1. Treatment of Breast Cancer in 2012
Where are we now?
Dr Janice Walshe
Consultant Medical Oncologist
St Vincent‟s University Hospital, Dublin

2. Outline
• Overview of treatment approach
• Updates in diagnostics and therapy
– Oncotype Dx
– Hormonal therapy advances
– Chemotherapy Advances
– “Targeted therapy advances”
• Hereditary breast cancer
• Follow-up and “what can I do”

3. Projected number of Breast Cancers to 2020
5000
4500
4000
new cases per year
3500
3000
2500
2000
1500
1000
500
0
1995
2000
2005
2010
2015
2020

4. risk of death from cancer before age 75 (%)
0%
1%
2%
3%
4%
1950
1954
1958
1962
1966
1970
1974
1978
1982
year of death 1986
1990
1994
1998
2002
2006
2010
2014
Deaths from Breast Cancer 1950-2014

5. Why?
• Incidence is increasing
– Mammographic screening
– Environmental Factors
• Mortality is decreasing
– Early Detection
– Better Treatment Options

6. Treatment Approach

7. Treatment for Breast Cancer
• Local therapy
– Lumpectomy + radiation
– Mastectomy (+/- radiation in
more advanced disease)
– Goal: treat primary site of
disease
• Systemic therapy
– Chemotherapy
– Hormonal therapy
– Targeted therapy

8. Special Environment
• Specialist Breast Cancer Unit
• Multidisciplinary Approach
– Histopathologist
– Surgery
– Medical Oncology
– Radiation Oncology
– Genetic Risk Assessment
– Nursing Expertise
– Support services (Dietician, social worker,
psychologist, OT)

9. What directs the sequence of the
Treatment?
Varies
• Clinical/ pathological stage and
subtype of the tumor
• Biological characteristics of the tumor

10. Staging Breast Cancer

11. Factors that Influence Treatment
Decisions
• Patient Age
• Histological Subtype & Grade
• Tumour Size
• Lymph Node Involvement
• Hormone Receptor Status
– Positive or Negative
• Her-2 neu Expression
– IHC graded 1+, 2+, 3+
– FISH amplified

12. Staging Breast Cancer
• Early Stage (Stage I & II)
• Locally Advanced (Stage III)
• Metastatic (Stage IV)

13. Systemic Therapy Setting & Purpose
Early Stage Locally Advanced Metastatic
No evidence of Render inoperable operable Disease
disease control
Commence systemic therapy
Reduce risk of
recurrence Reduce risk metastatic disease

14. Early Stage Disease
Hormones Herceptin Chemo Clinical Trial
Hormone HER-2 Risk of Access to
positive positive recurrence new
60% 20% therapies
Tumour size / Grade / Age / Co-morbidities

15. Rationale for Hormone Therapy
• Prevent breast
cancer cells from
receiving
stimulation from
endogenous
estrogen
Beatson, 1896

16. Estrogen Production in Premenopausal
and Postmenopausal Patients
Hypothalamus
Premenopausal Premenopausal and
Postmenopausal
Gonadotropins Adrenocorticotropic
(FSH + LH) hormone (ACTH)
Pituitary gland
Ovary
Prolactin
Adrenal gland
Growth Hormone
Corticosteroids
Estrogens Progesterone
Progesterone Androgens
Estrogens
Aromatase
inhibitors

17. Early Breast Cancer Trialists Group
Overview: Tamoxifen
EBCTCG, Lancet 2005,365: 1687

18. Side Effects of Tamoxifen
Common side effects
Hot flashes
Rare but serious side effects
Thromboembolic disease
Endometrial cancer
Cataracts
Issues with SSRIs

19. Hormonal Therapy in
Postmenopausal Women

20. Aromatase Inhibitors- Mechanism of Action
Smith et al., N Engl J Med 348(24):2431-42 2003

21. Recurrence Rate for HR+ Patients
25
A T HR 95% CI P-value
20 HR+ 424 497 0.83 (0.73–0.94) 0.005
ITT 575 651 0.87 (0.78-0.97) 0.01
Patients (%)
15
Anastrozole (A)
Tamoxifen (T)
10
5
Absolute
0 difference: 1.7% 2.4% 2.8% 3.7%
0 1 2 3 4 5 6
At risk: Follow-up time (years)
A 2618 2540 2448 2355 2268 2014 830
T 2598 2516 2398 2304 2189 1932 774
DFS includes all deaths as a first event
Howell A, et al. Lancet 2005

22. Aromatase Inhibitors
• Anastrazole (Arimidex), Femara (Letrozole),
Aromasin (Exemestane)
• Improve outcome in postmenopausal women
• Side Effects
– Osteopenia, Osteoporosis, Increased risk of
fractures
– Possible increase in cholesterol
– Arthralgias

23. Adjuvant
Chemotherapy

24. Progress in Chemotherapy for
Early Stage Breast Cancer
1970s Combination chemotherapy (CMF)
Use of anthracyclines
Addition of taxanes
Superior taxane containing regimens
2000s Addition of trastuzumab
BUT: ALL chemotherapy is associated with toxicities and
risks… need better ways to identify which patients will benefit
from treatment

25. Adjuvant Chemotherapy
• Degree of benefit varies according to nodal
status and patient age
• Degree of benefit varies according to
sensitivity of tumor to hormones (ER+ vs.
ER-)

26. Side effects
• Cardiac toxicity
– Anthracyclines increase risk of congestive heart failure
– Arrhythmias increased with taxanes
– Radiation
• Neuropathy
– Taxanes
• Hypersensitivity
– Taxanes, require steroids
• Ovarian ablation
– Premature menopause
» Infertility, Impaired quality of life, bone effects
• Second malignancies

27. SO…How can we do better?
• Better selection of patients for treatment with
chemotherapy
• Treat only those patients who are most likely to
recur AND who will therefore benefit most from the
addition of chemotherapy
• Take advantage of genomics

28. Oncotype DX or Recurrence Score (RS) Assay
for patients with ER + LN- disease
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION ESTROGEN RS = + 0.47 x HER2 Group Score
Ki-67 ER - 0.34 x ER Group Score
STK15 PR + 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
Survivin Bcl2 + 0.05 x CD68
Cyclin B1 SCUBE2 - 0.08 x GSTM1
MYBL2 - 0.07 x BAG1
GSTM1 BAG1
INVASION
Stromelysin 3 CD68 Category RS (0 – 100)
Cathepsin L2
REFERENCE Low risk RS < 18
HER2
Beta-actin Int risk RS ≥ 18 and < 31
GAPDH
GRB7 RPLPO High risk RS ≥ 31
HER2 GUS
TFRC

29. Recurrence Score as a Continuous Predictor
40%
Intermediate
Low Risk Group High Risk Group
Risk Group
35%
Distant Recurrence at 10 Years
My RS is 30, What is the chance of
30%
recurrence within 10 yrs?
25%
20%
15%
10%
5%
95% CI
0%
0 5 10 15 20 25 30 35 40 45 50
Recurrence Score

30. Oncotype DX™ Clinical Validation:
B-14 Results – DRFS
DRFS for the three distinct cohorts identified
100%
90%
80%
70%
60%
DRFS
50% P <0.00001
40%
30% Low Risk (RS <18) n = 338
20% Intermediate Risk (RS 18-30) n = 149
10% High Risk (RS 31) n = 181
0%
0 2 4 6 8 10 12 14 16
Years
Paik et al. N Engl J Med. 2004;351:2817-2826.

31. B-14 Benefit of Tamoxifen
By Recurrence Score Risk Category
1.0 1.0
0.8 0.8
DRFS
DRFS
0.6 0.6
0.4 0.4
Low Risk (RS<18) Int Risk (RS 18-30)
0.2
N N
0.2
Placebo 171 Placebo 85
Tamoxifen 142 Tamoxifen 69
0.0 0.0
0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
Years Years
1.0
0.8
Interaction P = 0.06
DRFS
0.6
0.4
High Risk (RS≥31)1 1 The results should not be used
0.2
N to indicate that tamoxifen should
99
Placebo
Tamoxifen 79 not be given to the high-risk
0.0 group
0 2 4 6 8 10 12 14 16
Years

32. Oncotype Dx: Chemotherapy benefit
RS < 18 RS 18-30 RS ≥ 31
1.0
1.0 1.0
0.9
0.9 0.9
0.8
0.8 0.8
0.7
0.7 0.7
0.6
0.6
DRFS
0.6
DRFS
DRFS
0.5
0.5 0.5
0.4
0.4 0.4
0.3 0.3
0.3
0.2 0.2 0.2
Low Risk Patients (RS < 18) Int Risk (RS 18 - 30) High Risk Patients (RS 31)
0.1 Tam + Chemo 0.1 Tam + Chemo 0.1 Tam + Chemo
Tam Tam Tam
0.0 0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12
Years Years Years
• Patients with tumors that have high Recurrence Scores
have a large absolute benefit of chemotherapy (similar
results with CMF and MF)
• Patients with tumors that have low Recurrence Scores
derive minimal, if any, benefit from chemotherapy
Paik et al, J Clin Oncol. 2006

33. Early Stage Breast Cancer –
Overtreatment & Inadequate Treatment
 Clinical features are not sufficiently predictive of relapse after
primary therapy, resulting in…
– Overtreatment, because…
– most patients with early stage disease will not have a future
recurrence
– Inadequate treatment, because either…
• treatment is not given because of favorable clinical features,
or
• relapse occurs despite treatment

34. Biological or Targeted
Therapy

35. Targeted therapies for
Early Stage Breast Cancer
• Treatments that „target‟ specific proteins or
receptors expressed by tumor
– Hormonal therapy was the first targeted therapy for
breast cancer
• Monoclonal antibodies
– Trastuzumab (Herceptin)

36. HER-2 Positivity
in Breast Cancer
• OVEREXPRESSION: marked increase in number of HER2
receptors on the cell surface
• AMPLIFICATION: increase in number of HER2/neu gene
copies in the nucleus
HER2-normal (HER2-) breast HER2-positive breast cancer cell
epithelium cell (~20,000 receptors) (up to 1-2 million receptors)
Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.

37. Anti-HER2 Antibodies:
Mechanism of Action
P
P
P
P P
P
P
P
Excessive cell proliferation, Potentiation of Inhibition of tumor cell Facilitation of
survival, and angiogenesis chemotherapy proliferation immune function
Baselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35.
Noonberg and Benz. Drugs. 2000;59:753.

38. NSABP B-31/N9831 Joint Analysis: Impact
of Adding Trastuzumab to AC Paclitaxel
on Disease-Free Survival*
% Surviving disease-free
100 Trastuzumab
87.1% (133 events)
90 85.3%
80 Median FU 2.0 y
Control
70 (261 events) 75.4%
67.1%
60
P<0.0001
HR=0.48
50
0
0 1 2 3 4 5
Years after randomization
No. at risk 3351 2379 1455 801 133 0
Control 1679 1162 689 374 59 0
Trastuzumab 1672 1217 766 427 74 0
* N9831 arm B (sequential trastuzumab Romond et al. N Engl J Med.,
after AC P) not included in joint
analysis. 2005;353:1673.

39. Adjuvant Trastuzumab:
Room to Improve
• Generally well tolerated
• Some patients will still recur
• Intravenous infusion q1-3 wks for one year
• Serious side effect: cardiotoxicity
Study Regimen Symptomatic
CHF
B31/NCCTG AC TH 3.5 – 4.1%
NCCTG AC T  H 2.5%
HERA Chemo  H 0.6%
BCIRG 006 TCH 0.4%
FinHER H  chemo 0%
Piccart-Gephardt, ASCO 2006

40. Early Stage Disease
Hormones Herceptin Chemo
Multiple regimens
Premenopausal Postmenopausal IV
4-6 months
3wkly for 1 year
Alopecia / Mucositis /
Tamoxifen Tamoxifen Cardiac monitoring
Sepsis
Aromatase Inhibitors

41. Locally Advanced Breast Cancer
• Same Treatment but Different
Sequence
• Systemic therapy first (CT/HT)
• Definitive surgery later

42. Metastatic disease: Principles of Treatment
• Hormonal therapy for indolent disease
• Single agent chemotherapy for
aggressive/symptomatic disease or
disease not responding to hormonal
therapy
• Polyagent chemotherapy for visceral crisis
or disease requiring rapid response
• Iv bisphosphonates for bone secondaries

43. Trastuzumab emtansine (T-DM1):
A unique ADC- KADLYCA
DM1
Thioether
Trastuzumab
linker
• The mAb, trastuzumab, is conjugated by a thioether linker to the highly potent
antimicrotubule agent DM1
– Targets HER2-positive tumor cells
Junttila et al. Br Cancer Res 2011

44. T-DM1 MoA:
Binding of T-DM1
• The trastuzumab component of T-DM1 binds to HER2 receptors on the tumor
cell surface
– Leads to downstream signaling inhibition/blockade
Lewis Phillips et al. Cancer Res 2008

45. T-DM1 MoA:
Endocytosis
• HER2 receptor–T-DM1 complex is internalized into the tumor cell via
endocytosis
Erickson et al. Cancer Res 2006

46. T-DM1 MoA:
Lysosomal degradation
• Once endocytosis is complete, trastuzumab and the HER2 receptor are
degraded and a cytotoxic metabolite* is released
*Lysine-bound emtansine plus linker Erickson et al. Cancer Res 2006
Lewis Phillips et al. Cancer Res 2008

47. How Much Breast and
Ovarian Cancer Is Hereditary?
15% 20%
5%–10% ~10%
Breast Cancer Ovarian Cancer
Sporadic
Family clusters
Hereditary
47

48. Features Consistent with
Hereditary Breast/Ovarian Cancer
 Multiple cases of early onset breast cancer
 Ovarian cancer (with family history of breast or
ovarian cancer)
 Breast and ovarian cancer in the same woman
 Bilateral breast cancer
 Ashkenazi Jewish heritage
 Male breast cancer
48

49. Treatment is finished- what now?
• Purpose of follow up:
– Deal with complications of therapy
– Detect recurrence / metastatic disease
– Encourage adherence to anti-hormonal therapy
• How?
– History, Examination & Annual Mammogram
– In asymptomatic women:
» Tumour markers / routine scanning are not
associated with a survival benefit and are not
recommended

50. Metastatic Disease is slightly different…
• Tumour markers may be helpful in making
clinical decisions
• Restaging studies every 3-6 months to
determine progression, sooner if
symptomatic, clinically warranted

51. Lifestyle Modifications
• Obesity increases risk of postmenopausal breast
cancer-Maintain a normal Body mass index
• Evidence suggests that physical activity
decreases risk of breast cancer and risk of
recurrence- Get Active
• Low fat diet decreases risk of breast cancer
recurrence – Balanced Healthy Diet
• Moderate alcohol intake-

52. Breast Cancer Treatment:
Progress and Promise
• Chemotherapy
– Better treatments
– Progress toward targeting only those who will benefit
• Hormonal therapy
– AIs improve outcome in postmenopausal women
– Premenopausal women – optimal hormonal treatment still
unknown
• Targeted therapy
– Trastuzumab decreases risk of recurrence and improves survival
– Promising new agents being studied
• Access and participation in well designed clinical
trials holds the key to further improvements