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

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

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

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

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

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?

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

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

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

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

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 (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) 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

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

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