Download The 12-Gene DCIS Score Assay and Quantative

The 12-gene DCIS Score Assay and Quantitative Gene Expression for ER, PR, and HER2: Experience with 3,947 Patients
Alvarado M,1 Tan V,2 Bailey H,2 Anderson J,2 Rothney M,2 Baehner FL,1,2 Sing AP2
1
University of California, San Francisco, CA; 2Genomic Health, Inc., Redwood City, CA;
Background
Results
• The incidence of ductal carcinoma in situ (DCIS) has increased in recent decades, largely because
of increases in mammography screening.1
• Women diagnosed with DCIS are at risk for local recurrence (LR), which is typically 50% DCIS and
50% invasive carcinoma.2
• Management of DCIS remains controversial.
-- Randomized studies have demonstrated that radiotherapy after excisional surgery reduces local
invasive and non-invasive recurrence rates by approximately 50%, but it has not been demonstrated
to prolong survival.2–12
-- However, some experts argue that DCIS is over-treated without any benefit in patient overall survival,
as there is variability in malignant potential, and not all patients with DCIS will develop invasive
breast cancer.1,13–16
• There is a need for an increased understanding of the biology of DCIS to identify subsets of patients
in which radiation therapy can be omitted, reserving aggressive therapies for those patients at high
risk of progression to invasive disease.
Figure 1. DCIS Histologic Subtypes
Results
Figure 6. Distribution of ER Single Gene Score by DCIS Subtypes
Table 1. Mean DCIS Score Result, ER, PR and HER2
by Age Category
Mean (Range)
HER2
ER
PR
(≥6.5 positive)
(≥5.5 positive)
(≥11.5 positive, 10.7–11.4
equivocal, <10.7 negative)
29 (0–100)
9.7 (3–14)
7.5 (3–12)
9.9 (6–14)
83 (2.1%)
29 (0–90)
9.0 (3–12)
8.0 (3–11)
10.2 (8–14)
40–49
711 (18.0%)
29 (0–100)
9.1 (3–13)
7.8 (3–11)
10.0 (7–14)
50–59
1,079 (27.3%)
30 (0–100)
9.6 (3–13)
7.4 (3–12)
10.0 (6–14)
≥60
2,073 (52.5%)
28 (0–100)
9.9 (3–14)
7.4 (3–11)
9.8 (7–14)
Age Category
All ages
<40
N (%)
DCIS Score Result
3,946 (100%)
• A wide range of DCIS Score results, ER, PR, and HER2 was noted.
• The DCIS Score distribution was similar across age groups (p=0.40).
• The median age of all patients is 60 years with a range of 21 to 94.
• Patients with papillary DCIS had the highest mean ER single gene scores.
• Patients with apocrine DCIS had the lowest mean ER single gene scores.
Figure 7. Distribution of PR Single Gene Score by DCIS Subtypes
Solid DCIS
Cribriform DCIS
DCIS with
comedonecrosis
Papillary DCIS
Table 2. Mean DCIS Score Result, ER, PR and HER2
by Tumor and Surgery Types
Micropapillary DCIS
Mean
• DCIS comprises a heterogeneous group of histopathologic lesions.
-- Several pathologic staging systems have been developed to identify favorable groups of patients,
including nuclear grade, architecture, and presence or absence of necrosis, but none have gained
universal acceptance.17
-- Subtypes based primarily on architectural pattern include solid, cribriform, comedo, papillary, and
micropapillary patterns.
N (%)
Tumor
Type
HER2
DCIS Score Result
ER
PR
(Range)
(≥6.5 positive)
(≥5.5 positive)
(≥11.5 positive, 10.7–11.4
equivocal, <10.7 negative)
Cribriform
1,575 (39.9%)
22 (0–90)
10.0
7.8
9.8
Solid
1,371 (34.7%)
34 (0–100)
9.5
7.2
9.9
Comedonecrosis
462 (11.7%)
47 (0–100)
8.4
6.3
10.3
Papillary
334 (8.5%)
17 (0–90)
10.9
8.6
9.6
• The Oncotype DX® assay for DCIS is the first molecular assay that gives additional independent and
Micropapillary
183 (4.6%)
25 (0–88)
9.4
7.3
10.0
18
individualized estimates of 10-year risk of any LR and invasive LR.
Apocrine
12 (0.3%)
27 (4–53)
7.4
6.0
9.9
• The DCIS Score™ result was clinically validated in a cohort of patients from the ECOG 5194 study
who were selected for observation after surgical excision based on characteristics conferring a low
Excision
2,919 (74%)
29 (0–100)
9.6
7.4
9.8
Surgery
risk of LR.
Type
Core biopsy
1,028 (26%)
29 (0–100)
9.8
7.6
10.0
-- The DCIS Score results showed that in this group of patients, there was a range of scores and
0.3% of patients were classified as DCIS, not otherwise specified
patients who could be categorized at low, intermediate, or high risk of LR based on the biology of
their disease as measured by the expression of 12 of the 21 genes in the Oncotype DX invasive • There was a wide range of mean values for DCIS Score result and single gene expression across
assay (7 cancer related genes and 5 reference genes) (Figure 2).
tumor types:
• Use of the score provides a personalized approach to management of women with DCIS, as it
-- DCIS Score result: 17 (papillary) to 47 (comedonecrosis); ER: 7.4 (apocrine) to 10.9 (papillary);
identifies 1) patients with a lower score for whom surgical excision alone may be adequate and 2)
PR: 6.0 (apocrine) to 8.6 (papillary); HER2: 9.6 (papillary) to 10.3 (comedonecrosis)
patients with a higher score for whom adding treatment after surgical excision should be considered. • There was no meaningful difference in the DCIS Score result and single gene expression based on
surgery type.
• Patients with papillary DCIS had the highest mean PR single gene scores.
• Patients with apocrine DCIS had the lowest mean PR single gene scores.
Figure 8. Correlation Pattern of ER and PR
Single Gene Expression
Figure 9. Correlation of ER and HER2 Single
Gene Expression
• The majority of samples (81.2%) were ERpositive and PR-positive.
• The majority of samples (78.4%) were ERpositive and HER2-negative.
• Very few (approximately 1%) of DCIS cases
were found to be ER-negative and PR-positive.
• Approximately 8.9% of samples were ERnegative and 3.3% were both ER-negative and
HER2-negative.
Figure 2. The DCIS Score 10-year Risk of LR
Figure 4. Distribution of DCIS Score Risk Groups by DCIS Subtype
• A total of 8.4% of DCIS cases were ER-positive
with concurrent elevated levels of HER2
expression.
Objective
Conclusions
• To examine the quantitative expression of the estrogen receptor (ER), progesterone receptor (PR),
Her-2/neu receptor (HER2), and DCIS Score result across clinicopathologic variables (patient age,
specimen type, DCIS subtypes) from submitted patient samples tested in the Genomic Health
laboratory
• The majority of samples submitted were ER/PR-positive and HER2-negative. A wide distribution of
DCIS Score results, quantitative ER and PR was noted.
-- Similar results were observed in the DCIS Score result, ER and PR gene expression between
excisions and cores.
Methods
-- DCIS with comedonecrosis (>50% comedonecrosis) had higher average DCIS Score results
than the other DCIS subtypes.
• A total of 3,947 patient samples from December 2011 through June 2014 that passed pathology
review and RT-PCR quality measures were included.
-- Papillary DCIS had lower average DCIS Score results than the other histologic subtypes.
-- There is no significant difference in DCIS Score results within age groups.
• Strengths: Approximately 4,000 cases of DCIS were analyzed using quantitative RT-PCR from
• Descriptive statistics for the DCIS Score, ER, PR, and HER2 values were obtained.
formalin fixed tissue, all cases were reviewed histologically by board-certified surgical pathologists,
-- Low, intermediate, and high risk categories are defined as DCIS Scores of <39, 39–54, and ≥55, • A wide DCIS Score distribution was observed in all subtypes, although the distribution varied across
RT-PCR is precise and reproducible with a wide dynamic range
respectively.
subtypes.
• Limitations: No long term follow-up for patient outcomes, only one slide per case reviewed, other
-- ER: ≥6.5 is positive
• This figure shows the proportion of scores for each subtype category; for apocrine and other, there
genes not assessed using the DCIS Score assay may be biologically important
-- PR: ≥5.5 is positive
are too few patients for interpretation regarding underlying biology.
• HER2 status in DCIS is an area of controversy. While the HER2 gene group is not included in the
-- HER2: ≥11.5 is positive, 10.7 to 11.4 is equivocal, <10.7 is negative
DCIS Score algorithm, the single gene expression is available. Of the ~4,000 samples processed,
the estimated rate of HER2 positivity is ~13% based on the single gene expression by RT-PCR.
Results
Figure 5. Distribution of DCIS Score Results by DCIS Subtype
Figure 3. Distribution of DCIS Score Groups (n=3,947)
Box plot legend
75th percentile
Median
25th percentile
Mean
Risk Group
DCIS Score <39 (Low)
N
Percent
• In the first two years of availability, there have been almost 4,000 samples sent for a DCIS Score
assay. The distribution of scores is consistent with the clinical validation study (ECOG 5194) and
the decision impact study (Alvarado ASCO 2014),19 with the majority of patients at low risk for local
recurrence. These observations reinforce the utility of the DCIS Score result and underscore the
importance of the underlying biology of the disease.
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Maximum
Minimum
2,660
67.4%
DCIS Score 39–54 (Intermediate)
682
17.3%
3.
DCIS Score ≥55 (High)
605
15.3%
4.
5.
• None of the histologic subtypes had a median score in the high risk category.
• Patients with comedonecrosis type of DCIS (>50% comedo-necrosis) had the highest mean DCIS
Scores.
• The distribution of Recurrence Score results was similar to the distribution observed in the ECOG • Patients with papillary DCIS had the lowest mean DCIS Score results.
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Oncotype DX, Recurrence Score, and Genomic Health are registered trademarks of Genomic Health, Inc.
The authors thank Emily Burke and Kevin Chew for their contributions.