Overcoming HER2 Targeted Therapy: Ongoing ChallengesDr Yoon-Sim YAP （葉 詠心）(엽영심 )Division of Medical Oncology,National Cancer Centre Singapore

Global Breast Cancer Conference 2016

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Outline

• Understanding the Biology of HER2+ Tumours• Challenges

– Mechanisms of Action of Anti-HER2 Therapies– Mechanisms of Resistance to Anti-HER2 Therapies

• Potential Therapeutic Strategies• Conclusion

(Only selected concepts/examples will be covered.)

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Understanding the Biology

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The HER2 Network

Arteaga et al, Nat Rev Clin Oncol 2012

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“Bleak Outcome” to “Best Outcome”

Dawood et al, JCO 2010

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Are all HER2+ Breast Tumours the Same?

• Why do some patients with metastatic HER2+ breast cancers seem to be long term survivors while others progress rapidly even with anti-HER2 therapies??

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HER2-derived prognostic predictor (HDPP)

Staaf et al, JCO 2010

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HER2-derived prognostic predictor (HDPP)

Staaf et al, JCO 2010

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Heterogeneity of Somatic Mutations (TCGA)

Ng et al, JNCI 2015

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Are all “HER2+” tumours HER2-enriched subtypes?

Carey et el, JCO 2016

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Are all “HER2+” tumours HER2-enriched subtypes?

Carey et el, JCO 2016

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Recommendations for HER2 Testing in Breast Cancer: ASCO/CAP ClinicalPractice Guideline Update

Wolff et al, JCO 2013

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HER2 Heterogeneity Affects TrastuzumabResponses and Survival in Patients With HER2-Positive Metastatic Breast Cancer

Lee et al, Am J Clin Path 2014

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In-situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer

Janiszewska et al, Nature Genetics 2015

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Heterogeneity of Circulating Tumour Cells (CTCs)

Leong et al, AACR 2016

HER2 equivocalHER2 gene copy number 

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ZEPHIR Trial – Molecular Imaging to predict outcomes on TDM-1

Gebhart et al, Ann Onc 2016

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Ongoing Challenges

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Mechanisms of Action of Anti-HER2 Therapies

Rimawi et el, AnnuRev Med 2015

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Potential Mechanisms of Resistance to Anti-HER2 Therapies

• Within the HER Network Receptor Layer• Compensatory Alternative Signaling and Survival

Pathways• Hyperactivation of Downstream Kinase Pathways• Deregulation of Apoptotic and Cell-Cycle Control

Regulators• Host and Tumour Microenvironment-Associated

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Within the HER2 Network

• Truncated forms of HER2 (eg p95-HER2) which lack the trastuzumab-binding epitope.

• More Constitutively Activated Receptors– HER2 extracellular –domain splice variant 16, which increases

stabilisation of HER2 homodimers.– Activating mutations in the kinase and the extracellular domains

of HER2• Decrease or Increase in HER2 Expression• Increased Expression of HER1 and/or HER3(Prof Yoon),

or excess ligands for these receptors.

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Truncated HER2 (p95HER2)• Expressed in

~1/3 HER2+ tumours.

• High p95HER2 associated with worse outcomes in metastatic and non-metastatic setting.

• ? differential sensitivity to lapatinib; not proven.

Pohlmann et al, CCR 2009; Arribas et al, Ca Res 2011; Scaltriti et al, JNCI 2007; Sperinde CCR 2010; Guaneri et al, Oncologist 2015; Scaltriti et al, CCR 2015

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HER2 extracellular-domain splice variant 16• HER2Δ16 forms stable

dimers, couples to multiple oncogenic signaling pathways and cooperates with Srckinase to promote cell invasion.

• HER2Δ16 expression is significantly associated with node+ breast cancer.

• HER2Δ16 expression enhances cell tumorigenicity.

• HER2Δ16-expressing cells are trastuzumabresistant but are sensitive to dasatinib

Mitra et al, Molecular Cancer Therapeutics 2009

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Mutations in the kinase and the extracellular domains of HER2

• Previously described in HER2– tumors and recently in some primary and metastatic HER2+breast cancers

Park et al, Oncotarget 2015

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Increased expression of HER2

Vasquez‐Martin et al, Int J Oncol 2007

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells.

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Loss of/Decrease in HER2 Expression• Eradication of HER2+ clones may lead to expansion of

HER2- cells with clonal selection and heterogeneity.• Epithelial mesenchymal transition (EMT)

MartinCastillo et al, Oncotarget 2015

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Framework for predicting the response of clinical HER2+ tumours to trastuzumab?

MartinCastillo et al, Oncotarget 2015

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Other Mechanisms within the HER Network• Increased HER1 or HER3 expression (Prof Yoon) • Steric hindrance of HER2-antibody interaction by

membrane-associated glycoproteins eg MUC1, MUC4

Nagy et al, Ca Res 2005Pohlmann et al, CCR 2009

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Activation of Compensatory and Alternative Signaling and Survival Pathways

• Receptor Tyrosine Kinase– IGF-1R; c-MET

• ER and additional transcription factors Raghav et al, CCR 2012; Pohlmann et al, CCR 2009

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HER2-Estrogen Receptor (ER) Cross-Talk• Bi-directional signaling between

ER and HER2 • HER2 downstream activation can

lead to ER activation and endocrine therapy resistance

• Blockade of HER2 signalingleads to increased transcriptional activity of ER-related genes

• The combination of an antiestrogen with an HER2 inhibitor results in enhanced anti-tumor activity in preclinical models of ER+/HER2+ breast tumors.

Montemurro et al, Ann Onc 2013

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Hyperactivation of Downstream Kinase Pathways

• PTEN/PI3K/Akt (covered by Prof Im)

• SRC family kinases (SFK)– Resistance to lapatinib: Upregulation of SFK activity; associated

with PI3K-Akt signalling.– Resistance to trastuzumab: PTEN no longer capable of

dephosphorylating Src.– Src activity also involved in resistance conferred by D16 HER2

isoform.– Src kinase mediates at least part of the resistance conferred by

activation of the erythropoietin receptor. EpoR activates Src via Jak2 and Src associates with HER2, where it is proposed to phosphorylate and inhibit PTEN.

– Activation of EphA2 seen after chronic trastuzumab treatment and onset of trastuzumab resistance is also mediated through Src.

Zhang et al, Muthuswamy Nature Med 2011

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Activation of SRC and Trastuzumab Resistance

Zhang et al, Muthuswamy Nature Med 2011

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Deregulation of Apoptotic and Cell-Cycle Control Regulators

• Upregulation of cell-cycle positive regulators – eg amplification of cyclin E

• Downregulation of cell-cycle negative regulators – eg CDK inhibitor p27Kip1.

• Upregulation of prosurvival factors– eg survivin, antiapoptotic Mcl-1

• Downregulation of proapoptotic molecules– eg BIM

Scaltriti et al, PNAS 2011; Nahta et al, Ca Res 2004; Tanizaki et al, Oncogene 2011

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Host and Tumour Microenvironment-Associated Mechanisms of Resistance

• Trastuzumab triggers antibody-dependent cellular cytotoxicity (ADCC) by interacting with the Fc receptors on immune effector cells.

Pohlmann et al, CCR 2009

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Association of FcγR SNPs and Outcomes

Hurvitz et al, CCR 2012Mellor et al, J Haem Onc 2013

Analysis of FcgReceptorIIIa and IIaPolymorphisms: Lack ofCorrelation with Outcome in Trastuzumab-Treated Breast Cancer Patients in BCIRG006 Study

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Loi et al, Oncoimmunology 2013

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Predictive Value of Tumor-Infiltrating Lymphocytes (TILs) in Phase 3 Adjuvant Trials for HER2-PositiveBreast Cancer

Adams et al, JAMA Oncology 2016

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Challenges

• Complexity– Multiple drivers and/or pathways– Heterogeneity: spatial and temporal with tumour

evolution• Toxicities

Need something potent and all-encompassing to eradicate tumour before developing too many resistant subclones!

• CNS Metastases

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Potential Therapeutic Strategies

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What was Hot

• HER2/broad spectrum TKIs• Targeting HER3• Inhibition of mTOR• Inhibition of PI3K• Inhibition of IGFR• Inhibition of HSP90• Inhibition of angiogenesis• Vaccines

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Which ones went on to randomised Phase III trials

• Lapatinib/Neratinib/Afatinib• Pertuzumab• TDM-1• Everolimus• Pazopanib• Bevacizumab

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What is New and Hot now?

• ?CDK Inhibition• ? MM302 – HER2-targeted liposomal doxorubicin

Immunomodulatory Therapies• ? Immune checkpoint Inhibition• ? HER2-TDB (HER2 T cell bispecific antibody)

• ? NK cell Infusion• ? Vaccines

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Conclusions

• Understanding the biology of HER2+ breast cancers• Elucidating the Mechanisms of Resistance• Developing novel therapeutics• Designing the right trials for the right patients• Minimising the toxicities• Improving access!

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Thank you for your attention!