Download Cancer in the 21st Century An Inside View from an Outsider

Cancer in the 21st Century
An Inside View from an Outsider
Edward J Benz, Jr.
Dana Farber Cancer Institute
Harvard Medical School
Boston, MA
Today’s Agenda:
•
Cancer 101 Cliff Notes Version:
 What is (are) Cancer(s)?
 Why are They So Hard to Cure?
• Conquering Cancer via Genomics, Big
Science and “Precision Medicine”:
 What has us Excited, Worried, Annoyed?
 How are we doing?
• The Future:
 Opportunities and Challenges
 Affordability and sustainability
 A prediction
Cancer Burden US and Worldwide
• In US, 1.685 million newly diagnosed patients
annually and 14 million cancer survivors.
• 585,000 annual deaths - leading cause of lost life
years.
• Nearly 1 in 2 men and 1 in 3 women in US will
develop a cancer.
• Cancer accounts for 10% of US health care costs
• Worldwide, 14 million cases and 8 million deaths
annually. 50-60% of cases in “developing” world.
• US accounts for ~12% of cancer cases but has
about ~30% of world’s oncologically trained
healthcare workforce.
“Cancer” is MANY Different
Diseases
• There are hundreds of forms of cancer
varying by organ site, cell type, etc.
• Even within a given tissue and cell type
there are many different molecular
subtypes,
• e.g., estrogen receptor, progesterone receptor,
and/or Her 2 positive or negative breast cancer
• An individual patient’s “cancer” is actually a
heterogeneous mix of subclones
The Essential Elements that Make a Tumor a Cancer
The Root Cause of Cancer is the Impact
of Environment on Genes
•
•
•
•
•
•
We all inherit a greater or lesser
propensity to develop particular
cancers (e.g., brca)
Environmental insults implicated as
“causing cancer” have in common
the ability to damage or alter
(mutate) DNA (i.e., genes)
In every cancer ever studied, one
finds many mutated genes
Altering these genes in normal
cells makes them cancerous
Cancers are caused by mutations
that derange normal genes
controlling cell growth, making
them behave improperly
“Cancer happens when good genes
go bad”
cell growth
accelerators
cell cycle brakes
suppressors of
apoptosis
promotors of
apoptosis
NORMAL CELL PROLIFERATION
NEOPLASTIC CELL PROLIFERATION
20th Century Cancer Treatment
• Surgery
• Radiation Therapy
• Cytotoxic Drugs (“chemo”)
• Results:
• “Cures” for a few – Hodgkin Disease, Testicular
• Modest/moderate prolongation of life or palliation
for many
• No benefit for way too many
• A lot of toxicity for most – “carpet bombing”
The Mutability and Heterogeneity of
Cancers Makes them VERY Hard to Cure
• Mutability – Almost all cancers carry mutations
•
•
•
impairing our mechanisms for repairing and
“proofreading” our DNA. They mutate and change,
i.e., evolve constantly.
Heterogeneity – Consequently, even a small
tumor is actually a collection of subclones of cells.
Each differs from the others in important ways
including sensitivity or resistance to cancer drugs.
Thus, even when initial therapy produces a
dramatic response, resistant subclones grow back.
Cancer cells employ many mechanisms to become
resistant, impeding efforts to defeat resistance
Game Changing Advance and Paradigm Shift:
Chronic Myelogenous Leukemia, bcr/abl, and Imatinib
Effect of Imatininib on Survival in CML
Year
Imatinib
1990-2000
1982-1989
1975-1981
1965-1974
Proportion surviving
1.0
95%
0.8
Total
230
960
365
132
123
Dead
7
334
265
127
122
0.6
0.4
0.2
0
0
2
4
6
8
Years from referral
10
12
14
A BRAF Mutation is a Common Driver of Melanomas
McDermott U et al. N Engl J Med 2011;364:340-350.
BRAF Inhibitor Prolongs Survival in Patients with Metastatic Melanoma
But ONLY in patients whose tumors have the BRAF mutation
Targeting Treatments Based on Knowledge of
the Mutation – Precision Cancer Medicine
Patient A
Mutation A
Drug A
A
Patient B
X
Malignant Cell Growth
Mutation B
Drug B
B
Patient C
X
Malignant Cell Growth
Mutation C
Drug C
C
X
Malignant Cell Growth
Targeted Therapies Report Card
Dramatic Responses in selected subsets of
patients – small percentage
Responses usually short lived – many resistance
mechanisms identified
Long term survival improved at best in a subset of
the subset of patients
Patients have taught us that it’s a lot more
complicated inside a tumor than it seemed
Actually giving care this way is complicated and
expensive
Role of PD-1 in Suppressing Antitumor
Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
B7.1
MHC-Ag
CD28
TCR Signal 1
(-)
(-)
(-)
PD-1
PD-L1
Inhibition
Tumor
Tumor
(anergy, exhaustion, death)
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Role of PD-1 in Suppressing Antitumor
Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
B7.1
MHC-Ag
CD28
TCR Signal 1
(-)
(-)
(-)
AntiPD-1
PD-1
PD-L1
Block Inhibition
Tumor
(no anergy, exhaustion,
death)
Tumor
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Repeated responses after resistance
develops
Van Allen, et al. Cancer Immunol. Res. 2015
The Transition of Cancer Science…a Dozen Years into the Genome Era
Cancer science is undergoing a major transformation
Pathologic Genome Anatomy
Genomic & Epigenomic
PathoPhysiology
Vascular
Tumor
Growth
Immune
Environment
Tumor Cell
Other
Host
Factors
Inflammatory
Reactors
Microenvironment

We’ve had some spectacular but limited success in using genomics to
direct and develop better cancer therapies

The future depends on how we figure out how to put massive amounts of
genomic information into a functional and pathophysiological context that
illuminates behavior of cancer cells and the tissues they form and use the
insights gained to provide meaningful clues for better therapy
Cancer Care Costs
 Annual direct cost of cancer care in the U.S. for the most
common cancers is estimated to be $124,600,000,000*
 By 2020, the cost is expected to increase by 39% to
$173,000,000,000*
 Increase based on an analysis of expected changes
in incidence, patterns of care, survival and aging
population
 Cancer patients constitute 0.68% of commercial payer
population but account for 10% of health care cost
incurred
Cancer Costs: Patient Implications
 Duke/DFCI evaluation of consequences of out
of pocket cancer care expenses (Medicare pts):
 45% perceived a significant or catastrophic financial
burden
 Expenses averaged $1266/month
 30% did not fill prescriptions
 20% took less medication than prescribed
 47% used all or part of their savings
 49% borrowed money to pay for prescription
Courtesy of Peter Bach, updated 2015
Monthly and Median Costs of Cancer Drugs at the
Time of FDA Approval 1965-2015
22
End-of-Life Cancer Care Costs
Source: Innovus
http://www.valuebasedcancer.com/article/big-cost-drivers-end-life-cancer-care-are-not-drugs
Options for Payment Reform
The Only Real Path to Sustainability:
Reduce the Number of Advanced Cancers
Requiring Expensive Treatment
PreventionNo brainers - ban tobacco, vaccinate against HPV, hepatitis, ban tanning
parlors, use of sunscreen
Likely to help – promote safe eating habits, exercise, reduce alcohol use,
reduce pollutants
Early detection – diagnose when curable by surgery or adjuvant
therapies
Very likely to help - Better technologies and broader use of
mammography, colon cancer screening, ?? “better PSA”, CT scanning of
high risk individuals for lung cancer
Needs to be done and better funded – biomarkers, scalable imaging
strategies, e.g., ovarian, pancreas, lung, glioblastoma
THANK YOU FOR YOUR ATTENTION
Tumor Genomic Profiling Today:
Single Genes with Specific Alterations
Imatinib
Dasatinib
Nilotinib
BCR-ABL
Trastuzumab
Lapatinib
Pertuzumab
T-DM1
ERBB2
(Her2)
EGFR
ALK
Erlotinib
Crizotinib
Cetuximab
Panitumumab
KRAS
BRAF
Vemurafenib
Nikhil Wagle
Tiers 3-5: non-actionable
Actionable OncoPanel Results
Tier 5
37
2%
Most actionable result, 18,000 cases
Tier 4
409
23%
Tier 1
322
18%
Tier 3
201
11%
Tier 2
835
46%