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

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

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

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

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

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)

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

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

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

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

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

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

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 200 400 600 800 1000 1200 1 25 50 75 100 125 150 175 200 225 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

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

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

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