One Disease!Breast Cancer is NOT One Disease!
Luminal Luminal Subtype ASubtype A
Luminal Luminal Subtype BSubtype B
HER-2+HER-2+Basal Basal SubtypeSubtype
Normal Normal Breast–likeBreast–like
Sorlie et al, Proc Natl Acad Sci 100:8418, 2003Sorlie et al, Proc Natl Acad Sci 100:8418, 2003
Subtypes vary with Subtypes vary with respect to:respect to:
•Likelihood of Likelihood of recurrencerecurrence
•Sites of Sites of metastasesmetastases
•Response to Response to treatmenttreatment
Agendia Mammaprint 70-Gene Prognostic Signature Agendia Mammaprint 70-Gene Prognostic Signature AssayAssay
Genomic Health Oncotype Dx 21-Genomic Health Oncotype Dx 21-Gene Recurrence Score AssayGene Recurrence Score Assay
Clinically Available Molecular Profiling Clinically Available Molecular Profiling Assays in Breast CancerAssays in Breast Cancer
Who Doesn’t Need Chemotherapy?Who Doesn’t Need Chemotherapy?Oncotype Dx 21-Gene Recurrence Score AssayOncotype Dx 21-Gene Recurrence Score Assay
Fixed (stored) tissueFixed (stored) tissue
Surgical Surgical removal of removal of
tissuetissue
Extract Extract tumor tumor RNARNA
Tumor Tumor evaluated evaluated
for 21 for 21 genesgenes
Recurrence Recurrence score score
resultsresults
•In lymph node negative, ER+ breast cancer:In lymph node negative, ER+ breast cancer:
•20% recurrence with tamoxifen only (may benefit from chemo)20% recurrence with tamoxifen only (may benefit from chemo)
•80% won’t recur with tamoxifen only (won’t benefit from chemo)80% won’t recur with tamoxifen only (won’t benefit from chemo)
Developed to help define which “low risk” patients do not need Developed to help define which “low risk” patients do not need chemotherapy, and which may benefitchemotherapy, and which may benefit
21 Gene Recurrence Score (RS) Assay: 16 21 Gene Recurrence Score (RS) Assay: 16 Cancer Genes and 5 Reference GenesCancer Genes and 5 Reference Genes
PROLIFERATIONKi-67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromolysin 3Cathepsin L2
HER2GRB7HER2
BAG1
GSTM1
REFERENCEBeta-actinGAPDHRPLPO
GUSTFRCCD68
Recurrence Score in LN-, ER+ if 5 Years TamoxifenRecurrence Score in LN-, ER+ if 5 Years Tamoxifen
21-Gene Recurrence Score Assay 21-Gene Recurrence Score Assay Results (OncoResults (Oncotypetype DX) DX)
Lower RSLower RS
• Less likelihood of recurrenceLess likelihood of recurrence• Greater tamoxifen benefitGreater tamoxifen benefit
• No to minimal chemotherapy benefitNo to minimal chemotherapy benefit
Higher RS
• Greater likelihood of recurrenceGreater likelihood of recurrence• Less tamoxifen benefitLess tamoxifen benefit
• Clear chemotherapy benefitClear chemotherapy benefit
RS of 39 = 27% 10 yr RS of 39 = 27% 10 yr distant relapse rate distant relapse rate despite tamoxifendespite tamoxifen
Endocrine TherapyEndocrine Therapy
Estrogen and Breast CancerEstrogen and Breast Cancer
EstrogenEstrogen
Cell Cell Growth Growth
and and DivisionDivision
Estrogen Receptor
SERMS, SERDSSERMS, SERDSAromatase Aromatase inhibitors, ovarian inhibitors, ovarian
suppressionsuppression
Endocrine Therapy in Breast CancerEndocrine Therapy in Breast Cancer
• Selective Estrogen Receptor ModulatorsSelective Estrogen Receptor Modulators– tamoxifen tamoxifen – toremifene toremifene – raloxifene raloxifene
• Aromatase inhibitorsAromatase inhibitors (postmenopausal) (postmenopausal)– anastrozoleanastrozole– letrozole letrozole – exemestane exemestane
• Medical or surgical oophorectomyMedical or surgical oophorectomy (premenopausal) (premenopausal)• Selective Estrogen Receptor DownregulatorsSelective Estrogen Receptor Downregulators
– fulvestrant fulvestrant • OthersOthers: Progestins, Estrogens, Androgens: Progestins, Estrogens, Androgens
Selective Estrogen Receptor ModulatorsSelective Estrogen Receptor ModulatorsEarly Breast Cancer Trialists’ Collaborative Group 2000 Early Breast Cancer Trialists’ Collaborative Group 2000
(Oxford Overview) (Oxford Overview)
Tamoxifen vs. Nil: Tamoxifen vs. Nil: Disease-free SurvivalDisease-free SurvivalER NegativeER Negative ER PositiveER Positive
5 years of adjuvant 5 years of adjuvant tamoxifen became tamoxifen became
standard in ER+ patientsstandard in ER+ patients
tamoxifentamoxifen
nilnil
ER status matters!!ER status matters!!
Aromatase InhibitorsAromatase Inhibitors
Adrenal HormonesAdrenal Hormones
CortisolCortisol AndrostenedioneAndrostenedione AldosteroneAldosterone
EstradiolEstradiol
TestosteroneTestosteroneEstroneEstrone
Aromatase inhibitors Aromatase inhibitors block block post-menopausal post-menopausal
estrogen productionestrogen production
AnastrozoleAnastrozoleLetrozoleLetrozole
ExemestaneExemestane
Adjuvant Aromatase InhibitorsAdjuvant Aromatase Inhibitors
AIs asAIs asInitial TherapyInitial Therapy
AIs AfterAIs After2-3 Yrs of TAM2-3 Yrs of TAM
AIs AfterAIs After5 Years of TAM5 Years of TAM
TAM X 5 Yrs
AI X 5 Yrs TAM X 2-3 AI X 2-3
TAM X 5 YrsTAM X 5 Yrs
PLAC X 5 Yrs
AI X 5 Yrs
Three StrategiesThree Strategies
Survival benefit for Survival benefit for AI armAI arm
ATAC and BIG1-98 studiesATAC and BIG1-98 studiesReduction in recurrencesReduction in recurrences
Upfront Use of Aromatase Inhibitors vs. Upfront Use of Aromatase Inhibitors vs. TamoxifenTamoxifen
ATAC Trial: Anastrozole vs. Tamoxifen ATAC Trial: Anastrozole vs. Tamoxifen Howell A et al, Lancet 365:60-62, 2005Howell A et al, Lancet 365:60-62, 2005
BIG 1-98 Trial: Letrozole vs. Tamoxifen BIG 1-98 Trial: Letrozole vs. Tamoxifen Thurlimann B et al, NEJM 353: 2747-57, 2005 Thurlimann B et al, NEJM 353: 2747-57, 2005
68 months follow-up:68 months follow-up:17% relative reduction in events for A vs T 17% relative reduction in events for A vs T
(3% absolute difference)(3% absolute difference)No difference in overall survivalNo difference in overall survival
26 months follow-up:26 months follow-up:19% relative reduction in events for L vs. T19% relative reduction in events for L vs. T
(3% absolute difference)(3% absolute difference)No difference in overall survivalNo difference in overall survival
Extended Adjuvant Hormonal Therapy Extended Adjuvant Hormonal Therapy TrialsTrials
MA17 Trial: Letrozole vs. Placebo After MA17 Trial: Letrozole vs. Placebo After Completing 5 Years of TamoxifenCompleting 5 Years of Tamoxifen
Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005
30 months of follow-up:30 months of follow-up:42% decrease in breast cancer events42% decrease in breast cancer events
Node positive patients show statistically significant Node positive patients show statistically significant improvement in survivalimprovement in survival
Ovarian Ablation in Early Stage Breast CancerOvarian Ablation in Early Stage Breast CancerEarly Breast Cancer Trialists’ Collaborative Group 2000 Early Breast Cancer Trialists’ Collaborative Group 2000
(Oxford Overview) (Oxford Overview)
Overall SurvivalOverall SurvivalAblation vs. NotAblation vs. Not Chemo/Ablation vs. ChemoChemo/Ablation vs. Chemo
ablationablation
No ablationNo ablation
ChemotherapyChemotherapy
EBCTCG (Oxford Overview) 2000 EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: DeathsChemotherapy vs. Not: Deaths
(Overall 14.8% +/- 2.1 reduction)(Overall 14.8% +/- 2.1 reduction)Entry AgeEntry Age Events/WomenEvents/Women
ChemoChemo ControlControl< 40< 40 293/960 293/960 335/908 335/908
(30.5%)(30.5%) (36.9%) (36.9%)
40-4940-49 674/2480 783/2391 674/2480 783/2391 (27.2%)(27.2%) (32.7%) (32.7%)
50-5950-59 1658/4880 1918/5143 1658/4880 1918/5143 (34.0%) (37.3%)(34.0%) (37.3%)
60-6960-69 1851/4886 2000/4967 1851/4886 2000/4967 (37.9%%) (40.3%)(37.9%%) (40.3%)
70+70+ 210/570 210/570 264/610 264/610 (36.8%)(36.8%) (43.3%) (43.3%)
Ratio annual deathsRatio annual deaths Chemo: ControlChemo: Control
1.01.00.50.5 1.51.5
26%+/-526%+/-5
29%+/-729%+/-7
11%+/-1111%+/-11
7%+/-47%+/-4
15%+/-315%+/-3
Survival Relative to Delivered DoseSurvival Relative to Delivered Dose
Adjuvant CMF Therapy - 20 Year Follow-upAdjuvant CMF Therapy - 20 Year Follow-upMilan Study (N = 386)Milan Study (N = 386)
Bonadonna G et al, N Engl J Med 1995Bonadonna G et al, N Engl J Med 1995
0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.05 10 15 20
Years after Mastectomy
Disease-free survival
Pro
ba
bil
ity
of
Re
lap
se
-fre
e S
urv
iva
l
5 10 15 20
Years after Mastectomy
0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Overall survival
Pro
ba
bil
ity
of
Ove
rall
Su
rviv
al
85% of dose85% of dose
<65% of dose<65% of dose
ControlControl
65-84% of dose65-84% of dose
Anthracyclines vs. CMFAnthracyclines vs. CMFEBCTCG (Oxford Overview) 2006 Meta-AnalysisEBCTCG (Oxford Overview) 2006 Meta-Analysis
Presented ASCO Educational Session 2007Presented ASCO Educational Session 2007
• Many studies Many studies with relatively with relatively low doses of low doses of anthracyclines anthracyclines included in included in analysisanalysis
• Magnitude of Magnitude of benefit benefit probably probably underestimatedunderestimated
CALGB 9344: AC +/- Paclitaxel in LN+ Breast CancerCALGB 9344: AC +/- Paclitaxel in LN+ Breast CancerHenderson IC et al, J Clin Oncol 2003Henderson IC et al, J Clin Oncol 2003
AA 60 vs 75 vs 90 mg/m2 + 60 vs 75 vs 90 mg/m2 + TT 175 mg/m2 q3 wks x 4 175 mg/m2 q3 wks x 4 CC 600 mg/m2 q3 wks x 4 600 mg/m2 q3 wks x 4 No TNo T
ACAC AC + TAC + TDFS (5 yrs)DFS (5 yrs) 65%65% 70% 70% HR = 0.83, p=0.0023HR = 0.83, p=0.0023OSOS 77%77% 80%80% HR = 0.82, p=0.0064HR = 0.82, p=0.0064
n=3,121n=3,121
Adjuvant TaxanesAdjuvant Taxanes
BCIRG 001: TAC vs FAC in Breast Cancer BCIRG 001: TAC vs FAC in Breast Cancer Martin M, et al, N Engl J Med 2005Martin M, et al, N Engl J Med 2005
FF 500 mg/m2 500 mg/m2 T T (Docetaxel) 75 mg/m2 (Docetaxel) 75 mg/m2AA 50 mg/m2 50 mg/m2 AA 50 mg/m2 50 mg/m2 CC 500 mg/m2 q3 wks x 6 500 mg/m2 q3 wks x 6 CC 500 mg/m2 q3 wks x 6 500 mg/m2 q3 wks x 6
TACTAC FACFACDFS (55 months)DFS (55 months) 75%75% 68% 68% HR = 0.72, p=0.001HR = 0.72, p=0.001OSOS 87% 87% 81%81% HR = 0.7, p=0.008HR = 0.7, p=0.008
n=1,491n=1,491vsvs
Biologic TherapyBiologic Therapy
26
HER-2 as a Target for TherapyHER-2 as a Target for Therapy
cell division
HER-2
nucleus
cancer cell
Trastuzumab (Herceptin) Anti-HER-2 Antibody
HER-2 Oncogene: amplified and HER-2 Oncogene: amplified and overexpressed in 20-25% of overexpressed in 20-25% of
breast cancerbreast cancer
Lapatinib (Tykerb) Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
Adjuvant Chemotherapy +/- Adjuvant Chemotherapy +/- Trastuzumab: NSABP B-31 and N9831Trastuzumab: NSABP B-31 and N9831
Romond E et al, N Engl J Med 353, 2005Romond E et al, N Engl J Med 353, 2005
0
50
100
150
200
250
300
Recurrence Death
Chemo Alone
Chemo +Trastuzumab
Number Number of of
patientspatients
•Risk of breast cancer recurrence reduced by 52% at 3 yrsRisk of breast cancer recurrence reduced by 52% at 3 yrs•Risk of death decreased by 33% at 2 yrsRisk of death decreased by 33% at 2 yrs
Adjuvant Therapy in Breast Cancer: Adjuvant Therapy in Breast Cancer: The FutureThe Future
• Clinical features, stage and biology all contribute to Clinical features, stage and biology all contribute to risk of recurrence!risk of recurrence!
• Endocrine therapy critical in ER+ breast cancerEndocrine therapy critical in ER+ breast cancer• In chemotherapy-sensitive breast cancers, In chemotherapy-sensitive breast cancers,
anthracycline and taxanes both add to disease controlanthracycline and taxanes both add to disease control• Many patients don’t need chemo!Many patients don’t need chemo!• Trastuzumab significantly reduces breast cancer Trastuzumab significantly reduces breast cancer
recurrence and death in HER2+recurrence and death in HER2+• Ongoing prospective trials are integrating traditional Ongoing prospective trials are integrating traditional
and novel markers of risk to better define tailored and novel markers of risk to better define tailored options for early-stage breast canceroptions for early-stage breast cancer