1. 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

2. 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 ER-positive 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

3. Outcome for patients with ER+ metastatic breast
cancer based on HER2 status
LET
ANAST
Progression free survival(months)
HER2-
HER2+/-
Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009, Bonneterre Cancer 2001,
Moridisen J Clin Oncol 2003, Nahta BRCT 2012

4. ER Target Gene Transcription
Why does HER2 cause endocrine-resistance?
IGF1R
EGFR/HER2
Increased upstream
signaling through
HER2/EGFR family
VEGFR P P P P P P
SOS
PI3-K
RAS
RAF
Akt
MEK
p90RSK
MAPK
Increased signaling
through PI3-K pathway
SERD AI T ER E2 P
p160
Basal
Transcription
Machinery
CBP ER
Cytoplasm
ERE
ER Target Gene Transcription
Nucleus
Plasma
Membrane
From Johnston CCR 2005

5. Pathologic complete response is consistently lower in
ER+ HER2+ breast cancers compared to
ER- HER2+ breast cancers T L
T/L P
T/P
P -> FEC
FEC -> P D
EC -> D
Percent PCR
Reviewed in Nahta and O’Regan BRCT 2012

6. DFS in HER2+ ER-negative breast cancers
based on PCR
von Mitchwitz et al SABCS 2011

7. 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

8. 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 ER-inhibition alone without HER2-inhibition
Perez J Clin Oncol 2011, Kaufman J Clin Oncol 2009

9. Why is this important?
We may (and probably are) over-treating 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)

10. 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

11. ER expression Likelihood of PCR is inversely related to level of
ER expression for HER2+ breast cancers
HER2+/HR-
HER2+/ER+
Percent PCR
HER2+/ER+++
ER expression
Bhargava Mod Path 2011, Nahta BRCT 2012

12. Prognostic ability of 70-gene signature in
HER2+, ER+ cancers: untreated patients (n = 89)
Knauer et al BJC 2010

13. Prognostic ability of 70-gene signature in
HER2+, ER+ cancers: all patients (n = 168)
Knauer et al BJC 2010

14. 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

15. x HER2 signaling decreases ER activation and inhibition of HER2
increases ER-regulated gene transcription ER
ERE
FOXO3a
PI3-K
AKT
HER2
HER1/2/3
ER-regulated gene transcription x
Ras
MEK
Erk1/2
Nucleus
Cytoplasm
Membrane
TKI
TRAST
Xia PNAS 2006, Valabrega Oncogene 2005

16. 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 ER-negative to ER-positive following trastuzumab-based chemotherapy
Mittendorf et al Clin Cancer Res 2009

17. Inhibition of ER and HER2 in ER+ HER2+
breast cancers in vivo
200
400
600
800
1000
1200
Tumor Volume (mm3)
Days E ED
ED + L
ED + T
ED + T + L
E = estrogen
ED – estrogen deprivation
T – Trastuzumab
L – lapatinib
L+T – Trast + Lap
M Rimawi. et al Clin Cancer Res 2011

18. Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks)
pCR
pCR + npCR 70 60 50
53%
56%
48% 40
pCR (%)
40% 30
28% 20
21% 10
All
ER+
ER -
All
ER+
ER-
npCR = < 1cm residual cancer in the breast
Chang Proc ASCO 2012

19. Conclusions ER plays a role in resistance to HER2-directed agents
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 HER2-directed agents

20. Possible schema for future clinical trials
ER-positive, HER2-positive breast cancer
Driven by ER
(high ER and PgR)
Endocrine therapy
+ HER2-directed agent
Driven by HER2
(Low ER and/or PgR)
Chemotherapy +
HER2-directed agent
± endocrine therapy
Nahta and O’Regan BRCT 2012