Metastatic Breast Cancer and Emerging Research

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Metastatic Breast Cancer and Emerging Research

• Kathryn J. Ruddy, MD MPH
• Assistant Professor of Oncology
• Mayo Clinic

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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

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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

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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

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Breast cancer subtypes

• There are three main subtypes of breast cancer
• Oncologists use breast cancer subtype to guide
  treatment decisions
• Clinical trials often focus on specific subtypes

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Subtypes
TALK to your doctor if you are not sure what type
of breast cancer you have
Slide courtesy of Nancy Lin
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Treatment
Hormone receptor positive
Triple-negative
HER2-Positive
Note, these are just examples. Each patient is
different and treatment is tailored accordingly.
Slide courtesy of Nancy Lin
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HER2 disease a paradigm for advances in
targeted therapy
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HER2 disease major advances
Three Large Adjuvant Trials Reported
Trastuzumab Approved
Lapatinib Approved
2007- 2008
Pertuzumab Approved
2013
2010
2002
2005
2005
1998
First Preoperative Trials Reported Paving The Way
For Use in Early Stage Disease
2012
Initial Trials of T-DM1, Neratinib
T-DM1 Approved
Preoperative Trials of Dual Blockade

• 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

Slide courtesy of Ian Krop
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Trastuzumab in HER2 metastatic breast cancer
Can combine with many different chemotherapies
(e.g., paclitaxel, docetaxel, vinorelbine,
capecitabine) and targeted agents (e.g.,
lapatinib)
Graphic adapted from image at http//www.gene.com/
gene/research/focusareas/oncology/herpathwayexpert
ise.jsp
Slamon et al, NEJM 2001
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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
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Pertuzumab with trastuzumab
HER2 receptor
Pertuzumab
Trastuzumab
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
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CLEOPATRA phase 3 study of pertuzumab in
untreated metastatic disease
Docetaxel trastuzumab placebo
HER2-positiveMBC
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Docetaxel trastuzumab pertuzumab
N808
Pertuzumab prolongs time until progression by six
months (from 12.5 to 18.5 months)
Baselga et al, SABCS 2011 and NEJM, 2011
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Toxicities
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)
Febrile neutropenia rate 12 vs 26 in Asia, 10
or less in all other regions --No difference in
cardiac toxicity rate (2 v 1)
Baselga et al, SABCS 2011 and NEJM, 2011
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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
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T-DM1 selectively delivers DM1 to HER2 cells
T-DM1 binds to the HER2 protein on cancer cells
HER2
Receptor-T-DM1 complex is internalized into
HER2-positive cancer cell
Potent antimicrotubule agent is released once
inside the HER2-positivetumor cell
Slide courtesy of Ian Krop
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EMILIA randomized trial comparing T-DM1 to
capecitabine and lapatinib in previously treated
patients

• HER2 MBC (N980)
• Prior taxane and trastuzumab

T-DM1 3.6 mg/kg q3w IV
PD
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Capecitabine 1000 mg/m2 orally bid, days 114,
q3w Lapatinib 1250 mg/day orally qd
PD
T-DM1 prolongs time until progression by three
months (from 6.4 to 9.6 months)
Blackwell et al, ASCO 2012
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Th3RESA randomized trial comparing T-DM1 to
physicians choice
HER2 positive Metastatic breast cancer Prior
trastuzumab, lapatinib and chemotherapy
Study treatment continues until disease
progression or unmanageable toxicity
2
1
Treatment of physicians choice
N 795 21 randomization
T-DM1 prolongs time until progression by three
months (from 3.3 to 6.2 months)
Wildiers et al, ECC-ESMO 2013
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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

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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
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ER disease improving on already very effective
treatments
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Endocrine therapy for metastatic disease

• Postmenopausal
• Tamoxifen
• Aromatase Inhibitor /- everolimus
• Fulvestrant
• Megace

• Premenopausal
• Tamoxifen
• Ovarian suppression/ablation
• Ovarian suppression aromatase inhibition
• Megace

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Targeting the PI3Kinase pathway
Polyak and Filho, Cancer Cell, 2012
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Everolimus is an MTOR inhibitor
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New drug approval everolimus
Median time from study entry until worsening of
cancer
Approved by the FDA in 2012 for patients with
metastatic, hormone-receptor positive,
HER2-negative breast cancer
Slide courtesy of Nancy Lin
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Whats next for everolimus?

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

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Testing the addition of an HSP90 inhibitor to
hormonal therapy
Slide courtesy of Nancy Lin
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Testing the addition of an HSP90 inhibitor to
hormonal therapy
Slide courtesy of Nancy Lin
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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

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Triple negative breast cancerstill searching
for a target
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Triple negative recurrences happen early
Rates of distant recurrence following surgery in
triple-negative vs other breast ca
Dent et al, Clin Cancer Res 2007
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There are many chemotherapies that are active
against metastatic disease

• Mitotic inhibitors
• vinorelbine
• paclitaxel
• docetaxel
• Antifolates
• methotrexate
• Topoisomerase inhibitors
• doxorubicin

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Platinums

• Sledge (JCO 1988) reported 47 response rate in
  first line metastatic disease
• Abandoned for many years because of concerns
  about toxicitylargely 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
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New chemotherapy eribulin

• Metastatic breast cancer
• At least 2 prior chemotherapies

Halichondria okadai
Approved by the FDA in 2011
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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

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Targeting the androgen receptor in triple
negative breast cancer
T
T
Inhibit binding to receptor (AR)
Cell cytoplasm
Inhibit nuclear translocation of AR
Tumor Death
Cell nucleus
Inhibit AR-mediated DNA binding
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Other agents of interest in triple negative
disease

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

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What does all this complexity mean?
half empty

• There is likely not going
• to be a single cure for cancer
• Different cancers may have
• different strengths weaknesses
• Figuring this out wont be easy!

Slide courtesy of Erica Mayer
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What does all this complexity mean?
half full

• There is likely not going
• to be a single cure for cancer
• Different cancers may have
• different strengths weaknesses
• Figuring this out wont be easy!

• The opportunity to individualize
• therapyone size doesnt 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
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Outstanding research questions

• 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?
• What causes resistance to hormonal therapy? To
  chemotherapy? Can it be prevented or overcome?
• What lifestyle factors (e.g., exercise?) might be
  important for patients with metastatic disease?
• How can we minimize toxicities of treatment?

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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

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Thank you!