breast cancer systemic adjuvant treatment 長庚紀念醫院 血液腫瘤科 張獻崑 醫師
TRANSCRIPT
Breast Cancer Systemic Adjuvant Treatment
長庚紀念醫院 血液腫瘤科 張獻崑 醫師
Early Disease Advanced Disease Adjuvant therapy
≒30%
≒50%
70%
Stage 4
Incurable!
More aggressive medical treatment !!!
Endocrine therapy and/or Chemotherapy ± Biologic therapies
Stage 1
Stage 2
Stage 3
Node negative
Node positive
BREAST CANCERBREAST CANCERDeterminants of RecurrenceDeterminants of Recurrence
BREAST CANCERBREAST CANCERDeterminants of RecurrenceDeterminants of Recurrence
Tumor sizeTumor size
Lymph node involvementLymph node involvement
Histological differentiationHistological differentiation
Tumor estrogen- and progesterone-receptor statusTumor estrogen- and progesterone-receptor status
Lymphatic/blood vessel invasion Lymphatic/blood vessel invasion
Specific factors:Specific factors:
— Ploidy or DNA indexPloidy or DNA index— Proliferation factors (s-phase fraction, Ki-67)Proliferation factors (s-phase fraction, Ki-67)— Oncogene amplification/expression Oncogene amplification/expression
(HER-2/neu)(HER-2/neu)
2007/11
Left breast cancer s/p left partial mastectomy and dissection of
axillary lymphatics
Stage IIA (T1cN1M0) , Grade III invasive ductal carcinoma
ER (3+), PR (3+) and Her-2 (1+)
Age:36 y/o, Premenopausal
2007/12 Plan of Adjuvant therapies
Chemotherapy :
Radiotherapy :
Endocrine therapy :
Patient’s Breast Cancer History
Breast Cancer Adjuvant Treatment
--- About Chemotherapy
Polychemotherapy for Early Breast Cancer : an overview of the randomized trials ( I )
TABLE 1. Adjuvant drug therapy: percentage reduction in the annualodds of either recurrence or death
Patient Therapy Reduction in Annual Reduction in AnnualAge (y) Odds of Recurrence (%) Odds of Death (%)
< 40 C/T vs. none 37 + 7 27 + 840-49 C/T vs. none 35 + 5 27 + 550-59 C/T vs. none 22 + 4 14 + 460-69 C/T vs. none 18 + 4 8 + 4
• C/T: polychemotherapy• Polychemotherapy reduce 20% annual odds of contra-lateral breast cancer• Adapted from EBCTCG Lancet 1998;352:930-42
Polychemotherapy for Early Breast Cancer : an overview of the randomized trials ( III ) -- Anthracycline-containing v.s CMF
TABLE 2. Adjuvant drug therapy: Anthracycline-containing
regimens versus CMF
Adjuvant Therapy Proportion Absolute
Reduction Reduction
(%) (%)
Recurrence A-containing vs. CMF 12 + 4 3.2 +1. 5
Death A-containing vs. CMF 11 + 5 2.7 + 1.4
*A-containing: Anthracycline-containing regimens
*Adapted from EBCTCG Lancet 1998;352:930-42
Evolution of Chemotherapy in Node-Positive Disease
CMFMilan
ACB-15
FEC50ICCG
= =
CEFMA.5
FACGEICAM
TACBCIRG 001
TCUS9735
AC-PC9344B-28
AC-TE1199
AC-PwE1199
AC2w-P2wC9741
FEC100FASG05
FEC-PwG9906
FEC-TPACS01
Polychemotherapy for Early Breast Cancer : an overview of the randomized trials ( II ) -- Node Positive and Node Negative
Breast Cancer Adjuvant Treatment
--- About Hormone Therapy
Estradiol
CoactivatorAF1
EREE
E+
AF1 + AF2
ACTIVE
Receptordimerization
Nuclear localization offully active ER
to ERE
Coactivator
ERE RNAPOLII
FULLY ACTIVATEDTRANSCRIPTION(tumor cell division)
AF1 and AF2recruit
coactivators
E
AF2
AF1
E
Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.
Mode of Action of Estradiol (Full Agonist)
Mechanisms of Action of Hormonal Therapies
Block estrogen action– Tamoxifen
Block estrogen synthesis– Ovarian ablation (premenopausal)
– Inhibition of aromatase (postmenopausal)
Tamoxifen
CoactivatorAF1
ER+ERE RNA
POLII
PARTIALLY INACTIVATEDTRANSCRIPTION(reduced rate of tumor cell division)
T TT
TT
AF1
Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.
Mode of Action of Tamoxifen
Tamoxifen Response in MBC
雌激素接受體 療效 病人數
ER PR 有效數 / 全部人
數 + + 71% 188/263+ - 32% 61/189- + 53% 8/15- - 9% 16/171
From Clark GM, McGuire WL:Breast Cancer Res Treat 3:157-163,1983.From Clark GM, McGuire WL:Breast Cancer Res Treat 3:157-163,1983.
Tamoxifen for Early Breast Cancer: an overview of the randomized trials
TABLE 5. Duration of Tamoxifenn Adjuvant Therapy on Percentage Reduction in the Annual Odds of Either Recurrence or Death
Reduction in Annual Reduction in Annual Group Odds of Recurrence (%) Odds of Death (%) Tamoxifen 1 y < 50 2 + 7 -2 + 8 50-59 28 + 6 21 + 6 All 20 + 3 11 + 3Tamoxifen 2 y < 50 14 + 5 10 + 6 50-59 32 + 4 19 + 5 All 29 + 3 17 + 3Tamoxifen 5 y < 50 45 + 8 32 + 10 50-59 37 + 6 11 + 8 All 47 + 3 26 + 4• Adapted from EBCTCG Lancet 1998;351:1451-67
Tamoxifen for Early Breast Cancer: an overview of the randomized trials(Node positive and Node negative)
Ovarian Ablation in Early Breast Cancer: an overview of the randomized trials ( I )
TABLE 6. Meta-analysis of the Effect of Ovarian Ablation
Reduction in Reduction Annual Odds Annual Odds
Group of Recurrence (%) of Death (%)
Ovarian ablation vs. no adju- 25 + 7 24 + 7
vant therapy (age < 50)
Ovarian ablation + chemo- 10 + 9 8 + 10
therapy vs chemotherapy
Adapted from EBCTCG Lancet 1996;348:1189-96
Ovarian Ablation in Early Breast Cancer: an overview of the randomized trials ( II )
-- Node Positive and Node Negative
Multiple steps involving P-450 enzymes and production of Multiple steps involving P-450 enzymes and production of steroid intermediatessteroid intermediates
Selective Versus NonselectiveAromatase Inhibition
Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Scientific American MedicineScientific American Medicine. . Section 3. Subsection IV. ©1997 Scientific American Inc. All rights reserved.Section 3. Subsection IV. ©1997 Scientific American Inc. All rights reserved.
CholesterolCholesterol
CortisolCortisol AndrostenedioneAndrostenedioneAldosteroneAldosterone
TestosteroneTestosterone
EstroneEstrone EstradiolEstradiol
Selective InhibitorsSelective Inhibitors
Nonselective InhibitorsNonselective Inhibitors
Arom
atas
e
Arom
atas
eArom
atase
Aromatase
* Surgery + radiotherapy + chemotherapy(Patients may start trial therapy while still receiving radiotherapy)
+
Postmenopausal women with invasive breast cancerPostmenopausal women with invasive breast cancer
Completion of primary therapy*Completion of primary therapy*
Randomization 1:1:1 for 5 yearsRandomization 1:1:1 for 5 years
Anastrozole 1mg od+
Tamoxifen placebo
Anastrozole placebo+
Tamoxifen 20mg od
Anastrozole 1mg od+
Tamoxifen 20mg od
Regular follow-up monitoring adverse eventsRegular follow-up monitoring adverse events
Trial endpointsTrial endpoints
ATAC Trial Design
Table of First Events in ITT Population
First event 317 379 383
Locoregional 67 83 81
Distant 156 181 202
Contralateral (invasive) 9 30 23
Contralateral (DCIS) 5 3 5
Death — breast cancer 2 1 2
Death — other reason 78 81 70
Tamoxifen(n=3116)
Anastrozole(n=3125)
Combination(n=3125)
Curves truncated at 42 months
HR 95.2% CI p-value
AN vs TAM 0.78 0.65–0.93 0.0054Comb vs TAM 1.02 0.87–1.21 0.7786
Time to event (months)
Pro
po
rtio
n e
ven
t fr
ee (
%)
Anastrozole
Tamoxifen
Combination
0
80
85
90
95
100
0 6 12 18 24 30 36 42
Kaplan–Meier Curves of Disease-free Survival
in Receptor-positive Population
*
AITamoxifen2-3 years’ prior
tamoxifen
Initial adjuvant trial
Switching trial
Extended adjuvant trial
TamoxifenAI
TamoxifenAI
Initial and sequencing trial
Tamoxifen AI
0 5Time (years)
AI
RandomisationPlacebo
5 years’ prior tamoxifen
Randomisation
Randomisation
Randomisation
Trial Design: types of adjuvant trial
TamoxifenAI
AI, aromatase inhibitor
2007/11 Age:36 y/o, Premenopausal
Left breast cancer s/p left partial mastectomy and dissection of
axillary lymphatics
Grade III invasive ductal carcinoma, stage IIA (T1cN1M0) ,
ER (3+), PR (3+) and Her-2 (1+)
2007/12~2010/07 Adjuvant therapies
Chemotherapy : Epirubicin, 5-FU, and cyclophosphamide (FE90C) x
4 cycles Taxotere+CDDP x 4 cycles
Radiotherapy (2008/6~2008/7)
Tamoxifen (20mg/day) since 2008/6/3 2010/8/6
Arimidex (1mg/day) since 2010/8/31 2011/3
Patient’s Breast Cancer History
Side Effect of TamoxifenSide Effect of TamoxifenSide Effect of TamoxifenSide Effect of Tamoxifen
Hot flashesHot flashes
Thrombo-embolic diseaseThrombo-embolic disease
Endometrial MalignancyEndometrial Malignancy
— Endometrial cancer Endometrial cancer — Uterine sarcomaUterine sarcoma
Tamoxifen Related Endometrial MalignancyTamoxifen Related Endometrial MalignancyTamoxifen Related Endometrial MalignancyTamoxifen Related Endometrial Malignancy
Endometrial CancerEndometrial Cancer
-- -- P-1 study: Tamoxifen chemo-preventive trial P-1 study: Tamoxifen chemo-preventive trial in high risk papulationin high risk papulation
Tam. Gr.:53 cases ; Placebo: 17 cases Tam. Gr.:53 cases ; Placebo: 17 cases Risk Ratio: 3.28 Risk Ratio: 3.28
Presentation: Vaginal bleedingPresentation: Vaginal bleeding67 cases: FIGO stage I 67 cases: FIGO stage I Exclusively age > 50 y/oExclusively age > 50 y/o
-- -- NSABP B-14: Tamoxifen adjuvant trial in N(-) HR(+) BC NSABP B-14: Tamoxifen adjuvant trial in N(-) HR(+) BC
Annual hazard rate of endometrial cancerAnnual hazard rate of endometrial cancer Tam. Gr.:1.6/1000 ; Placebo: 0.2/1000 Tam. Gr.:1.6/1000 ; Placebo: 0.2/1000
Relative Risk : 7.5 Relative Risk : 7.5 (population-based rate from SEER: (population-based rate from SEER:
relative risk: 2.2)relative risk: 2.2) Cumulative hazard rate (5yr): Cumulative hazard rate (5yr): 6.3/10006.3/1000 21/24 cases: FIGO 21/24 cases: FIGO stage I stage I
Tamoxifen Related Endometrial MalignancyTamoxifen Related Endometrial MalignancyTamoxifen Related Endometrial MalignancyTamoxifen Related Endometrial Malignancy
Uterine sarcomaUterine sarcoma --- SEER database --- SEER database
39,541 BC pts (Dx 1980~2000) treated with Tamoxifen 39,541 BC pts (Dx 1980~2000) treated with Tamoxifen v.sv.s. .
General Population :General Population :
Uterine corpus cancer relative risk [O/E] ratio: 2.17Uterine corpus cancer relative risk [O/E] ratio: 2.17
Malignant Mixed Mullerian Tumors: O/E ratio= 4.62Malignant Mixed Mullerian Tumors: O/E ratio= 4.62
Endometrial adenocarcinoma : O/E ratio= 2.07Endometrial adenocarcinoma : O/E ratio= 2.07
Recommendations for Monitoring Recommendations for Monitoring Women on Tamoxifen (ACOG) Women on Tamoxifen (ACOG)
Recommendations for Monitoring Recommendations for Monitoring Women on Tamoxifen (ACOG) Women on Tamoxifen (ACOG)
Premenopausal without known increased risk of uterine cancer: Premenopausal without known increased risk of uterine cancer:
no additional monitoring beyond routine gynecologic careno additional monitoring beyond routine gynecologic care
Postmenopausal : Postmenopausal :
annual gynecologic examinationannual gynecologic examination
Monitoring for symptoms of endometrial hyperplasia or cancerMonitoring for symptoms of endometrial hyperplasia or cancer
Investigate any abnormal vaginal symptomsInvestigate any abnormal vaginal symptoms
Limit tamoxifen use to 5-years duration Limit tamoxifen use to 5-years duration
Atypical endometrial hyperplasia: Atypical endometrial hyperplasia:
reassess tamoxifen use and appropriate gynecologic reassess tamoxifen use and appropriate gynecologic management management
Hysterectomy in women with atypical endometrial hyperplasia Hysterectomy in women with atypical endometrial hyperplasia whom tamoxifen therapy must be continuedwhom tamoxifen therapy must be continued
Thank you for your attention