Slide 1

Dana-Farber Cancer InstituteMetastatic Breast Cancer Forum 2016Research update for HER2-positive breast cancerShom Goel MD PhDInstructor in Medicine, Harvard Medical SchoolSeptember 24, 2016

What is HER2-positive breast cancer?15-20 percent of breast cancer is HER2-positive

Abundance of HER2 protein on cancer cellsAmplification of the HER2gene in tumor cells

HER2-positive metastatic breast cancer

Relapse after treatment for early stage breast cancer

De novo metastatic breast cancer

How is HER2-positive MBC treated?The primary treatment of HER2-positive MBC is with systemic medical therapyi.e. drugsSurgery and radiotherapy may play a role in specific situations

FDA-approved drugs for HER2-positive MBC

Herceptin(Trastuzumab, 1998)

Perjeta(Pertuzumab, 2012)

Lapatinib(Tykerb, 2005)

IV vs oralImmune effects of antibodiesUnique aspects of T-DM15

FDA-approved drugs for HER2-positive MBC

Kadcyla(T-DM1, 2013)

Perjeta(Pertuzumab, 2012)

Lapatinib(Tykerb, 2005)

IV vs oralImmune effects of antibodiesUnique aspects of T-DM16

FDA-approved drugs for HER2-positive MBC

Perjeta(Pertuzumab, 2012)

Lapatinib(Tykerb, 2005)

IV vs oralImmune effects of antibodiesUnique aspects of T-DM17

FDA-approved drugs for HER2-positive MBC

Perjeta(Pertuzumab, 2012)

Lapatinib(Tykerb, 2005)

IV vs oralImmune effects of antibodiesUnique aspects of T-DM18

The main issue we face today is drug resistanceIn many (not all) situations, HER2-positive MBC will respond well to existing therapies However, over time cancer cells develop resistance to existing therapiesIf we could completely overcome drug resistance, the disease would become chronic and/or curable

What causes treatment resistance?

Growing in certain locationsTumor heterogeneity

Turning off the immune system

Changes in cell signaling

10

How can we study treatment resistance?

In cellsIn miceIn our patientsInformation from clinical trialsBiopsies of drug resistant tumors

Two examples from our laboratory (1)

Resistant tumor cells respond to the CDK4/6 inhibitor abemaciclibCyclin D1A new transgenic mouse model of HER2-positive breast cancer

Goel et al Cancer Cell 2016

Combination of Herceptin and abemaciclib overcomes drug resistancePatient-derived xenograft

Goel et al Cancer Cell 2016

Two examples from our laboratory (2)Patient-derived models of HER2-positive brain metastasis

Ni, Ramkissoon, Xie et al Nature Medicine 2016

Updates from our laboratoryBoth of these findings are being translated into clinical trials for patients

New agents on the horizonPI3-kinase inhibitorsCDK4/6 inhibitorsImmune therapiesNew HER2 inhibitorsmTOR inhibitorsAntibody-drug conjugatesProgress is real and continuing

We have every reason to be optimistic

Thanks for your attention