This document provides an overview of hormone therapy (H/T) for breast cancer patients with estrogen receptor positive (ER+) tumors. It discusses H/T in the adjuvant, metastatic, and local-regional recurrence settings. For patients with ER+/HER2- tumors, H/T alone is not inferior to chemotherapy and may be superior. For patients with ER+/HER2+ tumors, combining an aromatase inhibitor with HER2-targeted therapy such as trastuzumab improves progression-free survival compared to an aromatase inhibitor alone in the metastatic setting.

1. 陳守棟
Overview of the treatment for
Breast Cancer women with ER
positive

2. 演講大綱
●H/T 概論
●H/T in adjuvant setting
●H/T in metastatic setting
●H/T in local-regional recurrence
●H/T in ER(+) Her-2(+)
●H/T in the future

3. 3
Periodic breast cancer incidence of Taiwan 1981-2005
Female breast cancer increased in each age stratum, not so-called young-aged
only.

4. Intrinsic Subtype
Of ER(+)
●Luminal A
●Luminal B Luminal B1
●Luminal Her-2 Luminal B2

6. Luminal A (IHC4)
ER(+)
PR(+) and/or
Her-2(-)
Ki-67 (14% 以下 )

7. Luminal A+
ER(+) 高 濃度
PR(+) 高 濃度
Her-2(-) 低
Ki-67 (14% 以下 ) 低
●高高低低

8. Ki-67 is a potential marker to identify
Luminal A or B
Summary of Immunohistochemical Criteria for Defining Breast Cancer Intrinsic Subtypes
TNP-Nonbasal
Luminal A
Luminal B
Basal like
Luminal HER2
HER2 Enriched

10. ER 濃度越高 H/T 效果越好

11. ER 濃度越高 H/T 效果越
好
●Adjuvant 經驗

14. 5-yearDFS
Subpopulations by ER (log scale)
4112902131541128461463224171310643
0
20
40
60
80
100
IBCSG trial IX: 1669 postmenopausal ER–/ER+ patients
IBCSG. J Natl Cancer Inst 2002
TAM
Randomiz
e CMF x 3 TAM
TAM ALONE
CMF + TAM
Interaction between level of ER expression
and sensitivity to adjuvant chemotherapy

15. ER 濃度越高 H/T 效果越
好
●Metastatic 經驗

16. Endocrine Therapy in MBC: ResponseEndocrine Therapy in MBC: Response
Relationship ofRelationship of ER levelER level
and response to ETand response to ET
1616
ER level
(fmol/mg)
N Response
Rate
3.0 22 5%
3.0-10.0 76 18%
10.1-30.0 219 37%
30.1-300.0 63 78%
>300.0 35 77%
Total 415
Disease of the Breast, 2004 4th
edition Proc ASCO 1980; 21:147

17. ER 是 Target

18. Different Signaling Pathways
SOS
RAS
RAF
Basal
transcription
machineryp160
ERE ER-mediated gene transcription
ER
CBPP
P P P
ER
P
p90RSK
Akt
P
MAPK P
Cell
survival
Cytoplasm
Nucleus
ER
PI3-K
P
P
P
PP
P
Cell
growth
MEK
P
Plasma
membrane
HER2
IGFR
Growth factor
Estrogen
Mackey JR, et al. SABCS 2006. Abstract 3.

19. Adjuvant Treatments for Breast
Cancer

20. Rate of Distant Recurrence Increases
with the Number of Positive Nodes for
All Recurrence Score Results
Dowsett M, et al. Cancer Res. 2009; 69(Suppl 2): Abstract 53.

21. SWOG 8814 (N+)
DFS by Recurrence Score and Nodal
Category
10-Yr DFS by Nodal Subset and RS
Albain et al, The Lancet Oncology 2010; 11:55-65

22. Oncotype vs Adjuvant! Online
TransATAC Study: mixed groups – LN+/-, C/T +/-
• RS and Adjuvant! correlate weakly
(Spearman R = 0.234)
• RS and Adjuvant! Online are
each
– Highly significant
– Independent
– Predict relapse in both node-
negative and positive
Correlation
Prediction of Relapse Rate:
Multivariate model
Adjuvant! Online Risk Using Central Grade (%)†
RSRisk,%*
0
10
20
30
40
0 10 20 30 40
Dowsett M et al, J Clin Oncol. 2010 Apr 10;28(11):1829-34.
Variable Δ Log Rank
Chi Square
P Value
Risk distant
recurrence
from RS
21.9 < .001
Risk relapse
from Adjuvant!
21.9 < .001

23. IHC4 score
(cheaper evaluation of tumor biology)
RS = + 0.47 x GRB7 group score
- 0.34 x ER group score + 1.04 x
proliferation group score + 0.10 x
invasion group score + 0.05 x CD68
- 0.08 x GSTM1 - 0.07 x BAG1 .
For example :
LN:0, Size: 1.5 cm, Grade3,
ER80%, PR5%, HER2-, Ki67 30%
IHC4 score = 34.3%
2009 SABCS

24. IHC4 vs. Oncotype – TransATAC
Node negative, T<2cm, poorly differentiated tumor receiving anastrozole
2009 SABCS

25. IHC4 score in Adjuvant H/T

26. LHRH agonist indication
in adjuvant setting
●Adjuvant intensive H/T instead of C/T
●Post C/T Amenorrhea
●Very young (35y 以下 )
●Patient Preference

27. 停經前乳癌審查規定
• 停經前（或更年期前）之嚴重乳癌，須完全符合以下二點：
(86/9/1 、 99/2/1)
• Ⅰ 荷爾蒙接受體陽性。
• Ⅱ. 無法忍受其他荷爾蒙製劑 (tamoxifen 、 megestrol
等 ) ，且為
• 停經前婦女有轉移性乳癌者。
• ( 發文日期：中華民國 99 年 12 月 22 日 , 發文字號：健保審字第
0990013434 號 )
• 停經前 ( 或更年期前 ) 之早期乳癌，且須完全符合以下六點：
(100/2/1)
• Ⅰ 與 tamoxifen 合併使用，作為手術後取代化學治療之輔助療法。
• Ⅱ 荷爾蒙接受體為強陽性： ER/PR 為 2+ 或 3+ 。
• III. Her-2 Fish 檢測為陰性或 IHC 為 1+ 。
• IV. 淋巴結轉移數目須≦ 3 個。
• V. 使用期限： goserelin 使用 3 年， tamoxifen 使用 5 年。

28. 80% of patients with high or medium
ER+ or PR+ expression (>50%)
30% of patient node positive

30. Main Findings
● Survival outcomes for entire cohort
– 5-year DFS: 94 %
– 5-year OS: 98.2 %
● No significant differences in survival outcomes between
tamoxifen and anastrozole
● DFS and RFS significantly improved with ZA vs
endocrine therapy alone

31. LHRHa agonist indication
in adjuvant setting
●Adjuvant intensive H/T instead of C/T
● Post C/T Amenorrhea
●Very young (35y 以下 )
●Patient Preference

32. Incidence and Prognostic Impact of Amenorrhea During
Adjuvant Therapy in High-Risk Premenopausal Breast
Cancer: Analysis of a National Cancer Institute of Canada
Clinical Trials Group Study—NCIC CTG MA.5
Wendy R. Parulekar, Andrew G. Day, Jon A. Ottaway, Lois E. Shepherd,
Maureen E. Trudeau, Vivien Bramwell, Mark Levine, Kathleen I. Pritchard
From the National Cancer Institute of Canada Clinical Trials Group, Queen's
University; Clinical Research Centre, Kingston General Hospital, Kingston;
Toronto Sunnybrook Regional Cancer Centre, Toronto; Juravinski Cancer
Centre, Hamilton Health Sciences, Hamilton, Ontario; and Tom Baker Cancer
Centre, Calgary, Alberta, Canada
Journal of Clinical Oncology, Vol 23, No 25
(September 1), 2005: pp. 6002-6008

33. Copyright © American Society of Clinical Oncology
Parulekar, W. R. et al. J Clin Oncol; 23:6002-6008 2005
Relapse-free survival by 12-month amenorrhea status

34. Copyright © American Society of Clinical Oncology
Parulekar, W. R. et al. J Clin Oncol; 23:6002-6008 2005
Overall survival by 12-month amenorrhea status

35. LHRHa agonist indication
in adjuvant setting
●Adjuvant intensive H/T instead of C/T
● Post C/T Amenorrhea
●Very young (35y 以下 )
●Patient Preference

36. Is the current treatment
enough for young-age
patient: What else can we
do?
中山醫學大學附設醫院
腫瘤 科 曾思文內

37. In women aged 40 years or younger, the
addition of an LHRH agonist significantly reduced rates
for recurrence by 25.2%
Lancet. 2007 May 19;369(9574):1711-23.

38. No significant difference for women older than 40
years
Lancet. 2007 May 19;369(9574):1711-23.

39. Conclusion
• Young age (<35 years or <40 years) ER+ breast cancer women
seem to have worse prognosis than older counterpart.
• Amenorrhea was associated with improved survival regardless
of the treatment and estrogen-receptor status.
• Different chemo regimens and age would affect the rate of
amenorrhea.
• Addition of LHRH agonist to chemotherapy with or without
tamoxifen has benefit for women younger than 40 years.
• The addition of zoledronic acid to adjuvant endocrine therapy
provided a sustained and durable disease-free survival benefit .

40. Optimal endocrine therapy for
premenopausal women with
endocrine-responsive, HER2-
negative early breast cancer
Breast and Endocrine Surgery
Gunma University Hospital
Jun Horiguchi

41. Take Home Messages
In clearly premenopausal women 5 years adjuvant
treatment of tamoxifen with ovarian suppression is
recommended .
Adjuvant hormonal therapy in premenopausal women
In women with uncertain menopausal status (after
chemotherapy)
Amenorrhea and E2-high (under 45y/o))
TAM+LH-RHa
Amenorrhea and E2,FSH postmenopausal
(45 y/o or older)
Initial treatment (first 2–3 years); TAM
Subsequent treatment (years 2–5); TAM, AI

42. LHRHa agonist indication
in adjuvant setting
●Adjuvant intensive H/T instead of C/T
● Post C/T Amenorrhea
●Very young (35y 以下 )
●Patient Preference

43. 演講大綱
●H/T 概論
●H/T in adjuvant setting
●H/T in metastatic setting
●H/T in local-regional recurrence
●H/T in ER(+) Her-2(+)
●H/T in the future

44. 迷思 ( 迷失 ?)
Visceral metastasis =Visceral crisis ?
Visceral metastasis---Chemotherapy?
Hormonal therapy

45. 1st International Consensus Guidelines for
Advanced Breast Cancer – ABC 1
F. Cardoso, MD
EORTC Secretary General
ESO Breast Cancer Program
Coordinator Director Breast Cancer
Unit
Champalimaud Cancer Center
Lisbon, Portugal

46. BIOPSY OF METASTATIC DISEASE
14) If the results of tumour biology in the metastatic lesion differ
from the primary tumour, it is currently unknown which result should
be used for treatment-decision making.
Since a clinical trial addressing this issue is difficult to undertake, we
recommend considering the use of targeted therapy (ET and/or anti-
HER-2 therapy) when receptors are positive in at least one biopsy,
regardless of timing.
(LoE: Expert opinion) (87%)

48. Premenopausal , Metastasis
● Ovarian suppression
● Ovarian ablation
Treated as Postmenopausal

50. First line
● SWOG S0226
Anastrozole PFS 13.5m
Anastrole+Fulvestrant 15m
● LEA Study
Letrozole or Fulvestrant PFS 13.8 m
Letrozole +Avastin 18.4m

51. Second line
Fulvestrant
PFS 250mg 5.5m
PFS 500mg 6.6m

52. Second Line H/T
NSAI----SAI(Aromasin)
4.1m

53. Second Line H/T
NSAI----SAI(Aromasin)
4.1m
Bone 5.3m
Visceral 2.8m

54. Second Line H/T
AI---Tamoxifen 4.5 m
Secondary hormone resistance 5.5 m

55. Second line
● CONFIRM trial
Fulvestrant 250mg 5.5 m
Fulvestrant 500mg 6.5 m
● BOLERO-2 trial
Aromasin 4.1 m
● TAMRAD trial
Tamoxifen 4.5 m 5.5m

56. Conclusion
Recurrence and Metastatic setting
ER(+) Her-2(-)
荷爾蒙治療不比化學治療差
荷爾蒙治療比化學治療好

57. Case experience

58. Local recurrence in ER(+)
●H/T alone ?
●H/T and C/T?

59. 演講大綱
●H/T 概論
●H/T in adjuvant setting
●H/T in metastatic setting
●H/T in local-regional recurrence
●H/T in ER(+) Her-2(+)
●H/T in the future

60. HR(+) and Her-2(+)
Luminal Her-2

61. HR(+) and Her-2(+)
In Metastatic setting

62. TAnDEM: Progression-free survival
A + H 103
A 104
48 31 17 14 13
36 22 9 5 4
0 5 10 15 20 25 30 35 40 45 50 55 60
Months
11
2
9 4 1 1 0 0
1 0 0 0 0 0
1.0
0.8
0.6
0.4
0.2
0.0
95% CI
3.7, 7.0
2.0, 4.6
p value
0.0016
Median PFS
4.8 months
2.4 months
Events
No. at risk
95% CI 0.47, 0.84
A + H 87
A 99
HR 0.63
Roche Medical
Affairs
5
Kaufman et al 2009A, anastrozole; H, trastuzumab; CI, confidence interval; HR, hazard

63. AI + Target
●Anastrozole 2.4m
●Anastrozole + Herceptin 4.8m

64. AI + Target
●Letrozole
●Letrozole+Lapatinib ?

65. EGF30008: Progression-free survival
0.8
0 10 15 20 25
Months
p value
0.019
Median PFS
8.2 months
3.0 months
HER2+ population
Events
88
89
HR 0.71
1.0
0.6
0.4
0.2
0.0
95% CI 0.53, 0.96
Let + lap
Let + p
5 30 35 40 45 50
No. at risk
Roche Medical
Affairs
9
Let, letrozole; lap, lapatinib; p, Johnston et al 2009
Let + lap 111 69 33 20 12 8 4 1 1
Let + p 108 43 26 18 12 7 5 2 2

66. AI + Target
●Letrozole 3.0m
●Letrozole+Lapatinib 8.2m

67. AI + Target
●Anastrozole 2.4m
●Anastrozole + Herceptin 4.8m
●Letrozole 3.0m
●Letrozole+Lapatinib 8.2m

68. AI + Target
● Anastrozole 2.4m
● Anastrozole + Herceptin 4.8m
● Letrozole 3.0m
● Letrozole+Lapatinib 8.2m
● ER(+) Her-2(-) 13m

69. ORRs in HER2/hormone receptor co-positive MBC
TAnDE
M
20
0
4
0
6
0
8
0
10
0
Trastuzumab
+
anastrozole
Lapatinib
+
letrozole
Trastuzumab
+ paclitaxel
Trastuzumab
+ docetaxel
M77001HO648g
EGF30008
Combination with
aromatase inhibitors
Combination with
chemotherapy
In HER2/hormone receptor co-positive patients the best overall
responses are observed when chemotherapy is added to anti-HER2
therapy
HER2/HR
co-positive
patients
KaufmaRnnoceht
ealM20e0d9i;cJaolhAnsftfoanirset
al 200 9 ; Brufsky et al 2004; Extra

70. Conclusions
Roche Medical
Affairs
71
• HER2/hormone receptor co-positive breast cancer is an aggressive
disease
• Chemotherapy in combination with trastuzumab for patients with
HER2/hormone receptor co-positive disease remains the treatment of
choice
• Anti-HER2 therapy in combination with hormonal therapy should be
reserved for patients who are not eligible for chemotherapy

71. HR(+) and Her-2(+)
Target therapy 加 H/T
In Metastatic setting
有效 但不夠強

72. 演講大綱
●H/T 概論
●H/T in adjuvant setting
●H/T in metastatic setting
●H/T in local-regional recurrence
●H/T in ER(+) Her-2(+)
●H/T in the future

73. Future
CDK 4/6 inhibitor
New in SABCS 2012

74. PFS 26.1
months
PFS 7.5
months

75. ER Image

76. Take Home Message

77. Take home message
Adjuvant setting
● . 歐 (St. Gallen) 美 (NCCN) 有差異
● Adjuvant online 可能 over evaluation
● IHC 4 Score 最接近 Oncotype
● 大部份 Luminal A 不必化療
● 絕大部份 Luminal A+ 不必化療
● Intensive H/T(Zoladex+Tamoxifen) 取代 C/T 是一選項
● 40 y/o 以下應 Ovarian suppressioon
● Premenopausal post treatment Amenorrhea 可能有幫助
● ER(+) Her-2(+) Herceptin 有 OS benefit 也許 6m 就夠

78. Take home message
Metastatic setting
● . 歐 (St. Gallen) 美 (NCCN) 一致 , H/T 是第一線 不是 C/T
● H/T 第一線 AI PFS 13m
● H/T 第一線 Fulvestran + Arimidex 15m
● H/T 第二線 Fulvestrant 500mg 6.5m
● H/T 第二線 NSAI---SAI viscreal meta 不行 (2.8m) Bone 5.3m
● H/T 第二線 NSAI---Tamoxifen 4.5 --- 5.5m
● H/T 第二線 Everolimus+Aromasin 11m, side effect?
● ER(+) Her-2(+) 以 C/T + Target therapy 為主 H/T alone 不夠

79. Thank You
80