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WILL WE EVER CURE BREAST CANCER ?
WHAT EXPLAINS THIS REMARKABLE ACHIEVEMENT ?
IMPROVEMENTS IN DETECTION
IMPROVEMENTS IN PREVENTION
SUCCESSFUL ADJUVANT THERAPY
IS BREAST CANCER ACTUALLY EVER CURABLE ?
William Stewart Halsted
Surgery does seem to matter
Trials of radiotherapy after mastectomy
and axillary dissection
Local recurrence by use of systemic therapy
Note: one trial did not supply local recurrence information, affecting 20 women in this pN category.
Axillary Lymph Node Metastases
Haagensen, Columbia Presbyterian 1935-1972; Mastectomy only-no adjuvant systemic therapy
Stage A 10 year Survival
1-3+ nodes 70.5%
4-7+ nodes 42.9%
>7+ nodes 18.8%
Stage B
1-3+ nodes 44.4%
4-7+ nodes 35.7%
>7+ nodes 15.6%
Haagensen, Diseases of the Breast 3rd Ed. 1986
What do we make of lymph node metastases ?
Why does 1 or 2 or 3 or 4 lymph nodes involved with
breast cancer have such profound predictive value ?
Why are microscopic lymph node metastases so relatively
unimportant ?
WHY DO SCATTERED BREAST CANCER CELLS IN A
LYMPH NODE HAVE A DIFFERENT PROGNOSIS FROM
A SMALL 2MM TUMOR MASS ?
AND WHY ARE PATIENTS WITH AXILLARY LYMPH NODES
COMMONLY CURABLE [ EVEN WITHOUT ADJUVANT THERAPY IN
SOME CASES ] WHILE PATIENTS WITH SUPRCLAVICULAR NODES
ALMOST NEVER ARE.
Braun, S. et al. N Engl J Med 2005;353:793-802
Bone Marrow Metastases: Pooled Analysis
Overall Survival, Median = 21.3 months
Progression-Free Survival, median = 11.5 months0.8
0.6
0.4
0.2
24 46 72 96 120 144 168 192 2160
0.0
1.0
240
Months From the Start of Treatment
Pro
po
rtio
n S
urv
ivin
g
Overall and progression free survival of 1581 patients with metastatic breast carcinoma treated on 18 successive, doxorubicin-containing standard dose chemotherapy protocols from 1973 to 1982 at the M.D. Anderson Cancer Center.
SURVIVAL FOLLOWING THE DIAGNOSIS OF METASTATIC BREAST CANCER
Why can we ‘cure’ in the adjuvant setting
and not with ‘real’ metastatic disease ?
And why is bulky locally advanced breast cancer ‘better’
than a small skin metastasis ?
Metastatic Breast Cancer
Why [mostly] do multiple sites of metastasis appear more
or less at the same time ?
WHY DON’T WE DO THE RIGHT THING ??
BREAST CANCER PREVENTION
ANTI-INFLAMMATORY TREATMENT
The Lancet · Volume 379· No. 9826· Pages 1602-1612· April 28, 2012
The Lancet · Volume 379· No. 9826· Pages 1591-1601· April 28, 2012
George Thomas Beatson, M.D.
The Lancet Oncology· Volume 13· Issue 5· Pages 476-486· May 2012
How much does the “host” matter ?
Inflammation
Obesity
Depression
THREE BIG ISSUES
MANY PATIENTS WHO APPARENTLY HAVE RESIDUAL BREAST CANCER EITHER DO NOT RELAPSE OR DO SO AT DELAYED TIMES WHICH ARE EXCEEDINGLY HARD TO EXPLAIN BY ANY KNOWN GROWTH KINETICS.
HOST FACTORS WHICH CAN CHANGE OVER TIME AND WHICH ARE UNLIKELY TO BE ASSOCIATED WITH PRIMARY CHANGES IN TUMOR CELLS THEMSELVES CLEARLY AFFECT RELAPSE AND SURVIVAL
EXACTLY THE SAME THERAPY WHICH CAN PREVENT BREAST CANCER AND APPARENTLY CURE MANY PATIENTS NEVER PROVIDES A CURE IN THE METASTATIC SETTING.
The ‘classic’ model of cancer
A normal cell is ‘changed’ or transformed into a cancer cell.
In inherited forms of cancer one of these changes or mutations is already present.
Multiple changes in cells eventually result in full blown malignancy
Blocking any of these steps will result in successful treatment.
TUMOR CELL SPECIFIC ANALYSES
THE ‘TRADITIONAL’ WAY TO GO
Tumour Phylogenetic Evolution(Renal Cell Cancer)
NormalKDM5C (missense)
Gerlinger, M., et al.; N Engl J Med; 2012
1.00E+00
1.00E+01
1.00E+02
1.00E+03
Log
Mu
tati
on
Rat
e p
er
10
Me
gab
ase
s
Background Mutation Rates Across Different Cancer Types
1 per Mbp
10 per Mbp
100 per Mbp
Pediatric cancers
De novo and secondary AMLs
GBMs OVCs BRCs LUCs
CAN SYSTEMIC INFLAMMATORY DISEASES MIMIC THE CYTOKINE PRODUCTION OF BREAST CANCERS TO
INDUCE METASTASIS ?
IN OTHER WORDS, CAN WE USE THIS
INFORMATION TO FIGURE OUT HOW A
WOMAN’S BODY ALTERS THE RISK OF
OCCURRENCE AND RECURRENCE OF
BREAST CANCER ?
AND, CAN WE EXPLOIT THIS
THERAPEUTICALLY?
All his life he suffered spells of depression,
sinking into the brooding depths of
melancholia, an emotional state which, though
little understood, resembles the passing
sadness of the normal man as a malignancy
resembles a canker sore.
William Manchester,
The Last Lion, Winston Spencer Churchill, Vol. I: Visions of Glory
(New York: Little, Brown & Company, 1989, p. 23)
47
48
Psychological Medicine (2010), 40, 1797–1810
Psychologic intervention
improves survival for breast
cancer patients:
A randomized clinical trial
Andersen et al., Cancer
113: 3450-3458, 2008
(N = 227; Median Follow-up 11 years)
Randomized Trials Showing Survival BenefitStudy Cancer N Psychological Outcome
Spiegel et al 1989 Metastatic Breast
Cancer
86 Less distress, pain
Richardson et al,
1990
Lymphoma,
leukemia
94 Better treatment adherence
Fawzy et al, 1993 Melanoma 66 Less distress, Better coping
Kuchler et al, 1999 GI cancers 271 Better stress management
McCorkle et al
2000
Solid Tumors 375 Less distress
Spiegel et al, 2007 Metastatic Breast
Cancer
125 Less distress, pain
Survival Interaction with ER
Status
Andersen et al,
2010
Primary Breast
Cancer
62 Improved Coping
Temel et al, 2010 Non Small Cell
Lung Cancer
107 Improved Q of L
Reduced Depression
Post-surgical depressive symptoms and long-
term survival in non-metastatic breast cancer
patients at 11-year follow-up
Michael H. Antoni, PhDa,b,c,1, Jamie M. Jacobs, PhDd,⁎,1, Laura C. Bouchard,
MS a, Suzanne C. Lechner, PhDb,c,
Devika R. Jutagir, MSa, Lisa M. Gudenkauf, PhDa, Bonnie B. Blomberg, PhDc,e,
Stefan Glück, MD, PhDf, Charles S. Carver, PhDa,c
a Department of Psychology, University of Miami, Coral Gables, FL, United States
b Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, United States
c Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
d Massachusetts General Hospital Cancer Center, Center for Psychiatric Oncology and Behavioral Sciences and Cancer Outcomes
Research Program, Boston, MA, United States
e Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
f Celgene Corporation, United States
Gen Hosp Psychiatry. 2017 Jan - Feb;44:16-21. doi:
10.1016/j.genhosppsych.2016.10.002. Epub 2016 Oct 22.
High depressive symptoms significantly associate
with poorer survival in breast cancer patients
Low symptoms: HDRS ≤ 7
High symptoms: HDRS > 7
Log-rank p-value = 0.036
We wanted to develop a model which
would look at both the tumor AND the
‘’patient’’ simultaneously.
56
Introduction
NSG model
• metastases frequently and consistently observed in orthotopic xenograft model using MDA231 cells in NSG mice
• 1x106 MDA231 cells injected into mammary fat pad of female NSG mice
• ~ 8 weeks post injection animals were sacrificed when tumors reached ~10% body weight according to IACUC guidelines
• animals were examined for presence of macroscopic metastases
1x106
MDA231 cells
Macroscopic metastasis frequency in NSG model
Metastatic site Frequency (%)
Liver 89
Left axillary lymph node 74
Lung 47
Diaphragm 32
Right axillary lymph node 11
Kidney 11
Colon 5
Salivary gland 5
Fascia lymph node 5
Contralateral mammary fat pad 5
57
Introduction
NSG model
Results
Stroma gene expression analysis: Analysis 3
• MOUSE ANALYSIS 3
• Identified genes differentially expressed between distant ‘normal’ stroma from tumor bearing mice and normal control stroma from non-tumor bearing mice
• Samples analyzed:
(2) distant ‘normal’ tissue not involved by tumor (mouse stroma)
(3) normal tissue from non-tumor bearing mice (mouse stroma)
RNA samples used for distant ‘normal’ stroma vs normal control stroma analyses
2
3
• primary mammary fat pad
• contralateral mammary fat pad
• liver
• diaphragm
1
23
118
124
219
250
308
341
363
404
IgV
IgC
IgC
TM
ICD
Extracellular
Plasma membrane
Intracellular
Receptor for Advanced Glycation End-products (RAGE)
Damage Associated Molecular Patterns (DAMPs)
RAGE is a multi-ligand receptor
Collagen I/IV
LPS
LPA
RAGE expression in breast tumor predict outcomes
RAGE IHC (n=205)
Murine gene expression analysis of breast cancer-bearing stroma
shows upregulation of RAGE ligands
Drews-Elgers et al, BCRT, 2014
RAGE gene knockout impairs breast cancer
progression
RAGE inhibitor FPS-ZM1 impairs
breast cancer progression
500,000 4175 cells injected into NSG mice (n=10 per group).
FPS-ZM1 (1mg/kg, twice per week I.P.)
RAGE inhibitor FPS-ZM1 impairs tumor metastasis
(RAGE knockdown model)
TO SUM UP
LOCAL THERAPY MATTERS BUT IT’S NOT LIKELY TO
FURTHER IMPROVE SURVIVAL VERY MUCH
WE COULD LIKELY PREVENT A LOT OF BREAST
CANCER IF WE ACTED ON WHAT WE ALREADY
KNOW
GOING AFTER MUTATIONS ONE AT A TIME IS
GOING TO BE A VERY SLOW AND POSSIBLY
UNREWARDING STRATEGY
THE HOST REALLY MATTERS AND I PREDICT WILL
YIELD MORE SUCCESSES NEAR TERM THAN
“PERSONALIZED” MEDICINE
I CANNOT SUFFICIENTLY THANK THE
AMAZINGLY PEOPLE IN WHOSE TRAINING I HAVE
BEEN PRIVILEGED TO PARTICIPATE
LARRY NORTON NEAL ROSEN
KENT OSBORNE RAIMUND JAKESZ
NANCY DAVIDSON SOON PAIK
BOB DICKSON MATTHEW ELLIS
DOUG YEE ROBERT CLARKE
ED GELMANN NILS BRUNNER
KEVIN CULLEN MICHAEL JOHNSON
SANDRA SWAIN CLAUDINE ISAACS
DORRAYA EL ASHRY GEORGE WILDING
JAMES RAE ERIK GOKA
ELIZABETH IORNS ANTON WELLSTEIN
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