Metastatic HER2+ Breast Cancer: Resistance

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Presentation transcript:

Overcoming Resistance to HER2-Targeted Therapy in Patients With Advanced Breast Cancer

Metastatic HER2+ Breast Cancer: Resistance

Overall Program Goals

Trastuzumab and Chemotherapy: Combination Index Scores for In Vitro Activity Against HER2+ BC Cell Lines

Trastuzumab: Activity in Combination With Multiple Chemotherapeutic Agents

BCIRG 007: Docetaxel + Trastuzumab vs Docetaxel + Carboplatin + Trastuzumab

BCIRG 007: Efficacy

HER2-Targeted Therapy Plus Endocrine Therapy

Trastuzumab Monotherapy Trials: Summary of Efficacy

Initial Treatment of HER2+ mBC

Initial Treatment of HER2+ mBC (cont)

Initial Treatment of HER2+ mBC

Is HER2 Still a Relevant Target After Progression With Trastuzumab?

Oncogene Addiction: Trastuzumab Beyond Progression in HER2+ mBC

Capecitabine vs Capecitabine + Trastuzumab: Time to Progression*

Capecitabine vs Capecitabine + Lapatinib

Combination of HER2-Directed Agents (Dual Blockade)

Total Blockade of HER2 May Provide Greater Antitumor Activity and Overcome Resistance

Lapatinib +/− Trastuzumab After Progression With Trastuzumab: PFS

Trastuzumab + Lapatinib in HER2+ mBC

NeoALTTO: Benefit of Combining HER2 Agents

First-Line Treatment of HER2+ mBC (Prior Trastuzumab Exposure)

Capecitabine vs Capecitabine + Lapatinib

Capecitabine vs Capecitabine + Lapatinib (cont)

Is Lapatinib Active After Progression?

HER2 Remains a Valid Target After Progression With Trastuzumab

Defining Trastuzumab Resistance

HER2 Signaling Pathway—Mechanisms of Trastuzumab Resistance

Mechanisms of Trastuzumab Resistance

HER2 Status After Preoperative Trastuzumab-Based Therapy

p95: A Truncated Form of the HER2 Protein

p95 Expression: Associated With Decreased Response Rates to Trastuzumab-Based Therapy

GeparQuattro Study Schema

Mechanisms of Trastuzumab Resistance (cont)

HER2:HER3 Dimers: A Trastuzumab Escape Mechanism?

Mechanisms of Trastuzumab Resistance (cont)

HER2+ Breast Cancer: Frequent Alterations in PI3K Pathway Signaling Components

Interaction Between PTEN Protein Status and Treatment Arm: Disease-Free Survival

HER2 Resistance: Critical Questions

First…the Bad News

Mechanisms of Trastuzumab Resistance (cont)

High Risk of Brain Metastases in Patients With HER2+ mBC

Median Survival (mo) After CNS Diagnosis by Subtype

LANDSCAPE: Phase 2 Lapatinb + Capecitabine as Upfront Therapy

Brain Metastases in HER2+ mBC

Summary