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Robbins pathologic basis of disease 8th ed
IARC Press 2012
GOALS
- IN SITU AND INVASIVE CARCINOMA
- SIGNIFICANCE OF ER/PR AND HER2
- MOLECULAR TESTING IN THE MANAGEMENT OF PATIENTS WITH BREAST CANCER
Ductal Carcinoma in Situ (DCIS)
• Definition – ‘ proliferation of malignant epithelial cells that has not breached the myoepithelial layer of the ductolobular system’– Highly heterogeneous
• Presentation
• Morphology
• Biomarker expression
• Underlying cytogenetic alterations
• Natural progression
Classification of DCIS
• Grade
– G1, G2, G3
– Necrosis
– Morphologic variants
• DCIS with microinvasion
Differential dx
• Atypical ductal hyperplasia (ADH) and low grade DCIS
• Solid low grade DCIS and lobular carcinoma in situ (LCIS)
• High grade DCIS and pleomorphic lobular carcinoma in situ (PLCIS)
• DCIS with microinvasion
Robbins pathologic basis of disease 8th ed.
Robbins Pathologic basis of disease 8th ed.
Molecular testing of breast cancersBeyond hormone receptor and Her2
status
• Intrinsic (molecular) subtypes
• Multigene prognostic test
Breast Cancer
Estrogen Receptor
Negative
Estrogen Receptor
Positive
Basal-like HER2 Enriched Luminal B Luminal A
Other: Molecular apocrine, Claudin low
2000’s
Do the intrinsic subtypes have value in current clinical practice?
• “The 12th St Gallen international Breast Cancer Conference (2011) expert panel adopted a new approach to the classification of patients for therapeutic purposes based on the recognition of intrinsic biological subtypes with the breast cancer spectrum”
• “… in the clincal practice the key question is not the seperation fo the molecularly-defined intrinsic subtypes, but the discrimination between patients who will or will not benefit from particular therapies”
Coates 2015
St Gallen 2015
Molecular diagnostics
• Oncotype DX
• PAM 50
• MammaPrint
NEJM 2004;351:2817
•668 ER+, N- patients enrolled
in NSABP B14
•RT-PCR assay on paraffin
sections (21 genes)
RS = +0.47 x HER2 group score
-0.34 x ER group score
+1.04 x proliferation group score
+0.10 x invasion group score
+0.05 x CD68
-0.08 x GSMT1
-0.07 x BAG1
<18 Low
18-31 Intermediate
>31 High
OncotypeDx
(Genomic Health, Inc.)
Oncotype DX
• Predicts the probability of distant recurrence in node negative patients treated with tamoxifen, and in those with ER+ breast cancer
– High
– Intermediate
– Low risk
0%
5%
10%
15%
20%
25%
30%
35%
40%
0 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Dis
tan
t R
ec
urr
en
ce
at
10
Ye
ars
Low-Risk Group High-Risk Group Intermediate-
Risk Group
Oncotype DX® Clinical Validation:
RS as Continuous Predictor
My RS is 30. What is the chance of recurrence within 10 years?
What is the impact of RS on clinical decision making?
Breast Cancer Res Treat, 2013
•8 studies
•1437 pts
Immunophenotyping to Approximate Molecular Subtype Using
Three Markers Brenton, 2005
Luminal A Luminal B HER2 Basal-like
ER + + - -
PR + + - -
HER2 - + + -
• Strongly endocrine responsive, low proliferation, good prognosis “luminal A- like” can be distinguished from less endocrine responsive, higher proliferation, poorer prognosis “luminal B like” tumors using IHC assays for ER, PR and Ki67
• But, use of KI67 requires knowledge of local laboratory values
1
Co
nfe
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ep
ort
Published: 31/03/2015 Received: 24/03/2015
ecancer 2015, 9:518 DOI: 10.3332/ecancer.2015.518
Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licens es/by/3.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.
Highlights from the 14th St Gallen International Breast Cancer
Conference 2015 in Vienna: Dealing with classification,
prognostication, and prediction refinement to personalize
the treatment of patients with early breast cancer
Angela Esposito, Carmen Criscitiello and Giuseppe Curigliano
Division of Experimental Cancer Medicine, Division of Radiotherapy and Division of Pathology , European Institute of Oncology, Milan, Italy
Correspondence to: Giuseppe Curigliano. Email: [email protected]
Abstract
The refinement of the classification, the risk of relapse and the prediction of response to multidisciplinary treatment for early breast cancer
has been the major theme of the 14th St Gallen International Breast Cancer Consensus Conference 2015. The meeting, held in Vienna,
assembled 3500–4000 participants from 134 countries worldwide. It culminated, on the final day, with the International Consensus Ses-
sion, delivered by 40–50 of the world’s most experienced opinion leaders in the field of breast cancer treatment. The panelist addressed
the “semantic” classification of breast cancer subtypes by pathology-based biomarkers (e.g. estrogen receptor, progesterone receptor and
HER2) vs genomic classifiers. They also refined the biomarker prognostication dissecting the impact of the various gene signatures and
pathologic variables in predicting the outcome of patients with early breast cancer in terms of early and late relapse. Finally they addressed
the challenges stemming from the intra- and inter-observer variability in the assessment of pathologic variables and the role of gene sig-
natures for the prediction of response to specific therapeutic approach such as endocrine therapy and chemotherapy and for personalizing
local treatment of patients with early breast cancer. The vast majority of the questions asked during the consensus were about controversial
issues. The opinion of the panel members has been used to implement guidance for treatment choice. This is the unique feature of the
St. Gallen Consensus, ensuring that the resulting recommendations will take due cognizance of the variable resource limitations in different
countries. Information derived from evidence based medicine and large meta-analyses is of obvious and enormous value. The weakness
of this approach is that it gives particular weight to older trials (which have accumulated more event endpoints) and is frequently unable to
collect sufficient detail on the patients and tumors in the trials to allow assessment of whether the treatments which are better on average
offer equal value to all currently definable patient subgroups. What St Gallen can provide is clinically useful updated breast cancer treat-
ment consensus for the majority of patients treated outside of clinical trials (>90%) in most countries.
Conclusions• ER, PR and Her2 testing using ASCO/CAP
guidelines remain the most important ancillary tests in the management of patients with breast cancer
• While molecular subtypes are of conceptual interest, clinically useful subgroups are defined by ER, PR and Her2 assay results
• Among patient’s with ER+/Her2- (“luminal”) disease, KI67 proliferation rate or multigene prognostic tests are of value in further defining risk of recurrence and potential benefit from chemotherapy in addition to endocrine therapy
• The major clinical role of genomic analysis at this time is to identify patients with advanced disease who may be candidates for targeted therapies based on specific genomic alterations
