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