How molecular diagnostics & targeted therapies have revolutionized treatment in Breast Cancers

Roger KC Ngan

COS, Department of Clinical Oncology, Queen Elizabeth Hospital

Director, Hong Kong Cancer Registry 1

Talk schema

• An overview of breast cancers in Hong Kong

• Paradigm shifts in prescribing systemic therapies for early breast cancers – from clinical to molecular and genomic diagnostics

• Revised algorithms of treatment in advanced breast cancers with novel targeted therapies

• Conclusions 2

Hong Kong Cancer statistics 2012

27%

14%

3

70%

41%

4

Leading female cancer in Hong Kong

• Commonest female cancer • Commonest cancer in females from 20 - 74

• Over 3,500 new cases and 600 deaths in 2012

• Most common in middle-aged women

• median age at diagnosis: 54 yr • median age at death: 59 yr

Projection of breast cancer incidence

Site Model(1) 2012 actual

2020 projected

2030 Projected (95%PI)(2)

% chg(3) (vs 2012)

Projected no. by stage in 2030(4)

I II III IV

Female breast 3 3,508 4,580 6,000 (5,720-6,270) +71 2,110 2,440 1,020 430

(1) Model used for projections as described in the Methods; (2) 95% PI = 95% prediction interval; (3) % chg = total % change in numbers compared with the 2011 actual

figures; (4) Stratified according to stage at diagnosis captured between 2010 and 2012. Unstaged cases were excluded in the calculation of distribution of stage.

Note: Poisson regression modeling was used to fit to the observed age-specific incidence rates using data from 1983 to 2012 and population projections and to estimate the projected number up to 2030.

Projection

5

2030

6

Female breast cancer statistics worldwide: Estimated age-standardized incidence and mortality rates in 2012

Country/City Incidence (per 100,000)

Mortality (per 100,000)

Japan 51.5 9.8

South Korea 52.1 6.1

Hong Kong 56.7 8.6

Singapore 65.7 15.5

Canada 79.8 13.9

Australia 86.0 14.0

Germany 91.6 15.5

USA 92.9 14.9

United Kingdom 95.0 17.1 Source: Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 27/02/2015.

Trends in breast cancer mortality in HK

APC= -0.1 (p=0.25)

7

8

Relative survival rates of Breast cancer patients, 1997-2001

Annals of Surgery 2011

9

Relative survival* (%) by Stage, 1997-2006

No. 1-yr 2-yr 3-yr 4-yr 5-yr 6-yr 7-yr

Overall 18,110 97.5 94.0 90.8 87.8 85.6 83.3 81.9

Stage I 4,485 99.9 99.7 99 98.3 97.8 97.1 96.4

Stage II 7,858 99.7 98 95.5 92.8 90.4 87.9 86.2

Stage III 2,402 96.8 88.8 81.2 74.9 70.4 65.9 62.5

Stage IV 971 66.0 45.6 32.2 25.7 20.6 17.8 16.4

Unknown

stage 2,394 94.5 89.6 86.4 82.6 80.2 78.1 77.2

* Maximum likelihood approach was used to estimate relative survival in all calculations.

Source: Hong Kong Cancer Registry, Hospital Authority

10

Relative survival (%) by receptor, 1997-2006

ER No. 1-yr 2-yr 3-yr 4-yr 5-yr 6-yr 7-yr

Positive 10,697 99.1 97.7 95.4 93.1 90.7 88.5 86.5

Negative 4,661 96 88.3 82.9 78.8 76.5 74.3 73.3

PR

Positive 8,386 99.3 98.2 96.1 94 92.3 90.3 88.4

Negative 6,760 96.6 90.5 85.9 82.1 79.2 76.7 75.3

Her-2

Positive 3,452 97.1 92.3 88.2 84.6 81.4 78.1 75.7

Negative 8,757 98.5 96.3 93.7 91.2 89.2 87.0 85.8

+14%

+8%

Strategies of systemic treatment for early breast cancers

Who to receive what – hormones, chemotherapy, targeted therapy?

11

BREAST CANCER－5-year survival as function of the

number of positive axillary lymph nodes

0%

20%

40%

60%

80%

5-Y

ea

r S

urv

iva

l

0 1 2 3 4 5 6-10 11-15 16-20 >20

Number of Positive Nodes Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557-1616.

high

risk

very high

risk

low

intermediate

risk

Heterogeneity in Breast Cancer

Evolution of selection criteria for adjuvant systemic therapy in early breast cancers

15

TNM

Grade

• Clinical & histopathology parameters

ER, PR, cerbB2

• Immunohistochemistry

• Molecular diagnostics

RS, ROR

BRCA

• Genomic tests

• Genetic tests

Adjuvant online!

Tumors

Cells

Genes

Nottingham prognostic index (UK): • T size • histological grade • axillary node+ number

Early Breast Cancer Trialist Collaborative Group Lancet. 2011; 378: 771–784.

Recurrence: All ER+, 13%^

BC mortality: All ER+, 9%^

Lancet 2008; 371: 29–40

Adjuvant chemotherapy in estrogen-receptor-poor breast cancer:

5872 patient-level meta-analysis of randomised trials

Recurrence 9-12%^ 10yr

Breast cancer mortality 6-9%^ 10 yr

Heterogeneity in Breast Cancer

The methodology for calculation of the Allred score for hormone receptors

Kingshuk Roy Choudhury et al. J Histochem Cytochem 2010;58:95-107

Copyright © by The Histochemical Society

clinicaloptions.com/oncology

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

HER2 Overexpression Shortens Survival

HER2 oncogene amplification

HER2 oncoprotein

overexpression

Shortened survival Median Survival From First Diagnosis

HER2 overexpressing 3 yrs

HER2 normal 6-7 yrs Slamon DJ, et al. Science. 1987;235:177-182.

Slamon DJ, et al. Science. 1989;244:707-712.

HER-2 testing by protein or gene expression

2013 Update on HER2 Testing: ASCO/CAP Guidelines

All newly diagnosed BC patients must have a HER2 test performed

HER2 is positive if:

IHC 3+ with complete, intense circumferential membrane staining (for protein)

ISH (in-situ hybridization) positive (for gene) Single probe average HER2 copy number > 6 signals/cell

Dual probe HER2/CEP17 ratio > 2.0 with average HER2 copy number > 4 or < 4 signals/cell

Dual probe HER2/CEP17 ratio < 2.0 with average HER2 copy number > 6 signals/cell

Wolff et al, JCO 2013

KLINIK UND POLIKLINIK

FÜ R FRAUENHEILKUNDE UND GEBURTSHILFE

KLINIKUM DER UNIVERSITÄ T MÜ NCHEN®

ER and or PR + Her2 -

ER, PR and HER2 - Her2 +

TNM (size; nodal status) Grading Molecular tests: • uPA/PAI-1 • Gen-Tests • Ki-67

High risk Low risk

Chemotherapy + AHT

Chemotherapy AHT

Chemotherapy + Trastuzumab +/- AHT

Harbeck, Salem, Gluz et al, 2010

ADJUVANT RX ALGORITHM

26

clinicaloptions.com/oncology

New Directions in the Treatment of Patients With HER2-Positive Breast Cancer

Normal (1x) ~ 25,000-50,000 HER2

receptors

Overexpressed HER2 (10-100x)

up to ~ 2,000,000 HER2 receptors

Excessive cellular division

HER2 Overexpression in Breast Cancer

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75.

Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71.

Slamon DJ, et al. Science. 1987;235:177-182.

HER2 is overexpressed in

~ 25% of breast cancers

ErbB / HER receptors in breast cancer

Ligands

ErbB1 ErbB3 ErbB4

Differentiation Cell cycle progression, proliferation,

survival, apoptosis

ErbB2

Tumour

cell membrane

1. Huang et al. Cancer Res 2010; 70:1204–1214; 2. Rowinsky. Ann Rev Med 2004; 55:433–457

Signaling activity

+ + + + + + + + + + +

HER2 is the preferred dimerization partner for all HER family members and can form homodimers and heterodimers1

This activates multiple signaling pathways, producing mitogenic effects on cells2

HER2 Containing Dimers Induce Potent Mitogenic Signaling

HER1:HER2 HER2:HER2 HER2:HER3 HER2:HER4

Mechanism & sites of action of targeted agents in

ErbB2+ breast cancer

VEGF

Ligands

ErbB1

Lapatinib inhibits ErbB1 and

B2 phosphorylation; neratinib inhibits ErbB1, B2 and B4(?)

phosphorylation

ErbB3 ErbB4 VEGFR

Angiogenesis Differentiation Cell cycle progression, proliferation,

survival, apoptosis

ErbB2

Pertuzumab blocks ErbB2/3

interaction Bevacizumab

blocks VEGF

interaction

with receptor

Endothelial

cell membrane

Tumour

cell membrane

Trastuzumab blocks ErbB2

activation

Adjuvant Trastuzumab studies

• 4 large randomized phase III studies

• All showed reduced recurrences (6 – 16%) and improved survivals (8%)

31

Study Treatments DFS RR reduction

Overall survival

HERA Chemo-H vs chemo

86% at 2yr (vs 78%)

46%

BCIRG 006

TCH/AC-TH vs AC-T

86-88% at 3yr (vs 82%)

33-40%

B31/N9831 (joint analysis)

AC-TH vs AC-T

87% at 3.5yr (vs 71%)

52%

87% at 8.3yr (vs 79%)

H=herceptin AC=adriamycin +cyclophospamide

T=paclitaxel TC=docetaxel +carboplatin

8% gain

無病存活率

Adjuvant Lapatinib (ALTTO) Schema

HER2+

ESBC

+ Trastuzumab X 1 year

+ Lapatinib X 1 year

+ Trastuzumab + Lapatinib X 1 year

+ Trastuzumab X 3 months →

Lapatinib X 9 months

Treatment arms after chemotherapy:

Piccart & Perez,

34

TCa = 6 cycles of docetaxel and carboplatin

Completed recruitment

on 31-Aug-2013

APHINITY ADJUVANT TRIAL (n=4805)

node negative

Biologic Heterogeneity – „intrinsic" subtypes

Sorlie et al., PNAS, 2001; 100: 10869-74

“Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications“

Survival months

RFS

Therapeutic recommendations in breast cancer

Harbeck Dtsch Med Wochenschrift, 2013; 138: 180-2

Luminal A Luminal B Intrinsic subtype

Clinical

classification

Therapeutic

recommendation

Basal-like Her2+

Endocrine

therapy

Chemotherapy

endocrine

Chemo-

therapy

Trastuzumab +

chemotherapy ±

Endocrine therapy

ER and PR

positive

Proliferation

(Ki-67) low

Recurrence

risk low

Chemotherapy (preferably

neoadjuvant)

ER a/o PR

positive ER and PR

and Her2

negative

Her2 positive

Proliferation

(Ki-67) high

Recurrence

risk high

Wissenstransfer in klinische Testsysteme, Prosigna™

2000

Researchers first describe

breast cancer intrinsic subtypes

based on microarray

experiments

2009

Researchers first describe

“PAM50” gene expression

signature

2010

NanoString exclusively licenses

PAM50 gene expression

signature

2012/13

Prosigna launches

after receiving CE

Mark for Europe &

Israel; FDA 510k

clearance in US

Perou et al., Molecular Portraits of Human Breast Tumors. Nature 2000; 406: 747-52

Parker et al., Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes, JCO 2009; 27: 1160-7

8192 genes 50 genes

Distribution of breast cancer intrinsic subtypes from PAM50 assay in a population-based cohort by race and ethnicity, LACE and Pathways studies.

Carol Sweeney et al. Cancer Epidemiol Biomarkers Prev 2014;23:714-724

© 2014 by American Association for Cancer Research

TransATAC & ABCSG-8 trials

• 1786 node-neg & 688 node+ (>2400)

• postmenopausal women with early-stage, HR+ breast cancer who

received 5 years of endocrine therapy after surgical resection of the

primary tumor

• The results of the validation studies constitute Level 1 evidence for

clinical validity of the Prosigna test for predicting the risk of distant

recurrence in postmenopausal women with HR+ BC

ROR (Risk of Recurrence) Score (Tumor size + nodal status)

Prosigna (PAM50) ROR Scoring

The Oncotype DX Recurrence Score® Result

uses Key Genes Linked to Critical Molecular Pathways

16 BREAST CANCER RELATED GENES

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

ER

PR

Bcl2

SCUBE2

GRB7

HER2

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

Stromelysin 3

Cathepsin L2 GSTM1

CD68

BAG1

Beta-actin GAPDH RPLPO GUS TFRC

5 REFERENCE GENES

Estrogen Proliferation HER2 Invasion Others

43

The Recurrence Score® Result Assesses

Individual Tumor Biology for ER+ Breast Cancer

Paik S, et al. N Engl J Med. 2004;351:2817; Paik S, et al. J Clin Oncol. 2006;24:3726; Habel LA, et al. Breast Cancer Res. 2006;8:R25-R39.

Dis

tan

t re

curr

en

ce a

t 1

0 y

ear

s

Recurrence Score value

CONTINUOUS BIOLOGY 4 0 %

3 5 %

3 0 %

2 5 %

2 0 %

1 5 %

1 0 %

5 %

0 % 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0

LOW RECURRENCE SCORE DISEASE Indolent

Hormone therapy-sensitive Minimal, if any, chemotherapy benefit

HIGH RECURRENCE SCORE DISEASE Aggressive

Less sensitive to hormone therapy Large chemotherapy benefit

44

Oncotype DX® Clinical Validation: NSABP B-14

• Objective: Prospectively validate the Recurrence Score® result as a predictor of distant recurrence in node-negative, ER+ patients

• Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan

Randomized

Registered

Placebo—not eligible

Tamoxifen—eligible

Tamoxifen—eligible

Paik S, et al. N Engl J Med. 2004;351:2817-2826. 45

Oncotype DX® Clinical Validation:

NSABP B-14, Distant Recurrence

Distant recurrence over time

10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6%

0 2 4 6 8 10 12 14 16

Years

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

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pro

po

rtio

n w

ith

ou

t d

ista

nt

recu

rren

ce

RS < 18, n = 338; 51%

RS 18-30, n = 149; 22%

RS ≥ 31, n = 181; 27%

All Patients, n = 668

P < 0.001

10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3%

10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4%

*10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001

RS, Recurrence Score® result

46

• Objective: Prospectively determine the magnitude of chemotherapy

benefit in node-negative, ER+ patients as a function of Recurrence

Score® result

• Multicenter study with prespecified 21-gene assay, algorithm,

endpoints, analysis plan

Tam

Oncotype DX® Clinical Validation: NSABP B-20

Randomized

Tam + MF

Tam + CMF

Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 47

High Recurrence Score® Result Correlates with

Greater Benefit from Chemotherapy (NSABP B-20)

RS, Recurrence Score result

Pro

po

rtio

n w

ith

ou

t d

ista

nt

recu

rren

ce

Years

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

2 4 6 8 10 12 0

4.4% absolute benefit

from tamoxifen +

chemotherapy

N Events

All patients Tamoxifen + chemotherapy

Tamoxifen

424

227

33

31 P = 0.02

RS 18-30 Tamoxifen + chemotherapy

Tamoxifen

89

45

9

4 P = 0.39

RS < 18 Tamoxifen + chemotherapy

Tamoxifen

218

135

8

4 P = 0.61

N Events

RS ≥ 31 Tamoxifen + chemotherapy

Tamoxifen

117

47

13

18 P < 0.001

PATIENTS WITH HIGH RS

28% absolute benefit from

tamoxifen + chemotherapy

Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 48

Meta-Analysis: Overall Impact of

Recurrence Score® on Treatment Decisions

52% 48% 88% 12%

Treatment plan prior to Oncotype DX®

Treatment plan after RS

Treatment plan after RS

CT + HT

HT

Overall, the RS led to a 37% change in treatment decisions • 33% from CT + HT HT • 4% from HT CT + HT

4% change 33% change

Hornberger J, et al. SABCS 2010. Poster P2-09-06.

RS, Recurrence Score result

49

2014 ESMO poster

Schema: TAILORx Study Design

Node-Neg, ER-Pos Breast Cancer

RS < 11 Hormone Therapy Registry

RS 11-25 Randomize

Hormone Rx vs.

Chemotherapy + Hormone Rx

RS >25 Chemotherapy

+ Hormone Rx

Oncotype DX® Assay Register

Specimen banking

Primary study group

Objective: Determine whether adjuvant hormonal therapy is not inferior to adjuvant chemohormonal Rx for patients in the “primary study group” (RS 11-25)

51

S1007: RxPONDER Trial Schema and Patient Flow

Node-positive (1-3 nodes)

HR-positive and HER2-negative RS < 25

RECURRENCE

SCORE

(N= 3,800)

Discuss alternative trials

for high risk patients

N= 5,600

Physician and patients

discuss randomization

knowing the RS

N= 2,000

Chemotherapy;

appropriate endocrine

therapy

N= 2,000

No Chemotherapy;

appropriate endocrine

therapy

STEP 2

REGISTRATION/

RANDOMIZATION

N= 4,000

Randomization

stratified by

1. RS

0-13 vs. 14-25

2. Menopausal status

3. Axillary node

dissection vs.

Sentinel node

biopsy

RS > 25 RS < 25

BRCA carriers – management strategies

• Optimal surgery is bilateral mastectomy – extended surgery benefits mortality reduction in second decade

• Risk of 2nd BC in contral breast 28-36% at 15 yrs

• 20 year mortality 26 – 30%

• Oophorectomy prevents recurrence, death, ovarian cancer, second 1y breast cancer

• Chemotherapy needed even for small node negative cancers

• Chemotherapy – more data on cisplatin needed to confirm the high 60% pCR rate in neoadjuvant series

• Combination of cisplatin and oophorectomy 53

Conclusions

• Translational & clinical research have helped to advance targeted therapeutics for early and advanced breast cancers

• Validated evidence exists to support incorporation of molecular and genomic diagnostics into treatment decision algorithms in early breast cancers for adjuvant targeted therapy and chemotherapy

• sparing treatment resources & toxicities

• Novel targeted therapies for both HER+ or HER-/HR+ diseases have revolutionized treatment strategies and improved patient outcomes

54

Systemic therapy for advanced recurrent or metastatic HER2+ breast cancers

When to give what – hormones, chemotherapy, targeted therapy?

55

1st line

2nd line

Metastatic or Recurrent HER2+ disease

ADC

• ADCs consist of:

– monoclonal antibody that targets receptors

– stable linker

– potent cytotoxic agent

• ADCs target tumour cells to deliver the cytotoxic specifically to cancer cells

– ADCs minimises the effects on normal tissue

– reduces cytotoxic side effects

T-DM1 is a novel Antibody-Drug-Conjugate (ADC) for HER2-positive metastatic breast cancer

Gerber et al. mAbs 2009.

Linker

DM1

Trastuzumab

Trastuzumab Emtansine (T-DM1): Mechanism of Action

Emtansine

release

Inhibition of

microtubule

polymerization

Internalization

HER2

Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

T-DM1

Lysosome

Nucleus

P P

P

Trastuzumab-specific MOA

• Antibody-dependent cellular

cytotoxicity (ADCC)

• Inhibition of HER2 signaling

• Inhibition of HER2 shedding

EMILIA Study Design

1:1

HER2+ (central)

LABC or MBC

(N=980)

• Prior taxane and

trastuzumab

• Progression on

metastatic tx or

within 6 mos of

adjuvant tx

PD

T-DM1 3.6 mg/kg q3w IV

Capecitabine

1000 mg/m2 orally bid, days 1–14, q3w

+

Lapatinib 1250 mg/day orally qd

PD

Verma et al , NEJM 2012

2nd line therapy for HER2+ MBC

6m median OS &

13% 2yr OS gain

Overall Survival: Confirmatory Analysis

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4

495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + Lap

T-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

urv

ivin

g

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of events

Cap + Lap 25.1 182

T-DM1 30.9 149

Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

Efficacy stopping boundary P=0.0037 or HR=0.727

Systemic therapy for advanced recurrent or metastatic HER2-/HR+ breast cancers

When to give what – hormones, chemotherapy, targeted therapy?

61

Conclusions

• Translational & clinical research have helped to advance targeted therapeutics for early and advanced breast cancers

• Validated evidence exists to support incorporation of molecular and genomic diagnostics into treatment decision algorithms in early breast cancers for adjuvant targeted therapy and chemotherapy

• sparing treatment resources & toxicities

• Novel targeted therapies for both HER+ or HER-/HR+ diseases have revolutionized treatment strategies and improved patient outcomes

62