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