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Understanding the Biology of
Breast Cancer:A Pathologist’s Perspective
Kimberly H All ison, MD
Breast Pathologist
Associate Professor of Pathology
Stanford University Medical Center
A Pathologist’s Perspective
�Current understanding of the biology of breast
cancer and its relevance to treating and
preventing the disease
�Pathology’s role in personalized medicine
GOALS
�Pathology’s role in personalized medicine
�What I learned going through treatment
WILL THERE BE A CURE BREAST CANCER?
WHAT IS BREAST CANCER?Understanding the Biology of Breast
Cancer is Key to Prevention and
Treatment!!!
BREAST CANCER UNDER THE
MICROSCOPE
� Histologic type
� Grade
� Size
� Lymph node statusPredict Behavior
WHAT DRIVES THE CANCER?
THERAPEUTIC TARGETS
�What proteins does
it express in
abnormal levels?
� Categorizes biologyHormone Hormone Hormone Hormone Her2 Her2 Her2 Her2 KiKiKiKi----67676767
� Categorizes biology
� Hormone + vs +
� HER2 + vs -
� Fast vs slow
proliferators
�Determines Therapy
Targets!
Hormone Hormone Hormone Hormone
Receptors:Receptors:Receptors:Receptors:
ER and ER and ER and ER and
PRPRPRPR
Her2 Her2 Her2 Her2 KiKiKiKi----67676767
CLINICALLY RELEVANT SUBTYPES OF
BREAST CANCER
ER+
ER-
??? ??? ??? ???
Hormone Hormone Hormone Hormone
TherapyTherapyTherapyTherapy
HER2+
HER2-
HER2-
“Triple Triple Triple Triple
NegativeNegativeNegativeNegative”
ER positiveER positiveER positiveER positive
HER2 positiveHER2 positiveHER2 positiveHER2 positive
HER2 HER2 HER2 HER2
Targeted Targeted Targeted Targeted
TherapyTherapyTherapyTherapy
� Based on similarity of
gene expression profiles
� 4 Distinct Subtypes:
� Luminal A (ER+)
� Luminal B (ER+)
GENE EXPRESSION BASED SUBTYPES
Perou, Nature 406, 747-752 (17 August 2000)
Luminal/ER
genes
Her2 genes
Basal genes
“Normal-
breast”
genes
� Luminal B (ER+)
� Her2+
� Basal- like
Outcomes by gene
expression based
subtype
NCI/WA
Sorlie et al, Proc Natl Acad Sci U S A. 2003 July 8; 100(14): 8418–8423.
COMBINING GENETIC AND
TRANSCRIPTIONAL INFORMATION
� Copy number aberrations and � Copy number aberrations and
gene expression
� 10 breast cancer subtypes
associated with outcome
dif ferences
doi:10.1038/ nature10983Curtis 2012
There is more There is more There is more There is more
diversity diversity diversity diversity
within each within each within each within each
subtype!subtype!subtype!subtype!
� 50% of driver mutations are present in < 10% of breast 50% of driver mutations are present in < 10% of breast 50% of driver mutations are present in < 10% of breast 50% of driver mutations are present in < 10% of breast cancers (TCGA)cancers (TCGA)cancers (TCGA)cancers (TCGA)
� Many mutations are unique!Many mutations are unique!Many mutations are unique!Many mutations are unique!
� If we want to personalize therapy with more targeted If we want to personalize therapy with more targeted If we want to personalize therapy with more targeted If we want to personalize therapy with more targeted drugs drugs drugs drugs ------------have to get very specific!have to get very specific!have to get very specific!have to get very specific!
subtype!subtype!subtype!subtype!
�Mutations are more common across cancer types
�Blurring lines
CHANGING PARADIGMS?
�Blurring lines between current cancer categories?
�Will molecular profiles tell us how to treat (and IF to treat?)
Pearce, Nature Methods 6666, (2009)
BREAST CANCER IS NOT ONE DISEASE
ER + ER -
HER2+ HER2-
Invasive Ductal
Carcinoma, NOS
Special
types
Sorlie 2003 Curtis 2012
CAN WE PREVENT CAN WE PREVENT
BREAST CANCER?
How does it develop?
What are the risk factors?
Who and how to screen?
BREAST CANCER BIOLOGY: WHAT WE
KNOW
Slow accumulation of
many minor mutations
Lower grade
Hormone-Driven Precursors
"Bad" mutation(s) as
initiating event
High grade
DCIS
Hormone Positive
Invasive Cancers
Hormone Negative
High Grade Invasive
Cancers
Luminal A
(slow growing)
Luminal B
(faster growing)
HER2
(fast growing)
Basal/
”Triple Negative”
(fast growing)
Anti-Hormone Therapies
Chemotherapy
Anti-HER2 Therapy
�More targeted
treatments
�Better prevention
UNDERSTANDING BIOLOGY �
PERSONALIZED MEDICINE
�Better prevention
strategies
Better
defined risk
groupsScreen all
Risk signature 1
Risk signature 2
Risk signature 3
Risk signature 4
Screening/management protocol 1
Screening/management protocol 2
Screening/management protocol 3
Screening/management protocol 4
PATHOLOGIST AS KEY TO PERSONALIZED
MEDICINE
Treatment Team Patient Factors
Individualized Treatment Decisions
Translation and integration of biologic information
� Ask your doctor if:
� Are they familiar with the pathologist?
� Do they specialize in breast pathology?
� Are there aspects of the diagnosis that
are borderline?
HOW DO I KNOW THE PATHOLOGY IS
ACCURATE?
are borderline?
�Most common disagreements:� Atypical ductal hyperplasia – DCIS spectrum
� Papillary lesions
� Invasive cancers:
� Grade
� HER2 IHC interpretation
� ER and PR status
� Second opinion from a specialist
DIAGNOSIS:
INVASIVE DUCTAL CARCINOMA
• 8 CM• GRADE 3 • ER/PR NEGATIVE• ER/PR NEGATIVE• HER2 POSITIVE• POSITIVE LN BX
Survival rate: 40%
�FEAR
�Panic –need to do
something now
EMOTIONAL IMPACT OF DIAGNOSIS
something now
�Defective
�What did I do wrong?
Addressing Fears
FIRST STEPS IN CLINICAL CARE
The longer it takes to
be seen the more they
magnify….
�Establishing a
clinical team
�Coordination of
CLINICAL ACTION PLAN
�Coordination of
treatment
�Second opinions
�My treatment plan:
�Chemotherapy first (AC+TH)
� Surgery (bilateral mastectomies)
RED SUNSHINE
mastectomies)
�Radiation
�1 year of antibody therapy Herceptin
� Participation in clinical trials
Adriamycin “The Red Devil”
�A team approach to the
patient
�Personalized medicine
matters
CLINICAL ACTION PLAN
matters
�Embracing therapy
�Healing you not just
treating the disease
�Everyone’s list is
HEALING TAKES MANY FORMS
�Everyone’s list is
unique
�Development of a
personal action plan
�Powerful to be able
to look directly at
my enemy
�Acknowledging that
CONFRONTING THE DISEASE
�Acknowledging that
cells make
mistakes (let go of
guilt)
�Offer to other
patients
Passage from “Staring Down the Beast”