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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
• Conclusions 2
Hong Kong Cancer statistics 2012
27%
14%
3
70%
41%
4
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
Projection of breast cancer incidence
Site Model(1) 2012 actual
2020 projected
2030 Projected (95%PI)(2)
% chg(3) (vs 2012)
Projected no. by stage in 2030(4)
I II III IV
Female breast 3 3,508 4,580 6,000 (5,720-6,270) +71 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.
Projection
5
2030
6
Female breast cancer statistics worldwide: Estimated age-standardized incidence and mortality rates in 2012
Country/City Incidence (per 100,000)
Mortality (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 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.
Trends in breast cancer mortality in HK
APC= -0.1 (p=0.25)
7
8
Relative survival rates of Breast cancer patients, 1997-2001
Annals of Surgery 2011
9
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
10
Relative survival (%) by receptor, 1997-2006
ER 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
PR
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
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
+14%
+8%
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
number of positive axillary lymph nodes
0%
20%
40%
60%
80%
5-Y
ea
r S
urv
iva
l
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.
high
risk
very high
risk
low
intermediate
risk
Heterogeneity in Breast Cancer
Evolution of selection criteria for adjuvant systemic therapy in early breast cancers
15
TNM
Grade
• Clinical & histopathology parameters
ER, PR, cerbB2
• Immunohistochemistry
• Molecular diagnostics
RS, ROR
BRCA
• Genomic tests
• Genetic tests
Adjuvant online!
Tumors
Cells
Genes
Nottingham prognostic index (UK): • T size • histological grade • axillary node+ number
Early Breast Cancer Trialist Collaborative Group Lancet. 2011; 378: 771–784.
Recurrence: All ER+, 13%^
BC mortality: All ER+, 9%^
Lancet 2008; 371: 29–40
Adjuvant chemotherapy in estrogen-receptor-poor breast cancer:
5872 patient-level meta-analysis of randomised trials
Recurrence 9-12%^ 10yr
Breast cancer mortality 6-9%^ 10 yr
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
clinicaloptions.com/oncology
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
HER2 Overexpression Shortens Survival
HER2 oncogene amplification
HER2 oncoprotein
overexpression
Shortened survival Median Survival From First Diagnosis
HER2 overexpressing 3 yrs
HER2 normal 6-7 yrs Slamon DJ, et al. Science. 1987;235:177-182.
Slamon DJ, et al. Science. 1989;244:707-712.
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
KLINIK UND POLIKLINIK
FÜ R FRAUENHEILKUNDE UND GEBURTSHILFE
KLINIKUM DER UNIVERSITÄ T MÜ NCHEN®
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 Low risk
Chemotherapy + AHT
Chemotherapy AHT
Chemotherapy + Trastuzumab +/- AHT
Harbeck, Salem, Gluz et al, 2010
ADJUVANT RX ALGORITHM
26
clinicaloptions.com/oncology
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Normal (1x) ~ 25,000-50,000 HER2
receptors
Overexpressed HER2 (10-100x)
up to ~ 2,000,000 HER2 receptors
Excessive cellular division
HER2 Overexpression in Breast Cancer
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.
HER2 is overexpressed in
~ 25% of breast cancers
ErbB / HER receptors in breast cancer
Ligands
ErbB1 ErbB3 ErbB4
Differentiation Cell cycle progression, proliferation,
survival, apoptosis
ErbB2
Tumour
cell membrane
1. Huang et al. Cancer Res 2010; 70:1204–1214; 2. Rowinsky. Ann Rev Med 2004; 55:433–457
Signaling activity
+ + + + + + + + + + +
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
HER2 Containing Dimers Induce Potent Mitogenic Signaling
HER1:HER2 HER2:HER2 HER2:HER3 HER2:HER4
Mechanism & sites of action of targeted agents in
ErbB2+ breast cancer
VEGF
Ligands
ErbB1
Lapatinib inhibits ErbB1 and
B2 phosphorylation; neratinib inhibits ErbB1, B2 and B4(?)
phosphorylation
ErbB3 ErbB4 VEGFR
Angiogenesis Differentiation Cell cycle progression, proliferation,
survival, apoptosis
ErbB2
Pertuzumab blocks ErbB2/3
interaction Bevacizumab
blocks VEGF
interaction
with receptor
Endothelial
cell membrane
Tumour
cell membrane
Trastuzumab blocks ErbB2
activation
Adjuvant Trastuzumab studies
• 4 large randomized phase III studies
• All showed reduced recurrences (6 – 16%) and improved survivals (8%)
31
Study Treatments DFS RR reduction
Overall survival
HERA Chemo-H vs chemo
86% at 2yr (vs 78%)
46%
BCIRG 006
TCH/AC-TH vs AC-T
86-88% at 3yr (vs 82%)
33-40%
B31/N9831 (joint analysis)
AC-TH vs AC-T
87% at 3.5yr (vs 71%)
52%
87% at 8.3yr (vs 79%)
H=herceptin AC=adriamycin +cyclophospamide
T=paclitaxel TC=docetaxel +carboplatin
8% gain
無病存活率
Adjuvant Lapatinib (ALTTO) Schema
HER2+
ESBC
+ Trastuzumab X 1 year
+ Lapatinib X 1 year
+ Trastuzumab + Lapatinib X 1 year
+ Trastuzumab X 3 months →
Lapatinib X 9 months
Treatment arms after chemotherapy:
Piccart & Perez,
34
TCa = 6 cycles of docetaxel and carboplatin
Completed recruitment
on 31-Aug-2013
APHINITY ADJUVANT TRIAL (n=4805)
node negative
Biologic Heterogeneity – „intrinsic" subtypes
Sorlie et al., PNAS, 2001; 100: 10869-74
“Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications“
Survival months
RFS
Therapeutic recommendations in breast cancer
Harbeck Dtsch Med Wochenschrift, 2013; 138: 180-2
Luminal A Luminal B Intrinsic subtype
Clinical
classification
Therapeutic
recommendation
Basal-like Her2+
Endocrine
therapy
Chemotherapy
endocrine
Chemo-
therapy
Trastuzumab +
chemotherapy ±
Endocrine therapy
ER and PR
positive
Proliferation
(Ki-67) low
Recurrence
risk low
Chemotherapy (preferably
neoadjuvant)
ER a/o PR
positive ER and PR
and Her2
negative
Her2 positive
Proliferation
(Ki-67) high
Recurrence
risk high
Wissenstransfer in klinische Testsysteme, Prosigna™
2000
Researchers first describe
breast cancer intrinsic subtypes
based on microarray
experiments
2009
Researchers first describe
“PAM50” gene expression
signature
2010
NanoString exclusively licenses
PAM50 gene expression
signature
2012/13
Prosigna launches
after receiving CE
Mark for Europe &
Israel; FDA 510k
clearance in US
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
8192 genes 50 genes
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
ROR (Risk of Recurrence) Score (Tumor size + nodal status)
Prosigna (PAM50) ROR Scoring
The Oncotype DX Recurrence Score® Result
uses Key Genes Linked to Critical Molecular Pathways
16 BREAST CANCER RELATED GENES
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
ER
PR
Bcl2
SCUBE2
GRB7
HER2
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
Stromelysin 3
Cathepsin L2 GSTM1
CD68
BAG1
Beta-actin GAPDH RPLPO GUS TFRC
5 REFERENCE GENES
Estrogen Proliferation HER2 Invasion Others
43
The Recurrence Score® Result Assesses
Individual Tumor Biology for ER+ Breast Cancer
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.
Dis
tan
t re
curr
en
ce a
t 1
0 y
ear
s
Recurrence Score value
CONTINUOUS BIOLOGY 4 0 %
3 5 %
3 0 %
2 5 %
2 0 %
1 5 %
1 0 %
5 %
0 % 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
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
44
Oncotype DX® Clinical Validation: NSABP B-14
• Objective: Prospectively validate the Recurrence Score® result as a predictor of distant recurrence in node-negative, ER+ patients
• Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan
Randomized
Registered
Placebo—not eligible
Tamoxifen—eligible
Tamoxifen—eligible
Paik S, et al. N Engl J Med. 2004;351:2817-2826. 45
Oncotype DX® Clinical Validation:
NSABP B-14, Distant Recurrence
Distant recurrence over time
10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6%
0 2 4 6 8 10 12 14 16
Years
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Pro
po
rtio
n w
ith
ou
t d
ista
nt
recu
rren
ce
RS < 18, n = 338; 51%
RS 18-30, n = 149; 22%
RS ≥ 31, n = 181; 27%
All Patients, n = 668
P < 0.001
10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3%
10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4%
*10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001
RS, Recurrence Score® result
46
• Objective: Prospectively determine the magnitude of chemotherapy
benefit in node-negative, ER+ patients as a function of Recurrence
Score® result
• Multicenter study with prespecified 21-gene assay, algorithm,
endpoints, analysis plan
Tam
Oncotype DX® Clinical Validation: NSABP B-20
Randomized
Tam + MF
Tam + CMF
Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 47
High Recurrence Score® Result Correlates with
Greater Benefit from Chemotherapy (NSABP B-20)
RS, Recurrence Score result
Pro
po
rtio
n w
ith
ou
t d
ista
nt
recu
rren
ce
Years
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
2 4 6 8 10 12 0
4.4% absolute benefit
from tamoxifen +
chemotherapy
N Events
All patients Tamoxifen + chemotherapy
Tamoxifen
424
227
33
31 P = 0.02
RS 18-30 Tamoxifen + chemotherapy
Tamoxifen
89
45
9
4 P = 0.39
RS < 18 Tamoxifen + chemotherapy
Tamoxifen
218
135
8
4 P = 0.61
N Events
RS ≥ 31 Tamoxifen + chemotherapy
Tamoxifen
117
47
13
18 P < 0.001
PATIENTS WITH HIGH RS
28% absolute benefit from
tamoxifen + chemotherapy
Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 48
Meta-Analysis: Overall Impact of
Recurrence Score® on Treatment Decisions
52% 48% 88% 12%
Treatment plan prior to Oncotype DX®
Treatment plan after RS
Treatment plan after RS
CT + HT
HT
Overall, the RS led to a 37% change in treatment decisions • 33% from CT + HT HT • 4% from HT CT + HT
4% change 33% change
Hornberger J, et al. SABCS 2010. Poster P2-09-06.
RS, Recurrence Score result
49
2014 ESMO poster
Schema: TAILORx Study Design
Node-Neg, ER-Pos Breast Cancer
RS < 11 Hormone Therapy Registry
RS 11-25 Randomize
Hormone Rx vs.
Chemotherapy + Hormone Rx
RS >25 Chemotherapy
+ Hormone Rx
Oncotype DX® Assay Register
Specimen banking
Primary study group
Objective: Determine whether adjuvant hormonal therapy is not inferior to adjuvant chemohormonal Rx for patients in the “primary study group” (RS 11-25)
51
S1007: RxPONDER Trial Schema and Patient Flow
Node-positive (1-3 nodes)
HR-positive and HER2-negative RS < 25
RECURRENCE
SCORE
(N= 3,800)
Discuss alternative trials
for high risk patients
N= 5,600
Physician and patients
discuss randomization
knowing the RS
N= 2,000
Chemotherapy;
appropriate endocrine
therapy
N= 2,000
No Chemotherapy;
appropriate endocrine
therapy
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
RS > 25 RS < 25
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
1st line
2nd line
Metastatic or Recurrent HER2+ disease
ADC
• ADCs consist of:
– monoclonal antibody that targets receptors
– stable linker
– potent cytotoxic agent
• ADCs target tumour cells to deliver the cytotoxic specifically to cancer cells
– ADCs minimises the effects on normal tissue
– reduces cytotoxic side effects
T-DM1 is a novel Antibody-Drug-Conjugate (ADC) for HER2-positive metastatic breast cancer
Gerber et al. mAbs 2009.
Linker
DM1
Trastuzumab
Trastuzumab Emtansine (T-DM1): Mechanism of Action
Emtansine
release
Inhibition of
microtubule
polymerization
Internalization
HER2
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
T-DM1
Lysosome
Nucleus
P P
P
Trastuzumab-specific MOA
• Antibody-dependent cellular
cytotoxicity (ADCC)
• Inhibition of HER2 signaling
• Inhibition of HER2 shedding
EMILIA Study Design
1:1
HER2+ (central)
LABC or MBC
(N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic tx or
within 6 mos of
adjuvant tx
PD
T-DM1 3.6 mg/kg q3w IV
Capecitabine
1000 mg/m2 orally bid, days 1–14, q3w
+
Lapatinib 1250 mg/day orally qd
PD
Verma et al , NEJM 2012
2nd line therapy for HER2+ MBC
6m median OS &
13% 2yr OS gain
Overall Survival: Confirmatory Analysis
496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4
495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5
Cap + Lap
T-DM1
No. at risk: Time (months)
78.4% 64.7%
51.8%
85.2%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n s
urv
ivin
g
Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).
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
Efficacy stopping boundary P=0.0037 or HR=0.727
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