Transcript Who should have extended AI adjuvant therapy past 5 years

ER signalling in HER2-positive breast cancer
18th Annual Perspectives in Breast Cancer
New York, August 18th 2011
Ruth M. O’Regan, MD
Professor and Vice-Chair for
Educational Affairs, Department of
Hematology and Medical Oncology,
Emory University,
Chief of Hematology and Medical
Oncology, Georgia Cancer Center for
Excellence, Grady Memorial Hospital
HER2-positive breast cancers are
intrinsically resistant to endocrine therapy
• Transfection of ER-positive breast cancer
cells with HER2 renders them resistant to
tamoxifen
• Retrospective analyses of trials in the ERpositive metastatic setting show a worse
outcome for cancers that co-express HER2,
compared to those that do not
• Median progression free survival is less than
6 months for ER+ HER2+ MBC treated with
aromatase inhibitors
Benz BRCT BRCT 1992, De Laurentiis J Clin Oncol 2005,
Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009
Progression free survival(months)
Outcome for patients with ER+ metastatic breast
cancer based on HER2 status
HER2-
LET
HER2+/-
LET
ANAST
LET
ANAST
Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009, Bonneterre Cancer 2001,
Moridisen J Clin Oncol 2003, Nahta BRCT 2012
Why does HER2 cause endocrine-resistance?
IGF1R
VEGFR
P
P
EGFR/HER2
P
P
P
P SOS
RAS
RAF
PI3-K
MEK
Akt
p90RSK
MAPK
SERD
AI
ER
T
E2
Cytoplasm
PP P P
ER ER p160 CBP
ERE
Plasma
Membrane
Increased upstream
signaling through
HER2/EGFR family
Increased signaling
through PI3-K pathway
Basal
Transcription
Machinery
ER Target Gene Transcription
Nucleus
From Johnston CCR 2005
Percent PCR
Pathologic complete response is consistently lower in
ER+ HER2+ breast cancers compared to
ER- HER2+ breast cancers
T
L T/L T L T/L T L
P
P -> FEC
T/L T
L
FEC -> P EC -> D
T P T/P T/P T/L
D
Reviewed in Nahta and O’Regan BRCT 2012
DFS in HER2+ ER-negative breast cancers
based on PCR
von Mitchwitz et al SABCS 2011
PCR is not prognostic in ER+ cancer regardless
of HER2 status
ER-positive, HER2-negative
ER-positive, HER2-positive
von Mitchwitz et al SABCS 2011
Other evidence supporting a
role for ER in HER2+ cancers
• In the adjuvant trastuzumab trials, DFS
is longer for ER+ cancers compared to
ER- cancers (at least up to 4-5 years)
• A subset of patients with ER-positive,
HER2-positive metastatic breast cancer
have prolonged disease control with ERinhibition alone without HER2-inhibition
Perez J Clin Oncol 2011, Kaufman J Clin Oncol 2009
Why is this important?
• We may (and probably are) overtreating a subgroup of ER+, HER2+
breast cancers in the (neo)-adjuvant
setting
• This subgroup of patients with ER+,
HER2+ breast cancers may suffer late
recurrences (similar to what we see
with luminal A cancers)
Is there an ongoing risk of recurrence for
HER2-positive breast cancers?
ER/PgR+ve
ER/PgR -ve
?
0.0
Number of patients at risk
HR+ placebo
927
880
845
814
789
757
626
420
193
HR– placebo
649
607
567
529
506
490
422
286
134
Goss SABCS 2011
Likelihood of PCR is inversely related to level of
ER expression for HER2+ breast cancers
Percent PCR
HER2+/HR-
HER2+/ER+
HER2+/ER+++
ER expression
Bhargava Mod Path 2011, Nahta BRCT 2012
Prognostic ability of 70-gene signature in
HER2+, ER+ cancers: untreated patients (n = 89)
Knauer et al BJC 2010
Prognostic ability of 70-gene signature in
HER2+, ER+ cancers: all patients (n = 168)
Knauer et al BJC 2010
Bi-directional cross-talk between ER
and HER2
• Signaling through EGFR family including HER2
down-regulates ER
• Conversely, inhibition of HER with
trastuzumab or lapatinib increases signaling
through ER
• ER signaling is increased in HER2-positive cell
lines that are resistant to HER2-directed
agents
• HER2 expression and activity is increased in
hormone-resistant cancers, compared to
hormone-sensitive cancers
Pinzone Mol Cell Biol 2004, Stoia J Endocrinol 2000, Sabnis Cancer Res 2009,
Xia PNAS 2006, Valabrega Oncogene 2005
HER2 signaling decreases ER activation and inhibition of HER2
increases ER-regulated gene transcription
TRAST
HER1/2/3
HER2
HER2
HER1/2/3
xx
Membrane
FOXO3a
Membrane
TKI
PI3-K Ras
PI3-K
Ras
AKT
AKT
MEK
MEK
Erk1/2
Cytoplasm
Erk1/2
Cytoplasm
FOXO3a
Nucleus
ER
ER
ERE
x
ER-regulated
gene
transcription
FOXO3a
Nucleus
ERER
ER-regulated
gene
transcription
ERE
Xia PNAS 2006, Valabrega Oncogene 2005
Clinical relevance of this cross-talk
• Inhibition of HER2 without inhibition of ER
may increase ER signaling allowing ER to act as
an escape mechanism
– This could contribute to the lower PCR seen in ER+
HER2+ breast cancers and have potential
implications in the metastatic setting
– There may be a subset of ER+ HER2+ breast
cancers where ER inhibition is critical
• Small series demonstrated a change from ERnegative to ER-positive following
trastuzumab-based chemotherapy
Mittendorf et al Clin Cancer Res 2009
Inhibition of ER and HER2 in ER+ HER2+
breast cancers in vivo
Tumor Volume (mm3)
1200
1000
E
800
ED
600
ED + L
400
200
ED + T
0
1
E = estrogen
ED – estrogen deprivation
T – Trastuzumab
L – lapatinib
L+T – Trast + Lap
25
ED + T + L
50 75 100 125 150 175 200 225
Days
M Rimawi. et al Clin Cancer Res 2011
Response to pre-operative trastuzumab
and lapatinib ± letrozole (12 weeks)
pCR + npCR
pCR
70
60
pCR (%)
50
40
30
20
10
0
28
%
21%
All
ER+
40%
53
%
56
%
48
%
ER -
All
ER+
ER-
npCR = < 1cm residual cancer in the breast
Chang Proc ASCO 2012
Conclusions
• Although HER2 signaling is associated with
intrinsic resistance to endocrine agents, a
subset of HER2+, ER+ cancers appear to be
driven, at least in part, by ER
• Identification of these cancers is crucial:
– They may require less aggressive treatment
approaches with earlier institution of ER inhibition
– May behave like ER+ HER2- cancers with late
relapses
• ER plays a role in resistance to HER2directed agents
Possible schema for future clinical trials
ER-positive, HER2-positive breast cancer
Driven by ER
(high ER and PgR)
Driven by HER2
(Low ER and/or PgR)
Endocrine therapy
+ HER2-directed agent
Chemotherapy +
HER2-directed agent
± endocrine therapy
Nahta and O’Regan BRCT 2012