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Harnessing the Harnessing the Power of GenomicsPower of Genomics

The OncoThe Oncotypetype DX DX®® Breast Cancer Assay for DCIS Breast Cancer Assay for DCIS

Deborah Davison, DNPDeborah Davison, DNPGenomic Health Medical AffairsGenomic Health Medical Affairs

Genomic Health, Inc. – A Commitment to Personalized Cancer Medicine

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Do I needDo I needImmediate Immediate therapy?therapy?

Do I needDo I needchemotherapy?chemotherapy?

Do I needDo I needradiation?radiation?

INVASIVEINVASIVEBREAST CANCERBREAST CANCER

INVASIVEINVASIVEBREAST CANCERBREAST CANCER

DCISDCISBREAST CANCER BREAST CANCER

DCISDCISBREAST CANCER BREAST CANCER PROSTATE CANCER PROSTATE CANCER PROSTATE CANCER PROSTATE CANCER

Do I have Do I have aggressiveaggressivedisease?disease?

STAGE II/IIISTAGE II/IIICOLON CANCERCOLON CANCER

STAGE II/IIISTAGE II/IIICOLON CANCERCOLON CANCER

2004 2011 2010 2013

Answers Key Critical Questions

The Oncotype DX® assay is based on genomic science. While genomics and genetics may sound similar and are related, they focus on different information.

•GENETICS examines the function of a single gene

•GENOMICS examines groups of genes and their relationships in order to identify their combined influence

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Genetics vs. Genomics

For genomic assays, key questions…

• Does the assay provide insight into the biology of the tumor?

• Does the assay provide information that we didn’t already have?

• Is there clinical significance to the result?

• Can I be confident in the result?

Approximately 20% of Approximately 20% of All New Breast Cancers in the US Are DCISAll New Breast Cancers in the US Are DCIS

• Advances in technologies for screening and diagnosis have led to an increase in detection of DCIS

– It is estimated that by 2020, over 1 million women in the US will be living with a diagnosis of DCIS compared to 500,000 in 20051

BUT….

• Methods for assessing risk of local recurrence (LR) and making treatment decisions have not kept pace with diagnostic advances

– Clinical and pathologic factors alone or combined by nomograms rely on population-based estimates of average risk and have not been able to separate which patients have a lower or higher risk of recurrence

61.Allegra et al. J Natl Cancer Inst. 2010.

Pathophysiology

How Do You Make a Treatment Decision for How Do You Make a Treatment Decision for Your Patient with DCIS?Your Patient with DCIS?

1. Ernster et al. J Natl Cancer Inst. 2002. 2. NCCN Guidelines in Breast Cancer. v3.2014. 3. Fisher et al. J Clin Oncol. 1998. 4. Wapnir et al. J Natl Cancer Inst. 2011. 5. Bijker et al. J Clin Oncol. 2006. 6. Emdin et al. Acta Oncol. 2006. 7. McCormick et al. ASCO 2012.

• LR rates with surgery alone range from 15-60% (about 50% are invasive)2

Goals of DCIS therapy are variedGoals of DCIS therapy are varied• Prevention of any LR and particularly an invasive LR is a primary considerationPrevention of any LR and particularly an invasive LR is a primary consideration• Cosmetic outcomes: mastectomy vs. breast conserving surgery (BCS)Cosmetic outcomes: mastectomy vs. breast conserving surgery (BCS)Multiple factors influence treatment decisionsMultiple factors influence treatment decisions• Estimated risk of LR based on clinical and pathologic features• Estimated risk of invasive LR (approximately 50% of recurrences)• Balancing toxicity of therapy for a non-life threatening disease • Patient preference

Treatments include:Treatments include:11

Breast Breast conserving conserving

surgerysurgery

Partial Partial or whole or whole

breast breast radiationradiation

MastectomyMastectomyPreventive Preventive hormonal hormonal therapytherapy

• Radiation therapy reduces LR by 50% but has not been shown to impact overall or disease-free survival3-7

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The OncoThe Oncotypetype DX DX®® Breast Cancer Assay Breast Cancer Assay for DCIS: for DCIS:

A Genomic Risk Stratification ToolA Genomic Risk Stratification Tool

The Oncotype DX® DCIS Assay

What is the test?

•A molecular diagnostic test that helps determine the likelihood of DCIS returning or the tumor returning as invasive breast cancer (local recurrence).

Who is the test for?

•Patients with DCIS (non-invasive) breast cancer (Stage 0) that has not spread to the lymph nodes

Why do the test

•To determine if a patient is at a high risk of local recurrence and whether those recurrences may be invasive

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PRPRKi-67Ki-67STK15STK15

SurvivinSurvivinCyclin B1Cyclin B1

MYBL2MYBL2

GSTM1GSTM1

Beta-actinBeta-actinGAPDHGAPDHRPLPORPLPO

GUSGUSTFRCTFRC

Hormone Receptor GroupProliferation Reference

The DCIS Score result:• Is a continuous variable • Is a quantitative risk assessment (number between 0 – 100)• Reflects each individual patient’s tumor biology

Solin et al. J Natl. Cancer Inst. 2013.

DCIS ScoreDCIS Score™ ™ Result: Gene SelectionResult: Gene Selection

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A Scientific Quote:Sponge Bob Square Pants

Sandy the Squirrel scientifically describes how a laugh is formed to Sponge Bob…

•Sponge Bob: “That sounds painful”

•Sandy: “Science makes everything sound

painful”

Clinical Validation of theClinical Validation of theOncoOncotypetype DX DX®® Breast Cancer Assay Breast Cancer Assay

for DCIS: for DCIS:The ECOG E5194 AnalysisThe ECOG E5194 Analysis

Summary: E5194 Validation of the Summary: E5194 Validation of the OncoOncotype type DXDX®® Breast Cancer Assay for DCIS Breast Cancer Assay for DCIS

• E5194 study validated the DCIS Score™ result as a strong independent predictor of LR risk

– Any (DCIS or invasive) LR

– An invasive LR

• The DCIS Score result quantifies the 10-year risk of LR

– As a continuous variable or a categorical variable by 3 pre-specified risk groups

Solin et al. J Natl Cancer Inst. 2013. 14

E5194: Patient and E5194: Patient and Tumor Characteristics of Analysis CohortTumor Characteristics of Analysis Cohort

Characteristic Number (N=327)

Patient age

Median> 50 yr

61 yrs261 (80%)

Postmenopausal 248 (76%)

Tumor size 7 mm (median)

Tumor size < 10 mm 260 (80%)

Negative margins > 5 mm 214 (65%)

Tamoxifen use 96 (29%)

ER positive (RT-PCR) 318 (97%)

Study cohort:

Cohort 1 (G1/2; ≤2.5 cm) 273 (83%)

Cohort 2 (G3; ≤1.0cm) 54 (17%)

Solin et al. J Natl Cancer Inst. 2013. 15

Solin et al. J Natl Cancer Inst. 2013.

E5194: E5194: Pre-specified Study ObjectivesPre-specified Study Objectives

• Primary– To determine whether there is a significant

association between the DCIS Score™ result and LR risk

• Secondary– To determine whether the DCIS Score result provides

value beyond standard clinical and pathologic factors

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Solin et al. J Natl Cancer Inst. 2013.

The ECOG 5194 study validated the DCIS Score result as a predictor of any LR or an invasive LR

•The DCIS Score result provides greater visibility into the risk of LR based on the underlying tumor biology and separates patients with a lower risk from patients with a higher risk of LR

DCIS ScoreDCIS Score™™ Result: 10-Year Local Recurrence Result: 10-Year Local Recurrence by Risk Group in E5194by Risk Group in E5194

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Any Local Recurrence Invasive Local Recurrence

Solin et al. J Natl Cancer Inst. 2013.

The ECOG E5194 study validated the DCIS Score result as a predictor of LR (increasing DCIS Score corresponds to increasing risk)•Any DCIS or invasive LR•An invasive LR

DCIS ScoreDCIS Score™™ Result: 10-Year Result: 10-Year Local Recurrence in E5194Local Recurrence in E5194

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Any Local Recurrence Invasive Local Recurrence

Hazard Ratio*(95% CI)

P value

Primary (Univariable) Analysis

DCIS Score™ result 2.31 (1.15, 4.49) 0.02

Multivariable Analyses

Excluding the DCIS Score result

Tumor size 1.54 (1.14, 2.02) 0.006

Postmenopausal 0.49 (0.27, 0.90) 0.02

Including the DCIS Score result

DCIS Score result 2.37 (1.14, 4.76) 0.02

Tumor size 1.52 (1.11, 2.01) 0.01

Postmenopausal 0.49 (0.27, 0.90) 0.02*Hazard ratio is for a 50-point difference. For study cohort, surgical margins, grade, comedo necrosis, and DCIS histologic pattern, all p > 0.46. For tamoxifen use, p = 0.09. Since all were not significant, none of these factors were included in the multivariate analyses.

Solin et al. J Natl Cancer Inst. 2013.

The DCIS Score result is a strong independent predictor of LR risk

Risk for Local Recurrence in E5194: Primary and Risk for Local Recurrence in E5194: Primary and Multivariable AnalysesMultivariable Analyses

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Summary: E5194 Validation of the Summary: E5194 Validation of the OncoOncotype type DXDX®® Breast Cancer Assay for DCIS Breast Cancer Assay for DCIS

• E5194 study validated the DCIS Score™ result as a strong independent predictor of LR risk

– Any (DCIS or invasive) LR

– An invasive LR

• The DCIS Score result quantifies the 10-year risk of LR

– As a continuous variable or a categorical variable by 3 pre-specified risk groups

Solin et al. J Natl Cancer Inst. 2013. 20

Second Validation of the OncoSecond Validation of the Oncotypetype DX DX®® Breast Cancer Assay for DCIS: Breast Cancer Assay for DCIS:

The Ontario Provincial The Ontario Provincial DCIS Cohort AnalysisDCIS Cohort Analysis

Clinical Implications: The DCIS ScoreClinical Implications: The DCIS Score™™ Result Result Provides Individualized Risk of Local Recurrence Provides Individualized Risk of Local Recurrence

The second study reconfirms the association of the DCIS Score result with LR as shown in E5194 and provides a strong, independent predictor of LR risk

•Provides a quantitative and individualized estimate of LR risk that goes beyond the risk associated with the traditional clinical and pathologic factors

Oncotype DX® helps patients and physicians better understand their underlying tumor biology and can help guide treatment

decisions by distinguishing low-risk from high-risk DCIS

22Solin et al. J Natl Cancer Inst. 2013. Rakovitch et al. SABCS 2014.

An Observational Patient CohortAn Observational Patient Cohort

• Registry of 5,752 patients with DCIS collected from the Canadian province of Ontario, between 1994 and 2003– 3,795 women with DCIS had BCS with or without XRT (1,658

without XRT)– All cases included in the primary analysis (BCS alone) had

central pathology review

• Analyses were prospectively designed as per standard methods used in the first validation study (E5194)

Rakovitch et al. Breast Cancer Res Treat. 2013. 23

Ontario Cohort Study ObjectivesOntario Cohort Study Objectives

Primary Objective•To evaluate if the DCIS Score™ result is associated with the risk of local recurrence (DCIS or invasive) in patients treated with BCS alone with negative margins (no tumor on ink) and no XRT

– Tested sequentially in ER-positive patients and then in all patients regardless of ER status

Main Secondary Objectives•To evaluate if the DCIS Score result is independently associated with local recurrence adjusting for other clinical and pathologic factors

•To evaluate if the DCIS Score result is associated separately with the risk of DCIS or invasive local recurrence

Rakovitch et al. SABCS 2014. 24

Characteristic N=571

Age Category Median 61 yrs

<50 yrs 110 (19.3%)

≥50 yrs 459 (80.7%)

Subtype Solid 358 (62.7%)

Cribriform 175 (30.6%)

Other 38 (6.7%)

Nuclear Grade Low 55 (9.6%)

Moderate 332 (58.1%)

High 184 (32.2%)

Rakovitch et al. SABCS 2014.

Ontario Cohort: Patient and Tumor Ontario Cohort: Patient and Tumor CharacteristicsCharacteristics

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Characteristic N=571

Comedo Necrosis

Present 350 (61.3%)

Tumor Size Category

≤10 mm 150 (26.3%)

>10 mm 140 (24.5%)

Missing 281 (49.2%)

Multifocality Present 114 (20.0%)

 

ER Status(PCR) Positive 541 (94.7%)

HER2 Status (PCR)

Positive 100 (17.5%)

Primary Analysis: Association of the DCIS Primary Analysis: Association of the DCIS ScoreScore™™ Result and Local Recurrence Risk Result and Local Recurrence Risk

Endpoint1 HR (95% C.I.)* P value*Local recurrence in all patients

2.15 (1.43, 3.22) <0.001

Local recurrence in ER+ DCIS 2.26 (1.41, 3.59) <0.001

1. Rakovitch et al. SABCS 2014. 2. Solin et al. J Natl Cancer Inst. 2013. 26

• The primary analysis showed that the DCIS Score result was a strong predictor of LR in the group of patients that had BCS alone and negative margins, confirming the results of E5194

• The association of the DCIS Score result with LR in the ER+ group was similar to the association in the overall population, indicating that ER status was not a driver of the score

*Cox model HRs for a 50-point difference in the DCIS Score result

• The HR for local recurrence in E5194 was 2.31 (1.15, 4.49)2

DCIS ScoreDCIS Score™™ Result: 10-Year Risk of Any Local Result: 10-Year Risk of Any Local Recurrence by Risk Group in the Ontario Recurrence by Risk Group in the Ontario

Provincial DCIS CohortProvincial DCIS Cohort

Rakovitch et al. SABCS 2014. 27

• The results confirmed the association of the DCIS Score result with LR and stratification of recurrence risk based on underlying biology that is not apparent in the population as a whole

• The proportion of patients within each risk group is also similar to what was observed in the E5194 study with the majority of patients (62%) having a low score

DCIS Score Groups Continuous DCIS Score

DCIS ScoreDCIS Score™™ Result: 10-Year Result: 10-Year InvasiveInvasive or or DCISDCIS Local Recurrence by Risk Group in the Ontario Local Recurrence by Risk Group in the Ontario

Provincial DCIS CohortProvincial DCIS Cohort

Rakovitch et al. SABCS 2014. 28

• As in the E5194 study, this study showed that the DCIS Score result stratifies patients for risk of an invasive LR

• Further, the DCIS Score result was able to stratify patients for risk of a DCIS LR

Invasive Local RecurrenceDCIS Local Recurrence

Multivariable Analysis: The DCIS ScoreMultivariable Analysis: The DCIS Score™™ Result Result Is an Independent Predictor of Local Is an Independent Predictor of Local

RecurrenceRecurrence

Characteristic NHR

(95% C.I.)P value

DCIS Score / 50

5711.68

(1.08, 2.62) 0.02

Age     0.03

≥50 459 1.0  

<50 1101.75

(1.07, 2.76) 

Subtype     0.04

Cribriform 175 1.0  

Solid 3581.63

(0.97, 2.88) 

Rakovitch et al. SABCS 2014. 29

DCIS Score result, tumor size, age, tumor subtype, and multifocality were all independent predictors of LR risk

Characteristic NHR

(95% C.I.)P value

Tumor size 0.01

≤10mm 150 1.0  

>10mm 1402.07

(1.15, 3.83) 

Multifocality     0.003

Absent/unkn

457 1.0

Present 1141.97

(1.27, 3.02) 

DCIS Score™ Result: Comparison of 10-Year Local Recurrence:

ECOG E5194 and Ontario Cohort

Rakovitch et al. SABCS 2014.

The DCIS Score™ result stratifies patients consistently as shown in two separate validation studies

E5194 Ontario Cohort

Clinical Implications: The DCIS ScoreClinical Implications: The DCIS Score™™ Result Result Provides Individualized Risk of Local Recurrence Provides Individualized Risk of Local Recurrence

The second study confirms the association of the DCIS Score result with LR as shown in E5194 and provides a strong, independent predictor of LR risk

•Validated in 898 patients across two studies with consistent results

•Provides a quantitative and individualized estimate of LR risk that goes beyond the risk associated with the traditional clinical and pathologic factors

•Reflects the underlying tumor biology and can help guide treatment decisions by distinguishing low-risk from high-risk DCIS

31Solin et al. J Natl Cancer Inst. 2013. Rakovitch et al. SABCS 2014.

Consistent Risk Stratification by the DCIS ScoreConsistent Risk Stratification by the DCIS Score™™ Result in Patient Cohorts from Validation Studies Result in Patient Cohorts from Validation Studies

and Genomic Health Laboratoryand Genomic Health Laboratory

67.4%

15.3%

17.3%

13.5%

16.2%70.3%

62.2%

21.2%

16.6%

1. Sing et al. ESMO 2014. 2. Solin et al. J Natl Cancer Inst. 2013 3.Rakovitch et al. SABCS 2014. 32

The DCIS ScoreThe DCIS Score™™ Result Provides Result Provides Information Beyond Clinical and Information Beyond Clinical and

Pathologic FactorsPathologic Factors

Comparing risk estimates of the DCIS Score result to Comparing risk estimates of the DCIS Score result to grade, age, size, DCIS pattern, and comedo necrosisgrade, age, size, DCIS pattern, and comedo necrosis

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CAP Nuclear Grade CAP Nuclear Grade

DCIS Score

There Is a Broad Range of DCIS ScoreThere Is a Broad Range of DCIS Score™ ™ Results Results Across Tumor Grade in E5194Across Tumor Grade in E5194

• There was no association between nuclear grade and LR risk• There was a broad range of DCIS Score results across each grade level

Solin et al. J Natl Cancer Inst. 2013.

There is a Broad Range of DCIS ScoreThere is a Broad Range of DCIS Score™™ Results Results Across Clinical and Pathologic Characteristics in Across Clinical and Pathologic Characteristics in

E5194E5194

Solin et al. J Natl Cancer Inst. 2013. 35

Comedo Necrosis

Menopausal StatusDCIS Pattern

Tumor Size

Rakovitch et al. Data on file. 36

There is a Broad Range of DCIS ScoreThere is a Broad Range of DCIS Score™™ Results Results Across Clinical and Pathologic Characteristics in Across Clinical and Pathologic Characteristics in

the Ontario Provincial Cohortthe Ontario Provincial CohortTumor Size

DCIS Pattern

Comedo Necrosis

Absent

Present

Age

The DCIS ScoreThe DCIS Score™™ Result Provides Information Result Provides Information Beyond Clinical and Pathologic FactorsBeyond Clinical and Pathologic Factors

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• Across two validation studies with different patient populations, there was a consistent and broad range of DCIS Score results across clinical and pathologic features

Age, grade, tumor size, comedo necrosis, and DCIS pattern alone cannot predict the DCIS Score result

Solin et al. J Natl Cancer Inst. 2013. Rakovitch et al. SABCS 2014.

Because each clinical or pathologic factor has a range of DCIS Score results, the factors cannot be used as a surrogate or

predictor of the DCIS Score result

Impact of the DCIS ScoreImpact of the DCIS Score™™ Result on Result on Physicians’ Treatment Physicians’ Treatment

RecommendationsRecommendations

A U.S. Multicenter StudyA U.S. Multicenter Study

Study DesignStudy DesignPrimary objective: to estimate the proportion of patients for whom the DCIS Score™ result led to a change in the recommendation for XRT

• Patient meeting study inclusion criteria is enrolled

•Patient characteristics

•Pathology; ER\PR

•Treatment recommendation

• DCIS Score report results

• Treatment recommendation

• Factors affecting physician recommendations

DCIS Score report

• 10 US centers; 115 patients included in the analysis

• Representative of a contemporary patient population

• Majority of patients – post-menopausal, ER+, < 2cm

• Both physician groups represented: 5 Rad Oncs, 5 Surg Oncs

Patient characteristics

Alvarado et al. ASCO 2014.

Prospective Enrollment Collected

Pre-Assay Data Collected

Post-Assay Data

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The DCIS ScoreThe DCIS Score™™ Result Impacts Recommendation Result Impacts Recommendation for XRT by Revealing Underlying Biologyfor XRT by Revealing Underlying Biology

84 (73.0%)68 (59.1%)

31 (27.0%) 47 (40.9%)

Alvarado et al. ASCO 2014. 40

• The DCIS Score result changed the recommendation for XRT 31% of the time (p= 0.008; McNemar’s test)

• This degree of change reflects the impact of the additional information regarding the risk of LR and the individual underlying tumor biology that is not evident with the clinical and pathologic features

Changes in Recommendation for XRT within Changes in Recommendation for XRT within DCIS ScoreDCIS Score™™ Groups Groups

Alvarado et al. ASCO 2014.

Num

ber

of p

atie

nts

XRT Recommendation

Pre-Assay

Pre-Assay

Pre-Assay

Post-Assay

Post-Assay

Post-Assay

Low Intermediate HighDCIS Score Group

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The OncoThe Oncotypetype DX DX®® Breast Cancer Assay Breast Cancer Assay for DCIS Report: A Tool for Shared for DCIS Report: A Tool for Shared

Treatment DecisionsTreatment Decisions

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Clinical Utility of the OncoClinical Utility of the Oncotypetype DX DX®® Breast Cancer Assay for DCISBreast Cancer Assay for DCIS

A Paired Case StudyA Paired Case Study

PATIENT A55-year-old patient with 1.4-cm tumorMenopausal Status: PostmenopausalTumor Type: DCISTumor Size: 1.4 cmER Status (IHC): Positive PR Status (IHC): Positive Histologic Grade: 2General Health: Good

PATIENT B60-year-old patient with 1.6-cm tumorMenopausal Status: PostmenopausalTumor Type: DCISTumor Size: 1.6 cmER Status (IHC): 90% Positive PR Status (IHC): 98% PositiveHistologic Grade: 3General Health: Hypertension, diabetes, morbid obesity

Cases are based on actual patients and are used for illustrative purposes.

Paired Case PresentationPaired Case Presentation

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PATIENT A RESULTSClinical ExperiencePatients with a DCIS Score of 56 had a 22% risk of

any local recurrence and a 12% risk of an invasive

local recurrence.

PATIENT B RESULTSClinical ExperiencePatients with a DCIS Score of 24 had a 13% risk of

any local recurrence and a 6% risk of an invasive

local recurrence.

Paired Case PresentationPaired Case Presentation

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Harnessing the Power of Harnessing the Power of Genomics for Personalized Management of DCISGenomics for Personalized Management of DCIS

The Oncotype DX® Breast Cancer Assay for DCIS is an important advancement in providing an individualized risk of local

recurrence and personalizing treatment for patients with DCIS

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Thank You!

Canadian Cancer Survivor Network Contact Info

Canadian Cancer Survivor Network1750 Courtwood Crescent, Suite 210Ottawa, ON K2C 2B5Telephone / Téléphone : 613-898-1871E-mail jmanthorne@survivornet.ca or mforrest@survivornet.ca Web site www.survivornet.caBlog: http://jackiemanthornescancerblog.blogspot.com/Twitter: @survivornetcaFacebook: www.facebook.com/CanadianSurvivorNet Pinterest: http://pinterest.com/survivornetwork/