Metastatic Breast Cancer: A Research Update

Nancy Lin, MD

Clinical Director, Breast Oncology Center Susan F. Smith Center for Women’s Cancers

Dana-Farber Cancer Institute October 15, 2014

Overview

• Breast cancer subtypes

• Recent drug approvals

• Exciting research directions

• Clinical trials

• There are three main subtypes of breast cancer

• Within these, there are other ways to further sub-divide breast cancers

• Oncologists use the breast cancer subtype to guide the kinds of treatments to recommend

• Clinical trials often will focus on specific subtypes

Breast Cancer Subtypes

Breast cancer subtype Estrogen receptor and/or Progesterone receptor

HER2

ER-positive (Hormone receptor positive)

+ - HER2-positive + or - +++ Triple-negative

- -

Breast Cancer Subtypes

Breast Cancer Subtypes

Breast Cancer Subtypes

ER-positive

HER2-positive

Triple-negative

TALK to your doctor if you are not sure what type of breast cancer you have

Hormonal therapy

Hormonal therapy

Chemotherapy Chemotherapy

Chemotherapy Chemotherapy Chemotherapy

Herceptin + perjeta +

chemotherapy TDM1

Lapatinib + Capecitabine

Herceptin + chemotherapy

Herceptin + chemotherapy

Hormone receptor positive

Triple-negative

HER2-Positive

*Note, these are just examples. Each patient is different and treatment is tailored accordingly.

How Do We Treat

Metastatic Breast Cancer?

New Drug Approvals:

Everolimus (Affinitor)

Approved by the FDA in 2012 for patients with metastatic, hormone-receptor positive, HER2-negative breast cancer

• 3.2 months* Aromasin

•7.8 months* Aromasin + Affinitor

*Median time from study entry until worsening of cancer. The median overall survival was 26.5 months in the aromasin group and 31 months in the aromasin+ affinitor group.

Side effects: tiredness, mouth sores low blood counts, etc

New Drug Approvals:

Eribulin (Halaven)

Approved by the FDA in 2011

Halichondria okadai •Metastatic breast cancer •At least 2 prior chemotherapies

New Drug Approvals:

Pertuzumab (Perjeta)

Approved by the FDA in 2012 for first-line treatment of HER2+ metastatic breast cancer

• 40.8 months* Trastuzumab + docetaxel

•56.5 months* Trastuzumab+

Docetaxel + Pertuzumab

*Median overall survival of patients enrolled on study

Side effects: more diarrhea, rash, low blood counts

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

T-DM1 binds to the HER2 protein on cancer cells

HER2

New Drug Approvals: TDM1 (Kadcyla)

New Drug Approvals: TDM1 (Kadcyla)

• Tested versus lapatinib (Tykerb) plus capecitabine (Xeloda) in 2nd line: superior

• Tested versus “treatment of provider choice” in patients who had received multiple prior treatments: superior

Approved by the FDA in 2013 for HER2+ metastatic breast cancer previously treated with trastuzumab and a taxane

What’s New on the Horizon?

Polyak and Filho, Cancer Cell, 2012

Polyak and Filho, Cancer Cell, 2012

What’s Exciting in ER+ Breast Cancer

• Testing of CDK4 inhibitors in clinical trials

• Discovery of ESR1 mutations in metastases

• New estrogen receptor modulators

• PI3K inhibitors

• Many more…

The Cell Cycle Pathway

CDK4 inhibitors: Palbociclib Abemaciclib LEE011

What’s Exciting in Triple-Negative

Breast Cancer

• Discovery of distinct subtypes of triple-negative breast cancer

• PARP inhibitors/combinations

• Androgen receptor antagonists

• Platinum agents

Triple-Negative Breast Cancer

Is Not All the Same Disease

Lehmann et al, JCI 2011

PARP Inhibitors in BRCA Carriers

•Tumors of BRCA 1/2+ patients lose 2 important ways to repair DNA when treated with a PARP inhibitor •Multiple trials testing PARP vs chemo in BRCA 1/2 carriers right now

What’s Exciting in HER2+ Breast Cancer

• New HER2-targeted drugs

– some cross the BBB

• Combinations of HER2-targeted drugs

• PI3K inhibitors

New HER2-Targeted Agents

in Clinical Trials

• Neratinib

• Afatinib

• ARRY-380/ONT-380

• KD019

• MM-302

Polyak and Filho, Cancer Cell, 2012

Targeting the PI3Kinase Pathway

Drugs Targeting PI3K in Trials

• BYL719

• GDC0032

• BKM120

• GDC 0941

• Many others

Immunotherapy

The Promise and Perils of “Specialty Gene Testing”

Obtain tumor

biopsy material

Extract DNA/RNA from

tumor to profile for somatic alterations

No proof as of yet that results of these tests should alter “standard of care” treatment. Primary purpose in breast cancer in 2014 is to identify patients for clinical trials

“I’m interested in clinical

trials. How can I find out if

there is one right for me?

Think about your goals and priorities

• Trials range in complexity, frequency of study visits, time commitment, need for travel.

– Ask yourself, what makes sense for me?

Educate yourself

• Learn what subtype of breast cancer you have

• Learn about the types of clinical trials

• Talk to your doctor and/or nurse

• Learn about your family history and consider BRCA testing

• Check out on-line resources

• Consider a second opinion at an academic practice with a focus on clinical trials

Types of Trials

Phase Typical # patients Visit intensity What is known about the drug

Randomization

I 15-30 Often high First-in-human, Or new combo

Typically no

II 30-50 (non randomized) 50-200 (randomized)

Intermediate Some preliminary data from phase I

Depends on trial

III Several hundred Usually the lowest

Typically have a good sense of the side effect profile and some preliminary anti-tumor results

Typically yes

On-Line Resources Organization Website

National Cancer Institute www.cancer.gov/clinicaltrials

National Cancer Institute www.cancer.gov/clinicaltrials/education/questions-to-ask-about-participating

American Society of Clinical Oncology

www.cancer.net/patient/All+About+Cancer/Clinical+Trials

American Cancer Society www.cancer.org/Treatment/TreatmentsandSideeffects/Clinicaltrials/index

Living Beyond Breast Cancer

http://www.lbbc.org

Breastcancertrials.org www.breastcancertrials.org

U.S. National Institutes of Health

www.clinicaltrials.gov www.nih.gov/health/clinicaltrials/findingatrial.htm

Coalition of cancer cooperative groups

www.cancertrialshelp/org/cancer-trial-search/

Hospital websites Many; look for academic institutions in your region

Summary

• Not all breast cancers are alike

• We have many clues and we are making progress

• But we need clinical trials and continued basic and translational research to make new breakthroughs for metastatic breast cancer