Transcript Adjuvant Systemic Treatment: Personalized Management of Breast

Adjuvant Systemic Treatment:
Personalized Management of Breast Cancer
Dr. Law Siu King
Department of Surgery
United Christian Hospital
Why do the patients with
operable breast cancer receive
adjuvant systemic therapy?
Role of adjuvant therapy for
operable breast cancer
 Systemic adjuvant treatment is used to tackles the
micrometastasis and that accounts for most of the
improved survival for operable breast cancer patient seen
in the last few decades.
What are the current evidences?
Current evidences of benefits of
adjuvant endocrine therapy
 Tamoxifen
 It has been shown Tamoxifen for about 5 years reduced the risk of
recurrence by 11.8% and the absolute risk of death by 9.2%.1
Recurrence↓11.8%
Mortality↓9.2%
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)* Lancet 2005;365:1687-1717
Current evidences of benefits of
adjuvant endocrine therapy
 Aromatase inhibitors
 AIs (letrozole and anastrozole) have each been shown to
improve DFS compared with tamoxifen when given as first line
adjuvant therapy for a planned 5 years in postmenopausal
women with hormonal receptor-positive early breast cancer 1,2.
1.BIG 1-98 Coatest et al
J CLin Onco 2007
2. ATAC trial Forbes JF
et al Lancet Onco2008
Current evidences of benefits of
adjuvant chemotherapy
 NSABP B20 study2, for early breast cancer patient with pathology
result of ER +ve & Node –ve who were treated with chemotherapy
and hormonal treatment, 4% of patients benefited from the
additional of chemotherapy. 11% has recurrence despite having
chemotherapy and 85% were disease free regardless of
chemotherapy.
Fisher et al. J Natl Cancer Inst 1997;89:1673-82
Current evidences of benefits of
adjuvant targeted therapy
 Adjuvant Transtuzumab ( Herceptin) has been shown
to be a major factor in improving survival from HER2Positive Breast Cancer1,2,3
↑
HERA trial, absolute benefit
for DFS 8.4 % ↑ at 2 yr
1.HERA Piccart-Gebhart,
NEJM 2005
2.Romond EH et al. NEJM 2005
3.Smith Et al Lancet 2007
Adjuvant Systemic Treatment
for Breast cancer
 General principle adjuvant treatment decisions are based
on the balance among
 risk of relapse,
 proven survival benefits of treatment, and
 the costs and toxicities of treatment, as well as
 on patient preference and co-morbidities.
How can we determinate the
prognosis ?
Determinants of prognosis
 For many years , the primary determinants of prognosis
included ER, PR and HER2 status, histology, grade,
tumor size and axillary LN status.
Prognostic tools
 Nottingham prognostic Index( NPI) has been used for
many years. It is based 3 factors using the following
formula:
 NPI=p tumor size (cm)x0.2+LN stage +histological
grade
 LN stage( score 1,2 or 3 with 1 =node negative , 2= 1-3 involved nodes and 3
=more then 3 nodes), histological grade ( score 1,2, or 3) + histological grade
 Arbitrary cut-off points of 3.4 and 5.4 are used to divide patients into 6
prognostic groups: excellent, good, moderate I and II, Poor and very Poor
Prognostic tools
 Other pathology based prognostic tool used in
breast cancer included
 Adjuvant!Online
 Adjuvant! Online can be accessed at www.adjuvantonline.com.
 It is a decision tool for assessing the risks of an individual
patient developing recurrent disease and/or dying within 10
years, when receiving specific treatment on the basis of well
validated factors
 Age, comorbidities, LN status, Tumor size, tumor grade and
hormonal receptor status
 St Gallen Criteria
St. Gallen Consenus
 St. Gallen derived algorithm
for selection of adjuvant
systemic therapy for early
breast cancer patients includes
 Tumor size and grade
 Nodal status,
 Menopausal status,
 Peri-tumoral vessels
invasion
 Endocrine status and
 HER 2 status.
Risk
Categories
Description
Low Risk
Node negative AND all of the following
features
•pT≤2cm
•Grade 1
•Absence of peri-tumoral vascular invasion
•HER 2 non-overexpression/ amplification
•Age ≥35
Intermediate
Risk
A.Node negative AND at least one of the
following features
•pT >2cm
•Grade 2-3
•Presence of peri-tumoral vascular invasion
•HER 2 overexpression/ amplification
•Age <35
B. Node positive (1-3 involved nodes)
AND HER 2 non-overexpressed/
amplified
High Risks
A.
Node positive (1-3 involved nodes)
AND HER 2 overexpressed/
amplified
B. Node positive (4 or more involved
nodes)
St. Gallen Expert Consensus Meeting 2007
Case discussion
Case Study
 Madam Choi, 59/F, Excellent Good Past Health
 Has newly Dx CA Left breast ,presented with left breast mass ,
 Confirmed by imaging (MMG/ USG) and histology (Core Biopsy)
 WLE + Sentinel lymph node biopsy
 Pathology:
 Primary tumor - 2.2cm ,Grade 2, invasive ductal carcinoma, clear




resection margins
ER 300(+++), PR 300(+++), cerb2 –ve.
No lymphovascular invasion
Sentinel lymph nodes – 0/2
Stage IIA (pT2 N0M0)
What adjuvant systemic therapy should the patient receive?
Should the patient receive chemotherapy?
Case Study
 Madam Choi, 59/F, Excellent Good Past Health
 Has newly Dx CA Left breast ,presented with left breast mass ,
 Confirmed by imaging (MMG/ USG) and histology (Core Biopsy)
 WLE + Sentinel lymph node biopsy
 Pathology:
 Primary tumor - 2.2cm ,Grade 2, invasive ductal carcinoma, clear




resection margins
ER 300(+++), PR 300(+++), cerb2 –ve.
No lymphovascular invasion
Sentinel lymph nodes – 0/2
Stage IIA (pT2 N0M0)
Base on the St. Gallen Criteria ,
She has intermediate risk (T2 and Grade 2 tumor)
Is hormonal therapy alone for her
enough ?
 Base on NSABP B14 study 1, for early breast cancer patient with
pathology result of ER +ve & Node –ve, 85% of women were disease
free with tamoxifen alone.
Is she belong to 85% ?
How can we know who
are these women?
Fisher et al. N Engl J Med 1989;320(8):479-84
Chemotherapy + Hormonal Therapy
for her ?
 Base on NSABP B20 study, by treating 100 women (early breast
cancer ER + LN-ve ) with chemotherapy and hormonal therapy only 4
would derive a benefit from chemotherapy treatment and 85 would
have done well with hormonal therapy alone.
How can we determine
which women will benefit
from chemotherapy,
Which 85% will do fine
without it?
Fisher et al. J Natl Cancer Inst 1997;89:1673-82
Are there any genomic tools that help to determine
those patients with highest risks of recurrence and
thus benefit most from chemotherapy?
The 21st Century: genomic era
Toward personalized medicine
 As new technologies emerge in the 21st century , a
number of gene expression signatures have been
developed . They can give us information on molecular
characteristics of cancer .
 to assess an individual’s risk of recurrence
 to provide personalized treatment plan
 to identify those patients who benefit most from
chemotherapy and those who will only benefit from
endocrine therapy can be spare the adverse effects of
chemotherapy.
Multi-gene assays for Breast Cancer
 Two commercially available assays that use in the
clinical setting have been developed.
 The 21-gene recurrence score ( Oncotype DX®; Genomic
Health, Red-wood City, Calif. ) and
 The Amsterdam 70-gene signature ( Mammaprint®;
Agendia, Amsterdam, The Netherlands )
Gene-Expression Signatures in Breast Cancer Molecular Origins of
Cancer Christos Sotiriou et al.
The New England Journal of Medicine.
Boston: Feb 19, 2009. Vol. 360, Iss. 8; pg. 790
What is 21-gene recurrence score assay
( Oncotype DX®)?
The 21-gene recurrence score (Oncotype DX®)
Oncotype DX Breast Cancer Test Evaluates 21 Genes
16 Cancer-Related and 5 Reference Genes From 3 Studies
Estrogen
Proliferation
HER2
Invasion
ER
PR
Bcl2
SCUBE2
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GRB7
HER2
Stromelysin 3
Cathepsin L2
Others
CD68
GSTM1
BAG1
Reference
Beta-actin
GAPDH
RPLPO
GUS
TFRC
It is an RT-PCR assay ( reverse-transcriptase-polymerase-chain-reaction ) that
measures the expression of 21 genes—16 cancer-related genes and 5
reference genes—in RNA extracted from paraffin-embedded tumor tissue
Paik S, et al. N Engl J Med. 2004;351:2817.
Levels of Gene Expression
Determine Recurrence Score
Higher expression levels of
“favorable” genes = ↓ RS
Higher expression levels of
“unfavorable” genes = ↑ RS
Cutoff points chosen based on
Results of NSABP trial B-20
A risk score is calculated from 0 -100
Sparano, J & Paik, S. JCO, 2008.
The 21-gene recurrence score (Oncotype DX)
Validation Study
 RS was significantly correlated
with relapse free interval & OS
(p<0.001)
 Rate of distant recurrence at 10
years:
 Low risk – 6.8%
 Intermediate risk – 14.3%
 High risk – 30.5%
No distant recurrence
(low risk) = 93.2%
No distant recurrence
(high risk) = 69.5%
p<0.001
1.NSABP B14 : National Surgical Adjuvant
Breast and Bowel Project clinical trial B-14
2.Paik S, et al. N Engl J Med. 2004;351:28172826
Oncotype DX Assay ® is the gene expression analysis give information
on molecular characteristics of cancer (gene signature), which is able to
allow design of tailor made treatment plans for breast cancer patients.
The Oncotype DX® Recurrence Score ® is a Continuous Predictor of
Recurrence Risk of breast cancer.
Category
Recurrence Score®
(0-100)
Low risk
<18
Intermediate risk
18-30
High risk
≥31
Lower RSs
• Lower likelihood of
recurrence
• Greater magnitude of TAM
benefit
• Likely minimal, if any,
chemotherapy benefit
1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006
3) Paik et al JCO 2006, 4) Gianni et al JCO 2005
Higher RSs
• Greater likelihood of recurrence
• Lower magnitude of TAM benefit
• Likely clear chemotherapy benefit
What is 70-gene profile
(Mammaprint )?
Web Source: Agendia
70-gene profile (MammaPrint)
 It is DNA microarray assay
and requires a fresh / frozen
sample of tissue that is
composed of a minimum of
30% malignant cells.
 It measures the expression of
70 genes and calculates a
prognostic score that
categorizes patients into
 “good” or
 “poor” risk groups.
Web Source :Agendia
1.van’t Veer LJ, et al. Nature 2002;415:530-6.
70-gene profile (MammaPrint)
 Mammaprint has been validated to be prognostic in both
node-negative and node- positive patient1and to be
superior to adjuvant! Online in predicting distant
recurrence 2 .
85.2%
50.6%
94.5%
54.6%
1.Van de Vijver et al.
NEJM, 2002
2. Buyse, M. ed al. J of
NCI, 2006
NB1, patient ages <53 with T1-2, LN-/+ primary breast cancer
NB2. patient with age<60, T1-2, LN-
Prospective Validation of
mammaprint : The MINDACT Trial
 There is an ongoing prospective randomized European
Study, the Microarray in Node- Negative Disease may
Avoid Chemotherapy ( MINDACT )
 to study the ability of the 70 gene profile to predict clinical
benefit from chemotherapy
Readiness of multi-gene assays for
clinical use?
 Oncotype DX® has been endorsed by ASCO1 and NCCN2
guidelines to assist clinicians in making decisions about
treatment.
 Mammaprint® has been cleared by the FDA for clinical
use .
 In St. Gallen Consensus 2009 , the panel agreed that
validated multi-gene tests, if readily available, could
assist in deciding whether to add chemotherapy in cases
where its use was uncertain after conventional markers.
1.Harris L,et al. J Clin Oncol. 2007;25(33):5287-312.
2.NCCN Clinical Practice Guidelines in Oncology™ Breast
Cancer, (Version 1.2011)
Case Study Revisited
 Madam Choi, 59/F, Excellent Good Past Health
 Has newly Dx CA Left breast ,presented with left breast mass ,
 Confirmed by imaging (MMG/ USG) and histology (Core Biopsy)
 WLE + Sentinel lymph node biopsy
 Pathology:
 Primary tumor - 2.2cm ,Grade 2, invasive ductal carcinoma, clear




resection margins
ER 300(+++), PR 300(+++), cerb2 –ve.
No lymphovascular invasion
Sentinel lymph nodes – 0/2
Stage IIA (pT2 N0M0)
Base on the St. Gallen Criteria, she was classified to have intermediate risks.
So she decided for further gene expression signatures test , Oncotype Dx
Oncotype DX®
Recurrence Score® result
RESULTS
Recurrence Score =
0
CLINICAL EXPERIENCE
Patients with a Recurrence Score of 0 in clinical validation study had an Average Rate of
Distant Recurrence at 10 years of 3% .
Oncotype DX®
Recurrence Score® result
RESULTS
Recurrence Score =
0
CLINICAL EXPERIENCE
Patients with a Recurrence Score of 0 in clinical validation study had an Average Rate of
Distant Recurrence at 10 years of 3% .
Her Recurrence score is 0 and
her average rate of distant recurrence at 10 years is 3%.
Lower likelihood of recurrence
Greater magnitude of tamoxifen benefit
Likely minimal, if any, chemotherapy benefit
Case study revisited
 She was recommended RT + Tamoxifen/ Aromatase
Inhibitor after joint discussion with oncologist and
surgeon.
 She finally decided for RT + Tamoxifen alone as
postoperative systemic adjuvant treatment.
 She can avoid the S/E of chemotherapy.
Conclusion
 Systemic adjuvant treatment improves survival for operable breast
cancer patient by tackling the micro-metastasis .
 Decision for adjuvant treatment are made after balancing the risks
and benefits.
 Gene expression signatures (OncotypeDx and Mammaprint) allow
us to determine individual’s risk of recurrence and to aid selection of
optimal therapy for individual patients.
 There are ongoing prospective randomized trial for the gene
expression signatures ( TAILORx and MINDACT).
Thank You!
Q&A
MammaPrint
Oncotype Dx
Provider
Agendia
Genomic Health
Type of assay
70-Gene Assay
21-Gene Recurrence Score
Type of tissue sample
Fresh or Frozen
Formalin-fixed, Paraffinembedded
Technique
DNA microarrays
Q-RT-PCR
Centrally certified
laboratory
Yes
Yes
Indication
To aid in prognostic prediction in
patients <61 year of age with stage
I or stage II, node-negative disease
with a tumor size of <=5cm
To predict the risk of recurrence
in patients with ER-Positive,
node-negative disease treated
with tamoxifen;
to identify patients with a low
risk of recurrence who may not
need adjuvant chemotherapy
Level of evidence (I-V)
III
II
FDA Clearance
Yes
No
Availability
Europe and United States
Europe and United States
Prospective Ongoing Trials
MINDACT
TAILORx
Christos Sotiriou et al. NEJM, 2009.
Risk categories for Patients with Operable Breast Cancer
Risk Categories
Description
Low Risk
Node negative AND all of the following features
• pT≤2cm
•Grade 1
•Absence of peri-tumoral vascular invasion
•HER 2 non-overexpression/ amplification
•Age ≥35
Intermediate Risk
A.Node negative AND at least one of the following features
•pT >2cm
•Grade 2-3
•Presence of peri-tumoral vascular invasion
•HER 2 overexpression/ amplification
•Age <35
B. Node positive (1-3 involved nodes) AND HER 2 nonoverexpressed/ amplified
High Risks
A. Node positive (1-3 involved nodes) AND HER 2
overexpressed/ amplified
B. Node positive (4 or more involved nodes)
St. Gallen Consensus 2009
Treatment Modality
Indication
Comment
Endocrine therapy
Any ER staining
ER Negative and PR Positive
probably artefactual
AntiHER2 therapy
ASCO/CAP HER2
positive(>30% intense and
complete staining (IHC) or
FISH>2.2+)
May use clinical trial
definitions
In HER2-postive disease
(with anti-HER2 therapy)
Trial evidence for
transtuzumab is limited to
use with or following
chemotherapy
Combined endocrine
therapy + Anti-HER2
therapy without
chemotherapy in strongly
ER-positive,HER2-positive
is logical but unproven
In triple-negative disease
Most Patients
No proven alternatives;
most at elevate risk
In ER-positive, HER2negative disease (with
Variable according to risk
See table 3
Chemotherapy
Table 3. Chemoendocrine therapy in patients with ER-positive, HER2-negative disease
Relative indications Factors not useful
for
for decision
chemoendocrine
therapy
Relative indications
for endocrine
therapy alone
Clinicopathological features
ER and PR
Lower ER and PR level
Higher ER and PR level
Histological grade
Grade3
Grade 2
Grade 1
Proliferation (Ki67labelling index)
High (>30%)
Intermediate(16-30%)
Low (<=15%)
Nodes
Nodes Positive (four or
more involved nodes)
Node positive (one to
three involved nodes)
Node negative
Peri-tumoral vascular
invasion(PVI)
Present of extensive
PVI
Pathological Tumor
size ( pT )
>5cm
Patient preference
Use all available
treatments
Absence of extensive
PVI
2.1-5cm
<=2cm
Avoid chemotherapy
related side effects
Multigene Assays
Gene signatures
High score
Intermediate score
Low Score
Trastuzumab ( Herceptin)
 Trastuzumab, a monoclonal antibody
 was successfully developed to attack the cell
 Surface receptors of Her2/Neu oncogene found in
breast cancer cells
Prognostic significance – HER2/neu
 20% of breast cancer patients have HER2/neu gene
amplification
 Gene amplification ® cytoplasm glucoprotein
overexpression
 HER2 amplification or overexpression has been associated
with higher tumour grade, negative ER status, higher
tumour proliferation (e.g. Ki-67); and therefore poor
prognosis
 IHC (expression) vs. FISH (gene amplification)