1. health and fitness
2. disease
3. cancer

Hormone receptor-positive, HER2-positive breast
cancer – which target dominates the phenotype
20th Annual NOCR meeting
Las Vegas, February 28th 2014
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
HER2 trumps ER when both
receptors are expressed…..
But is this true for all HR+ HER+ breast cancers?
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
PCR is prognostic in ER- cancer but not ER+
cancers that co-express HER2
ER-negative, HER2-positive
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
• Patterns of recurrence differ (ER+
more common in bone)
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)
• Can we identify this subgroup that is
driven by ER?
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
C40601: HER2+ Subtypes by
Hormone Receptor (HR)
HR-negative
HR-positive
Carey et al Proc ASCO 2013
Prognostic ability of 70-gene signature in
HER2+, ER+ cancers: untreated patients (n = 89)
21-gene signature not useful as HER2+ cancers have
intermediate or high recurrence scores
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 HER2 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 (more important than
chemotherapy)
Excellent outcomes for small ER+ HER2+ cancers
treated with trastuzumab-based chemotherapy
Tolaney SABCS 2013
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-
* NeoSphere: PCR 6% with dual HER2 inhibition without ER inhibition
npCR = < 1cm residual cancer in the breast
Rimawi CCR 2013
TEL trial: Pre-operative Trastuzumab,
everolimus and letrozole in HR-positive,
HER2-positive breast cancer (PI O’Regan)
HER2 +
ER+
breast
cancer
Stratify:
ER/PR > 50%
ER±PR < 50%
Trastuzumab
Letrozole (± LHRH agonist)
Everolimus
12 weeks*
Primary endpoint: PCR
*Adjuvant trastuzumab-based chemotherapy at
physicians discretion
Case history
• 46-year old with recent diagnosis of
stage 1A (T1B (8mm), N0), grade 2, ER
90%, PR 90%, HER2+ (FISH+) cancer
status post bilateral mastectomies
• Wants to avoid chemotherapy
• 70-gene signature: good prognosis
• Opts not to receive chemotherapy
• Receiving trastuzumab and tamoxifen
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
• Molecular profiling should be looked at in
more depth in these cancers