Metastatic Breast Cancer and Emerging Research

Kathryn J. Ruddy, MD MPHAssistant Professor of Oncology

Mayo Clinic

Overview

• What is metastatic disease?• Breast cancer subtypes

– Treatment of Her2+ disease– Treatment of ER+ disease– Treatment of ER-/Her2- disease

• Exciting new research directions

Metastatic breast cancer

• Stage IV disease– Has spread from the breast and axillary lymph

nodes to other organs

• Accounts for 5-10% of all breast cancer at the time of diagnosis

• Stage IV breast cancer is usually incurable, but can often be controlled for years utilizing sequential drug therapy

Treatment for metastatic disease

• Treated primarily with systemic therapy, but sometimes with palliative radiation also; surgery is rarely utilized

• After the disease develops resistance to one drug, a patient is switched to a new drug

• Aims of therapy are to:– Prolong time to progression– Prolong survival– Palliate

• Reduce tumor burden• Minimize treatment toxicity

• Disease subtype is critical to treatment decision-making

• There are three main subtypes of breast cancer

• Oncologists use breast cancer subtype to guide treatment decisions

• Clinical trials often focus on specific subtypes

Breast cancer subtypes

Subtypes

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

Slide courtesy of Nancy Lin

Hormone receptorpositive

Triple-negative

HER2-Positive

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

Slide courtesy of Nancy Lin

Treatment

HER2+ disease: a paradigm for advances in

targeted therapy

HER2+ disease: major advances

• HER2 is an important target; anti-HER2 drugs can be effective with chemo, with endocrine therapy, or alone

• Meaningful progress has been made with novel therapies that are well tolerated

• Resistance is a major challenge but new technologies are allowing this to be overcome

1998

TrastuzumabApproved

2002

First PreoperativeTrials Reported Paving

The Way For Use inEarly Stage Disease

2005

Three LargeAdjuvant Trials

Reported

2005

LapatinibApproved

2007-2008

Initial Trialsof T-DM1,Neratinib

2010

PreoperativeTrials of

Dual Blockade

PertuzumabApproved

2012

2013

T-DM1Approved

Slide courtesy of Ian Krop

Trastuzumab in HER2+ metastatic breast cancer

Graphic adapted from image at http://www.gene.com/gene/research/focusareas/oncology/herpathwayexpertise.jsp

Protein Receptor

HER2 Gene

Normal Cell

HER2+ Cell

Slamon et al, NEJM 2001

Can combine with many different chemotherapies (e.g., paclitaxel, docetaxel, vinorelbine, capecitabine) and

targeted agents (e.g., lapatinib)

Lapatinib

• Oral dual tyrosine kinase inhibitor of HER2 and EGFR

• FDA approved in combination with capecitabine for trastuzumab-resistant disease

• May have CNS penetration

• Well tolerated; common toxicities include rash and diarrhea

Geyer et al, NEJM 2006

Pertuzumab with trastuzumabHER2 receptor

Trastuzumab

Pertuzumab

Dimerisation domain of HER2

• Inhibitor of HER dimerization: binds HER2 and prevents formation of homo- or heterodimers

• Suppresses activation of several intracellular signaling cascades driving cancer cell growth

• Synergistic with trastuzumab• Approved for first-line treatment of metastatic Her2+ breast cancer in combination

with trastuzumab and taxane chemotherapy Slide courtesy of Ian Krop

CLEOPATRA: phase 3 study of pertuzumab in untreated metastatic disease

1:1 HER2-positiveMBC

Docetaxel + trastuzumab + placebo

Docetaxel + trastuzumab + pertuzumab

N=808

Pertuzumab prolongs time until progression by six months (from 12.5 to 18.5 months)

Baselga et al, SABCS 2011 and NEJM, 2011

Adverse event, n (%)

Placebo+ trastuzumab + docetaxel

(n = 397)

Pertuzumab+ trastuzumab + docetaxel

(n = 407)

Diarrhea 184 (46.3) 272 (66.8)

Alopecia 240 (60.5) 248 (60.9)

Neutropenia 197 (49.6) 215 (52.8)

Nausea 165 (41.6) 172 (42.3)

Fatigue 146 (36.8) 153 (37.6)

Rash 96 (24.2) 137 (33.7)

Decreased appetite 105 (26.4) 119 (29.2)

Mucosal inflammation 79 (19.9) 113 (27.8)

Asthenia 120 (30.2) 106 (26.0)

Peripheral edema 119 (30.0) 94 (23.1)

Constipation 99 (24.9) 61 (15.0)

Febrile neutropenia* 30 (7.6) 56 (13.8)

Dry skin 17 (4.3) 43 (10.6)

Toxicities

Baselga et al, SABCS 2011 and NEJM, 2011

*Febrile neutropenia rate 12% vs 26% in Asia, 10% or less in all other regions--No difference in cardiac toxicity rate (2% v 1%)*Febrile neutropenia rate 12% vs 26% in Asia, 10% or less in all other regions--No difference in cardiac toxicity rate (2% v 1%)

Trastuzumab Emtansine (T-DM1)

• T-DM1 is an antibody drug-conjugate

• Trastuzumab linked to a potent chemotherapy (DM1)

• Average of 3.5 DM1 per antibody

Slide courtesy of Ian Krop

T-DM1 selectively delivers DM1 to HER2+ cells

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

Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

T-DM1 binds to the HER2 protein on cancer cells

HER2

Slide courtesy of Ian Krop

EMILIA: randomized trial comparing T-DM1 to capecitabine and lapatinib

in previously treated patients

1:1

HER2+ MBC (N=980)

•Prior taxane and trastuzumab

PDT-DM1 3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD

Blackwell et al, ASCO 2012

T-DM1 prolongs time until progression by three months (from 6.4 to 9.6 months)

Th3RESA: randomized trial comparing T-DM1 to physician’s choice

Study treatment continues until

disease progression or unmanageable

toxicity

HER2 positive

Metastatic breast cancer

Prior trastuzumab, lapatinib and

chemotherapy

T-DM1 q3w

Treatment of physician’s choice

N = 7952:1 randomization

2

1

Wildiers et al, ECC-ESMO 2013

T-DM1 prolongs time until progression by three months (from 3.3 to 6.2 months)

T-DM1 is well-tolerated

• Common side effects:– Decreased platelet count– Elevated liver tests

• Does not cause typical chemotherapy side effects

• No hair loss• Significant nausea or diarrhea are not common• Does not cause immune suppression or significant

neuropathy

Novel HER2-directed agents in clinical development

Class Example(s)

HER2-targeted TKI Neratinib, afatinib, ARRY-380

HER2-targeted liposome

MM-302

Trifunctional antibody Ertumaxomab

HER2 vaccine AE37

ER+ disease: improving on already very effective

treatments

Endocrine therapy for metastatic disease

• Premenopausal– Tamoxifen– Ovarian

suppression/ablation– Ovarian suppression +

aromatase inhibition– Megace

• Postmenopausal– Tamoxifen– Aromatase Inhibitor +/-

everolimus– Fulvestrant– Megace

Polyak and Filho, Cancer Cell, 2012

Targeting the PI3Kinase pathway

Everolimus is an MTOR inhibitor

New drug approval: everolimus

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

*Median time from study entry until worsening of cancer

Slide courtesy of Nancy Lin

What’s next for everolimus?

• Multiple studies underway– In HER2+ cancers– In triple negative cancers– Studying this drug in combination with other

therapies

Testing the addition of an HSP90 inhibitor to hormonal therapy

Slide courtesy of Nancy Lin

Testing the addition of an HSP90 inhibitor to hormonal therapy

Ganetespib induces regression in tumors progressing on fulvestrant

Days of treatment

Tum

or v

olum

e (m

m3 )

Slide courtesy of Nancy Lin

Other agents of interest in ER+ disease

• Endoxifen • CDK 4/6 inhibitors• PI3Kinase inhibitors• Anti-IGF-1R Ab• SRC/Abl tyrosine kinase inhibitors• Combination therapy with targeted agents

that may overcome endocrine resistance

Triple negative breast cancer:

still searching for a target

Triple negative recurrences happen early

Dent et al, Clin Cancer Res 2007

Rates of distant recurrence following surgery in triple-negative vs other breast ca

There are many chemotherapies that are active against metastatic disease

• Mitotic inhibitors– vinorelbine– paclitaxel– docetaxel

• Antifolates– methotrexate

• Topoisomerase inhibitors– doxorubicin

Platinums

• Sledge (JCO 1988) reported 47% response rate in first line metastatic disease

• Abandoned for many years because of concerns about toxicity—largely replaced by taxanes

• Recent interest in patients with triple negative breast cancer

– DNA crosslinking mechanism of action

• New data from a series of neoadjuvant studies supports activity in TNBC

Sledge et al, JCO 2008; Silver et al JCO 2010; Gronwold et al, ASCO 2009; Sikov SABCS 2013

New chemotherapy: eribulin

Approved by the FDA in 2011

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

PARP inhibitors

• PARP1 is a protein that is important for repairing single-strand DNA breaks

• PARP inhibitors prevent DNA repair, leading to cell death

• Fast-dividing tumors and tumors containing BRCA mutations, which also impair DNA repair, may be most sensitive to PARP inhibitors

• Ongoing trials are investigating the efficacy of PARP inhibitors in breast cancer, particularly triple negative breast cancer and BRCA-associated breast cancer

Inhibit binding to receptor (AR)

T

AR

T

Cell nucleus AR

Cell cytoplasm

Inhibit nuclear translocation of AR

Inhibit AR-mediated DNA binding

Targeting the androgen receptor intriple negative breast cancer

Other agents of interest in triple negative disease

• PI3Kinase inhibitors• SRC/Abl tyrosine kinase inhibitors• HSP90 inhibitors• More to come…

What does all this complexity mean?

•There is likely not going to be a single “cure for cancer”

•Different cancers may have different strengths & weaknesses

•Figuring this out won’t be easy!

“half empty”

Slide courtesy of Erica Mayer

What does all this complexity mean?

•There is likely not going to be a single “cure for cancer”

•Different cancers may have different strengths & weaknesses

•Figuring this out won’t be easy!

“half full”

•The opportunity to individualize therapy—one size doesn’t fit all

•We may be able take advantage of specific weaknesses of cancers and knock out specific strengths

•But should be possible!

Slide courtesy of Erica Mayer

1. How many subtypes of breast cancer are there, and by understanding this, can we find new targets and new treatments? Can we better “tailor” treatments?

2. What causes resistance to hormonal therapy? To chemotherapy? Can it be prevented or overcome?

3. What lifestyle factors (e.g., exercise?) might be important for patients with metastatic disease?

4. How can we minimize toxicities of treatment?

Outstanding research questions

Summary

• Not all breast cancers are alike

• We have many clues to guide therapy

• But we need clinical trials and continued basic and translational research to make new breakthroughs that make a difference for patients

Thank you!