Treatment of Breast Cancer in 2012Where are we now?

Dr Janice WalsheConsultant Medical Oncologist

St Vincent’s University Hospital, Dublin

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”

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3000

3500

4000

4500

500019

95

2000

2005

2010

2015

2020

new

cas

es p

er y

ear

Projected number of Breast Cancers to 2020

0%

1%

2%

3%

4%

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50

19

54

19

58

19

62

19

66

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70

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74

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78

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82

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86

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90

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94

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98

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02

20

06

20

10

20

14

year of death

risk

of

de

ath

fro

m c

an

cer

be

fore

ag

e 7

5 (

%)

Deaths from Breast Cancer 1950-2014

Why?

• Incidence is increasing– Mammographic screening– Environmental Factors

• Mortality is decreasing– Early Detection– Better Treatment Options

Treatment Approach

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

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)

What directs the sequence of the Treatment?

Varies

• Clinical/ pathological stage and subtype of the tumor

• Biological characteristics of the tumor

Staging Breast Cancer

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

Staging Breast Cancer

• Early Stage (Stage I & II)

• Locally Advanced (Stage III)

• Metastatic (Stage IV)

Systemic Therapy Setting & Purpose

Early StageLocally Advanced Metastatic

No evidence of diseaseReduce risk of recurrence

Render inoperable operable

Commence systemic therapy

Reduce risk metastatic disease

Disease control

Early Stage Disease

Hormones Herceptin Chemo Clinical Trial

Hormone positive

HER-2 positive

Risk of recurrence

Access to new therapies

Tumour size / Grade / Age / Co-morbidities

60% 20%

Rationale for Hormone Therapy

• Prevent breast cancer cells from receiving stimulation from endogenous estrogen

Beatson, 1896

Hypothalamus

Gonadotropins(FSH + LH)

Ovary

EstrogensProgesterone

ProlactinGrowth Hormone

Pituitary gland

Premenopausal and Postmenopausal

Adrenal gland

ProgesteroneAndrogensEstrogens

Corticosteroids

Premenopausal

Adrenocorticotropichormone (ACTH)

Estrogen Production in Premenopausal and Postmenopausal Patients

Aromatase inhibitors

Early

Breast Cancer Trialists Group Overview:

Tamoxifen

EBCTCG, Lancet 2005,365: 1687

Side Effects of Tamoxifen

Common side effectsHot flashes

Rare but serious side effectsThromboembolic diseaseEndometrial cancerCataracts

Issues with SSRIs

Hormonal Therapy in Postmenopausal Women

Aromatase Inhibitors- Mechanism of Action

Smith et al., N Engl J Med 348(24):2431-42 2003

DFS includes all deaths as a first event

At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774

Follow-up time (years)

0

5

10

15

20

25

0 1 2 3 4 5 6

Absolute difference: 1.7% 2.4% 2.8% 3.7%

Pat

ien

ts (

%)

Anastrozole (A)

Tamoxifen (T)

HR

0.83

0.87

HR+

95% CI

(0.73–0.94)

(0.78-0.97)

P-value

0.005

0.01ITT

A

424

575

T

497

651

Howell A, et al. Lancet 2005

Recurrence Rate for HR+ Patients

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

Adjuvant Chemotherapy

Progress in Chemotherapy for

Early Stage Breast Cancer Combination chemotherapy (CMF)

Use of anthracyclines

Addition of taxanes

Superior taxane containing regimens

Addition of trastuzumab

1970s

2000s

BUT: ALL chemotherapy is associated with toxicities and risks… need better ways to identify which patients will benefit from treatment

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-)

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

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

RS = + 0.47 x HER2 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

Oncotype DX or Recurrence Score (RS) Assay for patients with ER + LN- disease

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Category RS (0 – 100)Low risk RS < 18Int risk RS ≥ 18 and < 31

High risk RS ≥ 31

0%

5%

10%

15%

20%

25%

30%

35%

40%

0 5 10 15 20 25 30 35 40 45 50

Recurrence Score

Dis

tan

t R

ec

urr

en

ce

at

10

Ye

ars

Low Risk Group High Risk Group Intermediate Risk Group

Recurrence Score as a Continuous Predictor

My RS is 30, What is the chance of recurrence within 10 yrs?

My RS is 30, What is the chance of recurrence within 10 yrs?

95% CI

Oncotype DX™ Clinical Validation: B-14 Results – DRFS

DRFS for the three distinct cohorts identified

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10%

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100%

0 2 4 6 8 10 12 14 16

Years

DR

FS

P <0.00001

Low Risk (RS <18) n = 338

Intermediate Risk (RS 18-30) n = 149

High Risk (RS 31) n = 181

Paik et al. N Engl J Med. 2004;351:2817-2826.

B-14 Benefit of TamoxifenBy Recurrence Score Risk Category

Low Risk (RS<18)N

171142

Int Risk (RS 18-30)N8569

High Risk (RS≥31)1

N9979

Interaction P = 0.06

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210 0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

Paik et al. ASCO 2004. Abstract #510.

1 The results should not be used to indicate that tamoxifen should not be given to the high-risk group

Oncotype Dx: Chemotherapy benefit

• 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

RS < 18 RS 18-30 RS ≥ 31

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

Low R isk Patients (R S < 18) T am + C hemo T am

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

Int Risk (RS 18 - 30) Tam + C hemo Tam

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

H igh R isk Patients (R S 31) T am + C hemo T am

Paik et al, J Clin Oncol. 2006

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

Biological or Targeted Therapy

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)

HER2-normal (HER2-) breast epithelium cell (~20,000 receptors)

HER2-positive breast cancer cell (up to 1-2 million receptors)

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

Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.

Anti-

HER2

Antibodies: Mechanism of

ActionBaselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35.

Noonberg and Benz. Drugs. 2000;59:753.

P

Excessive cell proliferation, survival, and angiogenesis

Potentiation of chemotherapy

Inhibition of tumor cell proliferation

Facilitation of immune function

PP

P PP P P

NSABP B-31/N9831 Joint Analysis: Impact of Adding Trastuzumab to AC Paclitaxel

on Disease-Free Survival*

*N9831 arm B (sequential trastuzumab after ACP) not included in joint analysis.

No. at risk 3351 2379 1455 801 133 0Control 1679 1162 689 374 59 0Trastuzumab 1672 1217 766 427 74 0

0

% S

urv

ivin

g d

isea

se-

free

1 2 3 4 50

50

60

70

80

90

100

Years after randomization

Trastuzumab(133 events)

P<0.0001HR=0.48

Control(261 events)

87.1%85.3%

67.1%

75.4%

Median FU 2.0 y

Romond et al. N Engl J Med., 2005;353:1673.

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

Early Stage Disease

Hormones Herceptin Chemo

Premenopausal Postmenopausal

Tamoxifen Tamoxifen

Aromatase Inhibitors

IV

3wkly for 1 year

Cardiac monitoring

Multiple regimens

4-6 months

Alopecia / Mucositis / Sepsis

Locally Advanced Breast Cancer• Same Treatment but Different Sequence

• Systemic therapy first (CT/HT)

• Definitive surgery later

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

Trastuzumab emtansine (T-DM1): A unique ADC- KADLYCA

• 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

Trastuzumab

DM1

Thioetherlinker

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

T-DM1 MoA: Endocytosis

• HER2 receptor–T-DM1 complex is internalized into the tumor cell via endocytosis

Erickson et al. Cancer Res 2006

T-DM1 MoA: Lysosomal degradation

• Once endocytosis is complete, trastuzumab and the HER2 receptor are degraded and a cytotoxic metabolite* is released

Erickson et al. Cancer Res 2006Lewis Phillips et al. Cancer Res 2008

*Lysine-bound emtansine plus linker

47

How Much Breast and Ovarian Cancer Is Hereditary?

Sporadic

Family clusters

Hereditary

Ovarian CancerBreast Cancer

5%–10% ~10%

15%-20%

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

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

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

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-

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