Contemporary Classification of Breast Cancer Laura C. Collins, M.D. Vice Chair of Anatomic Pathology Professor of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA
Outline Objectives of classification Added value of expression profiling Overview of molecular subtypes Immunophenotype as a surrogate Issues for luminal cancers (ki-67) Issues for BLC (ER-low) Where are we today?
Breast Cancer Classification Histologic Type Histologic Grade Tumor Size LVI Biomarker status
Life Cycle of Breast Cancer Classification Morphology Grade ER, PR, HER2 Molecular in ER+ Morphology in special types Type and Grade Molecular IHC ER, PR, HER2
Case 6 A 49 year old female was found to have a 1.3 cm spiculated mass on screening mammogram Ultrasound revealed a 1.2 cm hypoechoic mass with posterior shadowing and irregular margins Core needle biopsy revealed a 1.4 cm, grade 2, invasive ductal carcinoma that was ER+, PR- and HER2- Subsequent excision confirmed the tumor size and grade; No LVI was identified A sentinel lymph node was negative The medical oncologist requests OncotypeDX
Histologic Grade and Survival Nottingham data, 2005 patients HG1 399 (20%) HG2 686 (35%) HG3 920 (40%)
ER Status and Survival 9639 patients ER+ ER- DFS Yi, Ann Oncol, 2014
Breast Cancer Classification Provides prognostic information Provides predictive information Informs patient management
Breast Cancer Subtypes Determined by Gene Expression Profiling Sorlie, 2001 ER- ER+
Breast Cancer Classification Developments in our understanding of breast cancer initiation and progression permit refinement of classification and provide potential for new therapeutic options Ultimate goal is to personalize therapy Precision Medicine
Expression profiling used to determine relationships between molecular subtype and pathway deregulation Some pathways highly correlated with subtype Other pathways exhibit variable activity within a subtype Breast Cancer Res 2009
Bild, 2009
J Pathol, 2014 Activation of different signaling pathways Therapeutic implications
Signaling Pathways Under Blockade Higgins, JCI, 2011
Molecular Classification Breast Cancer Estrogen Receptor Negative Cancers HER2 Estrogen Receptor Positive Cancers Basal-like ER, PR, HER2 negative ~15% HER2 Enriched HER2+ ER/PR absent ~15% Luminal B-like LB-HER2-: ER+/HER2-, Either Ki-67 high or Ki-67 intermediate and PR-/low LB-HER2+: ER+/ HER2+ Any Ki-67, Any PR ~70% Luminal A-like ER+, HER2- and Ki-67 low or Ki-67 intermediate and PR high
Molecular classification has prognostic significance Parker, JCO 2009 Sorlie, 2003
Nielsen 2004, Clin Cancer Research
Immunophenotyping to Approximate Molecular Subtype Using Three Markers Brenton, 2005 Luminal A Luminal B HER2-E Basal-like ER + + - - PR + + - - HER2 - + + -
Pathologic Subtype vs. Molecular Subtype Viale, Br Can Res Treat, 2018
2015 Luminal AR TNBC Subtype Potential Therapeutic Targets AR; MUC1 Mesenchymal Growth factor receptors (PDGFR, c- Kit) BL-Immune suppressed BL-Immune activated PD1, VTCN1 (immune suppressing molecule) STAT signal transduction molecules and cytokines
Molecular Classification of Special Type Cancers Dieci, 2014
There is heterogeneity within the molecular subtypes
Nature, 2012
Stephens, Nature 2012 100 breast cancers 40 cancer genes 73 different combinations of mutated cancer genes!! Point mutations Copy number changes
Classifier using 3 genes (ER, HER2, Aurora Kinase A) compared with five other multi-gene classifiers (50-726 genes) on 36 publicly available datasets to determine molecular subtypes 3-gene classifier most robust for molecular subtyping JNCI, 2012
Molecular Subtypes Largely Defined by ER, HER2 and Proliferation Genes
Life Cycle of Breast Cancer Classification Morphology Grade ER, PR, HER2 Molecular in ER+ Morphology in special types Type and Grade Molecular IHC ER, PR, HER2
Immunophenotyping to Approximate Molecular Subtype Maisonneuve, BCR, 2014 Coates, Ann Oncol, 2015 Luminal A-like Luminal B-like HER2-enriched ER+, HER2-, Ki-67<14% or Ki-67 intermediate (14-19%) and PR>20%, ER+, HER2- Ki-67 intermediate (*14-19%) and PR- or low (<20%) or Ki-67>20% HR+, HER2+ ER-, PR-, HER2+ Basal-like ER-, PR-, HER2-, [CK5/6+ and/or EGFR+] *St. Gallen, 2015 considers PR 20-29% to be intermediate
Issues for Luminal Cancers
Surrogate Histologic and IHC Markers in Clinical Practice Proliferation markers used to differentiate Luminal A from Luminal B Unlike ER and HER2 which show bimodal distribution with clear cutpoints, proliferation determined by several genes with continuous distribution
Surrogate Histologic and IHC Markers in Clinical Practice Ki-67 Tumor grade most widely used as a surrogate for proliferation Ki67 most widely used proliferation marker Use of Ki67 shifts some luminal A-like tumors to luminal B-like (Cirqueira, 2015) No consensus on cutpoint or method of counting
Focke, BCRT, 2016
Using <20% cut point to define luminal A tumors Focke, BCRT, 2016
Surrogate Histologic and IHC Markers in Clinical Practice Ki-67 Digital image analysis an option (Healey, Br Can Res Treat, 2017)?Better to utilize prognostic signature in this scenario
Issues for ER low positive/tnbc cancers
The Oncologist 2015
The Oncologist 2015 * 84.4% *determined by PAM50
The Oncologist 2015 * 84.4% 43.5% *determined by PAM50
Some ER+ Cases of Today Would Have Been Categorized as ER- in the Past Current threshold for ER positivity (1%) lower than that used by many labs in the past Current IHC assays more sensitive than those of the past
Breast Cancers with Low Levels of ER (<10%) Differ From Other ER+ Tumors Most non-luminal by PAM50 and gene expression profiling Levels of ESR1 mrna and ER-associated genes similar to those of patients with ER negative tumors
Breast Cancers with Low Levels of ER (<10%) Differ From Other ER+ Tumors Retrospective studies Outcome more similar to ER- tumors than to more strongly ER+ tumors No benefit from endocrine therapy Frequency of deleterious germline BRCA mutations similar to that of ER- breast cancers Likely represent a heterogeneous group Prospective data needed Potential impact for enrollment in TNBC clinical trials
Do the intrinsic subtypes have value in current clinical practice?
The 12 th 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.
Goldhirsch, 2011
Caveat: Attempts to reproduce the intrinsic subtype distinction between Luminal A-like and Luminal B-like using conventional pathology have proved impractical St. Gallen, 2015
St Gallen 2015 in clinical practice the key question is not the separation of the molecularly-defined intrinsic subtypes, but the discrimination between patients who will or will not benefit from particular therapies. Coates, 2015
Coates, 2015 St Gallen 2015 Clinically Useful Groups ER/PR HER2 Therapy positive negative Endocrine +/-chemo (depending on level of risk) positive positive HER-2 targeted, chemo, endocrine negative positive HER2-targeted, chemo negative negative Chemo
St Gallen 2015 Strongly endocrine responsive, low proliferation, good prognosis luminal A-like tumors 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 Coates, 2015
Commercially Available Multigene Signatures Van de Vijver, 2014
OncotypeDx (Genomic Health, Inc.) 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 NEJM 2004;351:2817 <18 Low 18-31 Intermediate >31 High
Recurrence Score and Prognosis in ER+, N- Breast Cancer Paik, 2004
NEJM, 2002 MammaPrint (Agendia) Expression signature consisting of 70 genes identified good and poor prognosis groups among both N- and N+ patients Better than standard prognostic systems based on clinical and histologic features (e.g., St. Gallen, NIH) Drukker, BCRT, 2014
J Clin Oncol 2009 Prognostic value independent of: Nodal status Size Grade PAM50 Assay ER status Predicted benefit from neoadjuvant chemotherapy
Alvarado, Adv Ther, 2015
Viale, Br Can Res Treat, 2018 Among PS TNBC
Relevance to Clinical Practice Use of Expression Signatures in Clinical Practice Most can be performed on FFPE Almost all available data from retrospective analyses Prognostic value time dependent (reduced between 5-10 years) Cost
Relevance to Clinical Practice Use of Expression Signatures in Clinical Practice Which patients? All signatures more useful for assessing prognosis in ER+ cancers (i.e., luminal) and are of little value in ER- cancers (i.e., HER2 and basal molecular types)
Relevance to Clinical Practice Use of Expression Signatures in Clinical Practice Is this approach really better than using a combination of clinical and pathologic factors supplemented by appropriate biomarkers detected by IHC (e.g., ER, PR, HER2 and Ki67)?
Where are we today? ER, PR and HER2 status are the major drivers of clinical decision making regarding the type of systemic therapy Prognostic Multigene Assays (e.g. OncotypeDx) used in some patients with ER+ breast cancer to determine the need for chemotherapy
2015 Both studies have shown very low rates of recurrence among patients with low RS in whom chemotherapy was omitted 2016 Therefore, we are seeing 21-gene RS being used clinically with increasing frequency to identify patients with ER+ breast cancer who may safely be spared cytotoxic therapy Overall survival 98% at 5 years in TAILORx
Clinical-Path High/Mammaprint-Low group: Distant metastasis-free survival 94.8% at 5 years Overall survival only 1.5% less than those receiving chemotherapy 14% absolute reduction in use of CT when risk assessed with Mammaprint
Where are we today? Targeted sequencing for genomic alterations/mutations in patients with metastatic disease to determine eligibility for clinical trials (e.g. for PI3 kinase inhibitors)
Signaling Pathways Under Blockade in Luminal Cancers Ades, JCO, 2014
Conclusions Molecular classification has: Furthered our understanding of breast cancer molecular mechanisms Provided insight into the development of targeted therapies A role in determining prognosis and predicting response to therapy Incorporation of expression signatures into clinical practice is here
Current Status of Molecular Subtyping for Pathologists Intrinsic subtype terminology generally not included in pathology reports Subtypes may be inferred by clinicians from combination of ER/PR and HER2 status (and grade)
Current Status of Molecular Subtyping for Pathologists Inferred subtypes based on receptor IHC may not be the same as molecular subtypes defined by GEP or PAM50, even with the addition of Ki67, CK5/6 and EGFR Conceptual value > practical value since treatment driven by the presence or absence of targetable features such as hormone receptors, HER2 and stage
Life Cycle of Breast Cancer Classification Morphology Grade ER, PR, HER2 Low Risk vs. High Risk in ER+ Morphology/special types in TNBC Type and Grade Molecular IHC ER, PR, HER2
Discriminants of Benefits from Chemotherapy Histologic Type (e.g. special TNC types) Histologic Grade Tumor Size LVI Biomarker status (ER, PR and HER2) Multigene assays in a subset of patients (ER+, >5mm, N0 or N1mi)