Transcript Comparison - Digital Pathology Association

Quantitative Image Analysis of HER2
Immunohistochemistry Compared with
Manual Pathologist Analysis in Breast Cancer
A Pilot Study
Keith J.Kaplan, MD
Geoffrey L. Turner, MD PhD
Grace E. Kronauer
Northwestern University Feinberg School of Medicine
Johns Hopkins University
Background – HER2
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Human epidermal growth factor
receptor 2 gene ERBB2 (commonly
referred to as HER2) is amplified in
approximately 18% to 20% of breast
cancers.
HER2 overexpression is associated with
clinical outcomes in patients with breast
cancer.
HER2 status is also predictive for
several systemic therapies.
Background
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Several studies have now shown that agents
that target HER2 are remarkably effective in
both the metastatic and adjuvant settings.
Trastuzumab (Herceptin; Genentech, South
San Francisco, CA), a humanized
monoclonal antibody, improves response
rates, time to progression, and even survival
when used alone or added to chemotherapy
in metastatic breast cancer.
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Active as a single agent.
Approve for the treatment of metastatic disease.
Background
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HER2 testing should be routinely
performed in patients with a new diagnosis
of invasive breast cancer. However, the
best method to assess HER2 status, in
regards both to the type of assay used and
the optimal method to perform each assay,
remains controversial.
IHC with reflex of 2+ to FISH
 Overexpression by IHC (3+) or amplification
by FISH considered positive result
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Background
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Several assays have been used for HER2 determination
in tissue. US Food and Drug Administration regulations
also allow pathology laboratories to develop and
implement so called “home brew assays” using US
Food and Drug Administration–approved analyte
specific reagents.
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While some assays have been carefully validated,
others, especially “home brew assays,” have not.
Prospective substudies from two of the adjuvant
randomized trials of trastuzumab versus nil have
demonstrated that approximately 20% of HER2 assays
performed in the field (at the primary treatment site's
pathology department) were incorrect when the same
specimen was re-evaluated.
Background
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Such a disorganized practice and high rate of
inaccuracy, for such an important test that
dictates a critically effective yet potentially
life-threatening and expensive treatment, is
not acceptable.
Trastuzumab therapy is not without its
drawbacks.
Therapy recommended for 12 months
The drug cost of 52 weeks of trastuzumab in
the community setting in the United States is
approximately $100,000 based on average
sales price (www.accc-cancer.org).
Background
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Associated with a small risk of serious cardiac
toxicity.
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Approximately 5% to 15% of patients develop
cardiac dysfunction,
Approximately 1% to 4% develop significant
cardiac events (including symptomatic congestive
heart failure) while taking trastuzumab.
Taken together, the significant benefits
coupled with the high cost and potential
cardiotoxicity of trastuzumab demand
accurate HER2 testing.
Archives of Pathology and Laboratory Medicine: Vol. 131, No. 1, pp. 18–43.
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•Image analysis can be an effective tool for achieving
consistent interpretation. However, a pathologist must confirm
the image analysis result. Image analysis equipment, just as
other laboratory equipment, must be calibrated and subjected
to regular maintenance and internal quality control evaluation.
Image analysis procedures must be validated before
implementation. One issue identified during the panel
discussion was lack of calibration of the optical microscopes
used by pathologists, something which certainly contributes to
interpretive variation. If pathologists use several different
microscopes to read assays, a system of calibration of these
instruments should be implemented to ensure consistent
interpretation.
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Archives of Pathology and Laboratory Medicine: Vol. 131, No. 1, pp. 18–43.
Inconsistency of HER2 Test
Raises Questions
J Natl Cancer Inst 2007;99(14)1064-1065.
The tests that determine who gets the powerful breast
cancer drug trastuzumab (Herceptin) may not be as
reliable as previously thought, researchers reported at the
annual meeting of the American Society of Clinical
Oncology. That means some women who should be
getting trastuzumab treatment are not, while
other women who will not benefit are unnecessarily
exposed to a drug that can cause heart problems.
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Study Design
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Retrospectively reviewed 81 (81/122) breast
cancers newly diagnosed within 2006 and
tested for HER2 by IHC with reflex FISH
testing in equivocal (2+) cases (majority)
LIS searched for “FISH” and “HER2” in 2006
Whole slide scanned using ScanScope and
analyzed using membrane stain algorithm
provided
Algorithms not “calibrated” or “standardized”
to our laboratory.
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Slides not re-reviewed or IHCs re-scored
Non-sequential cases from 10 pathologists
Home-brewed assay
MA – 1+
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FISH non-amplified
IA – 0
MA – 2+
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FISH non-amplified
IA – 1+
MA – 2+
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FISH non-amplified
IA – 1+
MA – 2+
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FISH non-amplified
IA – 1+
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DB
MA – 3+
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FISH non-amplified
IA – 3+
MA – 3+
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FISH amplified
IA – 3+
Results
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IA more accurate than MA
68% (55/81)
 IA 1+ compared with MA 2+ IHC
 FISH non-amplified in all cases
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MA more accurate than IA
15% (12/81)
 8/12 overscored 3+ IHC (1+ IHC MA)
 8/8 FISH non-amplified
 4/12 underscored 1+ IHC (3+ IHC MA)
 3/4 FISH amplified
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IA equivalent to MA
17% (14/81)
 1+ to 3+ with majority (8/14) as 2+ IHC
Results
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Scan time on order of a few minutes
Processing time on order of 15 minutes
for whole slide
2 slides unable to be scanned
Extra resources needed to incorporate
into workflow
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Retrieval of material, scanning, processing,
analyzing and reporting
Caveats
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Cases signed out prior to guidelines in
2007
Home-brewed assay used for IHC
Using FISH as gold standard rather than
outcome
Low threshold for calling indeterminate
Conclusions
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IA appears to be more accurate than MA in HER2
IHC, particularly for 2+ cases (FISH nonamplified)
Algorithms appeared to overscore or underscore
a minority of cases, particularly 1+ IHC cases
(FISH non-amplified)
Pilot study suggests a role for IA in 2+ cases to
avoid unnecessary FISH testing in overscored
cases
Cost and time required for WSI analysis may still
be prohibitive for routine clinical use without
added resources in the laboratory for IA.
IA Workstation
Office
Molecular
Order HER2
Perform IA
Perform FISH?
Transcribe
Results
Sign out case
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Conclusions
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CPT 88360 – Morphometric analysis, tumor
immunohistochemistry (eg, Her2/neu,
estrogen/progesterone receptor), quantitative,
semiquantitative, each antibody; manual
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CPT 88361 – Morphometric analysis, tumor
immunohistochemistry (eg, Her2/neu,
estrogen/progesterone receptor), quantitative,
semiquantitative, each antibody; using computer
assisted technology
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PC+TC=$147.95
88361 PC+TC=$229.16 Δ(TC+PC)=$81.21
HER2 FISH
 88368 PC+TC=$710.00
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Acknowledgments
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Aperio Technologies, Inc.
Laura Nottoli, Craig Fenstermaker,
Holger Lange
Grace Kronauer
Geoffrey Turner MD PhD
Tracy Roberts
Thank You
www.tissuepathology.com
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