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How molecular diagnostics &
targeted therapies have
revolutionized treatment in
Breast Cancers
Roger KC Ngan
COS, Department of Clinical Oncology, Queen Elizabeth Hospital
Director, Hong Kong Cancer Registry
1
Talk schema
• An overview of breast cancers in Hong Kong
• Paradigm shifts in prescribing systemic
therapies for early breast cancers – from clinical
to molecular and genomic diagnostics
• Revised algorithms of treatment in advanced
breast cancers with novel targeted therapies
2
• Conclusions
Hong Kong Cancer statistics 2012
27%
70%
14%
3
41%
Leading female cancer in Hong Kong
• Commonest female cancer
• Commonest cancer in females from 20 - 74
• Over 3,500 new cases and 600 deaths in 2012
• Most common in middle-aged women
• median age at diagnosis: 54 yr
• median age at death: 59 yr
4
Projection of breast cancer incidence
Projection
2030
Site
Female breast
Model(1)
3
2012
actual
2020
projected
2030
Projected (95%PI)(2)
% chg(3)
(vs 2012)
3,508
4,580
6,000 (5,720-6,270)
+71
Projected no. by stage in 2030(4)
I
II
III
IV
2,110
2,440
1,020
430
(1) Model used for projections as described in the Methods; (2) 95% PI = 95% prediction interval; (3) % chg = total % change in numbers compared with the 2011 actual
figures; (4) Stratified according to stage at diagnosis captured between 2010 and 2012. Unstaged cases were excluded in the calculation of distribution of stage.
Note: Poisson regression modeling was used to fit to the observed age-specific incidence rates using data from 1983 to 2012
and population projections and to estimate the projected number up to 2030.
5
Female breast cancer statistics worldwide:
Estimated age-standardized incidence and mortality
rates in 2012
Incidence
Mortality
(per 100,000)
(per 100,000)
Japan
51.5
9.8
South Korea
52.1
6.1
Hong Kong
56.7
8.6
Singapore
65.7
15.5
Canada
79.8
13.9
Australia
86.0
14.0
Germany
91.6
15.5
USA
92.9
14.9
United Kingdom
95.0
17.1
Country/City
Source:
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN
2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International
Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 27/02/2015.
6
Trends in breast cancer mortality in HK
APC= -0.1 (p=0.25)
7
Relative survival rates of Breast cancer patients,
1997-2001
8
Annals of Surgery 2011
Relative survival* (%) by Stage,
1997-2006
No.
1-yr
2-yr
3-yr
4-yr
5-yr
6-yr
7-yr
Overall
18,110
97.5
94.0
90.8
87.8
85.6
83.3
81.9
Stage I
4,485
99.9
99.7
99
98.3
97.8
97.1
96.4
Stage II
7,858
99.7
98
95.5
92.8
90.4
87.9
86.2
Stage III
2,402
96.8
88.8
81.2
74.9
70.4
65.9
62.5
Stage IV
971
66.0
45.6
32.2
25.7
20.6
17.8
16.4
Unknown
stage
2,394
94.5
89.6
86.4
82.6
80.2
78.1
77.2
* Maximum likelihood approach was used to estimate relative survival in all calculations.
Source: Hong Kong Cancer Registry, Hospital Authority
9
Relative survival (%) by receptor,
1997-2006
No.
1-yr
2-yr
3-yr
4-yr
5-yr
6-yr
7-yr
Positive
10,697
99.1
97.7
95.4
93.1
90.7
88.5
86.5
Negative
4,661
96
88.3
82.9
78.8
76.5
74.3
73.3
ER
PR
+14%
Positive
8,386
99.3
98.2
96.1
94
92.3
90.3
88.4
Negative
6,760
96.6
90.5
85.9
82.1
79.2
76.7
75.3
+8%
Her-2
Positive
3,452
97.1
92.3
88.2
84.6
81.4
78.1
75.7
Negative
8,757
98.5
96.3
93.7
91.2
89.2
87.0
85.8
10
Strategies of systemic treatment for
early breast cancers
Who to receive what – hormones, chemotherapy,
targeted therapy?
11
BREAST CANCER－5-year survival as function of the
5-Year Survival
number of positive axillary lymph nodes
low
intermediate
80%
risk
60%
very high
risk
40%
high
risk
20%
0%
0
1
2
3
4
5
6-10 11-15 16-20 >20
Number of Positive Nodes
Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557-1616.
Heterogeneity in Breast Cancer
Evolution of selection criteria for adjuvant
systemic therapy in early breast cancers
Tumors
TNM
Grade
• Clinical & histopathology
parameters
Adjuvant
online!
Cells • Immunohistochemistry
ER, PR,
cerbB2
• Molecular diagnostics
Genes • Genomic tests
RS, ROR
BRCA
• Genetic tests
15
Nottingham prognostic index (UK):
• T size
• histological grade
• axillary node+ number
Recurrence:
All ER+, 13%^
BC mortality:
All ER+, 9%^
Early Breast Cancer Trialist Collaborative Group
Lancet. 2011; 378: 771–784.
Recurrence
9-12%^ 10yr
Adjuvant chemotherapy
in estrogen-receptorpoor breast cancer:
5872 patient-level
meta-analysis of
randomised trials
Breast cancer
mortality
6-9%^ 10 yr
Lancet 2008; 371: 29–40
Heterogeneity in Breast Cancer
The methodology for calculation of the Allred score for hormone receptors
Kingshuk Roy Choudhury et al. J Histochem Cytochem
2010;58:95-107
Copyright © by The Histochemical Society
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncology
HER2 Overexpression Shortens Survival
HER2 oncogene
amplification
HER2 oncoprotein
overexpression
Shortened survival
Slamon DJ, et al. Science. 1987;235:177-182.
Slamon DJ, et al. Science. 1989;244:707-712.
Median Survival From First Diagnosis
HER2 overexpressing
3 yrs
HER2 normal
6-7 yrs
HER-2 testing by protein or gene expression
2013 Update on HER2 Testing:
ASCO/CAP Guidelines
All newly diagnosed BC patients must have a HER2
test performed
HER2 is positive if:
 IHC 3+ with complete, intense circumferential membrane
staining (for protein)
 ISH (in-situ hybridization) positive (for gene)
 Single probe average HER2 copy number > 6 signals/cell
 Dual probe HER2/CEP17 ratio > 2.0 with average HER2 copy
number > 4 or < 4 signals/cell
 Dual probe HER2/CEP17 ratio < 2.0 with average HER2 copy
number > 6 signals/cell
Wolff et al, JCO 2013
ADJUVANT RX ALGORITHM
ER and or PR +
Her2 -
ER, PR and HER2 -
Her2 +
TNM (size; nodal status)
Grading
Molecular tests:
• uPA/PAI-1
• Gen-Tests
• Ki-67
High risk
Chemotherapy
+ AHT
Chemotherapy
+ Trastuzumab
+/- AHT
Low risk
AHT
Chemotherapy
Harbeck, Salem, Gluz et al, 2010
KLINIKUM DER UNIVERSITÄ T MÜ NCHEN®
26
KLINIK UND POLIKLINIK
FÜ R FRAUENHEILKUNDE UND GEBURTSHILFE
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncology
HER2 Overexpression in Breast Cancer
HER2 is overexpressed in
~ 25% of breast cancers
Normal (1x)
~ 25,000-50,000 HER2
receptors
Overexpressed
HER2 (10-100x)
up to ~ 2,000,000
HER2 receptors
Pegram MD, et al. Cancer Treat Res. 2000;103:57-75.
Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71.
Slamon DJ, et al. Science. 1987;235:177-182.
Excessive cellular division
ErbB / HER receptors in breast cancer
Ligands
Tumour
cell membrane
ErbB1
ErbB2
ErbB3
Cell cycle progression, proliferation,
survival, apoptosis
ErbB4
Differentiation
HER2 Containing Dimers
Induce Potent Mitogenic Signaling
HER2 is the preferred dimerization partner for all HER family members and can
form homodimers and heterodimers1
This activates multiple signaling pathways, producing mitogenic effects on cells2
HER1:HER2
HER2:HER2
HER2:HER3
HER2:HER4
+
+++
++++
+++
Signaling activity
1. Huang et al. Cancer Res 2010; 70:1204–1214; 2. Rowinsky. Ann Rev Med 2004; 55:433–457
Mechanism & sites of action of targeted agents in
ErbB2+ breast cancer
Trastuzumab
Ligands
Pertuzumab
blocks ErbB2
activation
blocks ErbB2/3
interaction
VEGF
Bevacizumab
blocks VEGF
interaction
with receptor
Tumour
cell membrane
Endothelial
cell membrane
Lapatinib inhibits ErbB1 and
B2 phosphorylation; neratinib
inhibits ErbB1, B2 and B4(?)
phosphorylation
ErbB1
ErbB2
ErbB3
Cell cycle progression, proliferation,
survival, apoptosis
ErbB4
Differentiation
VEGFR
Angiogenesis
Adjuvant Trastuzumab studies
• 4 large randomized phase III studies
• All showed reduced recurrences (6 – 16%) and improved
survivals (8%)
Study
Treatments DFS
RR
reduction
HERA
Chemo-H
vs chemo
86% at 2yr
(vs 78%)
46%
BCIRG
006
TCH/AC-TH
33-40%
vs AC-T
86-88%
at 3yr
(vs 82%)
B31/N9831 AC-TH
(joint
analysis)
vs AC-T
87%
at 3.5yr
(vs 71%)
52%
T=paclitaxel
TC=docetaxel
+carboplatin
H=herceptin
AC=adriamycin
+cyclophospamide
Overall
survival
87% at
8.3yr
(vs 79%)
8% gain
31
無病存活率
Adjuvant Lapatinib (ALTTO) Schema
Treatment arms after chemotherapy:
+ Trastuzumab X 1 year
HER2+
ESBC
+ Lapatinib X 1 year
+ Trastuzumab + Lapatinib X 1 year
+ Trastuzumab X 3 months →
Lapatinib X 9 months
Piccart & Perez,
Completed recruitment
on 31-Aug-2013
TCa = 6 cycles of docetaxel and carboplatin
APHINITY ADJUVANT TRIAL (n=4805)
34
node negative
Biologic Heterogeneity – „intrinsic" subtypes
“Gene expression patterns of breast carcinomas distinguish
tumor subclasses with clinical implications“
Survival months
RFS
Sorlie et al., PNAS, 2001; 100: 10869-74
Therapeutic recommendations in breast cancer
Intrinsic subtype
Luminal A
Luminal B
Basal-like
Clinical
classification
ER and PR
positive
ER a/o PR
positive
ER and PR
and Her2
negative
Proliferation
(Ki-67) low
Proliferation
(Ki-67) high
Recurrence
risk low
Recurrence
risk high
Therapeutic
recommendation
Endocrine
therapy
Chemotherapy
 endocrine
Harbeck Dtsch Med Wochenschrift, 2013; 138: 180-2
Her2+
Her2 positive
Chemotherapy (preferably
neoadjuvant)
Chemotherapy
Trastuzumab +
chemotherapy ±
Endocrine therapy
Wissenstransfer in klinische Testsysteme, Prosigna™
2000
2009
2010
2012/13
Researchers first describe
breast cancer intrinsic subtypes
based on microarray
experiments
Researchers first describe
“PAM50” gene expression
signature
NanoString exclusively licenses
PAM50 gene expression
signature
Prosigna launches
after receiving CE
Mark for Europe &
Israel; FDA 510k
clearance in US
8192 genes
50 genes
Perou et al., Molecular Portraits of Human Breast Tumors. Nature 2000; 406: 747-52
Parker et al., Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes, JCO 2009; 27: 1160-7
Distribution of breast cancer intrinsic subtypes from PAM50 assay in a population-based cohort
by race and ethnicity, LACE and Pathways studies.
Carol Sweeney et al. Cancer Epidemiol Biomarkers Prev
2014;23:714-724
© 2014 by American Association for Cancer Research
TransATAC & ABCSG-8 trials
• 1786 node-neg & 688 node+ (>2400)
• postmenopausal women with early-stage, HR+ breast cancer who
received 5 years of endocrine therapy after surgical resection of the
primary tumor
• The results of the validation studies constitute Level 1 evidence for
clinical validity of the Prosigna test for predicting the risk of distant
recurrence in postmenopausal women with HR+ BC
Prosigna (PAM50) ROR Scoring
ROR (Risk of Recurrence) Score
(Tumor size + nodal status)
The Oncotype DX Recurrence Score® Result
uses Key Genes Linked to Critical Molecular Pathways
16 BREAST CANCER RELATED GENES
Estrogen
Proliferation
HER2
Invasion
Others
ER
PR
Bcl2
SCUBE2
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GRB7
HER2
Stromelysin 3
Cathepsin L2
CD68
GSTM1
BAG1
5 REFERENCE GENES
Beta-actin
GAPDH
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
RPLPO
GUS
TFRC
43
The Recurrence Score® Result Assesses
Individual Tumor Biology for ER+ Breast Cancer
Distant recurrence at 10 years
CONTINUOUS BIOLOGY
4 0%
3 5%
3 0%
2 5%
2 0%
1 5%
1 0%
5%
0%
0
5
10
15
20
25
30
35
40
45
50
Recurrence Score value
LOW RECURRENCE SCORE DISEASE
Indolent
Hormone therapy-sensitive
Minimal, if any, chemotherapy benefit
HIGH RECURRENCE SCORE DISEASE
Aggressive
Less sensitive to hormone therapy
Large chemotherapy benefit
Paik S, et al. N Engl J Med. 2004;351:2817; Paik S, et al. J Clin Oncol. 2006;24:3726; Habel LA, et al. Breast Cancer Res. 2006;8:R25-R39.
44
Oncotype DX® Clinical Validation:
NSABP B-14
• Objective: Prospectively validate the Recurrence Score®
result as a predictor of distant recurrence in nodenegative, ER+ patients
Placebo—not eligible
Randomized
Registered
Tamoxifen—eligible
Tamoxifen—eligible
• Multicenter study with prespecified 21-gene assay,
algorithm, endpoints, analysis plan
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
45
Oncotype DX® Clinical Validation:
Proportion without distant recurrence
NSABP B-14, Distant Recurrence
Distant recurrence over time
100%
10-Year rate of recurrence = 6.8%*
90%
95% CI: 4.0%, 9.6%
80%
10-Year rate of recurrence = 14.3%
70%
95% CI: 8.3%, 20.3%
60%
10-Year rate of recurrence = 30.5%*
95% CI: 23.6%, 37.4%
50%
40%
All Patients, n = 668
30%
RS < 18, n = 338; 51%
20%
RS 18-30, n = 149; 22%
10%
RS ≥ 31, n = 181; 27%
P < 0.001
0%
0
2
RS, Recurrence Score® result
4
6
8
10
12
14
16
Years
*10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
46
Oncotype DX® Clinical Validation:
NSABP B-20
•
Objective: Prospectively determine the magnitude of chemotherapy
benefit in node-negative, ER+ patients as a function of Recurrence
Score® result
Tam + MF
Randomized
Tam + CMF
Tam
•
Multicenter study with prespecified 21-gene assay, algorithm,
endpoints, analysis plan
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
47
Proportion without distant recurrence
High Recurrence Score® Result Correlates with
Greater Benefit from Chemotherapy (NSABP B-20)
1.0
0.9
0.8
PATIENTS WITH HIGH RS
28% absolute benefit from
tamoxifen + chemotherapy
0.7
0.6
0.5
N
Events
0.4
All patients
Tamoxifen + chemotherapy
Tamoxifen
424
227
33
31
P = 0.02
0.3
RS < 18
Tamoxifen + chemotherapy
Tamoxifen
218
135
8
4
P = 0.61
0.2
RS 18-30
Tamoxifen + chemotherapy
Tamoxifen
89
45
9
4
P = 0.39
RS ≥ 31
Tamoxifen + chemotherapy
Tamoxifen
117
47
13
18
P < 0.001
0.1
0
2
4
6
8
10
4.4% absolute benefit
from tamoxifen +
chemotherapy
12
Years
RS, Recurrence Score result
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
48
Meta-Analysis: Overall Impact of
Recurrence Score® on Treatment Decisions
Treatment plan prior
to Oncotype DX®
Treatment
plan after RS
12%
88%
4% change
CT + HT
HT
Treatment
plan after RS
52%
48%
33%
change
Overall, the RS led to a 37% change in treatment decisions
• 33% from CT + HT  HT
• 4% from HT  CT + HT
RS, Recurrence Score result
Hornberger J, et al. SABCS 2010. Poster P2-09-06.
49
2014 ESMO poster
Schema: TAILORx Study Design
Objective: Determine whether adjuvant hormonal therapy is not inferior to adjuvant
chemohormonal Rx for patients in the “primary study group” (RS 11-25)
Node-Neg, ER-Pos Breast Cancer
Register
Specimen banking
Oncotype DX® Assay
RS 11-25
RS < 11
Hormone
Therapy
Registry
Randomize
Hormone Rx
vs.
Chemotherapy + Hormone Rx
RS >25
Chemotherapy
+
Hormone Rx
Primary study
group
51
S1007: RxPONDER Trial Schema and Patient Flow
Node-positive (1-3 nodes)
HR-positive and HER2-negative RS < 25
RECURRENCE
SCORE
RS > 25
(N= 3,800)
Discuss alternative trials
for high risk patients
RS < 25
N= 5,600
Physician and patients
discuss randomization
knowing the RS
STEP 2
REGISTRATION/
RANDOMIZATION
N= 4,000
Randomization
stratified by
1. RS
0-13 vs. 14-25
2. Menopausal status
3. Axillary node
dissection vs.
Sentinel node
biopsy
N= 2,000
Chemotherapy;
appropriate endocrine
therapy
N= 2,000
No Chemotherapy;
appropriate endocrine
therapy
BRCA carriers – management strategies
• Optimal surgery is bilateral mastectomy – extended surgery
benefits mortality reduction in second decade
• Risk of 2nd BC in contral breast 28-36% at 15 yrs
• 20 year mortality 26 – 30%
• Oophorectomy prevents recurrence, death,
ovarian cancer, second 1y breast cancer
• Chemotherapy needed even for small node negative cancers
• Chemotherapy – more data on cisplatin needed to confirm
the high 60% pCR rate in neoadjuvant series
• Combination of cisplatin and oophorectomy
53
Conclusions
• Translational & clinical research have helped to advance
targeted therapeutics for early and advanced breast
cancers
• Validated evidence exists to support incorporation of
molecular and genomic diagnostics into treatment
decision algorithms in early breast cancers for adjuvant
targeted therapy and chemotherapy
• sparing treatment resources & toxicities
• Novel targeted therapies for both HER+ or HER-/HR+
diseases have revolutionized treatment strategies and
improved patient outcomes
54
Systemic therapy for advanced
recurrent or metastatic HER2+
breast cancers
When to give what – hormones, chemotherapy,
targeted therapy?
55
Metastatic or
Recurrent HER2+ disease
1st line
ADC
2nd line
T-DM1 is a novel Antibody-Drug-Conjugate (ADC)
for HER2-positive metastatic breast cancer
Linker
• ADCs consist of:
– monoclonal antibody that targets
receptors
– stable linker
– potent cytotoxic agent
DM1
• ADCs target tumour cells to
deliver the cytotoxic specifically
to cancer cells
– ADCs minimises the effects on
normal tissue
– reduces cytotoxic
side effects
Gerber et al. mAbs 2009.
Trastuzumab
Trastuzumab Emtansine (T-DM1): Mechanism of
Action
Trastuzumab-specific MOA
• Antibody-dependent cellular
cytotoxicity (ADCC)
• Inhibition of HER2 signaling
• Inhibition of HER2 shedding
HER2
T-DM1
Emtansine
release
P
Inhibition of
microtubule
polymerization
P
P
Lysosome
Internalization
Nucleus
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
EMILIA Study Design
HER2+ (central)
LABC or MBC
(N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic tx or
within 6 mos of
adjuvant tx
T-DM1
3.6 mg/kg q3w IV
1:1
Capecitabine
1000 mg/m2 orally bid, days 1–14, q3w
+
Lapatinib
1250 mg/day orally qd
2nd line therapy for HER2+ MBC
Verma et al , NEJM 2012
PD
PD
Overall Survival: Confirmatory Analysis
Median (months) No. of events
Cap + Lap
25.1
182
T-DM1
30.9
149
Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006
1.0
Proportion surviving
85.2%
Efficacy stopping boundary P=0.0037 or HR=0.727
0.8
78.4%
64.7%
0.6
51.8%
0.4
6m median OS &
13% 2yr OS gain
0.2
0.0
0
2
4
No. at risk:
Cap + Lap 496 471 453
T-DM1
495 485 474
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
159 133 110 86
197 164 136 111
63
86
45
62
27
38
17
28
7
13
4
5
Time (months)
435 403 368 297 240 204
457 439 418 349 293 242
Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).
Systemic therapy for advanced
recurrent or metastatic HER2-/HR+
breast cancers
When to give what – hormones, chemotherapy,
targeted therapy?
61
Conclusions
• Translational & clinical research have helped to advance
targeted therapeutics for early and advanced breast
cancers
• Validated evidence exists to support incorporation of
molecular and genomic diagnostics into treatment
decision algorithms in early breast cancers for adjuvant
targeted therapy and chemotherapy
• sparing treatment resources & toxicities
• Novel targeted therapies for both HER+ or HER-/HR+
diseases have revolutionized treatment strategies and
improved patient outcomes
62