2013 SABCS Review
Shou-Ching Tang
MD, PhD, FACP, FRCP (C)
GRU Cancer Center
Disclosure
Nothing to declare
outline
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Prognostic and predictive biomarkers
Prevention
Early breast cancer
locally advanced breast cancer
Advanced breast cancer
Targeted therapy
Conclusion
Prognostic and predictive biomarkers
Genetic landscape of MBC
Bachelot et al, #S6-07, SABCS 2013
• Exome sequencing of 100 pairs of MBC and normal
breast tissue DNA (Integragen Inc, Hiseq platform)
• Targeted sequencing of 100 genes in 240 MBC
biopsies
• PIK3CA 26%, AKT1 4%, PTEN 4%, ERBB 2%, K-Ras 1%,
ATM 1%, CDH1 2%, GATA3 2%. PTPN11 1%, PTPRD
1%, ROS1 1%
• Many of them are drugable and involved in
metastatic process and drug resistance
Exome sequencing to identify
actionable mutations in mTNBC
Blackwell et al, S4-04, SABCS 2013
• 38 pts with mTNBC and matched specimens of
germ-line DNA, primary and metastatic tumors
• Whole-exome sequencing by Agilent solutionbased system of exon capture with 10 GB of
sequencing data
• Striking genetic heterogeneity between primary
and metastatic tumors
continues
Exome sequencing to identify actionable
mutations in mTNBC
Blackwell et al, S4-04, SABCS 2013
• No single driver mutation that was common to
metastatic tumors, indicating diverse genetic
pathways contributing to metastasis
• Mutations in APC and mTOR more frequent in
metastatic than primary tumors
• Nonsense mutations of ER in primary and metastatic
tumors but not in germ-line DNA
• EGFR and HER2 mutations not detected
Gene mutations and protein
expression in TNBC vs non-TNBC
O’Shaughnessy et al, #PD4-1, SABCS 2013
• 5500 pts evaluated for mutation (Sanger or Illumina
Truseq), protein expression (IHC) and/or
amplification/rearrangement (FISH or CISH), 16%
with TNBC
• Mutation: TNBC has higher p53 mutation (60% vs
30%), lower PIK3CA (12% vs 31%)
• Amplification: TNBC has higher amplification of EGFR
(24% vs 13%), lower HER2, PIK3CA, cMYC and TOP2A
• IHC: TNBC has higher AR (56% vs 15%)
Community-based NGS to guide clinical
trial selection
Yardley et al, abst PD4-3, SABCS 2013
• 594 advanced BC profiled
• Most frequently altered gene: PIK3CA (24%), followed by
RUNX1 (4%) and FGFR3 (2%)
• Infrequent: PIK3R1, MET, KRAS, KIT, FGFR2, HER2, BRAF,
SMO, MYC, DDR2 and AKT1, one pt each
• 6% pts enrolled in phas I trials based on NGS (PI3K and
mTOR inhibitor), 29% pts potentially eligible for ongoing
trials at SCRI
• PIK3CA mutation accounted for 70% of 35% actionable
mutations detected
10
PI3KCA mutation predicts resistance in
HER2+/ER+ BC
Loibl et al, #S4-06, SABCS 2013
• Prospectively analyzed 512 pts from Geparsixto
and validated in 225 pts from GeparQuinto trials
• PI3KCA mutation found in 19.2% HER2+ tumors,
more in HER2+/ER+, 21.5%
pCR in pts with and without PI3KCA mutation
22.7 vs 43.6 %, p=0.001
with HER2+/ER+ tumors
6.5% vs 30.8%, p=0.005
No difference in HER2+/ER- tumors
42.9% vs 46.1%, p=0.852
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PIK3CA mutation and/or low PTEN predict
resistance to lapatinib and trastuzumab
Contreras, et al, #PD1-2, SABCS 2013
• Neoadjuvant L plus T (no chemo) x 12 wks
• 59 pts tested for PTEN (IHC) and 33 for PI3KCA
mutation (36% by NGS)
• pCR: overall 16%
high vs low PTEN
32% vs 9% p=0.04
PIK3CA mutation:
0% p=0.06
low PTEN and PIK3CA mutation vs normal:
0% vs 36%
p=0.01
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Prognostic value of tumor infiltrating
lymphocytes (TIL’s)
• % of lymphocyte infiltration in tumor stroma
reflects host immune reaction
• The presence of TIL’s was correlated with benefit
from:
– trastuzumab in HER2+ EBC in 156 pts from the
neoadjuvant GeparQuattro trial (Loi et al, #S1-05,
SABCS 2013)
– the addition of carbo to neoadjuvant therapy in TN
and HER2+ EBC in Geparsixto trial (Dunkert, et al, #S106)
– adjuvant therapy in ECOG 2197 and 1199 in TNBC
(Adams et al, #S1-07, SABCS 2013)
SWOG S0500 CTC’s in guiding CT in MBC
Smerage et al, #S5-07, SABCS 2013
(CTC found in 75% MBC, half >5CTC/7.5 ml whole blood)
Primary end point: OS
SWOG S0500 CTC’s in guiding CT in
MBC
Smerage et al, #S5-07, SABCS 2013
• Conclusion:
– CTC prognostic in MBC at baseline and after first
chemo
– Changing chemo based on CTC after first chemo
does not affect OS or PFS
prevention
IBIS-II Chemo-prevention in high risk
postmenopausal women
Cuzick et al, #S3-01, SABCS 2013
• Randomized phase III UK trial
• 3864 women with high risks of BC, median
f/u 5.03 yrs
• Primary end point: incidence of BC, including
DCIS
• Anastrozole vs placebo for 5 years
IBIS-II: Chemo-prevention in high risk
postmenopausal women
Cuzick et al, #S3-01, SABCS 2013
• 5-yr BC incidence: 53% reduction, p<0.0001
• Significant reduction in all invasive BC (50%), ER+ BC
(58%) and DCIS (70%)
• Significant reduction of cancer at other sites (RR=0.58)
• Deaths from BC and other causes similar in both arms
• Musculoskeletal and vosomotor events higher and
bone # non-significantly higher in anastrozole arm
• In support of other chemoprevention trials: TAM
(NSABP P-1), raloxifen (STAR)and exemestane (MAP3)
Early breast cancer
Hormone and physical exercise (HOPE)
in EBC
Irwin et al, #S3-03, SABCS 2013
• Randomized phase III multicenter US trial
• 121 pts on adjuvant AI for > 6 m and with >3/10 worst
joint pain on Brief Pain Inventory-Short form (BPI)
• 150 min/wk mod-intense aerobic exercise and twicewkly supervised resistance exercise or usual care
• Primary end point: change in BPI worse joint pain
score between 0-12 momths
• reduction of BPI score (20% vs 3% , p=0.017), joint
pain intensity (p=0.025), body wt (p=0.0057) and
increase in cardiopulmonary fitness (p=0.024)
• Impact on adherence to AI’s and survival?
Bisphosphonates and survival in EBC:
meta-analysis
Coleman et al, #S4-07, SABCS 2013
36 randomized trials, 22,982 pts
Primary end point: time to recurrence, to first distance recurrence
and breast cancer mortality
Bisphosphonates and survival in EBC:
meta-analysis
Coleman et al, #S4-07, SABCS 2013
All pts
BC mortality
distance recurrence
Post-menopausal pts
BC mortality
distance recurrence
RR
10-yr gain % 2p value
0.91
0.92
1.7
1.3
0.04
0.05
0.83
0.83
3.1
3.3
0.004
0.0007
Bisphosphonates and survival in EBC:
meta-analysis
Coleman et al, #S4-07, SABCS 2013
• Reduction in bone relapse in postmenopausal pts
similar regardless of type of BP tx, duration and
schedule or concomitant chemotherapy
• Adjuvant BP improves survival in postmenopausal
pts with EBC
• No benefit in premenpausal pts in bone or other
recurrences
• Currently indicated for prevention or treatment of
bone loss
Phase II study of TH in HER2+ and
node- EBC
Tolaney, S et al, #S1-04, SABCS 2013
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410 pts, HER2+ EBC
T1mi 3%; T1a 27%, T1b 20%, T1C 41%, T2<3 cm 9%
Wkly paclitaxel x12 with trastusumab for one year
Null hypothesis: 3-year failure rate of 9.2% (failure)
Alternative hypothesis: 3-year failure rate of 5%
(success)
• Due to limited number of events, DMSB approved data
release with 1316 PYFU and median f/u of 3.2 years
TH in node-/HER2+ EBC
• TH is highly effective and well tolerated
• Can be considered an option in majority of stage
1 HER2+ EBC
• Single arm study, 67% HR+ tumor, limited follow
up of 3.6 years
• Superior survival data suggest not all pts with
stage 1 HER2+ EBC require trastuzumab-based
chemotherapy, esp those with T1aN0 tumor
• Addition of another biological agent to TH
backbone is unlikely to have substantial benefit in
this pt population (TDM-1 vs TH ongoing)
Primary results of BETH trial in
HER2+, node+ or node- high risk EBC
Slamon D et al, #S1-03, SABCS 2013
3509 pts, phase III
Median f/u 3 years
Invasive disease-free survival
(IDFS)
BETH Trial
Docetaxel x 6
Carboplatin x 6
Trastuzumab x 1 y
or
Docetaxel x 3
Trastuzumab x 1 y
Bevacizumab 15mg
q3 wk x 1 y
92%
5-FU x 3
Epirubicin x 3
Cylophos x 3
8%
Observation
BETH primary result
• Addition of one year bevacizumab to
chemotherapy did not prolong invasive diseasefree survival (IDFS)
• TCH is an effective adjuvant regimen for pts with
HER2+ EBC, including node+ tumors
• No new or unexpected safely signals
• No added benefit of bev in MBC, LABC and EBC in
unselected pts, biomarker studies urgently
needed (ongoing repeat of ECOG trial with
biomarkers included)
GIM-2 EC or FEC with dd P or not in node+
EBC
Cognetti et al, # S5-06, SABCS 2013
• Italian multicenter randomized phase III 2x2
design
• 2019 pts, node+, < 70 yo, median f/u 7 yrs
• EC x4 or FEC x4 then P q 2 (with G) or 3 wks x4
• Primary end point: DFS
• DD CT improved DFS and OS : HR 0.78 (p=0.007)
and 0.68 (p=0.002) respectively
• Benefit of DD CT independent of HR status
• Addition of F to EC did not improve outcome
PRIME II: Adjuvant RT in pts > 65 yo
Kunkler et al, #S2-01, 2013 SABCS
• Multicenter UK trial, 1326 pts, median f/u 5 yrs
• >65 yo, T 1-2 (up to 3 cm), N0/M0, HR+, margin > 1mm, could
be grade 3 or LVI but not both, required adjuvant hormonal
therapy
• Primary end point: ipsilateral breast tumor recurrence
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–
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–
–
IBTR
OS
Regional relapse
Contralateral relapse
Distance relapse
no RT (%)
4.1
93.8
1.4
0.9
1.0
RT (%)
1.3
94.2
0.5
1.9
0.3
p
0.01
0.24
• Results similar to CALGB, ECOG and RTOG trial (pASCO 2010)
• Omission of adjuvant RT safe in selected older pts
10-yr survival update of NSABP B-32
Julian et al, #S2-05, SABCS 2013
• Randomized phase III of SLND plus ALND or
ALND
• 5611 pts
• Still no difference in OS, DFS and loco-regional
relapse (HR 1.09, p=0.35; HR 1.02, p=0.72; HR
0.96, p=0.77 respectively)
• No difference in OS and DFS in pts with occult
mets detected by IHC with or without ALND
• IHC has no prognostic role in EBC
Locally advanced breast cancer
Neo ALTTO Survival update
Piccar-Gebhart, M et al, #S1-01, SABCS 2013
Invasive operable
HER2+ BC
T > 2 cm
(inflammatory BC
excluded)
LVEF  50%
N=450
Stratification:
• T ≤ 5 cm vs. T > 5 cm
•ER or PgR + vs.
ER & PgR –
• N 0-1 vs. N ≥ 2
•Conservative surgery
or not
R
A
N
D
O
M
I
Z
E
trastuzumab
paclitaxel
lapatinib
trastuzumab
paclitaxel
6 wks + 12 wks
Median f/u 3.77 years
lapatinib
lapatinib
paclitaxel
S
U
R
G
E
R
Y
trastuzumab
lapatinib
trastuzumab
34 weeks
52 weeks of anti-HER2 therapy
NeoALTTO Efficacy – pCR and tpCR
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response HR: hormone receptors
Baselga J et al. SABCS 2010; abstract S3-3
NeoALTTO survival update
• First study to show that pts with pCR had
significantly better EFS and OS with HER2+
tumors
• Study was powered to detect difference in
pCR, but underpowered to detect moderate
difference in survival
• Dual HER2 blockade is superior
• HER2+/HR- and HER2+/HR+ subgroups are
different diseases
TRIO-US B07 final analysis
Hurvitz S et al, #S1-02, SABCS 2013
• Randomized phase II of neoadjuvant H or L or
both in stage 1-3, HER2+ EBC
• 106 pts in 13 US centers, primary end point, pCR
• Run-in cycle of H or L or both followed by 6 cycles
of TCH (A) vs TCL (B) or TCHL (C)
• Overal pCR: 42% (A 43%, B 25% and C 52%,
p=0.069)
• Pair-wise comparison: pCR in B significantly lower
than C (p=0.021), not different between A and B
(p=0.14) and A and C (p=0.45)
CALGB 40603 (Alliance) neoadjuvant carbo
+/- Bev in TNBC
Sikov et al, #S5-01, SABCS 2013
2x2 randomized phase II in locally advanced TNBC in 545 pts
CALGB 40603 (Alliance) neoadjuvant carbo
+/- Bev in TNBC
Sikov et al, #S5-01, SABCS 2013
• pCR (%, breast and axilla):
No
Bev
Bev
Cb benefit
no Cb
Cb
28.2
42.4
42.6
50.0
10.3 p=0.033
Bev effect
10.5
p=0.031
• Addition of Cb or Bev to NAC significantly increases
pCR in TNBC, and the increases are additive
• Several studies now support the addition of Cb to
standard CT in LABC (CALGB 40604, GeparSixto and ISpy 2), adjuvant trials ongoing
I-SPY 2 TRIAL:
Learn, Drop, Graduate, and Replace Agents Over Time
Paclitaxel+
Trastuzumab
Randomize
HER 2 (+)
Paclitaxel +
Trastuzumab* +
New Agent A
Paclitaxel +
Trastuzumab* +
New Agent B
AC
Surgery
Learn and adapt from
each patient as we go
along
Paclitaxel
Paclitaxel ++
Trastuzumab*
Trastuzumab* ++
New
New Agent
Agent FC
Patient is
on Study
Paclitaxel
Key
Randomize
MRI
Residual
Disease
(Pathology)
HER 2
(–)
Paclitaxel +
F
New Agent C
Paclitaxel +
New
NewAgent
AgentGH
D
AC
Surgery
Paclitaxel +
New Agent E
*Investigational agent may be used in place
I-SPY 2: the first graduate
Rugo et al, #S5-02, SABCS, 2013
• Primary end point: pCR
• Graduate regimens have >85% Bayesian predictive
probability of success in a 300-pts biomarker-linked
neoadjuvant phase III trial
• Veliparib+carbo met the 85% predictive probability
criterion in HR-/HER2- and all HER2- pts
%
All HER2HR+/HER2TNBC
pCR
35 vs 20
14 vs 15
52 vs 24
p V+Cb better
97%
44%
99%
p of successful phase III
71%
16%
92%
• V/Cb graduated with a TNBC signature and recommended
for future trial
• Biomarker study? (lesson from iniparib)
NATAN, post-neoadjuvant zoledronate trial
von Minckwitz et al, #S5-05, SABCS 2013
• Randomized phase III trial in 693 pts with residual
tumor after at least 4 cycles of NAC with taxanes
and anthracyclines, median f/u 48 m
• Z q4wks x6m, q3mx2yrs and q6mx2.5 yrs for 5 yrs
vs no
• Primary end point: EFS at 5 years
• DFS: HR 0.96 p=0.7885
• OS: HR p=0.4082
• Decreased BC mortality in post-menopausal pts:
RR 0.83 (SE 0.06)
Metastatic breast cancer
Resection of primary BC and ALN in MBC
Badwe et al, #S2-02, SABCS 2013
• Randomized phase III trial, local regional treatment
(LRT) or not, 350 pts, median f/u 17 months,
• Primary end point: OS
• Median survival (M): 18.8 vs 20.5, HR=1.07, p=0.60
• Overall survival at 2-yr (%): 40.8 vs 43.3
• No difference in OS after adjusting age, ER, HER2,
site and # of metastasis in Cox regression model
(p=1.00)
• LRT should be reserved for palliative reasons
Resection of primary BC in de novo
stage IV MBC
Soran et al, #S2-03, SABCS 2013
• Randomized Turkish trial of LRT vs not, 278 pts,
median f/u 21.2 +/- 14.5 m
• Type of LRT and systemic therapy at the
discretions of SO and MO
• Primary end point: OS
• OS at 5 m (%): 35 vs 31, p=0.24
• OS longer in pts with bone only, HR+, age <50 yr
but shorter in TNBC
• Ongoing US cooperative trial (E2108)
ROSE/TRIO-12 trial of ramucirumab in
MBC
Mackey et al, #S5-04, SABCS 2013
• Randomized multicenter phase III trial of
ramucirumab (anti-VEGFR2) or placebo in first
line HER2- MBC, with biomarker study
• 1144 pts, 1:2 randomization
• Primary end point: PFS
• Median f/u 16.3 m
Targeted therapy
Cross-talks among signal transduction
pathways
Dual function of YAP-1 in caner
Wang and Tang, Can and Met Rev, 2013
Letrozole plus dasatinib improves PFS
in MBC
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Paul et al, #S3-07, SABCS 2013
Randomized phase II multicenter USO trial
HR+, HER2- MBC first line, 116 evaluable pts
Adjuvant AI allowed if completed > 1yr before entry
Letrozole +/- dasatinib (Src TKI), cross over allowed
Primary end point: CBR (PR/CR/SD>6m)
DL
L
CBR (%)
71
66
PFS (M)
22
11
p=0.05
Toxicities: fatigue (38%), nausea (38%), anemia (25%), rash
(23%), pleural effusion (16%) and edema (13%)
27% pts required dose reduction for dasatinib
Other promising drugs: everolimus, palbociclib, HDACI,PI3KI
New Drugs to Overcome Resistance in
Hormonal Therapy
Afinitor
Product W
Product X
Product Y
Mechanism of
Action
•
mTOR inhibitor
•
CDK4/6 kinase
inhibitor
•
HDAC inhibitor
•
P13K inhibitor
Comparator
•
Exemestane
•
Letrozole
•
Exemestane
•
Fulvestrant
Median PFS
•
Afinitor +
Exemestane -7.8
months vs.
Exemestane
alone -3.2
months (HR =
0.45)
•
Product W +
Letrozole -26.1
months vs.
Letrozole alone
-7.5 months (HR
= 0.37)
•
Product X +
Exemestane -7.1
months vs.
Exemestane
alone -4.1
months (HR =
0.58)
N/A
Median OS
•
OS results are
not mature
N/A
Product X +
Exemestane -29.3
months vs.
Exemestane alone 22 months (HR =
0.75)
N/A
Ziaudinn and Tang
Review paper in preparation
Summary
• Genetic alteration is common in primary and
metastatic tumors and in tumors undergoing
treatment
• Identification of biomarkers and drugable
mutations by genome sequencing will not only
unravel mechanismS of drug resistance but
help to offer pts tailored targeted therapy
• TIL’s are associated with favorable response to
breast cancer chemotherapy
Summary-2
• Biosphophonates reduce tumor relapse in
postmenopausal women with EBC, current
approval is for their use in bone loss
• Pts with stage I HER2+ tumors may be offered
TH chemotherapy
• Anti-angiogenesis (bev and ramucirumab) is
unlikely effective in unselected pts with BC,
biomarker studies are urgently needed
Summary-3
• Veliparib and/or carboplatin added to taxane
backbone increase pCR in TNBC
• Surgical management of primary tumor in pts
with MBC does not improve survival and should
only be considered for symptom control and in
clinical trials
• Dasatinib increases the efficacy of letrozole in
MBC. Blocking cross talks of ER pathways will help
to overcome drug resistance
Acknowledgement
• Industry supporters: Amgen, Genomic Health
and Merck
• GRU support team: Susan Everitt, Lisa
Middleton and Caroline English
• GRU Cancer Center Leadership and
educational grant
Thank you