Metastatic Breast Cancer and
Emerging Research
Kathryn J. Ruddy, MD MPH
Assistant 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
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
Subtypes
TALK to your doctor if you are not sure what type of breast cancer you have
Slide courtesy of Nancy Lin
Treatment
Hormone receptor
positive
Triple-negative
HER2-Positive
Herceptin +
perjeta +
chemotherapy
Hormonal
therapy
Chemotherapy
TDM1
Hormonal
therapy
Chemotherapy
Chemotherapy
Herceptin +
chemotherapy
Chemotherapy
Chemotherapy
Lapatinib
+Herceptin
Herceptin +
chemotherapy
*Note, these are just examples. Each patient is different and treatment is tailored accordingly.
Slide courtesy of Nancy Lin
HER2+ disease:
a paradigm for advances in
targeted therapy
HER2+ disease: major advances
Three Large
Adjuvant Trials
Reported
Trastuzumab
Approved
Lapatinib
Approved
2002
1998
First Preoperative
Trials Reported Paving
The Way For Use in
Early Stage Disease
2005
2005
20072008
Initial Trials
of T-DM1,
Neratinib
2010
Pertuzumab
Approved
Preoperative
Trials of
Dual Blockade
2012
2013
T-DM1
Approved
• 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
Trastuzumab in HER2+
metastatic breast cancer
Protein
Receptor
HER2
Gene
Normal Cell
HER2+ Cell
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/herpathwayexpertise.jsp
Slamon et al, NEJM 2001
Lapatinib
• Oral dual tyrosine kinase inhibitor of
HER2 and EGFR
• FDA approved in combination with
capecitabine for trastuzumabresistant disease
• May have CNS penetration
• Well tolerated; common toxicities
include rash and diarrhea
Geyer et al, NEJM 2006
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
CLEOPATRA: phase 3 study of pertuzumab
in untreated metastatic disease
Docetaxel + trastuzumab
+ placebo
HER2-positive
MBC
1:1
N=808
Docetaxel + trastuzumab
+ pertuzumab
Pertuzumab prolongs time until progression by six
months (from 12.5 to 18.5 months)
Baselga et al, SABCS 2011 and NEJM, 2011
Toxicities
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)
Adverse event, n (%)
*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
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
HER2
Receptor-T-DM1 complex is
internalized into HER2-positive
cancer cell
T-DM1 binds to the HER2 protein
on cancer cells
Potent antimicrotubule
agent is released once inside
the HER2-positive
tumor cell
Slide courtesy of Ian Krop
EMILIA: randomized trial comparing
T-DM1 to capecitabine and lapatinib
in previously treated patients
T-DM1
HER2+ MBC
(N=980)
PD
3.6 mg/kg q3w IV
1:1
• Prior taxane and
trastuzumab
Capecitabine
1000
mg/m2 orally
bid, days 1–14, q3w
+
Lapatinib
PD
1250 mg/day orally qd
T-DM1 prolongs time until progression by three months
(from 6.4 to 9.6 months)
Blackwell et al, ASCO 2012
Th3RESA: randomized trial comparing
T-DM1 to physician’s choice
HER2 positive
T-DM1 q3w
Metastatic breast cancer
Prior trastuzumab,
lapatinib and
chemotherapy
2
1
Treatment of
physician’s choice
Study treatment
continues until
disease
progression or
unmanageable
toxicity
N = 795
2:1 randomization
T-DM1 prolongs time until progression by three months
(from 3.3 to 6.2 months)
Wildiers et al, ECC-ESMO 2013
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
Targeting the PI3Kinase pathway
Polyak and Filho, Cancer Cell, 2012
Everolimus is an MTOR inhibitor
New drug approval: everolimus
Exemestane
Exemestane
+
everolimus
• 3.2
months*
•7.8 months*
*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
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
Tumor volume
(mm3)
Testing the addition of an
HSP90 inhibitor to hormonal therapy
Ganetespib
induces
regression in
tumors
progressing on
fulvestrant
Days of treatment
Fulvestrant
ER+ and HER2negative breast
cancer
Fulvestrant +
ganestespib
Fulvestrant +
ganetespib
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
Rates of distant recurrence following surgery in triple-negative vs other breast ca
Dent et al, Clin Cancer Res 2007
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
•Metastatic breast cancer
•At least 2 prior
chemotherapies
Approved by the FDA in 2011
Halichondria okadai
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
Targeting the androgen receptor in
triple negative breast cancer
T
T
Inhibit binding to receptor (AR)
AR
Cell cytoplasm
Inhibit nuclear translocation of AR
Cell nucleus
AR
Inhibit AR-mediated DNA binding
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?
“half empty”
•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!
Slide courtesy of Erica Mayer
What does all this complexity
mean?
“half full”
•There is likely not going
to be a single “cure for cancer”
•The opportunity to individualize
therapy—one size doesn’t fit all
•Different cancers may have
•We may be able take advantage
different strengths & weaknesses of specific weaknesses of cancers
and knock out specific strengths
•Figuring this out won’t be easy!
•But should be possible!
Slide courtesy of Erica Mayer
Outstanding research questions
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?
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!