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Hormone receptor-positive, HER2-positive breast cancer – which target dominates the phenotype 20 th Annual NOCR meeting Las Vegas, February 28 th 2014. Ruth M. O’Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University, - PowerPoint PPT Presentation
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Hormone receptor-positive, HER2-positive breast cancer – which target dominates the phenotype
20th Annual NOCR meetingLas Vegas, February 28th 2014
Ruth M. O’Regan, MDProfessor 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 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
LET LET LETANAST ANASTProg
ress
ion
free
surv
ival
(mon
ths) HER2- HER2+/-
Outcome for patients with ER+ metastatic breast cancer based on HER2 status
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?
T TTTT LLLL T/LT/LT/LT/L P T/P T/P
P P -> FEC FEC -> P DEC -> D
Perc
ent P
CRPathologic complete response is consistently lower in
ER+ HER2+ breast cancers compared to ER- HER2+ breast cancers
Reviewed in Nahta and O’Regan BRCT 2012
PCR is prognostic in ER- cancer but not ER+ cancers that co-express HER2
von Mitchwitz et al SABCS 2011
ER-negative, HER2-positive ER-positive, HER2-positive
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
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?
HER2+/HR-
HER2+/ER+
HER2+/ER+++
Perc
ent P
CR
ER expression
Likelihood of PCR is inversely related to level of ER expression for HER2+ breast cancers
Bhargava Mod Path 2011, Nahta BRCT 2012
C40601: HER2+ Subtypes by Hormone Receptor (HR)
Lum B 6%
Basa
l-like
15%
Norm
al-like 7%
Lum A 16% HER2-E 52%
HER2-E 18%
Lum B 34%
Lum A 43%
Normal-like 10%
HR-negative HR-positive
Carey et al Proc ASCO 2013
Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89)
Knauer et al BJC 2010
21-gene signature not useful as HER2+ cancers have intermediate or high recurrence scores
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
ERER
ERE
FOXO3a
PI3-K
AKT
HER2 HER1/2/3
FOXO3a
ER-regulated gene transcription
x
Ras
MEK
Erk1/2
Nucleus
Cytoplasm
Membrane
ERER
ERE
FOXO3a
PI3-K
AKT
HER2 HER1/2/3
ER-regulated gene transcription
Ras
MEK
Erk1/2
Nucleus
Cytoplasm
Membrane
TKIxx
TRAST
HER2 signaling decreases ER activation and inhibition of HER2 increases ER-regulated gene transcription
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)
0102030405060
pCR
(%)
70
All ER+ ER -
40%
21%28%
53%
56%
48%
All ER+ ER-
pCR pCR + npCR
Rimawi CCR 2013npCR = < 1cm residual cancer in the breast
*
* NeoSphere: PCR 6% with dual HER2 inhibition without ER inhibition
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%
TrastuzumabLetrozole (± LHRH agonist)Everolimus12 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