ER signalling in HER2-positive breast cancer

18th Annual Perspectives in Breast CancerNew York, August 18th 2011

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

Why does HER2 cause endocrine-resistance?

From Johnston CCR 2005

ER Target Gene Transcription

SOS

P PP P

PI3-K

Akt

PP

RASRAF

MEK

MAPKp90RSK

ER

Pp160

BasalTranscriptionMachineryCBPERER

PP P

ERE

PlasmaMembrane

Cytoplasm

Nucleus

E2

SERD

AI T

IGF1REGFR/HER2

Increased signalingthrough PI3-K pathway

Increased upstream signaling throughHER2/EGFR family

VEGFR

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

DFS in HER2+ ER-negative breast cancers based on PCR

von Mitchwitz et al SABCS 2011

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

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

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)

0.0

Is there an ongoing risk of recurrence for HER2-positive breast cancers?

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

ER/PgR -ve

ER/PgR+ve

?

Goss SABCS 2011

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

Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89)

Knauer et al BJC 2010

Knauer et al BJC 2010

Prognostic ability of 70-gene signature in HER2+, ER+ cancers: all patients (n = 168)

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

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

• Small series demonstrated a change from ER-negative to ER-positive following trastuzumab-based chemotherapy

Mittendorf et al Clin Cancer Res 2009

Inhibition of ER and HER2 in ER+ HER2+ breast cancers in vivo

0

200

400

600

800

1000

1200

1 25 50 75 100 125 150 175 200 225

Tum

or

Volu

me (

mm

3)

DaysE = estrogenED – estrogen deprivationT – Trastuzumab L – lapatinibL+T – Trast + Lap

M Rimawi. et al Clin Cancer Res 2011

E ED

ED + L

ED + T ED + T + L

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

Chang Proc ASCO 2012npCR = < 1cm residual cancer in the breast

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

• ER plays a role in resistance to HER2-directed agents

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

Possible schema for future clinical trials

Nahta and O’Regan BRCT 2012