The Present and Future of
Genomics in DCIS
On Demand Post-SABCS 2011
Update
Steve Shak, MD
Chief Medical Officer
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Agenda
• Background and Unmet Need
• Algorithm Development for the DCIS
Score™
• Clinical Validation
• Clinical Applications
• Future Research
• Closing Remarks
DCIS Background and Unmet
Need
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DCIS Background
• Ductal carcinoma in situ (DCIS) is a pre‐invasive form of
breast cancer
– ~45,000 new cases in 2010 in the U.S.
• Women diagnosed with DCIS are at risk for local
recurrence, which may be either DCIS or an invasive
breast cancer
• Approximately 70% of women with DCIS are treated with
radiation following surgical excision
• The addition of radiation for DCIS has been shown in
clinical trials to reduce local recurrence risk, but has not
been demonstrated to prolong survival
Viani GA et al. Radiat Oncol 2007; 2:28.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). J Natl Cancer Inst Monogr 2010; 162-177.
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Key Radiation Trials in DCIS
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). J Natl Cancer Inst Monogr 2010; 162-177.
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Unmet Need
• Reliable methods for making treatment decisions based
upon patient specific tumor biology in DCIS have not
been previously established
• There is a need to quantitatively assess the risk of
invasive breast cancer recurrence in newly-diagnosed
patients with DCIS
• There is a significant unmet need for validated tests that
identify:
– low risk disease which may be treated with surgery alone,
avoiding toxicities and costs associated with radiation
– high risk disease for which the addition of radiation may be
considered
Algorithm Development: DCIS
Score™
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DCIS Score™: Gene Selection and
Algorithm Development
•
•
DCIS Score developed from analysis of multiple correlative science studies
Compared gene expression in invasive and DCIS
–
–
•
Analyzed local and distant recurrence risk in published data in invasive breast cancer
(NSABP B-14: randomized trial of tamoxifen vs. placebo in ER+ patients2,3 and Kaiser:
case-control study in ER+ tamoxifen-treated and untreated and ER- untreated patients4)
–
–
–
•
Recurrence Score® tumor biology of invasive breast cancer and DCIS are similar1
Differences seen in the distribution of proliferation genes1
Selected genes that predict local recurrence
Selected genes that predict recurrence risk regardless of tamoxifen treatment
Coefficients selected on multiple considerations from prior breast and colon studies
Scaling and category cutpoints based on analysis of DCIS Score in separate cohort of
DCIS patients
1. Baehner FL et al. San Antonio Breast Cancer Symposium 2008; Abstract 2066. 2. Paik S et al. N Engl J Med. 2004; 2817-2826.
3. Mamounas EP et al. J Clin Oncol. 2009; 1677-1683. 4. Habel LA et al. Breast Cancer Res. 2006; R25.
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DCIS Score™: Gene Selection
Proliferation
Hormone Receptor Group
Reference
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
PR
Beta-actin
GAPDH
RPLPO
GUS
TFRC
GSTM1
DCIS Score:
• Continuous variable
• Number between 0 – 100
Clinical Validation for DCIS
Score™
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DCIS Score™ Pre-specified for
Validation
• All aspects of the study were pre-specified in a
final protocol prior to initiation of sample
processing for the E5194 clinical validation
study. This included:
–
–
–
–
Pre-analytical and analytical methods
Gene coefficients for DCIS Score
Scaling and centering coefficients
DCIS Score risk groups
• Low < 39, Intermediate 39 – 54, High ≥ 55
A QUANTITATIVE MULTIGENE RT-PCR ASSAY FOR
PREDICTING RECURRENCE RISK AFTER SURGICAL
EXCISION ALONE WITHOUT IRRADIATION FOR DUCTAL
CARCINOMA IN SITU (DCIS): A PROSPECTIVE VALIDATION
STUDY OF THE DCIS SCORE FROM ECOG E5194
Solin LJ, Gray R, Baehner FL, Butler S, Badve S, Yoshizawa C,
Shak S, Hughes L, Sledge G, Davidson N, Perez EA, Ingle J,
Sparano J, Wood W
Eastern Cooperative Oncology Group (ECOG)
North Central Cancer Treatment Group (NCCTG)
Genomic Health, Inc (GHI)
2011 San Antonio Breast Cancer Symposium
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ECOG E5194 (PARENT STUDY)
Prospective multicenter study 1997-2000 (n = 670)
Cohort 1: Low/intermediate grade, size < 2.5 cm
Cohort 2: High grade, size < 1 cm
Study treatment
- Surgical excision
- Minimum 3 mm negative margin width
- No radiation
- Tamoxifen option beginning May 2000
Reported outcomes at 5 and 7 years (Hughes, JCO, 2009)
- Currently 10-year outcomes
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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PRESPECIFIED STUDY OBJECTIVES
Primary:
• To determine whether there is a significant
association between the DCIS Score and the risk
of an ipsilateral breast event (IBE)
Secondary:
• To determine whether the DCIS Score provides
value beyond standard clinical and pathologic
factors
Conditional (if DCIS Score validated):
• To evaluate the Recurrence Score as a predictor
of risk of an ipsilateral breast event (IBE)
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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METHODS FOR DCIS SCORE VALIDATION STUDY
Prospective-retrospective study design
Pre-specified: Study objectives, population,
laboratory assays, endpoints, statistical methods
Oncotype DX assay performed (n = 327; 49%)
Standardized methods for 21 gene assay
Central pathology review
Calculated: DCIS Score and Recurrence Score
Study endpoint: Ipsilateral breast events (IBE)
1o Endpoint: Any IBE (DCIS or invasive carcinoma)
2o Endpoints: Invasive IBE
DCIS IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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PATIENT AND TUMOR CHARACTERISTICS
Characteristic*
Number
Patient age
61 years (Median)
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:
273 (83%)
54 (17%)
Cohort 1
Cohort 2
*Similar to parent trial for all variables except for tumor size
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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PRIMARY ANALYSES OF THE RISK FOR AN
IPSILATERAL BREAST EVENT (IBE)
Hazard Ratio*
(95% CI)
P value
Primary Analysis
DCIS Score
Tamoxifen use
2.34 (1.15, 4.59)
0.56 (0.24, 1.15)
0.02
0.12
Conditional Analysis
Recurrence Score
0.70 (0.15, 2.65)
0.62
*Hazard ratio is for a 50 point difference
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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DCIS SCORE: 10-YEAR IPSILATERAL BREAST
EVENTS (IBE) BY RISK GROUP
ANY IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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DCIS SCORE: 10-YEAR IPSILATERAL BREAST
EVENTS (IBE) BY RISK GROUP
ANY IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
INVASIVE IBE
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DCIS SCORE: 10-YEAR RISK OF AN
IPSILATERAL BREAST EVENT (IBE)
ANY IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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DCIS SCORE: 10-YEAR RISK OF AN
IPSILATERAL BREAST EVENT (IBE)
ANY IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
INVASIVE IBE
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MULTIVARIABLE MODELS OF RISK FOR IBE
Hazard Ratio
(95% CI)
P value
Excluding the DCIS Score
Tumor size
Postmenopausal
1.54 (1.14, 2.02)
0.49 (0.27, 0.90)
0.01
0.02
Including the DCIS Score
DCIS Score
Tumor size
Postmenopausal
2.41 (1.15, 4.89)
1.52 (1.11, 2.01)
0.49 (0.27, 0.90)
0.02
0.01
0.02
For study cohort, surgical margins, grade, comedo necrosis, and DCIS pattern,
all p > 0.46. For tamoxifen, p = 0.09.
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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EXPLORATORY ANALYSES OF DCIS SCORE:
CONSISTENT ASSOCIATION ACROSS SUBGROUPS
No.
Overall
327
Pre Menopausal
Post Menopausal
79
248
Lesion Size ≤ 10
Lesion Size > 10
260
67
Negative Margins < 5 mm
Negative Margins ≥ 5 mm
113
214
Low/intermediate Grade
High Grade
216
111
Tamoxifen Treated
Not Treated
96
231
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
2.4
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ASSOCIATION BETWEEN THE DCIS SCORE
AND CLINICAL AND PATHOLOGICAL
CHARACTERISTICS
• For each characteristic (including tumor grade, tumor size,
margin width, patient age, menopausal status), a wide
distribution of DCIS Score values was seen within each
subgroup
• Although lesion size and menopausal status were, as
expected, significantly associated with IBE risk, adjusting
for these characteristics in multivariate models did not
change the estimated association between the DCIS Score
and IBE risk
– This demonstrates that the DCIS Score provided additional
information on IBE risk beyond these characteristics
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SUMMARY: DCIS SCORE
1. Present study validates the DCIS Score as a predictor of
an ipsilateral breast event (IBE) and invasive IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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SUMMARY: DCIS SCORE
1. Present study validates the DCIS Score as a predictor of
an ipsilateral breast event (IBE) and invasive IBE
2. DCIS Score quantifies 10-year risk of IBE
- Continuous variable or 3 risk groups
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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SUMMARY: DCIS SCORE
1. Present study validates the DCIS Score as a predictor of
an ipsilateral breast event (IBE) and invasive IBE
2. DCIS Score quantifies 10-year risk of IBE
- Continuous variable or 3 risk groups
3. DCIS Score provides independent information on IBE risk
beyond clinical and pathologic variables
- Including tamoxifen, grade, and negative margin width
- Identifies underlying tumor biology
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
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SUMMARY: DCIS SCORE
1. Present study validates the DCIS Score as a predictor of
an ipsilateral breast event (IBE) and invasive IBE
2. DCIS Score quantifies 10-year risk of IBE
- Continuous variable or 3 risk groups
3. DCIS Score provides independent information on IBE risk
beyond clinical and pathologic variables
- Including tamoxifen, grade, and negative margin width
- Identifies underlying tumor biology
4. DCIS Score provides a new clinical tool to guide treatment
selection for patients with newly diagnosed DCIS
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
Clinical Applications for DCIS
Score™
The DCIS Score™ Provides
Clinical Insights
• Clinicians and patients desire objective evidence
regarding risk of local recurrence (DCIS or invasive) to
assist in treatment decision-making
– In situations where clinicians and patients are uncertain about
radiation
– In situations where clinical and pathological parameters might
indicate treatment and the patient does not wish to receive
therapy
– In situations where clinicians recommend forgoing therapy and
the patient is not convinced
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DCIS Sample Report: Local
Recurrence
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DCIS Sample Report: Local
Recurrence
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DCIS Sample Report: ER and PR
Scores
Future DCIS Research
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Future Research
• Additional research that provides confirmation and more
experience in certain groups (e.g., higher risk DCIS and
ER negative DCIS)
• Identification of predictive genes for radiation sensitivity
and/or resistance
• Next Generation Sequencing to explore whether new
genes might be identified that actually cause progression
to invasive disease
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Additional Information on DCIS
• The Oncotype DX® Breast Cancer Assay for DCIS
patients will be commercially available starting on
December 28, 2011
• For additional resources on DCIS visit
http://www.oncotypedx.com/enUS/Breast/HealthcareProfessional/DCIS.aspx
• If you have further questions, please contact Customer
Service at customerservice@genomichealth.com or 1866-ONCOTYPE
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Further Education
• In January 2012 you will receive an email blast to
register for our “On Demand Post-SABCS 2011 Update”
summarizing the important developments in breast
cancer
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Closing Remarks
• Oncotype DX® reveals the underlying biology that can
help guide DCIS treatment decisions
• Oncotype DX is the first and only clinically validated
commercial genomic assay for patients with DCIS
• Oncotype DX predicts the risk of any local recurrence
(DCIS or invasive) and the risk of local invasive
carcinoma
• Oncotype DX allows for personalized treatment based
on tumor biology as determined by the DCIS Score™
Thank you