Metastatic Breast Cancer
Dr. Christine Simmons, MD MSc FRCP(C)
Medical Oncologist, St. Michael’s Hospital
Assistant Professor, University of Toronto
simmonsch@smh.ca
Christine.simmons@womenincancer.org
Objectives
• What do medonc residents need to know
about management of MBC
– For clinical practice?
– For exams?
• What follows is my meagre attempt at both!
The facts on Breast Cancer
• Most common cancer among Canadian women
• 1 in 9 Canadian women will develop breast cancer in
their lifetime
• In 2011, over 23,000 Canadian women will be
diagnosed with breast cancer
• A woman diagnosed with early stage breast cancer
today has about an 85% chance of being alive and
disease free in 5 years
But…
• Breast cancer is the second leading cause of
cancer related deaths in Canadian women
– Second only to lung cancer
• Metastatic breast cancer can be devastating
diagnosis for pts
Diagnosing Metastatic Breast Cancer
• Breast cancer pts at highest risk for
development of mets within first 2 years of
diagnosis
– Trend continues within first 5 years
…it changes perspectives…
…it changes perspectives…
Risk depends on:
• Severity of disease
– Intial T, N status
• Receptor status
• Triple negative pts – ironically do better if no
recurrence by 2-3 years
….there is hope
• Metastatic breast cancer can be controlled
– Patients are living longer WITH breast cancer
– Treatments have improved SURVIVAL and
QUALITY OF LIFE in this population
– Median survival of patient with metastatic breast
cancer 2-3 years
Metastatic Breast Cancer
Indolent and slow
growing
Aggressive and
treatment
resistant
As an example…
• Patient X
– 63 yo woman
– Diagnosed with breast cancer in 2002 and was treated at
that time to prevent recurrence
– Recurred in 2006
• Bone and liver
–
–
–
–
–
Started treatment and did well
Cancer progressed further to lungs in 2009
Has been on treatment with good response since
Currently her disease is stable
Between treatments she travels the world
On the other end of the spectrum…
• Patient Y
– 49 yo woman
– Diagnosed in 2008 with breast cancer, received
treatment
– “triple negative”
– Recurred in 2009 in the chest wall and bone
– Disease progressed through 4 different types of
chemotherapy, did not respond to any treatment
– Passed away August 2010.
Most common scenario
• 65 yo woman treated for a T2N2 tumour 2
years ago presents with increasing back pain
in T10 area x 6 weeks
– What do you do?
Most common scenario
• 65 yo woman treated for a T2N2 ER+PR-Her2tumour 2 years ago presents with increasing
back pain in T10 area x 6 weeks
– History: as above, fatigue associated, generally
not feeling well
– Physical exam: tenderness over T10
Metastatic Breast Cancer
• Bone scan:
– Lesion at T10 and in lumbar spine
– How common is this kind of presentation?
Metastatic Breast cancer
• 70% of patient with MBC will have bone
involvement at some point in course of their
disease
• Most common site of first metastases
• Other common sites:
– Liver, lung, chest wall, brain
Why treat?
• MBC patients have a prognosis that overall is
quite good due to multitude of treatment
options
– Average survival after diagnosis of mets is 18-24
months
• Likely better with current therapies
Which medicine to offer?
• Treatment options are based on many factors,
including the features of the patients cancer
– Sensitivity to estrogen and progesterone
– Her2 status
• These factors may change with time…
Cancer can change too!
Factors Influencing Treatment Choice in
Metastatic Breast Cancer
Patient preferences
(e.g. oral vs. iv treatment)
Prior therapy
Pace of disease
HER2 receptor status
Choice of
treatment
Performance status
ER/PR receptor status
Treatment approach
• Goals of care:
– Quality of life AND quantity of life
• Identify available options
– Clinical Trial
• Comet clinical trials consortium
• www.clinicaltrials.gov
– Options based on
• Severity of disease
• Pathological features of disease
Current therapeutic options for MBC
Anti-estrogen therapy
• For any pt with hormone
sensitive disease
• Best in strongly hormone
sensitive
• Takes longer to elucidate
response overall*
• Great option in pts with
bone only disease
Chemotherapy
• More toxic but response is
usually faster
• Be aware of funding
regulations at your centre!
• Be aware of changes in
evidence
• Consider overall “cost” to
your pt
Anti-estrogen therapies
• Tamoxifen
• Aromatase Inhibitor
• Cheap
• Remember LU codes!
– Letrozole (Femara)
– Anastrozole (Arimidex)
– Exemestane (Aromasin)
• Fulvestrant
• More $$, may be
available in clinical trial
But is hormone therapy good enough?
Approach to Chemotherapy for MBC
• CCO funding regulations
– ONE line of chemotherapy is funded, beyond first
line it is the institution that picks up the tab!
• Each institution will vary in what is feasible to fund
depending on global budget
• Not uncommon for breast ca pts to still be well after
multiple lines of chemo
Generally….
• Most patients receive an anthracycline and
taxane adjuvantly
– Depending on DFI may consider re-challenge with
Taxane
• Paclitaxel
• Nab-paclitaxel (funded only if pt doesn’t tolerate the
Paclitaxel)
• Goal is QUALITY of life
– Generally offer single agent over combination therapy
• Capecitabine + Taxotere example
Beyond first line….
• Evidence for response to:
– Xeloda (oral)
– AC
– Single agent adriamycin weekly
– Taxotere
– Vinorelbine
– Gemcitabine
– CMF (IV or oral)
– Gem-Cisplatin (triple negatives)
Does treatment make a difference?
• “Why bother with treatment if I can’t be cured? My life is over!”
• “Why take treatment again, it didn’t work the first time!”
• “With all the attention in the media, why haven’t you cured this
yet?”
• “Don’t make me take chemo again, I can’t handle it!”
• “What is going to happen to me?”
• “How long am I going to live?”
Impact of New Agents on Survival over
time
• Access to new therapeutic agents for metastatic
breast cancer have significantly improved patient’s
survival over time
Median Survival
(days)
Cohort
1991–1992
Baseline
436
1994–1995
Paclitaxel and vinorelbine
450
1997–1998
Docetaxel and aromatase inhibitors
564
1999–2001
Capecitabine and trastuzumab
661
Chia SK et al. Cancer 2007;110:973-9.
BUT can we do better than just plain
old chemo?
• What about fancy targeted agents?
AVADO: double-blind, placebo-controlled trial
Previously untreated
LR or mBC
(N=736)
Stratification factors
•Region
•Prior taxane/time to
relapse since adjuvant
chemotherapy
•Measurable disease
•Hormone receptor
status
Docetaxel* + placebo
q3w x9
Docetaxel*
+ bevacizumab
7.5mg/kg q3w x9
Docetaxel*
+ bevacizumab
15mg/kg q3w x9
Treat
with
placebo
to PD or
unblind
Treat
with
bevacizumab
to PD
Possible
open-label
bevacizumab
to PD
after
unblind
All patients
given option
to receive
bevacizumab
with
second-line
chemotherapy
• Primary endpoint: PFS
• Secondary endpoints: ORR, 1-year survival, OS, TTF, duration of response,
quality of life, safety
*Docetaxel: 100mg/m2 q3w
Miles DW, et al. ASCO 2008
AVADO: updated PFS 7.5mg dose
1.0
Placebo + docetaxel (n=241)
Bevacizumab 7.5mg/kg q3w + docetaxel (n=248)
PFS estimate
0.8
Unstratified HR=0.86 (0.72–1.04), p=0.1163*
0.6
8.2
8.1
0.4
9.0
Stratified HR‡=0.80 (0.65–1.00), p=0.0450*
0.2
0
0
6
12
18
Time (months)
Intent-to-treat analysis; *p values are of exploratory nature
‡censored for non-protocol therapy prior to progressive disease
24
30
36
Miles DW, et al. SABCS 2009.
AVADO: updated PFS 15mg dose
1.0
Placebo + docetaxel (n=241)
Bevacizumab 15mg/kg q3w + docetaxel (n=247)
PFS estimate
0.8
Unstratified HR=0.77 (0.64–0.93), p=0.0061*
0.6
8.2
8.1
0.4
10.1
10.0
Stratified HR‡=0.67 (0.54–0.83), p=0.0002*
0.2
0
0
6
12
18
Time (months)
Intent-to-treat analysis; *p values are of exploratory nature
‡censored for non-protocol therapy prior to progressive disease
24
30
36
Miles DW, et al. SABCS 2009.
AVADO OS: median follow-up 25
months
Placebo + docetaxel (n=241)
1.0
Bevacizumab 7.5mg/kg q3w + docetaxel (n=248)
Bevacizumab 15mg/kg q3w + docetaxel (n=247)
OS estimate
0.8
HR=1.03 (0.79–1.33), p=0.8528*
HR=1.05 (0.81–1.36), p=0.7198*
0.6
31.9
30.8
30.2
0.4
0.2
0
0
6
12
Unstratified analysis; *p values are of exploratory nature
18
Months
24
30
36
Miles DW, et al. SABCS 2009.
AVADO: patients were permitted to receive
bevacizumab with second-line therapy
Previously untreated LR or mBC
N=736
Docetaxel + placebo
q3w
n=241
Docetaxel + bevacizumab
7.5mg/kg q3w
n=248
Docetaxel + bevacizumab
15mg/kg q3w
n=247
Second-line therapy
n=175
Second-line therapy
n=172
Open-label bevacizumab
to PD after unblind
n=14
Second-line therapy
n=170
Without bev
n=80
With bev
n=90
Miles DW, et al. SABCS 2009.
Without bev
n=99
With bev
n=76
Without bev
n=119
With bev
n=53
AVADO: Bevacizumab + Docetaxel in First-line
Treatment of Advanced Breast Cancer
• Adding bevacizumab to docetaxel in first-line treatment of
advanced breast cancer improves PFS but not OS[1]
– Previous analysis: addition of bevacizumab to docetaxel significantly
improved PFS in locally recurrent or metastatic breast cancer with
both 7.5-mg/kg and 15.0-mg/kg doses[2]
• Updated results confirmed preliminary findings: addition of
bevacizumab 15 mg/kg to docetaxel
– Significantly increased ORR
– Prolonged PFS
– Toxicity profile similar among treatment arms
1. Miles DW, et al. SABCS 2009. Abstract 41. 2. Miles D, et al. ASCO 2008. Abstract LBA1011.
RIBBON-2: Phase III Trial of Second-Line
Bevacizumab + Chemotherapy in MBC
Patients with
previously treated
MBC (HER2
negative or HER2
status unknown)
(N = 684)
Bevacizumab 15 mg/kg every
3 wks or 10 mg/kg every 2 wks† +
Chemotherapy
(n = 459)
Chemotherapy
Regimens*
Taxane or
Gemcitabine or
Capecitabine or
Vinorelbine
Stratified by chemotherapy regimen,
time between MBC diagnosis and first
PD, and hormone receptor status;
randomized 2:1
Treat
until
disease
progression
Placebo + Chemotherapy
(n = 225)
*Dose and schedule of chemotherapy regimens (selected by investigator):
Taxane: paclitaxel 90 mg/m2/wk for 3 of 4 wks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, or docetaxel 75100 mg/m2 every 3 wks.
Gemcitabine 1250 mg/m2 on Days 1 and 8 every 3 wks.
Capecitabine 2000 mg/m2 on Days 1-14 every 3 wks.
Vinorelbine 30 mg/m2/wk every 3 wks.
†Dose of bevacizumab dependent on chemotherapy regimen used.
Brufsky A, et al. SABCS 2009. Abstract 42.
Primary Endpoint of PFS, ITT
Population
Median PFS, 7.2 vs. 5.1 months
HR = 0.78, p= 0.0072
Brufsky A, et al. SABCS 2009. Abstract 42.
Cohort-Specific Analyses of PFS, ITT Population
Chemo+PL
n=225
Events
Median
(mo)
684
184/225
Taxanes
304
Gemcitabine
HR
Events
Median
(mo)
HR
(95% CI)
5.1
372/459
7.2
0.77
(0.64–0.93)
84/103
5.8
151/201
8.0
0.64
(0.49–0.84)
160
43/52
5.5
84/108
6.0
0.90
(0.61–1.32)
Capecitabine
144
39/47
4.1
87/97
6.9
0.73
(0.49–1.08)
Vinorelbine
76
18/23
7.0
50/53
5.7
1.42
(0.78–2.59)
Cohort
All subjects
Total
(n)
Chemo+BV
n=459
Chemo+PL
Better
Chemo+BV
Better
Chemo
5.0
Brufsky A, et al. SABCS 2009. Abstract 42.
2.0
1.0 0.5
0.2
Safety Summary by Chemotherapy Cohort,
Safety Population
n (%)
Tax/PL
(n=101)
Tax/BV
(n=200)
Gem/PL
(n=52)
Gem/BV
(n=108)
Selected AE (Grade ≥3)
29 (28.7)
79 (39.5)
5 (9.6)
34 (31.5)
SAE
12 (11.9)
53 (26.5)
8 (15.4)
25 (23.1)
4 (4.0)
12 (6.0)
4 (7.7)
6 (5.6)
0 (0)
3 (1.5)
2 (3.8)
2 (1.9)
Cape/PL
(n=46)
Cape/BV
(n=97)
Vin/PL
(n=22)
Vin/BV
(n=53)
2 (4.3)
20 (20.6)
14 (63.6)
30 (56.6)
12 (26.1)
18 (18.6)
7 (31.8)
16 (30.2)
AE leading to BV/PL
discontinuation or death
4 (8.7)
6 (6.2)
1 (4.5)
4 (7.5)
AE leading to death
2 (4.3)
1 (1.0)
1 (4.5)
0 (0)
AE leading to BV/PL
discontinuation or death
AE leading to death
n (%)
Selected AE (Grade ≥3)
SAE
AE=adverse event, SAE=serious adverse event, Tax=taxane, Gem=gemcitabine, Cape=capecitabine,
Vin=vinorelbine.
RIBBON-2: Phase III Trial of Second-Line
Bevacizumab + Chemotherapy in MBC
• Study met primary endpoint
– Improved PFS with combination bevacizumab + standard
chemotherapy vs chemotherapy alone for second-line treatment of
HER2-negative MBC
• Observed improvement in PFS supported by secondary
endpoint of ORR
– OS data immature
• Bevacizumab combination chemotherapy regimens well
tolerated with no unexpected adverse events
• Feasible to consider bevacizumab in second-line setting
Brufsky A, et al. SABCS 2009. Abstract 42.
What about Bev?
In 2008 FDA approves Bev for use in MBC first
line in combination with Taxol!
• In June 29, 2011, FDA yanks the approval!!!
– progression-free survival benefit was small and
overshadowed by the risk of serious side effects.
– Adding Avastin to chemotherapy didn't increase
overall survival
– Adding Avastin to chemotherapy didn't ease
metastatic breast cancer symptoms.
Improving on chemo
• Under construction!
• Sorafenib + Capecitabine
– Slight improvement in PFS, much worse HFS
(45%!)
• Sutent + Capecitabine
– Patients in control arm do appreciably better!
Her2+ metastatic breast cancer
• Adding Trastuzumab to chemotherapy for
Her2+ breast cancer significantly improves
outcome
– PFS and OS
Benefit of anti-Her2 therapy in MBC
• In patients with MBC previously treated with
chemotherapy
– Trastuzumab induced ORR of 18% as single agent
– Trastuzumab + chemo induced ORR of 35%
• In patients with MBC treated first line with
Trastuzumab
– Trastuzumab + chemo associated with
• longer TTP (median, 7.4 vs. 4.6 months; P<0.001)
• higher ORR (50% vs. 32%, P<0.001)
• longer OS (median survival, 25.1 vs. 20.3 months; P=0.046)
Cobleigh et al. JCO 1999
Slamon et al. NEJM, 2001
But what about beyond first line?
• 3 RCTs
– Von Minckowitz
• Trastuzumab + Capecitabine vs. Capecitabine in ≥2nd
line therapy
– Cameron 2008 (Geyer 2006)
• Lapatinib + Capecitabine vs. Capecitabine in pts who
have progressed on Trastuzumab, anthracycline, and
taxane
– O’Shaughnessey
• Lapatinib + Trastuzumab vs. Lapatinib in > 2nd line
therapy
Von Minckwitz et al, JCO 2009.
Cameron et al. Breast Cancer Res Treat 2008.
Geyer et al. NEJM 2006.
In context of what we know….
Tras +/- Cape
Lap +/- Cape
Lap +/- Tras
PS
3% KPS < 60
ECOG 0-1 only
ECOG 2 in 5%
Prior Rx
100% Tras
70% Anthra
85% Taxane
99% Tras
99% Anthra
99% Taxane
Median 3 prior
Tras regimens,
> 5 lines 30%
TTP
T + C = 8.2 mos
C = 5.3 mos
L + C = 6.2 mos
C = 4.2 mos
L + T = 3 mos
L = 2 mos
OS
T + C = 25.5 mos
C = 20.4 mos
L + C = 15.6 mos
C = 15.4 mos
L + T = 14 mos
L = 9.5 mos
It seems…
• Continuing anti-Her2 therapy beyond first line
results in improved outcomes
• Using more than one agent to inhibit Her2 is
probably good
– Pertuzumab --- one to watch!
• Cost-utility is a huge hurdle to overcome!
Pragmatically…
• Considering options to continue anti-her2
therapy
– Lapatinib + Capecitabine
• Oral regimen
• Reasonable to consider beyond first line
– Clinical trial
TDM4374g
A Phase II Study of Trastuzumab-DM1 (T-DM1),
a Novel HER2 Antibody–Drug Conjugate, in Patients with
HER2+ Metastatic Breast Cancer who Were Previously
Treated with an Anthracycline,
a Taxane, Capecitabine, Lapatinib, and Trastuzumab
Ian Krop,1 Patricia LoRusso,2 Kathy D. Miller,3 Shanu Modi,4
Denise Yardley,5 Gladys Rodriguez,6 Sam Agresta,7 Maoxia Zheng,7
Lukas Amler,7 Hope Rugo8
1Dana
Farber Cancer Institute, Boston, MA; 2Karmanos Cancer Institute, Detroit, MI; 3Indiana
University Melvin-Bren Simon, Indianapolis, IN; 4Memorial Sloan-Kettering Cancer Center, New York,
NY; 5Sarah Cannon Research Institute, Nashville, TN; 6South Texas Oncology/Hematology, San Antonio,
TX; 7Genentech, South San Francisco, California; 8University of California–San Francisco
Comprehensive Cancer Center,
San Francisco, CA
Trastuzumab-DM1 in Heavily Pretreated HER2+
MBC
• T-DM1, an antibody-drug conjugate, combines biologic effect
of trastuzumab against HER2-expressing cells with highly
potent antimicrotubule agent DM1
– MOA likely involves receptor-mediated internalization of T-DM1
after binding to HER2, resulting in intracellular release of DM1[1]
• Multisite, open-label, single-arm phase II study based in the
United States (N = 110)[2]
• Primary endpoints: ORR by independent review at 24 wks
after last patient in; safety and tolerability at 24 wks after last
patient in
1. Austin CD et al. Mol Biol Cell. 2004;15:5268-5282. 2. Krop I, et al. SABCS 2009. Abstract 5090.
Prior Chemotherapy and Anti-HER2 Therapy
Median number of agents for metastatic disease (range)*
7.0 (1–15)
Median number of agents in all therapy setting (range)*
8.0 (1–19)
Number of patients with 5 prior agents, n(%)**
109 (99.1)
Prior trastuzumab
Median duration of prior trastuzumab in metastatic setting,
months (range)
Prior lapatinib
Median duration of prior lapatinib in metastatic setting,
months (range)
19.4 (2–116)
6.9 (0–23)
* Includes all agents intended for the treatment of breast cancer except hormonal
therapy
* * One patient did not receive a taxane.
Krop I, et al. SABCS 2009. Abstract 5090.
Trastuzumab-DM1 in Heavily Pretreated HER2+
MBC
• T-DM1 demonstrated significant clinical benefit in heavily
pretreated HER2+ metastatic breast cancer patients
– ORR (by independent review): 32.7%
– CR + PR + SD ≥ 6 mos (by independent review): 44.5%
– Median PFS: 7.3 mos
• T-DM1 well tolerated with manageable adverse effects
• Offers therapeutic option for heavily pretreated HER2+
patients
– Possible utility in earlier therapeutic strategies
The “Wins”
• Discovery and development of new agents has
prolonged survival in patients living with
metastatic breast cancer
• Quality of life measured in clinical trials
– So we know that treatment will make patients feel
better, not worse
• Multiple lines of treatment
– “endless menu”
Supportive Therapy
• Bone is most common site of spread from
breast cancer
– Development of drugs that strengthen normal
bone has reduced and delayed the onset of bone
complications in MBC patients
– Significantly improve quality of life!
The work still to be done…
• Identifying who will respond to therapy (and
who won’t) earlier
• Developing new strategies for treating those
who don’t respond to standard regimens
• Doing all of this while minimizing side effects
and toxicity
– Allowing patients to LIVE LIFE
The work still to be done…
• Linking the transitions in a patients’ disease
course
– From diagnosis to recurrence to palliative support,
every “transition” can be distressing to our
patients
– This is magnified when communication is not
smooth or streamlined between clinicians
– Introduction of “patient navigators” has improved
this immensely
The work still to be done…
• Knowledge translation
– Getting the information required to patients and
to clinicians to improve quality of care
• Improving access
– Support
– Medications
…when the “endless menu” ends
• Most difficult and most important point in
patient’s journey
An example…
• Patient A
– 62 yo woman, MBC x 2 years
– Spread to bone, liver and lung
– Self referred to palliative care clinic
– “In my opinion, the 2 most important points in a
persons life is your birth and your death, and I
want to live mine to the fullest”
Another example
• Patient B
– 37 yo woman, MBC x 10 months, rapidly
progressing
– “I’m tired. I’m tired of all the pink. The pink is
not breast cancer. Look at me, this is breast
cancer, and its not pretty and its not pink.”
The “Wins” when we are losing
• Improved access to palliative care facilities,
increased education in pain management
– Pain free
• Research is making advances in treatment and
support of women with MBC
In Summary
• Metastatic breast cancer affects thousands of
patients
• Treatments with chemotherapy, hormone therapy,
and targeted therapy does prolong life and improve
quality of life
• Advances in supportive care also improve quality of
life at critical points in the course of disease
Conclusions
• MBC patients have a lot of therapeutic
options!
• Goals of care, performance status, severity of
disease and pathological features can guide
choice of agent
• Consider clinical trial at every outset
• Also remember – things with change with
time!
Thank You