Oncotype DX a Genomic Approach to Breast Cancer

Pathology: 20th and 21st Century

Size

Age

Phenotype

Nodal status

Protein/Gene

“Genomic Profiling”

Role of Traditional Markers in ER+ EBC

• Markers are used to determine diagnosis, estimate prognosis and to inform treatment decisions

• Some markers (tumour grade, nodal status and genomic tests) are prognostic; some are predictive of treatment benefit. Some are both predictive and prognostic (ER, PR, HER2 and Oncotype DX® assay)

• Standardisation and / or reproducibility of a test may present a challenge

• Variability in interpretation of results• Despite the use of many markers, a large proportion of

patients are classified as intermediate risk and there is a population in whom treatment decisions are not clear

Cianfrocca and Goldstein. Oncologist. 2004;9(6):606-616; Lonning PE. Ann Oncol. 2007;18(suppl 8):viii3-viii7

What are Genetics and Genomics?

Genetics • Genes (units of heredity) carry

the instructions for making proteins, which direct the activities of cells and functions of the body

• Study of a single gene, its roles in inheritance and its effects

• Examples of genetic disorders include cystic fibrosis, Huntington's disease, and in oncology; BRCA

Genomics • Study of all of a person's genes

(the genome), interactions of the genes with each other and with the environment

• Study of complex diseases such as heart disease, asthma, diabetes, and cancer because these diseases are typically caused more by a combination of genetic and environmental factors than by individual genes

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Oncotype DX® Breast Test

• It is a genomic test of the expression of 21 genes (16 tumor genes and 5 housekeeping genes)

• Utilizes RT-PCR technology on FFPE tissue

• Quantitatively predicts the likelihood of breast cancer recurrence in women with newly diagnosed, early stage invasive breast cancer

• Assesses the likely benefit from both hormonal therapy and chemotherapy

• Is the only multi-parameter gene expression assay to show clinical utility in breast cancer

• Is recommended by clinical practice guidelines (St Gallen, ESMO, ASCO, NCCN) and NICE

Harris L, et al. J Clin Oncol. 2007;33(25):5287-5312.

NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 2. 2008.

Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed December 8, 2008.

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Oncotype DX® Breast Test Genes

16 CANCER RELATED GENES

Paik 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

The centralisation of the Oncotype DX testing allows >97% reliability

ORDER ENTRY INTAKE PATHOLOGYANALYTICAL

LABORATORYREPORT FULFILLMENT

MATERIAL

RETURN

Order Entry

Benefits Investigation

Patient Information

Retrieval

Specimen

Retrieval

Specimen

Accessioning

Pathology

Review

Histopath

Extraction

Quantitation

gDNA Detection

Reverse Transcription

Results Generation

Billing

Report

Delivery

Materials

Return

Online

QPCR

Online or Fax Phone

Fax Request

FedEX FedEx

The GHI lab has processed >400,000 tests from >70 countries

*Anderson JM et al, 2009.

10-14 working days

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Automation is Central to Laboratory Processes

• Quantifies expression of a panel of genes which is expressed as a Recurrence Score®

• The Recurrencence Score® is a continuous value ranging from 0 to 100; and classifies patients into 3 risk categories:

– Low (<18) – minimal benefit from adjuvant chemotherapy1,2

– Intermediate (18-30) - ?1,2

– High (≥31) - significant benefit from adjuvant chemotherapy1,2

The Oncotype DX® Breast Test Results

1. Paik et al. J Clin Oncol. 2006;,

2. Albain et al. Lancet Oncol 2010

The Precision of the Oncotype DX® Recurrence Score® Defines Individual Biology for ER Positive 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.

LOW RECURRENCE SCORE DISEASE

Indolent

Hormone Therapy Sensitive

Minimal, If Any, Chemotherapy Benefit

Dis

tant

Rec

urre

nce

at 1

0 Ye

ars

Recurrence Score

CONTINUOUS BIOLOGY

HIGH RECURRENCE SCORE DISEASE

Aggressive

Hormone Therapy Insensitive

Large Chemotherapy Benefit

RS 30 = 20% risk of distant

recurrence at 10 years

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.

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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

RS 18-30, n = 149

RS ≥ 31, n = 181

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

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• Objective: Prospectively determine the relationship between Recurrence Score® result and chemotherapy benefit in node-negative, ER+ patients

• 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.

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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 10 120

4.4% absolute benefit from tamoxifen +

chemotherapy

N Events

All patientsTamoxifen + chemotherapyTamoxifen

424227

3331 P = 0.02

RS 18-30Tamoxifen + chemotherapyTamoxifen

8945

94 P = 0.39

RS < 18Tamoxifen + chemotherapyTamoxifen

218135

84 P = 0.61

N Events

RS ≥ 31Tamoxifen + chemotherapyTamoxifen

11747

1318 P < 0.001

PATIENTS WITH HIGH RS

28% absolute benefit from tamoxifen +

chemotherapy

Paik S, et al. J Clin Oncol. 2006;24:3726-3734.14

Clinical Experience Supports Findings from NSABP B-14 and NSABP B-20RS Groups by Patient Age

RS Groups by Tumor Size

RS Groups by Tumor Grade

Liebermann N, et al. ASCO 2011. Abstract 632 (poster presentation).

<50 yrs

(n=367)

≥50 yrs (n=1497)

≤2 cm

(n=1447)

>2 cm

(n=402)

• Small tumors have proportionately fewer high RS values.

• However, there is a range of RS values across both categories of tumor size.

• Not all grade 1 tumors have low RS values.

• Only 31% of grade 3 tumors have high RS values.

Grade 1

(n=277)

Grade 2

(n=964)

Grade 3

(n=289)

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The Oncotype DX® Assay The Only Multi-gene Assay Incorporated into all Major Guidelines to Predict Adjuvant Chemotherapy Benefit

in ER+, HER2- EBC

ASCO® GuidelinesNode negative

NCCN Guidelines®> 0.5 cm, node negative, N1mi

St Gallen Consensus

Node negative, node positive

Quantifies risk of recurrence as a continuous variable and predicts responsiveness to both tamoxifen and

chemotherapy1

Provides not only prognostic but also predictive information regarding the utility of cytotoxic therapy in

addition to endocrine therapy3

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NICE

Node negative

Recommended as an option for guidance of chemotherapy decisions in patients at intermediate risk* of distant

recurrence4

ASCO is a trademark of the American Society of Clinical Oncology. NCCN and NCCN Guidelines are trademarks of the National Comprehensive Cancer Network. The guidelines do not endorse products or therapies.

*Intermediate risk of distant recurrence is defined as NPI score ≥ 3.4 or at intermediate risk by other decision making tools or protocols

Predicts the risk of recurrence and may be used to identify patients likely to benefit from tamoxifen or

chemotherapy2

ESMO

Node negative

Provides additional prognostic and/or predictive information to complement pathology assessment and to

predict response to adjuvant chemotherapy4

1 NCCN Practice Guidelines in Oncology. V.3.2013.

2 Harris L, et al. J Clin Oncol. 2007.

3 Goldhirsch A, et al. Ann Oncol. 2013.

4 NICE Diagnostics Guidance 2013.

Oncotype DX test funding in England

• Recommended by NICE– Oncotype DX is recommended as an option for guiding adjuvant

chemotherapy decisions for people with oestrogen receptor positive (ER+), lymph node negative (LN−) and human epidermal growth factor receptor 2 negative (HER2−) early breast cancer if:

• The person is assessed as being at intermediate risk and• Information on the biological features of the cancer provided by

Oncotype DX is likely to help in predicting the course of the disease and would therefore help when making the decision about prescribing chemotherapy

• Progressing through NHS England, policy document out for comment by 14 March– Intermediate risk defined as an OS benefit of >3% with Predict tool– Registration of patients and collection of information required by NHS England

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Which Patients may Benefit from the Oncotype DX® Test?

Clinical indication NICE guidance

NICE guidance DG10. http://guidance.NICE.org.UK/DG10 Accessed 14 Jan 2014

Use of the Oncotype DX®

breast cancer assay in the

N+ setting validated for

post-menopausal patients

ER: Oestrogen receptor

HER2: Human Epidermal Growth Factor Receptor 2

40.1% Chemo +

Hormonal

Therapies

59.9% Hormonal

Therapy Only

Holt S et al. BJC 2013

Pre-Recurrence Score®

Recommendation

14.1% Chemo +

Hormonal Therapies85.9% Hormonal

Therapy

54.4% Chemo +

Hormonal Therapies

45.6%

Hormonal

Therapy

Treatment Recommendation

with Recurrence Score Report

Analysis based on 142 ER+ N- and N+ (micrometastatic) invasive breast cancer patients

Treatment decision changed in 26.8% of patients after Oncotype DX®

Holt study (n=142), N0,1 ER+, EBC patients

Chemotherapy

No Chemotherapy

Retrospective Budget Impact Analysis on the use of the Oncotype DX test in Ireland

Estimation of real life budget impact associated with use of the Oncotype DX test in Irish clinical practice during the first year of reimbursement (October 2011 - Sept 2012)

Falahee M et al St Gallen Breast Cancer Congress 2013

Number of pts tested and no pts receiving CT

No

of p

ts

Hospitals

• 75% pts tested were not given CT

• All pts with a low RS and 57% pts with an intermediate

RS avoided CT

• In first year of reimbursement, ODX test was

associated with savings of €856,440 to the

chemotherapy budget

Conclusions

• Oncotype DX® is a consistent and effective test that compliments current decision making tools– Recommended in all major international treatment guidelines

• The Recurrence Score® cannot be predicted by standard clinico-pathological data• 31.9% change in treatment recommendations

• Oncotype DX® was shown to be consistently cost effective across different countries and is expected to generate cost savings

Conclusions• Despite the use of traditional markers, a proportion of patients are classified

as intermediate risk and in whom treatment decisions are not clear

• Recurrence Score® results reflects individual tumor biology

• The risk of distant recurrence or chemotherapy benefit can't be accurately predicted by relying on conventional tools alone

• Oncotype DX the only assay that has been demonstrated to be predictive of likelihood of benefit from chemotherapy allowing chemotherapy to be given to those most likely to benefit2,3 (Level I Evidence)

• Only assay incorporated into ASCO®, NCCN® , ESMO, St Gallen and NICE guidelines

• Oncotype DX® was shown to be consistently cost effective across and is expected to generate cost savings

ASCO is a trademark of the American Society of Clinical Oncology and NCCN is a trademark of the National Comprehensive Cancer Network.

ASCO and NCCN do not endorse any therapy or product.

1. Harris L, et al. J Clin Oncol. 2007;33(25):5287-5312. 2. Paik S, et al. J Clin Oncol. 2006;24:3726-3734;, 3. Albain et al. Lancet Oncol 2010; 11: 55 - 65 4. NCCN Practice Guidelines in Oncology. V.3.2013. 5 . Goldhirsch A,

et al. Ann Oncol. 2013. 6. NICE Diagnostics Guidance DG10 2013.

Patient Cases

PATIENT A

68-year-old patient with 1.1-cm tumor

Menopausal Status: Postmenopausal

Tumor Type: Infiltrating Ductal Carcinoma (IDC)

Tumor Size: 1.1 cm

ER Status (IHC): Positive

PR Status (IHC): Positive

HER2/neu Status: Negative

Histologic Grade: 2

Lymph Node Status: Negative

General Health: Fair

______________________________________

CASE SUBMITTED BY:

Victor G. Vogel, MD

PATIENT B

69-year-old patient with 1.3-cm tumor

Menopausal Status: Postmenopausal

Tumor Type: Infiltrating Ductal Carcinoma (IDC)

Tumor Size: 1.3 cm

ER Status (IHC): Positive (2)

PR Status (IHC): Positive (2)

HER2/neu Status: Negative (IHC)

Histologic Grade: 3

Lymph Node Status: Negative

General Health: PS 0

______________________________________

CASE SUBMITTED BY:

Ella Tepper, MD

Can You Guess the Recurrence Score®?68 & 69 year-old patients, small node-negative tumors, grade 2 & 3

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PATIENT B RESULTS

Clinical Experience

Patients with a Recurrence Score of 11 in the clinical validation study had an Average Rate of Distant

Recurrence at 10 years of 7% (95% CI: 5%-10%).

PATIENT A RESULTS

Clinical Experience

Patients with a Recurrence Score of 34 in the clinical validation study had an Average Rate of Distant

Recurrence at 10 years of 23% (95% CI: 18%-28%).

Can You Guess the Recurrence Score®?68 & 69 year-old patients, small node-negative tumors, grade 2 & 3

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PATIENT A

45-year-old patient with 0.9-cm tumor

Menopausal Status: Premenopausal

Tumor Type: Infiltrating Ductal Carcinoma (IDC)

Tumor Size: 0.9 cm

ER Status (IHC): Positive (99%)

PR Status (IHC): Positive (13%)

HER2/neu Status: Negative (1.7 by FISH)

Ki-67: 38%

Histologic Grade: 2

Lymph Node Status: Negative (0/2 SLNs)

______________________________________

CASE SUBMITTED BY:

Barbara Schwartzberg, MD

PATIENT B

46-year-old patient with 0.7-cm tumor

Menopausal Status: Premenopausal

Tumor Type: Infiltrating Ductal Carcinoma (IDC)

Tumor Size: 0.7 cm

ER Status (IHC): Positive (91%)

PR Status (IHC): Positive (99%)

HER2/neu Status: Negative (0.7 by FISH)

Ki-67: 35%

Histologic Grade: 3

Lymph Node Status: Negative

______________________________________

CASE SUBMITTED BY:

Barbara Schwartzberg, MD

Can You Guess the Recurrence Score®?45 & 46 year-old patients, small node-negative tumors, grade 2 & 3

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PATIENT A RESULTS

Clinical Experience

Patients with a Recurrence Score of 15 in the clinical validation study had an Average Rate of Distant

Recurrence at 10 years of 10% (95% CI: 7%-12%).

PATIENT B RESULTS

Clinical Experience

Patients with a Recurrence Score of 35 in the clinical validation study had an Average Rate of Distant

Recurrence at 10 years of 24% (95% CI: 18%-30%).

Can You Guess the Recurrence Score®?45 & 46 year-old patients, small node-negative tumors, grade 2 & 3

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Questions

The Oncotype DX® Report Provides Valuable Information Along a

Continuum of ER+ Breast Cancer

• The Oncotype DX report provides valuable information on:– Node-negative prognosis

– Node-negative predicted chemotherapy benefit

– Quantitative data on ER/PR/HER2

• Node-positive report contains an additional page with prognosis and predicted chemo benefit information specific to node-positive patients

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The Oncotype DX® Breast Cancer Assay• Quantitatively predicts the likelihood of breast cancer recurrence and assesses

the benefit from both hormonal therapy and chemotherapy (Level I Evidence)• High and low Recurrence Score® results reflect different intrinsic tumor biology• You cannot predict the risk of distant recurrence or chemotherapy benefit by relying on

clinical and pathological variables• Changes treatment decisions based on traditional measures 37% of time, sparing

patients the negative health and QOL impact of unnecessary chemotherapy and resulting in cost savings

• Only assay incorporated into ASCO®, NCCN® and St Gallen’s clinical practice guidelines

• Longest history of commercial genomic assays with over 200,000 patients tested worldwide

ASCO is a trademark of the American Society of Clinical Oncology and NCCN is a trademark of the National Comprehensive Cancer Network.

ASCO and NCCN do not endorse any therapy or product.

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