1. 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

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. HER2 trumps ER when both receptors are expressed…..
But is this true for all HR+ HER+ breast cancers?

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. 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

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
Patterns of recurrence differ (ER+ more common in bone)
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)
Can we identify this subgroup that is driven by ER?

10. 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

11. C40601: HER2+ Subtypes by Hormone Receptor (HR)
HR-negative
HR-positive
Normal-like 7%
Normal-like 10%
Lum B 6%
Basal-like 15%
HER2-E 18%
Lum B 34%
Lum A 16%
HER2-E 52%
Lum A 43%
Carey et al Proc ASCO 2013

12. 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

13. 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

14. 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

15. 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)

16. Excellent outcomes for small ER+ HER2+ cancers
treated with trastuzumab-based chemotherapy
Tolaney SABCS 2013

17. Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks)
pCR
pCR + npCR 70 60 *
* NeoSphere: PCR 6% with dual HER2 inhibition without ER inhibition 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
Rimawi CCR 2013

18. 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 18

19. 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

20. 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