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 ANASTPro

gre

ssio

n f

ree s

urv

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

PC

RPathologic 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

PC

R

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%

Bas

al-lik

e 15

% Norm

al-lik

e 7

%

Lum A 16%HER2-E 52%

HER2-E 18%

Lum B 34%

Lum A 43%

Norm

al-lik

e 1

0%

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)

0

10

20

30

40

50

60

pC

R (

%)

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