resistance to endocrine therapy in er+ breast cancer: insights from bedside...
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Resistance to Endocrine Therapy in ER+ Breast Cancer:
Insights from Bedside to Bench Studies
Carlos L. Arteaga, MD
Professor of Medicine
Director, UTSW Harold C. Simmons Comprehensive Cancer Center
Lisa K. Simmons Distinguished Chair in Comprehensive Oncology
Associate Dean of Oncology Programs
Disclosures
• Grant/Research Support from PUMA Biotechnology and Radius
• Consultant for Roche, LabCorp, AstraZeneca, Novartis, Lilly, Kiyatek, Radius, Symphogen and Celgene
• Stock/Shareholder in Provista
• Other Financial/Material Interest - Susan G. Komen Foundation (Board Member).
Targeted
Therapy
Chemotherapy
Anti-HER2 Therapy(trastuzumab, lapatinib,
pertuzumab, T-DM1)
Endocrine Therapy(tamoxifen, aromatase
inhibitors, fulvestrant)
Breast Cancer
Clinical Subtypes
75%
20%
15%
HER2
(ERBB2)
Triple
Negative
ERPR
Antiestrogen Therapies
• Reduction of estradiol levels in host and tumor
– Aromatase inhibitors (anastrozole, letrozole,
exemestane) and surgical or medical ovariectomy
(LHRH superagonists)
• Selective ER modulators (SERMs) with agonistic
and antagonistic activity
– Tamoxifen, raloxifene
• Pure antagonistic activity (partial downregulation
of ER)
– Fulvestrant, other investigational drugs
ER+ breast cancers exhibit a long-term risk of recurrence
0
0.1
0.2
0.3
0 1 2 3 4 5 6 7 8 9 10 11 12
Re
cu
rre
nc
e h
aza
rd r
ate
Years
Saphner et al. J. Clin. Oncol. 14:2738, 1996
ER/PR– (n=1305)
ER/PR+ (n=2257)
Sorlie et al. PNAS 100:8418-23, 2003
By gene expression, ER+ breast cancers can be
Luminal A or Luminal B (B is not that good)
Luminal B
Lower ER levels
PR negative
Higher mitotic rate
Higher tumor grade
TP53 mutations (?)
PAM50 score
Mammaprint
DAPI Pan-CK Ki67
10-25 ROIs per tumor
>10,000 nuclei counted
Short term estrogen deprivation with letrozole inhibits
tumor cell proliferation (Ki67) in ER+ breast cancers
Sensitive (54%)
Ln ≤1.0 (≤2.7%)
Intermediate (24%)
Ln 1.1-1.9 (2.8-7.3%)
Resistant (22%)
Ln ≥2.0 (≥7.4%)
Ln (2-wk %Ki67)<1.0 1.1-1.9 ≥2.0
Baseline category:
Lum A Lum B
Pre-ER
Post-ER
Pre-PR
Post-PR
Around 20% of ER+ cancers retain high proliferation (Ki67) after
short term estrogen suppression and harbor somatic
alterations associated with drug resistance
2-wk Ki67
Most frequent recurrent somatic alterations associated with resistance to
estrogen deprivation (letrozole)
PIK
3C
A
WH
SC
1L
1
FG
FR
1
CC
ND
1
FG
F3
,4,1
9
0
1 0
2 0
3 0
4 0
5 0
6 0
% O
cc
urre
nc
e
S e n s i t iv e
R e s is ta n t
m u t A M P
n s
* * * *
*
*
F is h e r 's E x a c t
* p 0 .0 5
* *p 0 .0 1
PIK
3C
A
WH
SC
1L
1
FG
FR
1
CC
ND
1
FG
F3
,4,1
9
0
1 0
2 0
3 0
4 0
5 0
6 0
% O
cc
urre
nc
e
S e n s i t iv e
R e s is ta n t
m u t A M P
n s
* * * *
*
*
F is h e r 's E x a c t
* p 0 .0 5
* *p 0 .0 1
Gitnane J, Hutchinson K, Stricker T, et al. Sci Transl Med 2017
MC
F7
-
FG
FR
1
DMSO Fulvestrant Lucitanib Fulv+Luci
MC
F7
-
eG
FP
β-actin
p-Erk1/2
ERα
FGFR1
MCF7-eGFP MCF7-FGFR1
*** p<0.001
Overexpression of FGFR1 attenuates response
to estrogen deprivation and to fulvestrant
ER+/FGFR1-amplified patient-derived xenografts are potently
inhibited by fulvestrant and FGFR TKI lucitanib
Formisano et al. Clin. Cancer Res. 2017
Comparison of mutational frequency between ER+ metastatic vs. primary tumor (in TCGA) suggest cancers change over time
ESR1
ERBB2
CCND1
CDKN2A
FOXP1
KRAS
MAP2K4
RB1
MYC
Significance
Enri
chm
ent
FGFR1
TP53
MBC N=149TCGA N=739
Mutation Type:SNVHigh amplificationBiallelic inactivation
Fisher's exact test
Courtesy of Nikhil Wagle, MD (presented at SABCS 2015)
Targeted therapies against mechanisms
of endocrine resistance
Mechanisms of endocrine resistance
• HER2 amplification
• Ligand-independent ER, CCND1
amplification
• PIK3CA mutations bbbbbbb
• FGFR1 amplification
• ESR1 mutations, amplification,
fusions
• HER2 mutations
Targeted
therapies
Trastuzumab, lapatinib, T-DM1
CDK4/6 inhibitors (palbociclib)
TORC1 inhibitors (everolimus), pan-
PI3K and PI3Kα inhibitors
FGFR inhibitors
Fulvestrant (?), novel ER
antagonists/degraders
Neratinib
S310FBladder: 1Breast: 3Cervical: 1Colorectal: 2Lung adeno: 2Ovarian: 2 Stomach: 1CCLE: 1 (bladder)
L755S/M/P/W
Breast: 4Colorectal: 2Endometrial: 1Kidney (pap): 1Melanoma: 1Stomach: 1CCLE: 3 (colorectal, stomach, brain)
V777L/ABreast: 1Colorectal: 2GBM: 2
V842IBreast: 1Colorectal: 4Endometrial: 2CCLE: 4 (Lung, ovarian, endometrial)
R678QBreast: 1Colorectal: 1Endometrial: 1Stomach: 2CCLE: 1 (colorectal)
774-776insLung adeno: 6CCLE: 1 (lung)
Rec L domain Furin-like Rec L domain Kinase domain
ERBB2 mutation hotspots across cancer types
ERBB2 mutant (L755_E757delinsS) ER+/HER2– breast carcinoma
Confirmed PR: 70% reduction by RECIST following neratinib monotherapy
Baseline 8 weeks 16 weeks
Extraordinary response of patient with breast cancer
to HER2 (ERBB2) tyrosine kinase inhibitor neratinib
HER2 mutations confer resistance to estrogen deprivation (aromatase inhibitors) and to fulvestrant
W T G 3 0 9 A L 7 5 5 S V 7 7 7 L
0
5
1 0
1 5
2 0
G ro w th in E s tro g e n D e p r iv a t io n
Ce
ll C
ou
nt
x1
04
/mL
* * * ** * * *
ns
W T G 3 0 9 A L 7 5 5 S V 7 7 7 L0
1 0
2 0
3 0
4 0
5 0G ro w th in 1 M F u lv e s tra n t
% V
iab
ilit
y c
om
pa
red
to
DM
SO
co
ntr
ol
* * * *
* * * *
ns
T a rg e te d W T G 3 0 9 A L 7 5 5 S V 7 7 7 L
0 .0
0 .5
1 .0
1 .5
2 .0
5
1 0
1 5
E R E R e p o r te r A s s a y
Fo
ld C
ha
ng
e o
f
Re
lati
ve
to
DM
SO
co
ntr
ols
V e h ic le
E s tra d io l
F u lv e s tra n t
F u lv + E 2
T a rg e te d W T G 3 0 9 A L 7 5 5 S V 7 7 7 L0
5
1 0
1 5
2 0
2 5
Ce
ll C
ou
nt
x1
05/m
L
D M S O
1 u M F u lv e s tra n t
2 0 0 n M N e ra tin ib
C o m b in a tio n
- 9 1 %
- 9 1 %
- 6 7 % - 7 1 %
n s
n s
- 7 3 % - 5 3 %
n s
- 4 2 %
- 5 4 % - 5 1 %
Estrogen rescues ER+/HER2 mutant cells:Combined blockade of HER2 and ER is required
Croessman S, ….., Arteaga CL. Unpublished
Exceptional response to dual blockade of mutant HER2 and ERin a patient with ER+/HER2 lobular breast cancer
ERBB2 mutant (S310F) ER+/HER2– lobular breast cancer
Complete response by RECIST and PET response criteria after 8 weeks
Patient had progressed on prior fulvestrant therapy
SUMMIT Trial: CR following neratinib + fulvestrant
Hyman et al, 2015 San Antonio Breast Cancer Symposium
Targeted therapies against mechanisms
of endocrine resistance
Mechanisms of endocrine resistance
• HER2 amplification
• Ligand-independent ER, CCND1
amplification
• PIK3CA mutations bbbbbbb
• FGFR1 amplification
• ESR1 mutations, amplification,
fusions
• HER2 mutations
Targeted
therapies
Trastuzumab, lapatinib, T-DM1
CDK4/6 inhibitors (palbociclib)
TORC1 inhibitors (everolimus), pan-
PI3K and PI3Kα inhibitors
FGFR inhibitors
Fulvestrant (?), novel ER
antagonists/degraders
Neratinib
PIK
3C
A
TP
53
TCGA: PI3K pathway mutations are the most common
in breast cancer, particularly in ER+ (luminal) tumors
PIK3CA (p110a) mutations are
gain-of-function oncogenes
Vector H1047RE545KWild-type
DM
SO
BK
M1
20
MCF10A cells
Chakrabarty et al. Oncogene 2010
p110a
P-Akt
Akt
ERK
P-ERK
P-S6eIF4E
exon 9 exon 20
E545K
E542KH1047R
Combined inhibition of ER and PI3K induces complete
regression of ER+/PIK3CA-mutant MCF7 LTED xenografts
Miller et al. Cancer Discovery 1:338, 2011
Some reasons why PI3K inhibitors are not
inducing exceptional responses (as many
expected them to do)
• Insulin production is increased upon inhibition of PI3K
• Therapeutic inhibition of PI3K is followed by
compensatory upregulation of several RTKs (ERBB
receptors, Ins/IGF-IR, FGFRs), ERa, BCL2
• PI3Ka inhibitors are not mutant specific so they also
inhibit the wild type enzyme
• ‘Dialing up’ inhibition of PI3K causes severe rash and
hyperglycemia, thus inhibition of PI3K is suboptimal and
transient
11/2013 08/2014
PIK
3C
AH
10
47
R
04/2013 03/2014
PIK
3C
A D
44
7-L
45
5_
de
lCombination of PI3Ka inhibitor alpelisib and letrozole
is active against breast cancers with mutant PIK3CA
0 6 12 18
H1047R
E545K
Q546P
D939G, E78K, E726K
E542K
E545K
E545K
H1047R, E542Q
C420R
E545K, I273V
H1047R
Q546K
H1047R
P447_L455del
H1047R
H1047R
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Months on Treatment
Pati
en
tsPIK3CA
mutation
PD
PR
SD
Toxicity
Best response
(RECIST)
H1047R
Ø
Ø
H1047R
E542K
Duration on therapy: Letrozole + BYL719 (alpelisib)
Mayer et al. Clin Cancer Res 2016
PIK3CA C2 domain deletions disrupt binding of p110a to p85
P IK 3 C A W T 4 4 7 d e l 4 5 0 d e l
-8 0
-7 5
-7 0
-6 5
-6 0
A v e ra g e B in d in g E n e rg y o f
T o p 1 0 C o m p u ta tio n a l M o d e ls
Av
era
ge
Bin
din
g E
ne
rgy
dG
* * * *Croessmann S, et al. In review
Implications
• There are PIK3CA mutations outside the known
gene ‘hot spots’ that also associate with tumor
PI3K dependence and clinical benefit to PI3K
inhibitors that can be easily missed by assays
that do not sequence the whole PIK3CA gene
• Mutations in PIK3R1 (p85a), the regulatory
subunit of PI3K, that disrupt the association with
PIK3CA (p110a) should also respond to PI3K
inhibitors
Miller TW, et al. Cancer Discov. 2011;1(4):338-351.
CDK4/6 Is Required for Estrogen-Independent Growth
of ER+ Breast Cancer Cells
ERFulvestrant
PI3K inh
E2FBCL2
ProliferationSurvival
Aromatase
Inhibitor ERBB3 IGF1R
S6K mTOR EverolimuspS167
GATA3
PalbociclibCDK4CCND1
PIK3CA
pRb
Dual blockade of the ER pathway with ER and CDK4 inhibitors
First-Line, No Prior Endocrine Therapy
PALOMA2 MONALEESA2
Finn RS, et al. N Engl J Med. 2016;375(20):1925-1936. Hortobagyi GN, et al. N Engl J Med. 2016;375(18):1738-1748.
Number of patients at risk
PCB + LET 222 171 148 131 116 98 81 54 22 12 4 2
PAL + LET 444 395 360 328 295 263 238 154 69 29 10 2
Pro
gre
ss
ion
-F
re
eS
urv
iva
l,%
Time, months
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 24 27 30 33 21
Number of Events
Median (95% CI) PFS
HR (95% CI);
1-sided P value
194 (44%)
24.8
(22.1- NR)
0.58 (0.46-0.72);
P <.000001
137 (62%)
14.5
(12.9-17.1)
PAL +L ET
(N = 444)
PCB+LET
(N = 222)
P = 3.29 x 10-6 for superiority
ORF kinome screen in MCF7 cells treated with
fulvestrant ± CDK4/6 inhibitor ribociclib
Formisano L, ….., Arteaga CL. Unpublished
p-R
b
p-F
GF
R1
FGFR inhibitor lucitanib enhances action of fulvestrant and
palbociclib against MCF-7FGFR1 xenografts
Combined inhibition of ER, CDK4/6 and FGFR1 potently
inhibits growth of ERa/FGFR1-amplified breast cancers PDXs
Guardant 360 (plasma tumor DNA):
14/34 (41%) FGFR pathway alterations:
9/34 FGFR1 amplification
1/34 FGFR2 amplification
1/34 FGFR1 mutation (N546K)
2/34 FGFR2 mutation (N549K)
FGFR pathway aberrations correlate with progression on
therapy with antiestrogens plus CDK4/6 inhibitors
FGFR Inhibitors
Tabernero et al. JCO 33:3401-3408, 2015
Breast Cancer: 25 pts with
amplification (22 with
FGFR1, with FGFR2) 3/25
PRs (Investigator’s
Brochure)
JNJ-42756493
IC50 (nM)
BGJ398
IC50 (nM)
AZD4547
IC50 (nM)
Lucitanib
IC50 (nM)
FGFR1 < 1 4.55 < 1 21
FGFR2 < 1 28.1 < 1 41
FGFR3 1.05 19.5 2.52 51
FGFR4 < 1 376 40.6 --------------
FGFR3
(G697C)
1.90 28.8 5.25 --------------
VEGFR1 --------------- -------------- -------------- 1
VEGFR2 -------------- -------------- -------------- 1.1
VEGFR3 -------------- -------------- -------------- 7.1
PDGFRα -------------- -------------- -------------- 0.43
PDGFRβ -------------- -------------- -------------- 0.26
Phase Ib/II trial of fulvestrant + a CDK4/6 inhibitor + pan-FGFR
inhibitor in ER+/FGFR(1-4) amplified metastatic breast cancer
Primary Endpoints
• Safety, pharmacokinetics (phase Ib)
• Clinical Benefit Rate for 6 months (phase II)
Secondary Endpoints
• Progression Free Survival
• Overall response rate
Exploratory Endpoints
• Concordance of NGS and ctDNA (focusing
on FGFR1, FGFR2, FGFR3, FGFR4, CCND1,
CCND2, CDK4, CDK6, RB1 and ESR1 point
mutations, CDK4, CDK6, FGFR1, FGFR2
amplifications)
• FGFR1 FISH
• PD Assessments (serum phosphate,
sVGFR1, sVGFR2, FGF23, sFGFR2,
sFGFR3 and sFGFR4)
Randomization (2:1)
(after determination of MTD/ RP2D for FGFR inhibitor +
CDK4/6 inhibitor + fulvestrant combination)
Postmenopausal women with FGFR-altered*/ER+/HER2–
locally advanced or metastatic breast cancer that
progressed on/after AI therapy
N ~ 100 (phase Ib/II)
FGFR inhibitor +
CDK4/6 inhibitor +
fulvestrant
CDK4/6 inhibitor +
fulvestrant
* FGFR alteration = FGFR1-4
Targeted therapies against mechanisms
of endocrine resistance
Mechanisms of endocrine resistance
• HER2 amplification
• Ligand-independent ER, CCND1
amplification
• PIK3CA mutations bbbbbbb
• FGFR1 amplification
• ESR1 mutations, amplification,
fusions
• HER2 mutations
Targeted
therapies
Trastuzumab, lapatinib, T-DM1
CDK4/6 inhibitors (palbociclib)
TORC1 inhibitors (everolimus), pan-
PI3K and PI3Kα inhibitors
FGFR inhibitors
Fulvestrant (?), novel ER
antagonists/degraders
Neratinib
Acknowledgements
Ingrid Mayer, MD Julie Scott, RN
Ingrid Meszoely, MD Theresa Adkins
Vandana Abramson, MD Kathleen Sanders, RN
Brent Rexer, MD, PhD Violeta Sánchez
Melinda Sanders, MD Tammy Lewis-Burgan
Valeria Estrada, MD
Ariella Hanker, PhD James Pauff, MD, PhD
Valerie Jansen, MD, PhD Jena Giltnane, MD, PhD
Yao Lu, PhD Katie Hutchinson, PhD
Justin Balko, PharmD, PhD Luis Schwarz, MD
Luigi Formisano, MD Kyung-min Lee, PhD
Christian Young, PhD Angel Guerrero, MD
Neil Bhola, PhD Teresa Dugger
Monica Red-Brewer, PhD Preston Moore
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