Personalized Breast Cancer Care
Sunil Patel, MD
Medical Oncology and Hematology
Collom and Carney Clinic.
No financial disclosure
Personalized Breast Cancer Care
Topics
• Role of genetic/familial high risk assessment
• Role of specific markers on breast tissue in
decision making of treatment.
• For some patients, more(=chemo) is not
better.
- Role of genetic profiling of the tumor in
decision making.
Breast Cancer Progress Report
• Breast Cancer mortality
rates have decreased by
2.3% annually since
1990
• The decline in
mortality is primarily
due to early detection
and new treatment
methods
Source: Breast Cancer Facts and Figures 2005-2006
National Center for Health Statistics data as analyzed by NCI
The Stages of Breast Cancer
Breast Cancer is diagnosed according to stages (stages 0 through IV) under
the TNM classification.
Factors used in staging of Breast Cancer:
• Tumor Size
Size of primary tumor
• Nodal status
Indicates presence or absence of cancer cells in lymph nodes
• Metastasis
Indicates if cancer cells have spread from the affected breast to other areas
of the body (i.e. skin, liver, lungs, bone)
Source: National Cancer Institute
Genetics Help us Identify Patients at
High Risk of Developing Breast Cancer
Genetics
– Genetics is the study of heredity
• While genetics influence genomics, genetics is responsible for
only 5-10% of breast cancer
• Genetics focuses primarily on the
likelihood of developing cancer
• Genetic tests find mutations, not
disease
Source: Understanding Cancer Series: Gene Testing,
National Cancer Institute
Genomics Help us Look at the Patients
Individual Tumor Biology
Genomics
Genomics is the study of how genes interact and are
expressed as a whole
• Genomics and gene expression profiling tools focus on the
cancer itself and can help determine
How aggressive is the cancer (prognosis)
What is the likely benefit from treatment (prediction)
Examples of Genetic and Genomic
Tests
Genetic Test
• BRCA1 and BRCA2
• The genetic make up of patients is tested for BRCA1 and
BRCA2 mutations. Patients with those mutations have
higher chances of developing breast cancer.
Genomic Test
• Oncotype DX® Breast Cancer Assay
• The expression level of 21 genes is measured in tumor
tissue from patients that have already been diagnosed with
breast cancer. This assay evaluates if a patient is going to
recur (prognostic) and predicts benefit from chemotherapy
and hormonal therapy (predictive)
•Mammaprint assay
Genetic Risk Factor Assessment
• NX 42 year old white female with no family
history of breast cancer, now has 4 cm right
breast cancer.
• Biopsy confirmed IDC,ER+, HER2/neu +
• What’s next? – Surgery- ipsilateral or bilateral
mastectomy, chemo, hormonal therapy? Or
more?
Breast & Ovarian Cancer Risk
Assessment – for patients
-
Age 50 y or younger
Triple negative breast cancer ( ER-PR-Her2/Neu-)
Two breast cancer primaries
Breast cancer at any age
- 1 or more close relative with breast or ovarian cancer at age 50 or
younger
-2 or more close relatives with breast and/or pancreatic cancer
-women of Ashkenazi Jewish descent at any age breast/ovarian
cancer.
- Other cancer history – Thyroid, sarcoma, adrenal , endometrial,
pancreatic, brain cancer
- Ovarian cancer
- Male breast cancer.
Patient NX
• NX 42 year old white female with no family
history of breast cancer, now has 4 cm right
breast cancer.
• Biopsy confirmed IDC,ER+, HER2/neu +
• What’s next? – Surgery- ipsilateral or bilateral
mastectomy, chemo, hormonal therapy? Or
more?
Patient NX
• Should go I go for surgery first? Then chemo?
• Blood for BRCA 1 and 2 mutation.
Patient MB
• MB is a 53 year old white male with right
sided breast cancer, stage I.
BReastCAncer Genes
BReast CAncer
• Women have about a 1 in 7 chance of getting
breast cancer in their lifetime.
• Most cancer is sporadic, about 5-10% of cases
are genetically linked
• Women inheriting mutation of BRCA gene
have increased chance of disease
• Also can lead to ovarian cancer
The Numbers
Frequency of BRCA Mutations in the U.S.
U.S. citizens
1 in 500
Ashkenazi Jews
1 in 40
Women with breast cancer under age 50
Approx. 1 in 13
Women with breast cancer under age 40
1 in 10
Ashkenazi Jews with breast cancer under age 50
Approx. 1 in 8
BRCA Genes
• BRCA 1 and BRCA 2
• Roles they play
Life is all about the right balance.
What are they?
• BRCA 1 and BRCA 2
– Known as breast and ovarian cancer susceptibility
genes
– Tumor suppressor genes
• regulate the cycle of cell division by keeping cells from
growing and dividing too rapidly or in an uncontrolled
way
• inhibit the growth of cells that line the milk ducts in the
breast
– Involved in many other functions including control
of DNA replication and damage repair
BRCA 1
• Cloned in 1994 (Miki et al)
–Mapped to chromosome 17q21
–5,592kb long
–24 exons
BRCA 2
•
•
•
•
Cloned in 1995 (Wooster et al.)
Mapped to chromosome 13q12-13
10,254 kb (3,418 aa)
27 exons
More Numbers
Type of Cancer
General
Population That
Will Develop
Disease
People With
BRCA1 Mutation
Who Will Develop
Disease
People With
BRCA2 Mutation
Who Will Develop
Disease
Breast
12.5%
55 – 85%
33 – 86%
Ovarian
1.43%
28 – 44%
10 – 30%
Prostate
4 – 6%
12 – 18%
Male breast cancer
Less than 1%
6%
4 – 14%
Pancreatic
0.6%
not applicable
6 – 7%
12 – 18%
Patient NX
• BRCA 1 mutation positive
• Neo-adjuvant chemotherapy then bilateral
skin sparing mastectomy.
• Hormonal therapy
• Prophylactic bilateral salpingo-oopherectomy
• Genetic counseling for family members.
Patient MB
•
•
•
•
BRCA 2 mutation positive
Chemotherapy
Contra-lateral mastectomy
PSA screening test.
Topics
• Role of genetic/familial high risk assessment
• Role of specific markers on breast tissue in
decision making of treatment.
• For some patients, more is not better.
- Role of genetic profiling of the tumor in
decision making.
How Do We Assess Risk
in Breast Cancer Patients?
Classic Pathological Criteria
Lymph Node
Status
Tumor
Size
Age
Tumor
Grade
AdjuvantOnline!
ER/PR
HER2
Computer-based
model
ER/PR/Her2-Neu
• Estrogen receptor
• Progesterone receptor
• Her2/Neu – Human epidermal growth factor
Receptor 2
• ER/PR+ Her2/Neu –
• ER/PR – Her2/Neu – (Triple negative)
• ER/PR – Her2/Neu +
• ER/PR+ Her2/Neu +
Triple-Positive Breast Cancer
H&E
ER-Pos
PR-Pos
HER2/neu-Pos
Triple-Negative Breast Cancer
H&E
ER-Neg
PR-Neg
HER2/neu-Neg
Treatment options
 Chemotherapy
 Endocrine therapy – Tamoxifen or Aromatase
inhibitor - Anastrozole (Arimidex) , Letrozole
(Femara) , Exemestane (Aromasin)
 Trastuzumab (Herceptin)
HerceptinTM(trastuzumab)
Triple negative breast cancer
Hormone Receptor - /HER2 • Chemotherapy for tumor more than 0.5 cm.
• Nodal involvement.
Hormone Receptor Positive,
HER2 Positive Breast Cancer
• 0.5 cm or less tumor size – Adjuvant endocrine
therapy
• 0.6 to 1 cm – Adjuvant endocrine +/- chemo with
trastuzumab.
• > 1 cm tumor size and/or lymph node involvement –
adjuvant endocrine therapy, chemotherapy with
trastuzumab.
Hormone Receptor Negative,
HER2 Positive Breast Cancer
• 0.5 cm or less tumor size – No chemo.
• 0.6 to 1 cm – Consider chemo with trastuzumab.
• > 1 cm tumor size and/or lymph node involvement –
chemotherapy with trastuzumab.
• HORMONAL THERAPY NOT USEFUL.
Hormone Receptor Positive,
HER2 Positive Breast Cancer
• 0.5 cm or less tumor size – Adjuvant endocrine
therapy
• 0.6 to 1 cm – Adjuvant endocrine +/- chemo with
trastuzumab.
• > 1 cm tumor size and/or lymph node involvement –
adjuvant endocrine therapy, chemotherapy with
trastuzumab.
Hormone Receptor Positive
HER2 Negative Breast Cancer Tumor size
• Tumor size < 0.5 Cm and No LN involvement –
Adjuvant endocrine therapy. No chemotherapy
• T > 0.5 Cm and No LN involvement adjuvant endocrine therapy +/- ??
Chemo.
Hormone Receptor Positive
HER2 Negative Breast Cancer
• Nodal involvement > 2mm focus – adjuvant
endocrine therapy + chemotherapy
• 1 to 3 Lymph nodes or >3 nodes
involved – does every one need
chemo?
Topics
• Role of genetic/familial high risk assessment
• Role of specific markers on breast tissue in
decision making of treatment.
• For some patients, more(=chemotherapy) is
not better.
- Role of genetic profiling of the tumor in
decision making.
How Do We Assess Risk
in Breast Cancer Patients?
Classic Pathological Criteria
Lymph Node
Status
Tumor
Size
New tools in the
Genomic Era…
Genetic Profiling
of Tumor
Age
Tumor
Grade
ER/PR
HER2
AdjuvantOnline!
Computer-based
model
Adjuvant Treatment for Early Stage Breast
Cancer Today
Hormonal Therapy
Based on the Landmark NSABP B-14 Study using Tamoxifen
If 100 women with ER+, N- disease are treated with hormonal
therapy how many will recur within 10 years?
15
Recurrence
Disease free
85
Fisher et al. N Engl J Med 1989;320(8):479-84
Chemotherapy and Hormonal Therapy
Based on the Landmark NSABP B-20 Study using Tamoxifen +
Chemotherapy
If all 100 women with ER+, N- disease are treated with
chemotherapy and hormonal therapy, how many will benefit
from the addition of chemotherapy?
4
11
Benefited from
Chemotherapy
Relapsed despite
Chemotherapy
85
Disease free
regardless of
Chemotherapy
Fisher et al. J Natl Cancer Inst 1997;89:1673-82
Outcomes of Adjuvant Chemotherapy in
Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
Cop yrigh t © A m erican S oc ie t y o f C lin ical O ncolog y
How Do We Assess Risk
in Breast Cancer Patients?
Classic Pathological Criteria
Lymph Node
Status
Tumor
Size
New tools in the
Genomic Era…
Genetic Profiling
of Tumor
Age
Tumor
Grade
ER/PR
HER2
AdjuvantOnline!
Computer-based
model
Patient A
Patient B
Patient C
With Genomic Tools We Can Now
Analyze Cancer at the Molecular Level
1. Patient’s tumor
2. Oncotype DX® Assay
5. Shared Decision Making
4. Oncotype DX® Report
3. Analyze expression of tumor’s genes
Oncotype DX®: A Genomic Assay
Oncotype DX® 21-Gene
Recurrence Score® (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
INVASION
Stromelysin 3
Cathepsin L2
ESTROGEN
ER
PR
Bcl2
SCUBE2
GSTM1
CD68
BAG1
HER2
GRB7
HER2
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Paik et al. N Engl J Med. 2004;351: 2817-2826
Oncotype DX® 21-Gene
Recurrence Score® (RS) Assay
Calculation of the Recurrence Score Result
Coefficient x Expression Level
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 GSTM1
Category
- 0.07 x BAG1
Low risk
RS (0-100)
RS <18
Int risk
RS ≥18 and <31
High risk
RS ≥31
Paik et al. N Engl J Med. 2004;351: 2817-2826
The Oncotype DX® Assay mostly used
for N-, ER+ Breast Cancer Patients
Invasive
Breast
Cancer
Stage I
ER-
Stage II
ER+
N-
ER-
Stage III
N+
ER+
Stage IV
Patient A
Patient A
• Patient was identified
as low risk by
Oncotype DX® with a
Recurrence Score ®
result of 4
• Patient received
hormonal therapy
since she was in a
group in which
chemotherapy does
not provide benefit
Patient B
Patient B
• Patient was identified as
high risk by Oncotype
DX® with a Recurrence
Score® result of 34
• The Recurrence Score
helped convince the
patient on the likely
benefits of taking
chemotherapy given the
biology of her disease
• Patient received
chemotherapy and
hormonal therapy
Patient C
Patient C
• Patient was identified as
intermediate risk by
Oncotype DX® with a
Recurrence Score® result
of 25
• Is there benefit from
chemotherapy for this
patient? The TAILORx
trial evaluates the utility
of chemotherapy in the
mid-range risk group
Outcomes of Adjuvant Chemotherapy in
Breast Cancer
Walgren et al. JCO 2005;23:7342-7349
Cop yrigh t © A m erican S oc ie t y o f C lin ical O ncolog y
The Promise of Personalized Medicine
in Breast Cancer
Tamoxifen
Women with
HR+ breast
Cancer
Aromatase
Inhibitor
Chemotherapy
Biologic agents
Her2, EGFR, VEGF, Parp
Anth, Taxane,
Platimun
The Molecular Portrait Hypothesis
You can recognize the
Mona Lisa by her smile
and her nose and her eyes and even her hands – if you are really good,
but not the sky or the trees
Thank you.
Questions?