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SPECIALSECTION

CREDIT:ANNEWESTON/CANCERRESEARCHUK/VISUALSUNLIMITEDINC.

CONTENTS

News

U.S. Cancer Trends

Reviews

M. R. Stratton

C. L. Chaffer and R. A . Weinberg

R. D. Schreiber et al.

See also Editorial p. 1491; Report p. 1612; and Science

Translational Medicine includingResearch Article by L. Sequist

et al., ScienceSignaling, ScienceCareers, Video, and Science

Podcast at www.sciencemag.org/special/cancer2011/.

Cancer Crusadeat 40

I N T R O D U C T I O N

In this issue of Science, we commemorate the 40th anniversary of the U.S.

National Cancer Act, which provided a massive stimulus for cancer research.

At the star t of this Cancer Crusade, researchers were already tackling some

tough questions, as reflected in papers published by Sciencein 1971. Among

them: How do abnormalities in chromosome number arise in tumor cells? Can

tissue-specific markers be used to determine the epithelial versus mesenchymalorigin of a solid tumor? Can the immune system be manipulated so that it recog-nizes tumor cells as foreign invaders that must be eliminated from the body? Do

viruses play a role in human cancer?

Skeptics might argue that 40 years later, cancer researchers continue to grap-ple with the same questions. Perhaps theres some truth in this. But our hope is

that the selection of articles in this special section of Sciencewill explain why

many of these questions have proved so challenging and, more importantly, how

contemporary cancer research is providing a clearer view of the biology that will

lead to answers. Stratton (p.) discusses international efforts to sequence

the complete genomes of a wide range of human tumor types and the impact

that this sequence information is anticipated to have on our understanding of

cancer biology as well as our ability to detect, diagnose, and treat the disease. A

working model for cancer cell metastasis is presented by Chaffer and Weinberg

(p. ), who highlight the important role of cancer stem cells and a develop-mental process called the epithelial-mesenchymal transition. Schreiber et al.(p.

) describe cancer immunoediting, a conceptual framework that integrates

the immune systems dual roles in inhibiting and promoting cancer growth.News repor ts examine other significant challenges for the field: Jocelyn

Kaiser (p. ) describes how even the best new drugs eventually seem to fail

and how they might be made more effective. David Malakoff (p. ) outlines a

key social issue: the fast-rising cost of care. Martin Enserink (p. ) reports on

efforts to close the huge disparity between cancer treatment in rich and develop-ing countries. And Mitch Leslie (p. ) describes how researchers are taking

a new look at the role of p53 and the related proteins p63 and p73 in tumors.A video report by Robert Frederick appears online at www.sciencemag.

org/special/cancer2011/, along with links to additional reading material.

ScienceCareers features an article on cancer clinical trials training (http://scim.ag/cancertrialstraining) and a Q&A with Memorial Sloan-Kettering clinician-investigator David Solit (http://scim.ag/solitqanda).

It is worth noting that at least one of the questions that concerned cancer

researchers writing in Scienceback in 1971 has been definitively answered. We

now know that viruses do in fact play a causal role in certain human cancers,

and, thanks to decades of tumor virology research, vaccines against these viruses

have been developed into successful cancer-preventive agents. Thats something

to celebrate. PAULA KIBERSTIS AND ELIOT MARSHALL

1539www.sciencemag.org SCIENCE VOL 331 25 MARCH 2011

pecialIntropage.indd 1539 3/18/11 4:42

See also Science Translational Medicine including Research Article

by L. Sequistet al., Science Signaling, Science Careers, Video, and

Science Podcast at www.sciencemag.org/special/cancer2011/.

www.sciencemag.org SCIENCE 1


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CANCERCrusade at 40

U.S. Cancer Trends

SOURCE FOR CANCER STATISTICS: NCI SURVEILLANCE RESEARCH PROGRAM; PHOTOS (LEFT TO RIGHT): LINDA BARTLETT/NCI; BILL BRANSON/NCI; N

010

20

30

40

50

60

70

80

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Lung & Bronchus

The good news: Lung cancer incidence amongmen began to decline in the early 1980s; the deathrate, in the early 1990s. This shows the power ofpreventionthrough a campaign to curb tobaccouse. The bad news: The death rate is far higher forAfrican-American men than for white men, anddeaths among women (of all races) continued toclimb until recent years.

Incidence per100,000

Cancer Research and

The $90 Billion MetaphorTHERE NEVER WAS AN OFFICIAL WAR ON CANCER. THAT PHRASE FROM NEWSreports and debates attached itself to the U.S. program that began when Presi-dent Richard Nixon signed the National Cancer Act in December 1971. Thelaw made big promises and gave the U.S. National Cancer Institute (NCI) atoken measure of independence. It also encouraged the idea that cancer could

be targeted, like a trip to the moon, and cured. The law was important forresearch, RAND medical historian and policy analyst Richard Rettig has writ-ten: It stopped a decline in NCIs budget.

This reversal began in Congress. Urged on by health activists such as MaryLasker, leading Democrats in 1970 adopted curing cancer as their cause. Awarethat it might become a national issue, Nixon embraced it, too. The resulting leg-islation raised NCIs budget almost overnight by 23% to $233 million; NCIsfunding has continued to climb since then to more than $5 billion per yearalthough in recent years inflation has grown faster. Since the 1971 act, NCI hasspent about $90 billion on science, treatment, and prevention of cancer.

The war metaphor remains part of this legacyand a target for skeptics. In1986, former NCI biostatistician John Bailar stirred controversy with a bleakanalysis in The New England Journal of Medicine, noting that cancer inci-dence and mortality rates hadnt changed fundamentally in 15 years. He sug-gested that the nation was losing the war against cancer. Sweeping declara-tions continued. In 2003, thenNCI Director Andrew von Eschenbach set agoal of ending suffering and death from cancer by 2015. Such broad claimsinvite balloon-pricking.

But if one sets aside the rhetoric, says Allen Lichter, executive director ofthe American Society of Clinical Oncology, its evident that the cancer cam-

paign has changed therapy and saved lives (see indicators for the seven dead-liest cancers, right). It is true that for certain cancersof the pancreas, brain,and liver, for examplethe picture has not improved. But the overall U.S. can-cer mortality rate began to decline in the 1990s. And clinical care looks noth-ing like it did 40 years ago, says Lichter, who began training as an oncolo-gist in the 1970s. He speaks of a revolution that took lessons from the 1960sadvances against childhood leukemia to develop adjuvant therapy: the crazyidea that chemotherapy should be given to patients in remission to treat pre-sumed microscopic disease that has spread. His list of benefits continues with

breast-conserving and microscopic surgery, imaging for diagnosis and diseasemanagement, molecular analysis of tumors and targeted drug therapy, longersurvival times, and much better palliative care. Looking for progress in cancercan feel like watching the hands of a clock, Lichter admits. But things aredefinitely moving in the right direction.

ELIOT MARSHALL

Deaths per 100,000

50

60

70

0

10

20

30

40

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Incidence per 100,000

Deaths per 100,000

Colon & Rectum

The U.S. National Cancer Institute (NCI) spotlighteddeclining colorectal cancer trends in its 2010Annual Report to the Nation on the Status of Can-cer. Improved diet and screening with colonoscopy,among other early-detection techniques, are help-

ing to control the second-deadliest cancer. NCIsmodeling predicts that overall mortality could drop50% by 2020.

40 Years of the War on Cancer

1971

President RichardNixon signs theNational CancerAct promoting theNational CancerInstitute.

1973

NCI launchesSurveillanceEpidemiologyand End Resultsprogram tocollect U.S.cancer data.

1978

Clinical test-ing begins ofinterferon-,the first bio-logical cancertherapy.

1980

Robert Gallo and others isolatehuman T-lymphotropic virus-a cause ocancer.

2010EstimatedDeaths 157,300


FDA approvestamoxifen toprevent breastcancer recurrence.

1979

Researchersdiscover p53,the mutatedgene most oftenseen in tumors.

5-YearMortalityTrend -1.6%


NEWS

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Breast (female)

Efforts to detect and treat invasive breast cancer partly explain whyincidence rose dramatically in the 1980s, reaching a peak for allraces in 1999. Death rates from breast cancer have been decliningsteadily since 198990, although 5-year survival continues to be farhigher for whites than African Americans.

0

30

90

120

150

60

757779 8183 85878991 93 95 97 99 010305 07


Deaths per 100,000

Pancreas

In part because it is difficult to detect early, pancreatic cancerremains the fourth-deadliest cancer, and incidence and mortalityhave hardly budged. The average patient diagnosed with advanceddisease will live only 6 months.

10

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14

0

2

4

6

8

757779 8183 85878991 93 95 97 99 010305 07


Deaths per 100,000


0

40

80

120

160

200

240

757779 8183 85 87 899193 959799 010305 07

Deaths per 100,000

Incidenceper 100,000

Leukemia

Death rates for the four main types of leukemia have slowlydeclined, thanks largely to treatments that combine chemotherapy

drugs. The survival rate is now about 80% for childhood acutelymphoblastic leukemia.

10

12

14

16

2

0

4

6

8

757779 8183 85 87 899193 959799 010305 07


Deaths per 100,000

SOURCE FOR CANCER STATISTICS: NCI SURVEILLANCE RESEARCH PROGRAM; PHOTOS (LEFT TO RIGHT): ISTOCKPHOTO; THINKSTOCK; NCI; PAUL SAKUMA/AP

1983

Researchers createsevere combinedimmunodeficientmice, a model forcancer research.

1989

Nobel Prize fordiscovering the firstproto-oncogene(Src) awarded toHarold Varmus andMichael Bishop.

1981

First cancer-prevention vaccineintroducedagainst humanhepatitis B virus.




1985

Randomizedtrial shows thatlumpectomy plusradiation areas effective asmastectomy forbreast cancer.

1986

Biostatistician JohnBailar writes in TheNew England Jour-nal of Medicine, Weare losing the waragainst cancer.


5-YearMortalityTrend +0.6%



Liver

Mortality and incidence for liver and bile duct cancers have risensteadily, linked to infections with hepatitis B and C, which are top riskfactors, along with alcohol abuse. Because tumors usually cannot beremoved with surgery, post-diagnosis survival is brief.

5

6

7

8

0

1

2

3

4

757779 8183 85878991 93 959799 010305 07


Deaths per 100,0002010Estimated

Deaths18,910

5-YearMortality

Trend +2.2%

Prostate

The incidence of prostate cancer, the second most common cancerin men, spiked in the early 1990s after regulators approved theprostate-specific antigen (PSA) screening test. Most men treatedafter a PSA test had nonlethal tumors.

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ONE OF THE BEST HOPES FOR ANTICANCER

drugs in the past decade comes from a simple

idea: Find a weak point in a tumors molec-

ular machinery and throw a well-aimed

wrench into it. The strategy has led to some

dramatic successes, stopping the growth of

certain cancers in their tracks while doing

little or no harm to healthy tissue. But the

pursuit of whats known as targeted ther-

apy has taken many of those involved on

a roller-coaster ride. The new treatments,

after a brilliant debut, tend to lose potency

as tumors develop resistance. After a pause

lasting weeks or months, the cancer may

begin to grow again.

Understanding why this occurs and devis-

ing therapies that will overcome resistance

are the main focus of a growing community

of cancer researchers. A recent example of

their quest involves a drug designed to stop

metastatic melanoma, a highly aggressive

disease for which there is no effective treat-

ment today.

In late 2007, Roche and a biotech com-

pany called Plexxikon began testing a new

targeted drug called PLX4032

for patients with advanced

melanoma. When research-

ers presented the first scans

from treated patients, audi-

ences were stunned: In some

cases, the tumors had almost

disappeared. Eighty percent of

patients got better, a remark-

able response that seemed to

validate the concept of targeted

therapy. There was jubila-tion about how well it works,

says Charles Sawyers, a can-

cer researcher at Memorial Sloan-Kettering

Cancer Center (MSKCC) in New York City.

Sawyers is a pioneer of the targeted approach

and co-developer of the drug Gleevec that

has been spectacularly effective against

chronic myelogenous leukemia (CML).

But then came the letdown: After about

7 months, most melanoma patients on the

PLX4032 pill saw their tumors begin to

grow again; many died. Last fall, trying to

learn what enabled that puzzling regrowth,

several research teams showed that resistant

tumor cells had found ways to switch back

on the cell pathway that the PLX4032 drug

had jammed. They gave some of the relapsed

patients another new drug that blocks the

pathway at another point, hop ing their

tumors would shrink under the dual assault.

The results are still coming in.

In the past few years, researchers have

reported dramatic responses to a hand-

ful of new drugs that are given to patients

with a specific mutation in their tumors. But

the emerging pattern is that although these

drugs can shrink solid tumors and extend

patients lives, they never completely elim-

inate the cancer. For reasons still not well

understood, the initial success is only a foot

in the door, says cancer geneticist Michael

Stratton of the Wellcome Trust Sanger Insti-

tute in Cambridge, U.K., whose team hasfound several genetic weak spots in tumors.

Researchers are still working out exactly

what to do next. On the surface, the answer

is straightforward: Identify the ways that

tumors resist the drug, then find or develop

second-generation drugs that block these

escape routes. With the right drugs on hand,

researchers envision designing a cocktail

perhaps two, three, or more drugsthat, if

given when a patient is first diagnosed, could

stop tumors from ever evading the block-

ade. This approach has worked for patients

infected with HIV, who usually take three

antiviral drugs. Sawyers and many other

researchers say theres no reason it shouldnt

work for cancer.

But getting a therapy to work and getting

it to endure are two different things. Even if

a combination therapy stops tumor growth,

it may not buy patients more than a tempo-

rary reprieve, researchers admit. To stretch

the benefit over years, it might be necessary

to devise one complex cocktail after another,

each tailored to a patients evolving tumors.

Tossing in the wrench

Molecular targeting builds on what research-ers have learned from 30 years of work on

the genetic changes behind cancer. Uncon-

Combining Targeted Drugs

To Stop Resistant TumorsEven the most successful targeted therapies lose potency with time. Researchers hope

to figure out how tumors escape; they aim to turn months of survival into years

NEWS

1991

NationalBreast CancerCoalitionlaunched, inthe AIDSactivist style.

1992

FDAapprovessyntheticyew barkderivative, Taxol(paclitaxel), forbreast cancer.

1993

Congress ordersstudy of environmen-tal causes of breastcancer on LongIsland; the 10-yearstudy will yield nosignificant findings.

1994

BRCA1gene,identified as arisk for breastand ovarian can-cer, is cloned;BRCA2clonedthe next year.

Sciencenamesp53 Moleculeof the Year.

1998

FDA approvesHerceptin (trastu-zumab), a mono-clonal antibody, formetastatic breasttumors that over-produce HER2.

1996

American CancerSociety and oth-ers report the firstsustained decline inoverall U.S. cancerdeaths, a drop of 2.6%from 1991 to 1995.

POSSIBLE COCKTAILS OF TARGETED CANCER DRUGS

Median time PossibleDrug Cancer Target to resistance cocktails

Gleevec chronic myelogenous BCR-ABL fusion 5 years Dasatinib or nilotinib leukemia protein (17% of patients) + T315I inhibitor

Iressa, non-small cell lung EGFR receptor 12 months Tarceva + T790M Tarceva cancer with inhibitor + (MET inhibitor EGFR mutation or PI3K inhibitor)

PLX4032 melanoma with V600E BRAF protein 7 months PLX4032 + MEK inhibitorBRAF mutation



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15MAY2008);NCI;GLOGAUPHOTO

GRAPHY/NCI;NCI

trolled cell growth is often driven by an

aberrant protein in the cell membrane

that transmits a spurious signal to the

nucleus, instructing it to divide. Anti-

bodies or small molecules can be used

to block these overactive cell recep-tors, or a mutated protein farther down

the signaling chain, causing tumors to

shrink dramatically. (By contrast, stan-

dard chemotherapy targets all dividing

cells in the body, which makes it much

more toxic.)

But because tumors are geneti-

cally diverse, resistance seems inev-

itable. Once a targeted drug wipes

out the bulk of a tumor, cells harbor-

ing resistance genes, or alternative

growth instructions, have a chance to

grow. Even a tiny population of resis-

tant cells can expand and take over.

Every single targeted therapy will

select for resistance in this way, says

Carlo Maley, who studies the evolution

of cancer at the University of Califor-

nia, San Francisco.

Gleevec is the classic example. In

95% of patients with CML, the can-

cer is driven by a gene called BCR-ABLthat

is formed when two chromosomes swap

pieces, making a fused segment known as

the Philadelphia chromosome. Gleevec,

made by Novartis, is a small molecule that

blocks the BCR-ABL fusion protein. The

drug was approved for CML by regulators

10 years ago this May, and many patients on

it live for at least a decade. But about 17%

of patients develop resistance within 5 years.

Gleevecs developers anticipated this,

they say. Sawyers and others have shown

that in most cases resistance results from

mutated versions of the BCR-ABL pro-

tein that are not affected by the drug and

continue to tell cells to grow. Companies

developed other specific drugs, dasatinib

and nilotinib, that block most forms of the

mutated enzyme and are given to patients

who relapse. Trials published last year showthat the drugs work so well as an alterna-

tive to Gleevec as initial therapy for CML

patients that they may delay resistance for

years, Sawyers says.

However, no cocktail for CML has yet

been tested as an initial therapy in a clinical

trial. One reason, Sawyers says, is that the

cocktail mix is not quite complete. There is

one important mutant version of the BCR-

ABL protein, T315I, that no existing drugs

target. (A promising candidate is in clinical

trials, though.) Furthermore, patients arent

that interested in enrolling in a combina-

tion trial because Gleevec alone works very

well for most patients, says Gleevec co-

developer Brian Druker of Oregon Health

and Science University (OHSU) in Portland.

And as a researcher, Druker says he finds it

hard to ask people to take an experimental

drug as well as Gleevec when only a small

fraction will likely do any better than they

would on Gleevec alone. Would I treat 90people for the benefit of 10? Druker asks.

People are so comfortable with one drug,

Sawyers says.

Gleevec has been used with good

effect to treat another cancer, gastro-

intestinal stromal tumor (GIST), a

rare disease usually caused by muta-

tions in genes called PDFGRA orKIT, says Michael Heinrich of OHSU.

But resistance mutations can appear

in the KIT protein. Although a drug

called sunitinib targets some of them,

theres no current drug that can patch

up all the holes, Heinrich says. And

because GIST patients live a relatively

long time on Gleevec5 years versus

15 months on chemotherapyits hard

to interest companies in testing a cock-

tail for GIST, he says.

Resistance is a more urgent prob-

lem for lung cancer patients treated

with Iressa and Tarceva (gefitinib and

erlotinib), the first big success for tar-

geted therapy after Gleevec. These

nearly identical drugs block a cell

receptor called EGFR that transmits

growth signals. The drugs didnt help

most patients in trials for non-small

cell lung cancer, but researchers real-

ized that they work extremely well on the

roughly 10% of patients who have an EGFR

mutation in their tumors (they tend to be

women, never-smokers, or Asian). Some of

these patients tumors almost vanish when

they receive an EGFR inhibitor. However,the average patient develops resistance after

about a year.

As with Gleevec for leukemia and GIST,

the trouble is often that tumor cells appear

in which the EGFR receptor has a specific

new mutation (T790M) that prevents the

drugs from binding well. Companies are still

moving toward clinical trials of drugs that

block EGFR proteins with this mutation,

which about half of all patients develop, says

Jeffrey Engelman of Massachusetts General

Hospital (MGH) in Boston. Lung cancer

cells have another way of evading the drug,

moreover: They can make more of a differ-ent cell receptor, called MET, that can take

over for EGFR and maintain the growth sig-

CEGFR

Akt

ERBB3 MET

p85

P13Kp110

P P

Akt

ERBB3

p85

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P

A EGFR

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ERBB3

p85

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P P

B EGFRT790M

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MET

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2001

FDA approvesGleevec (imatinib),a targeted drug, forchronic myelog-enous leukemia;Timecalls it amagic bullet.

Childhood cancer landmark:nearly 80% of those treatedfor acute lymphoblasticleukemia are free of cancerevents for 5 years or more.

1998

Nobelist JamesWatson tells TheNew York Timesthatblocking the growthof tumor bloodvessels (antiangiogenesis)can cure cancer in 2 years.

2003

NCI Director Andrewvon Eschenbach vowsto eliminatesufferingand deathfrom cancerby 2015.

2004

FDA approvesAvastin, an anti-angiogenesisdrug, for coloncancer, withchemotherapy.

2005

NIH launches TheCancer GenomeAtlas to cataloggenomic changes intumors.

Two ways out. (A) The lungcancer drug Tarceva (bluespheres) blocks the EGFRreceptor from transmitting asignal. (B) The T790M muta-tion prevents the drug frombinding. (C) Tumor cells canalso overexpress the METreceptor, which takes overwhen EGFR is blocked.

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C R E D I T S ( T O P T O

B O T T O M ) : C O U R T E S Y M E M O R I A L S L O A N K E T T E R I N G C A N C E R C E N T E R ; C O U R T E S Y M A S S A C H U S E T T S G E N E R A L H O S P I T A L ( 2 ) ; J U P I T E R I M A G E S / T H I N K S T O C K

naling pathway. These escape routes and a

couple of others are problematic but a man-

ageable list, says Jeffrey Settleman, who

left MGH last year for Genentech in South

San Francisco, California.

Hoping to close off two escape routesat once, a few companies are running tri-

als combining an EGFR inhibitor and a

MET inhibitor. Early results are mixed,

Engelman says. One problem is that the

cocktails didnt target the T790M muta-

tion, says William Pao of Vanderbilt-

Ingram Cancer Center in Nashville. Pao

is optimistic about another early clini-

cal trial, however, that is treating patients

who became resistant to Tarceva or Iressa

with a new, more potent EGFR inhibitor

and an approved EGFR-blocking antibody

called cetuximab; the combination shrank

T790M-carrying tumors in mice. Initial

results are expected this summer.

New escape routesHow melanoma tumors become resistant to

the initially powerful PLX4032 drug is more

complex. Plexxikon began developing the

drug after Strattons team reported 9 years

ago that tumors in half of advanced mela-

noma patients have the same mutation in aprotein called BRAF. This protein is part of

a key growth signaling pathway. Because

PLX4032 blocks mutated BRAF and inhib-

its this pathway only in tumor cells, it can be

given at high doses (Science, 18 December

2009, p. 1619). But nobody was surprised,

says trial co-leader Keith Flaherty of MGH,

when patients on PLX4032 whose tumorsmelted away eventually relapsed.

But researchers were surprised to find

that biopsied tumors from patients who

developed resistance didnt have mutations

in the BRAF protein. Instead, several teams

reported recently that tumor cells appear

to use three different escape routes. This

was disappointing, but some also saw good

news: Two of these forms of resistance func-

tion in the same wayrestoring the growth

pathway by activating a downstream protein

called MEK. This suggests, says David Solit

of MSKCC, that combining a BRAF inhibi-

tor and a drug that blocks MEK could block

both escape routes.

These studies still dont account

for the lions share of resistance cases,

Flaherty says; there is more work to be

done. But they have inspired GlaxoSmith-

Kline, which makes a BRAF inhibitor simi-

lar to PLX4032, to launch a trial combining

its drug with a MEK inhibitor. This will

provide proof of concept of the cocktailidea, Sawyers says, within a couple of years.

Another cocktail combining PLX4032

with an immunotherapy drug developed

at MSKCC is also under study (Science,

22 October 2010, p. 440).

Cocktails with caveats

Testing combinations of drugs is not new incancer research. But these cocktails would

be different because they would be ratio-

nally designed to block tumor escape

routes, researchers say. Although research-

ers are eager to begin, they will need to over-

come some barriers.

One is commercial competition. Many

drugs that target the newly found resistance

pathways are still in development. Compa-

nies are loath to test two unapproved drugs

simultaneously, especially if one comes

from a business rival. They worry that side

effects from one product will bloody a

drug that is safe on its own, Flaherty says.

People in my line of work are all about try-

ing to make this happen because the biology

is so obvious, he says, but drug develop-

ment is another matter.

Flaherty and others are encouraged,

however, by recent examples of compa-

nies teaming up: In 2009, Merck and Astra-

Zeneca agreed in a groundbreaking deci-

sion to test a Merck MEK inhibitor and a

drug blocking another key pathway, PI3K/

Akt. Since then, a couple more companies

have signed such agreements. The motiva-

tion is not just to overcome resistance butalso to explore an exciting possibility: It has

become increasingly clear from cell stud-

ies that pairing two drugs aimed at different

pathways can result in synergistic effects,

says D. Gary Gilliland, senior vice president

and franchise head for oncology at Merck in

North Wales, Pennsylvania. He also praises

new draft U.S. Food and Drug Administra-

tion guidelines that allow for flexibility for

testing combinations.

Researchers testing combinations must

also face the fact that tumors are constantly

evolving, Engelman notes. His group pub-

lished a study on non-small cell lung can-cer this week in Science Translational Medi-

cine(STM) that illustrates this complexity.

Retargeting.Gleevec co-developer Charles Sawyers, lung cancer researcher Jeffrey Engelman, and mela-

noma trial co-leader Keith Flaherty are working on ways to overcome acquired resistance to targeted drugs.

Sawyers Engelman Flaherty

FDA approvesProvenge, an immunetreatment for meta-static prostate cancer.It extends life about4 months and costs$93,000.

2011

PLX4032, atargeted cancerdrug, extendslife in patientswith advancedmelanoma.

2010

NationalLung CancerScreeningTrial findsthat helical CT screeningcan reduce cancer deathsamong smokers.

2009

James Watson writes thatits time to turn from cancergenetics to understand-ing the chemical reactionswithin cancer cells,or cell metabolism.

2007-2008

Breast cancerincidence declines,attributed to betterscreening andreduced use of hor-mone replacementtherapy.

2006

FDA approvesGardasil vac-cine to preventHPV infection,which can leadto cervicalcancer.



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LOFTHENATIONALCANCERINSTITUTE

103,2(19JANUARY2011)

THE AFTERNOON JEFF GUSTAFSON LOST HISlife to stomach cancer, a rainbow appearedabove his Arlington, Virginia, hospice.Even if the shimmering arc had led to a

pot of gold, however, its not clear whetherthe treasure would have covered the costof treating the 48-year-old

builder, who was known for hiswit and compassion. The billsfor just 4 months of dogged,full-tilt treatment totaled morethan $350,000including

one drug that cost more than$12,000 per dose.Gustafsons story isnt that

unusual to experts who trackthe costs of treating cancer inthe United Statesand areincreasingly worried aboutwhere they are headed. Overthe past 3 decades, total U.S.spending on cancer care hasmore than quadrupled, reach-ing $125 billion last year, or5% of the nations medical bill,

according to a recent estimate. By 2020, itcould grow by as much as 66%, to $207 bil-lion. Multiple forces are driving the spiral:a growing and aging population, more peo-

ple living longer with cancer, and new per-sonalized, or targeted, therapies that can

come with sticker-shock prices of $50,000or more per patient.

New and more costly, however, haventnecessarily meant better. Although tar-geted treatments, which attack a molecu-lar weak spot in the tumors support sys-tem, have helped improve survival rates formany cancers, some extend life for just afew weeks or months (see p. 1542). And the

prices can be sobering: more than $1.2 mil-lion to extend a lung cancer patients life for1 year in one scenario involving a costly butcommon drug. That example is unusual, butsuch numbers have sparked a growingand

sometimes feistydebateover how best to calculate the

benefits of new cancer treat-ments, whether their use willlower or raise per-patientexpenses, and who should

decide whether using them isworth the cost. The questionis, Are we spending too muchfor too little? says oncolo-gist Antonio Tito Fojo of theU.S. National Cancer Institute(NCI) in Bethesda, Maryland.

Demographic driversTallying the current andfuture costs of treating can-cer isnt easy. Cancer nowincludes more than 100 dif-

His team analyzed 37 biopsy samples frompatients with the EGFR mutation who weregiven Iressa or Tarceva and later becameresistant. Although some resistance mutationswere known, others were new, and for 30% of

the samples, his team could not identify themechanism. Some tumors even morphed intoa different type of lung cancer that requiresan entirely different treatment. In addition,

biopsies from three patients collected duringthe course of treatment showed that tumorschanged: Some that developed resistancemutations later lost them. Its very, very com-

plex. Its not fitting into the simple boxes thatweve made until now, Engelman says.

Cocktail therapy will face another issuethat has not been well explored so far: the riskthat combining two drugsparticularly onesthat target different pathways used by normalcellscan lead to unacceptable side effects.Engelman thinks that for this reason, patientswill be able to tolerate a cocktail for only ashort time. He envisions putting them on asingle drug, then intermittently giving them a

pulse of a cocktail for several days. As hisSTMstudy suggests, clinicians would need toconstantly biopsy patients and tailor the cock-tail to the mutations in their tumor. This couldstretch responses out to years, Engelman says.

A lot of this is going to have to be doneby trial and error, Pao agrees. Sawyers andothers point out, however, that such combi-nation therapies developed in the 1960s and70s eventually vanquished most cases ofchildhood leukemia, Hodgkin lymphoma,and testicular cancer.

Major cancer centers are already rou-tinely genotyping biopsies from patientsthroughout their treatment using proce-dures that are less invasive than surgery,such as collecting a few tumor cells with athick needle. Engelman says this is essen-tial: We cant be afraid to rebiopsy to seewhats going on.

Cancer researchers acknowledge thatcoming up with cocktails to corner can-cer will be much more difficult than it waswith HIV. Cancer geneticist Bert Vogelstein

of Johns Hopkins University in Baltimore,Maryland, points out that cancer is differentfrom AIDS: Among other things, tumors varymore from patient to patient than HIV does;the genetic heterogeneity of cancer cells

within a single patient is orders of magni-tude greater than HIV genotypes in patients,so tumors have a much larger reservoir ofresistance mechanisms that go beyond thosealready uncovered. Unfortunately, weve got

billions of cancer cells ready to become resis-tant, and it takes 15 years to develop each newdrug, Vogelstein says. Moreover, to wipe outa tumor completely, he and others say, a cock-tail might also have to include a drug that tar-gets stem celllike cells in a tumor that con-tinuously give rise to tumor cells.

Turning cancer into a manageable dis-ease, however, would be wonderful, Vogel-stein says, if it can be done. Advocates oftargeted therapy think they will get there.Melanoma was completely untreatable18 months ago, says Neal Rosen of MSKCC.Give us a chance. JOCELYN KAISER

Can Treatment Costs Be Tamed?More patients and the rising costs of new cancer treatments spark debate over how

much is too muchand who should decide

NEWS

5% increase in annual costs,first and last year of care

2% increase in annual costs

Population growth only

Current trends in incidenceand survival, projected

PROJECTED COSTS OF TOTAL U.S. CANCER CARE, 201020

1002010 2020

160

140

120

200

U.S.

$(billio

ns)

180

220

Four scenarios.Experts predict total U.S. spending on cancer care could rise by

as much as 66% by 2020, depending on shifts in disease incidence and survival,

and treatment costs.




9/35

C R E D I T S ( T O P T O

B O T T O M ) : C O U R T E S Y M O L L Y S I M ; ( G R A P H S O U R C E ) : A

M A R I O T T O

E T A L

J O U R N A L O F T H E N A T I O N A L C A N C E R I N S T I T U T E

1 0 3

2 ( 1 9 J A N U A R Y 2 0 1 1 )

ferent diseases that affect more than 13 mil-lion people in the United States each year,and there is no single source of uniform sta-tistics. To come up with their recent fore-casts, a team led by NCIs Angela Mariotto

turned to a massive trove of data kept bythe federal governments Medicare healthinsurance program, which now covers some40 million Americans over age 65. Sievingthe data, they were able to extract a roughsnapshot of the costs associated with treatingnearly 1.8 million Medicare patients diag-nosed with cancer between 1975 and 2005.Overall, they examined incidence, survival,and cost trends for 13 cancers in men and 16cancers in women, and estimated costs for

patients younger than 65.The result, published last January in

the Journal of the National Cancer Inst i-tute (JNCI), reveals some of the complexdemographic and technological forces thatare pushing costs down, even as the over-all total rises. Earlier studies, for instance,have suggested that average per-patientcosts for many cancers have declinedslightly in recent years, largely becauseoutpatient treatment has often replacedmore expensive in-hospital stays. TheJNCIstudy, however, shows that those savingsare being swamped, in part, by the grow-ing number of older people, who are morelikely to get cancer. Medicare predicts itsrolls will nearly double, to 70 million peo-

ple, by 2020. And theJNCIstudy forecaststhat some 16% of these older Americansabout 11.4 million peoplewill have can-cer, up from 8 million today. Another 6.6million younger people will also be livingwith cancer. Even if all other trendssuchas the cost of individual treatmentdontchange, they estimate that those demo-graphic changes alone will push nationalcancer care costs up 27% by 2020.

Ironically, another factor driving up costsis that people are now surviving cancers thatmight have killed them quickly decades ago.

Some of the largest projected cost increases,for instance, are linked to providing con-tinuing care for people living with breastand prostate cancer, a group expected togrow by as much as 41%, to nearly 8 mil-lion in 2020. It will cost some $18 billionto provide continuing care for these patients,the team estimates, some 30% to 40% morethan current costs.

The study notes, however, that spendingtends to follow a u-shaped curve over the

period of cancer treatment, with the highestcosts coming just after diagnosis and in the

last year of life, but with relatively less spentin between. For instance, men under 65 withstomach cancersuch as Gustafsonspentan average of $94,000 per year on initialcare in 2010 and $161,000 in the last year oflife, but just $4200 per year for continuingcare. In part, thats because stomach can-cer can kill quickly, and for those who dontdie early, end-stage costs can be very high.But the numbers also reflect the fact that

younger patients typically get more aggres-siveand more costlycare than olderones, perhaps because society perceives agreater potential benefit to extending thelife of a younger person. Patients under 65now make up about 40% of all cancer cases,the JNCI team estimated, and typicallyreceive care that costs about 35% more thanthat of older patients.

Worth the cost?

T he i m pend i ngdemographical lydriven increases areinevitable, the

authors note. Harderto pin down, how-ever, is the futureimpact of techno-logical changes that,overall, have beenrapidly pushing upcosts. In particular,chemotherapy priceshave been esca-lating faster thanother medical costs,largely because ofthe introduction oftargeted drugs thatcome with price tagshigher than those of

many older compounds. Although studiessuggest that cancer drugs typically accountfor less than 15% of a patients total treat-ment costs, experts say that is changing.For instance, an increasingly used drugcalled bevacizumabsold under the nameAvastincan cost from $30,000 to $62,000

per patient per course of treatment, depend-ing on the targeted cancer, according toestimates compiled by NCIs Fojo and col-

leagues. In contrast, some drugs used at thebeginning of the war on cancer in 1971 costjust a few hundred dollars per patient.

Part of the problem, Fojo and his col-leagues have argued in a pair of provocative

papers, is that the new, costlier drugs oftenfail to improve survival appreciably. Theydont work for all patients, and when theydo work, the effect is often limited. To high-light such problems, in both a 2009JNCI

paper and a 2010 paper published inClinicalCancer Research, Fojos team focused on abreakthrough treatment that was toutedat a major annual cancer research meeting

in 2008. A study had shown that non-smallcell lung cancer patients treated with cetux-imab (sold as Erbitux) lived, on average,1.2 months longer than those receiving stan-dard treatments. One scenario, which calledfor using cetuximab for 18 weeks at a costof $40,000, translated to a cost of $496,000for one extra quality-adjusted life year(QALY). In contrast, they noted, kidneydialysis, a lifesaving technology Medicaremade universally available in 1972, costs$129,090 per QALY.

Another scenario, using bevacizumab

Number of people living with cancer

0 2 4 6 8 10 12Millions

2020

2010

Younger than 65

65 and older

U.S. CANCER PREVALENCE

Surviving.One of the major drivers of increasedcosts is that more people are living longer withcancer.

One life. After standard treatments failed to stop Jeff Gustafsons stomach can-cer, his insurer approved the experimental use of one expensive drug, but itfailed to extend his life.



10/35

CREDIT(GRAPHSOURCE):A.MARIOTTO,ETAL.,JOURNALOFTHENATIONALCANCERINSTITUTE

103,2(19JANUARY2

011)

at a cost of $30,000, translated to a QALYcost of $1.2 million. And such drugs are notalone among treatments offering marginal

benefit at very high cost, they wrote: Morethan 90% of the cancer drugs approved by

the U.S. Food and Drug Administration(FDA) in the previous 4 years had cost morethan $20,000 for 12-week treatments. Wemust stop deluding ourselves into thinkingthat prescribing expensive chemothera-

pies and tests are an aberration, a temporarydeviation from an otherwise reasonable costtrajectory, they concluded.

Along with their critique, Fojo and his col-leagues offer solutions. They argue that Medi-care and other U.S. insurers, for instance,shouldnt pay for drugs that would cost morethan $129,090 per QALY. That would stillmake the United States somewhat more gen-erous than other nations, including the UnitedKingdom, Australia, and Canada, whose gov-ernment-run health services routinely rejectthe use of new cancer drugs because theycant meet certain QALYcosts. Fojos group alsosays that drug compa-nies shouldnt fund tri-als designed to detectsurvival improvementsof fewer than 2 monthsunless the drug will costless than $20,000 andshould even considerreducing charges if adrug doesnt work in a

particular patient. Doc-tors should use costlydrugs only in the subsetof patients proven to gain

benef it, they say, andavoid using new drugsoff-label, i.e., to treatcancers other than thosefor which the drug wasapproved by FDA. Suchsteps, Fojo says, would

focus our attention on using drugs that deliverproven benef its until researchers can f indbetter ways to efficiently develop and use tar-geted therapies.

Some disagree sharply. Such ideas arebased on flawed premises, Joshua Cohenand William Looney of Tufts UniversitySchool of Medicine in Boston argue in a

November 2010 response published inNatureBiotechnology. Using QALY calculationsto rule out therapy, for instance, is a biased,blunt instrument that ends up denyingdrugs to patients who need them, the authors

say. They view this as a radically egalitar-ian approach that forces insurers to choose

between drugs they can afford for all, asopposed to those they will fund for no one.They also argue that preventing doctors from

using drugs off-label would hobble the provenpractice of freeing doctors to find promisingnew uses for existing drugs. And it wouldstand in stark contrast with clinical practice.Studies, for instance, suggest that up to 75%of anticancer drugs are already used off-label.And price controls would, they argue, ulti-mately cause investors to reduce funding forresearch into new drugs because they couldnt

be sure of recouping their costs. There is onething the two sides do agree on: Better, moreorganized studies could help steer the rightdrugs to the right patients. Better genetic tests,for instance, could identify patients unlikelyto benefit from a particular drug. They couldalso help researchers design smaller, lesscostly trials that better identify smaller groupsof patients likely to respond; current trials

often wash out these drugs because the ben-efits seem statistically negligible.Another idea gaining ground is cover-

age with evidence development (CED),in which insurers link payments for certaindrugs to efforts to collect data on compara-tive effectiveness, with the aim of discontinu-ing coverage for drugs that dont work. Cohenand Looney even suggest that CED could becombined with risk-sharing arrangements,in which insurers and manufacturers agreeto link a drugs price to its performance. U.S.Medicare managers have already launched

a number of CED experiments, and the newhealth care reform law authorizes extensivenew efforts to compare the effectiveness ofdifferent medical treatments, including cancerdrugs. In 2014, it also requires private insur-

ers to cover the routine costs of enrolling can-cer patients in clinical trials, removing a major

barrier to their participation.

Agonizing decisionsAlthough such studies didnt help Gustafson,his treatment did reflect both the challengeand opportunity inherent in efforts to tampdown the costs of cancer care. His oncolo-gists, for instance, talked with him and hiswife, Molly Sim, about the costs they werelikely to encounter. Thats something that arecent statement from the American Societyof Clinical Oncologists says needs to happenmore often, given how many families exhausttheir savings fighting cancer. We were for-tunate, we had really good insurance, saysSim, who ended up paying less than $6000

out of pocket.Gustafsons doctors

also gave him genetictests to determinewhether he should begiven one expensive but

promising drug; unfor-tunately, the tests indi-cated that he wouldnt

benefit. But when hefailed to respond tostandard treatments,they proposed a last-ditch strategy: Sim suc-cessfully appealed toher insurer to pay foroff-label use of Avas-tin at a cost of nearly$40,000. Gustafsondied in November 2009,

before he could com-plete the treatment.

Its a story that

Fojowho urges caution in using expensivedrugssays he knows all too well. In theabstract, you say using these marginal drugsis crazy, he said recently, shortly after com-ing off his rounds treating cancer patients.But when you have the patient in front ofyou, and nothing else is working, well, Imight try the crazy thing, too. We used to doit with cheap drugs, but now we are doing itwith really expensive drugs. The problem isthey really dont work any better.

DAVID MALAKOFF

David Malakoff is a writer in Alexandria, Virginia.

Last yearContinuingInitial

THE PRICE OF TREATMENT

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

(under65)

(65 andover)

Female-Breast

Annualizedmeannetcostsin2010dollars

(under65)

(65 andover)

Female-Brain

(under65)

(65 andover)

Male-Stomach

(under65)

(65 andover)

Male-Lung

(under65)

(65 andover)

Female-Pancreas

Male-Pancreas

Varying costs. The average annual cost of treatment can vary, depending on the patients age andcancer type. In general, costs are higher just after initial diagnosis and in the last year of life.




11/35

BOSTONIn one of his PowerPoint presen-tations, Lawrence Shulman has a series of

photographs that are hard to forget. One

shows Tushime, an 11-year-old girl in

Rwanda suffering from rhabdomyosarcoma,

a rare cancer of the muscles. A tumor resem-

bling a cauliflower is growing out of her

right cheek.

The good news comes in Shulmans

next three slides. Over a 10-week treatment

course with drugs donated by a U.S. pro-gram, the mass started to shrink until even-

tually it could be removed surgically. The

last picture shows Tushime, standing with

her happy family anddespite a somewhat

lopsided facelooking healthy.

Shulman is chief medical officer at the

Dana-Farber Cancer Institute here, which

is affiliated with Harvard Medical School

(HMS), and to him the pictures carry a pow-

erful message: Given that treatments are

readily available, how can you not treat a

child suffering from a very curable cancer?

Its a message that is beginning to be

heard. Global health has gained in promi-

nence on political agendas in recent years, but

attention has been overwhelmingly focused

on infectious diseases. Now, some

argue, its time to start closing anequally unconscionable gap between

rich and poor nations in cancer pre-

vention, diagnosis, and treatment.

The numbers speak volumes. A

child suffering from leukemia in

Western Europe has an 85% chance

of survival; in the 25 poorest coun-

tries in the world, its just over 10%.

For a man with testicular cancer,

the numbers are about 95% and just

over 40%. Estimates suggest that

less than 5% of the worlds cancer

resources are spent in the develop-

ing world. In many countries, even

painkil lers are hard or impossible

to come bya violation of human

rights, Shulman says.

In a bid to change that, oncolo-

gists at topflight centers in the United

States and Europe are now taking time out

to help improve cancer care in low- and

middle-income countries. In an article last

month, World Health Organization Director-

General Margaret Chan said that cancer

needs to be acknowledged as a vital part of

the global health agenda. Cancer will also

feature on the agenda at the United Nations

High-level Meeting on Non-Communicable

Diseases in September in New York City.

Shulman and Harvard School of Public

Health Dean Julio Frenk co-chair the new

Global Task Force on Expanded Access

to Cancer Care and Control in Develop-

ing Countries (GTF.CCC), which aims to

move cancer up on the global

priori ties list . The group

which combines expertise in

cancer, global health, eco-

nomics, finance, and policy

published a 10-page cal l to

action last year inThe Lancet

and is now working on a col-

lection of papers for the same

journal that details what needs

to be done.

The obstacles are major, and

some people question whether

battling cancer is the wisest use

of scarce global-health money.

Similar doubts were once raised

about infectious diseases,

says HMS physician and GTF.

CCC member Paul Farmer:

A Push to Fight Cancer in theDeveloping WorldCancer and other chronic diseases have received little attention from global healthadvocates. Thats beginning to change

NEWS

Ratioofmortality

toincidence

Low

Country incomeLower middle Upper middle High

THE CANCER SURVIVAL GAP

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Breast

Prostate

Colorectal

Cervix uteri

Non-Hodgkin lymphoma

Thyroid

Testicular

Hodgkin lymphomaLeukemia (0-14 years of age)

Life and death.For many cancers, the case fatality rate (of whichthe ratio of mortality to incidence is a proxy) is much higher inpoor countries than in rich countries.

Prevention.Women wait to be screenedfor cervical cancer at a Partners In Healthclinic in Rwanda.



12/35

15 years ago people questioned the logistical

and financial feasibility of treating HIV and

multidrug-resistant tuberculosis (TB) in poor

countries. Yet as Farmer points out, both are

now being addressed on a large scale. Great

strides have been made recently in a range ofother tropical diseases, too. So why cant it be

done for cancer?

A more difficult jobCancer takes a markedly different toll

depending on the country. Lung cancer, a

major killer in the West, is rarer in Africa,

where fewer people smoke and life expec-

tancy is shorter. Several virus-related can-cers, on the other hand, are much more

prevalent in poor countries. Cervical can-

cer, caused by the human papillomavirus

(HPV), has become quite rare in rich coun-

tries thanks to screening with Pap smears.

But it is common in the developing world,

where 93% of the estimated 273,000 annual

deaths from this disease occur.Taken together, however, the burden

of cancer is still lower in the poorer coun-

CREDIT:KENTDAYTON/HSPH/PRESIDENTANDFELLOWSOFHARVARDCOLLEGE

SUDBURY, MASSACHUSETTSYou can ask me absolutely anything,says Felicia Knauland shes serious. Knaul, a health economist atHarvard Medical School in Boston, doesnt mind telling in detail howbreast cancer changed her marriage, her family, and her career. In hermission to shatter taboos around the disease and improve the lives ofpatients in developing countries, her professional and private lives havebecome one.

Knaul is one half of a Mexican-Canadian power couple that aims toend the neglect of cancer as a disease of the poorand will succeed,if anyone can, say colleagues. The other half is Julio Frenk, the formerhealth minister of Mexico and a much admired reformer, who is now deanof the Harvard School of Public Health (HSPH).

Knaul, born and raised in Toronto, says she has always had a keeninterest in poverty and health. She lived in Bogot for 2 years in the early90s, working on a project for street children and helping the Colom-bian government reform its health system. After meeting Frenk, whocomes from a family of doctors, she moved to Mexico; she now considersit home. She joined the Mexican Health Foundation in Mexico City, whereshe still leads a research group. When Frenk became minister in VicenteFoxs Cabinet in 2000, she worked pro bono to help him push through amajor reform that extended basic health coverage to the countrys poor-est and took effect in 2003.

That didnt prepare her for her own terrifying brush with illness. InOctober 2007, a technician in Cuernavaca discovered a lump in Knaulsleft breast. It was malignant. After weeks of anguish, she underwent amastectomy and started on chemotherapy. Knaul says she was lucky. Shehad access to the best doctors in Mexico, andbecause her husbandtook a job at the Bill and Melinda Gates Foundation after he left thegovernment in 2006she even had insurance coverage in the UnitedStates. Knaul used it to seek additional treatment at the Seattle CancerCare Alliance. She now rates her 5-year survival chance at between 85%and 90%.

Thats much more than most Mexican women with breast cancer can

expect. Coverage for breast cancer treatment was added to Frenks insur-ance plan for the poorest in 2007; in reality, some women still dont gettreatment, for instance, if they live far from a hospital. Early diagnosis israre. Many women forgo mammograms even where they are available,Knaul says, and a culture of machismo often leads men to abandon theirwives or girlfriends if they lose a breast. Knaul recalls a woman recentlydiagnosed with breast cancer at one public event saying: A woman with-out breasts is ugly. I dont want to be ugly.

Knaul decided to start a programit is now a not-for-profit groupcalled Cncer de Mama: Tmatelo a Pecho(Breast Cancer: Take It to Heart)that aims to raise awareness of and improve access to prevention, earlydetection, and treatment. Sharing her own story might help other women,

she thought, so she wrotea frank book about herexperience. The resultingTV interviews with her andFrenk made waves.

She and Frenk took thecampaign to the next levelafter he was appointed deanof HSPH in 2008 and shebecame director of the Har-vard Global Equity Initiative,a research program foundedby Nobel laureateAmartya Sen. Shehad the idea to starta global task force toexpand cancer care inpoor countries. Frenknow co-chairs it withLawrence Shulman,chief medical officer ofthe Dana-Farber CancerInstitute in Boston. Many of their well-placed friends signed on: formerUNAIDS chief Peter Piot, director of the London School of Hygiene andTropical Medicine; Columbia University economist and poverty warrior Jef-frey Sachs; and CNN chief medical correspondent Sanjay Gupta. They havereally brought this to the doorstep of many people at high levels, says Car-los Rodriguez, a pediatric oncologist at Dana-Farber.

The task force is now collecting evidence on how cancer care in devel-oping countries can be improved, she says. To do so, she has helpedrecruit a series of papers for publication in The Lancet(see main text,p. 1548). Her own story, she realizes, is atypical for a woman in Mexico. Still,it reinforces her message, she says: When you say at a meeting, I have

cancer, people listen in a way that happens with very few other diseases.Her frankness is part of her strategy. Mexican couples thanking herfor her book will sometimes mention chapter 18, she says, in which shediscusses how the chemotherapy-induced menopause shut down her sexlife. At her art-filled house 30 kilometers west of Boston, Knaul also dis-cussed, matter-of-factly, why, in her case, reconstructive surgery was notsuccessful. (The implant dropped a couple of inches, she says, becauseof a lack of tissue to hold it up.)

Her own marriage didnt suffer, she addson the contrary, the dis-ease brought the two closer, and for the book, Frenk contributed frag-ments of four love letters written when she was i ll. As Knaul wrote, I hadmy boyfriend back. M.E.

In sickness and in health.

Felicia Knaulwith hus-

band, Julio Frenkwroteabout her disease.

,f

I

Making Her Life an Open Book to Promote Expanded Care




13/35

C R E D I T T H I N K S T O C K

T A B L E S O U R C E

L

S H U L M A N

tries, which is one reason why it has failedto get global health policymakers full atten-tion. Unfortunately, the developing world iscatching up. In many middle-income coun-tries, life expectancy is increasing, and obe-

sity and smoking are on the rise, all of whichlead to more cases of cancer. Women arehaving their children later in life and breast-feeding for a shorter time, which increasestheir risk of breast cancer.

And treating cancer is much more dif-ficult than treating malaria or TB, Shulmansays. Diagnosis is complex, requiring com-

petently staffed and well-equipped pathol-ogy labs. Physicians in many countries are

in short supply; oncologists are extremelyscarce. There arent enough surgeons oroperating rooms; 30 countrieshalf ofthem in Africadont have a single radia-

tion therapy machine.Still, in The Lancetpaper, Shulman andcolleagues at the task force identified a listof cancers for which a lot can be done evenin places with poor infrastructure (see table).These measures include battling tobaccousewhich increases the risk of variouscancers as well as cardiovascular diseasevaccinating against HPV and hepatitis B,improving early detection, treating eminentlycurable tumors such as Tushimes sarcomaand childhood leukemia, and improving life-extending treatment for cancers like Kaposi

sarcoma, an HIV-related cancer of the skin.The price of drugs is not insurmount-

able, says HMS health economist and breastcancer advocate Felicia Knaul, who runsthe task forces secretariat (see sidebar,

p. 1549). Of a list of 27 essential cancerdrugs compiled by the task force, 24 are off-

patent, and prices could be brought downfurther through negotiations with the phar-maceutical industry, Knaul says. A recentstudy showed that drugs needed to treat acase of Burkitts lymphomaa cancer that

primarily affects African children and isassociated with the Epstein-Barr viruscost less than $50, a bargain in terms of life

years saved per dollar.The biggest challenges in combat-

ing canceras for other diseasesareto build up expertise and infrastructureand extend care to the poorest people.Some private groups are interveningdirectly. For the past 18 years, pediat-ric oncologists at St. Jude ChildrensResearch Hospital in Memphis, Ten-nessee, which sets aside about 1% of itsannual budget for global health, have

pioneered so-called twinning programsthat provide assistance to hospitals in20 countries to improve cancer care forchildren. Several other pediatric hospi-tals have followed suit. The impact isreal: In El Salvador, where the twin-

ning started, the 5-year survival rate forchildren with acute lymphoblastic leu-kemia went from 10% to 60%, and isstill climbing.

Partners In Health (PIH), bestknown for its pioneering work fight-ing AIDS and TB in Haiti, has longtreated cancer patients as well, saysco-founder and director Farmer: Theyoften go from one clinic to the next,

seeking care. But PIH is also working withgovernments to strengthen their health sys-temsand expanding cancer care is a keygoal. The Rwandan government is very keen

on it, Farmer says.Currently, the PIH network still relies onBostons medical infrastructure for backup.Brigham and Womens Hospitals pathol-ogy department examines specimens toidentify tumors, for instance, an indispens-able part of diagnosis. (Shulman himselfhas returned from Malawi with a suitcasefull of specimens. Fortunately, nobody atcustoms checked, he says.) But the plan isto develop pathology expertise and infra-structure locally. Brigham and Womens hasdonated equipment for Haiti and Rwanda,

and its chief technologist is training staffmembers. Were totally committed to doingthis, Shulman says.

Going horizontal

Expanding cancer care will cost money. Takethe new HPV vaccines. So far they have beenintroduced in wealthy countries, but can-cer experts say they would prevent far morecases of cervical cancer in poor countries,where Pap smears are seldom done. Theircost, more than $300 per vaccinated teenagegirl in the West, has been a barrier to theirintroduction in the developing world.

But with the economy in a global dip, itshard to see where the money will come from.Cancer is competing for attention with theinfectious diseases, which have seen a majorincrease in program support over the pastdecade but are still underfunded. Meanwhile,other diseases such as diabetes and mentalillness are vying for attention as well. Men-tal health advocates are already disappointedthat they wont have a seat at the SeptemberU.N. meeting on noncommunicable diseases,where the task force is trying to make cancerwell-represented. But its not one or the other,Farmer argues: We have to get away from thewhole notion of choosing between diseases.

Gene Bukhman, head of Harvards Pro-gram in Global Non-communicable Diseaseand Social Change, advocates building up

health systems broadly so that they can dealwith not just cancer but also diabetes, heartdisease, and a variety of other chronic ail-ments that each make up a small percentageof the disease burden. But this approachsometimes dubbed horizontal as opposedto vertical disease-specific programsisnt

particularly popular. The Bill and MelindaGates Foundation is spending its billionsmostly vertically, focusing on specific dis-eases. Likewise, many advocacy groups wantto extend their worksay, on breast or prostatecancerto the worlds poor, but theyre lessinterested in helping fledgling health systems.

Farmer, too, wants to channel the enthu-siasm generated by single diseases into helpfor a better health system: The breast canceradvocate needs to see that without a properhealth system were never going to get earlydetection or good treatment. Emotionalappeals can help, Bukhman says, and that iswhere Tushimes pictures come in. I dontthink weve said this enough. When you seesomeone dying needlessly of cancer, it is anobscene inequalityno different from see-ing someone die from TB or HIV.

MARTIN ENSERINK

AREAS OF OPPORTUNITY

Here are some cancer types for which expertssay major progress could be made in developingcountries:

Curable with early detection and treatment

Breast cancer Cervical cancer

Curable with inexpensive chemotherapy

Non-Hodgkin lymphoma Hodgkin lymphoma Testicular cancer Sarcoma in children Acute lymphoblastic leukemia in children

Palliation with systemic treatment

Advanced breast cancer Kaposi sarcoma

Preventable

Tobacco-related: lung cancer, head andneck cancer, bladder cancer

Vaccine-preventable: cervical cancer(HPV) and liver cancer (hepatitis B)



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CREDITS(TOPTOBOTTOM):PETERANDMARIAHOEY/W

WW.PETERHOEY.COM;(TABLESOURCE)PUBMED

YOUVE HEARD OF CHARLES DARWIN, BUTdoyou know of his elder brother, Erasmus?He was a physician, inventor, and philoso-

pher of some repute. Familiar with Cassandra

Austen, the amateur painter and Janes sister?

Probably not. Famous brothers and sisters

often overshadow their siblings.

The same thing happens in molecular

families. Take p53, the tumor-suppressor

protein that was named Sciences Molecule

of the Year in 1993 and has been dubbed

guardian of the genome. Few nonspe-

cialists know that the celebrated p53 is

closely related to two other proteins, p63

and p73. Yet these unheralded siblings are

grabbing the attention of cancer biologists.

New research suggests that p63 and p73 are

fierce cancer killers that deserve equal bill-

ing with p53. Instead of a single genome

protector, theres a family of guardians,

says cancer biologist Elsa Flores of M. D.

Anderson Cancer Center in Houston, Texas.

Because efforts to exploit p53 in can-

cer therapies havent yet paid off, some

researchers are now looking to p73 and p63

as alternative tumor treatments. Research-

ers have shrunk or prevented tumors in ani-

mals by targeting p73, and the first clini-

cal trialsattempting to use p73 to combat

a hard-to-treat type of breast cancerhave

already started. It would be very attrac-

tive to find a way to activate these proteins

in people with tumors, says cancer biologist

Alexander Zaika of Vanderbilt University

Medical Center (VUMC) in Nashville. Strate-

gies that capitalize on the tumor-fighting capa-

bility of the p53 family belong in the arma-

mentarium against cancer, adds molecular

oncologist Wafik El-Deiry of the Penn State

Hershey Cancer Institute in Pennsylvania.

p53, the hard target

When a cell suffers DNA damage that can

lead to uncontrolled growth, p53 comes

to the rescue. The p53 protein can trig-

ger DNA repair, stop the dodgy cell from

dividing, or, when the damage is grievous,

prompt it to commit suicide. Because p53

is so potent, cells normally keep levels of

the protein low. Spurring cancer cells to

produce more protein, the argument goes,

could prompt tumors to self-destruct. p53

is a g reat therapeutic target, says cancer

biologist Kevin Ryan of the Beatson Insti-

tute for Cancer Research in Glasgow, U.K.

Its involvement in tumor suppression is

without question.

Scientists are pursuing a number of

strategies to enlist p53 in the cancer fight

(Science, 2 March 2007, p. 1211). They

have completed or are running several clini-

cal trials for gene therapy approaches, which

involve introducing extra copies of the p53

gene into cancer cells. Researchers at six

institutions in the United States and the

United Kingdom have also begun safety tri-

als on a compound, developed by the phar-

maceutical company Roche, that hikes p53

levels in cells by impeding the proteins nat-

ural recycling.

So far, however, no p53-based treat-

ments have been approved for clinical use

in the United States. The practical difficul-ties are formidable. For one thing, thanks to

a variety of mutations in p53s gene, more

than half of all tumors

dont carry a working

version of the protein.

Some harbor misshapen

mutants that are inert or

that turn traitor and sub-

vert antitumor defenses.

Even when cancer cells

have a functional form of

p53, they often neutralize

it, for example, by overproducing enzymes

that prompt the proteins destruction.

Attacking many kinds of tumors through

p53 will require pharmacological feats

restoring the gene or reshaping the mal-

formed proteinthat are tougher than the

standard tactic of blocking a molecules

unwanted function. Many of us appreci-

ated it [p53] would be difficult to target,

says cancer biologist Leif Ellisen of Harvard

Medical School (HMS) in Boston. Throw-

ing a wrench into the system is much easier

than fixing the system. Yet many research-

ers remain confident that they will eventu-

ally overcome these obstacles. My personal

bet is still on p53, says cancer biologist

Anna Mandinova, also of HMS. But in the

meantime, researchers are looking at other

options, namely, p63 and p73.

Band of molecular brothers

Scientists discovered the p53 protein in

1979 but didnt recognize its importance for

cancer until 10 years later. In 1997, biolo-

gists identified p73 as a molecular relative,

after discovering a DNA sequence closelyresembling the gene for p53. That came

as a bit of a surprise, says cancer biologist

Gerry Melino of the University of Rome

Tor Vergata in Italy. Nobody expected

a protein so close to p53. Yet researchers

reported another relative, p63, the next year.

Although p53 was the first family member

discovered, p63 and p73 are the older siblings,

evolutionarily speaking. Comparisons of

their genes suggest that p53 evolved from the

ancestral version of p63 and p73 more than

450 million years ago. These elders have a

range of responsibilities. Unlike p53, p63 and

p73 are essential during embryonic develop-ment. Shaping limbs and giving the skin its

layered structure are among p63s tasks in

an embryo. Formation of

brain regions such as the

hippocampus and cor-

tex depends on p73, as

does maturation of the

immune system. Both

proteins are also neces-

sary for female fertility.

For cancer research-

ers, p63 and p73 have

Brothers in Arms Against CancerCancer researchers are trying to harness siblings of p53, the famous tumor-blocking protein

NEWS

Total PubMed Citations

p53

56,939

p63

2149

p73

1541




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CREDIT(GRAPHSOURCE):PUBMED

a big advantage over their sibling: Their

genes are almost never mutated in or lost

from cancer cells. So p63 and p73 could in

theory take over for p53 in almost all can-

cers, and researchers wouldnt have to fret

about restoring a lost gene or reshaping a

distorted protein.

That strategy will work, of course, only if

p73 and p63 are tumor suppressors like their

brother. But that turned out to be surpris-

ingly tough to confirm. A standard experi-

ment for gauging a molecules relevance

to cancerdeleting its gene from mice

didnt clarify the issue. Whereas mice miss-

ing p53 live to adulthood and are beset by

tumors, mice lacking p63 or p73 die young

from other causes, revealing little about their

cancer susceptibility. Complicating the mat-

ter, although some studies found that levelsof p73 or p63 fell in cancer cells, suggesting

that the proteins are antitumor, other work

indicated that their levels soared, implying

that they foster abnormal growth.

The solution to that apparent contra-

diction may lie in the discovery more than

10 years ago that cells dont manufacture

just one kind of each protein. They can fash-

ion at least 12 variants, or isoforms, of the

p73 protein, and at least eight isoforms of

the p63 protein. Scientists divide these vari-

eties into the longer, or TA, isoforms and the

shorter, or N, isoforms. In 2008, Melino,

molecular geneticist Tak Mak of the Univer-sity of Toronto in Canada, and colleagues

engineered mice that lack all of the TA iso-

forms of p73 but retain the N versions.

The mice were prone to cancer, though they

werent as vulnerable as rodents lacking

p53. The TA isoform-deficient mice really

convinced people that these genes are act-

ing as tumor suppressors, says Flores.

Researchers now hypothesize that in can-

cer, TA isoforms are generally good guys,

suppressing unchecked cell growth. The N

isoforms, for the most part, are bad guys.

They can latch on to and disable p53 and

the good TA isoforms, thus aiding cancer.For example, cancer biologist Alea Mills

of Cold Spring Harbor Laboratory in New

York and colleagues reported in February in

Cell Stem Cellthat a common N isoform

of p63 spurs the growth of skin tumors.

Taking on tumorsp63 and p73 battle cancer in several ways.

Like their famous brother, the proteins cull

cells that carry potentially cancer-causing

DNA damage, activating their apoptotic, or

cell suicide, pathways. Fortuitously, some

chemotherapy already takes advantage of

this ability, causing DNA damage that spurs

p63 or p73 to kill tumor cells.Recent studies suggest that p63 also reins

in metastasis, the migration of tumor cells to

a new location in the body; thats what usu-

ally kills cancer patients. In 2009 in Cell, a

team led by Stefano Piccolo of the Univer-

sity of Padua School of Medicine in Italy

revealed that some mutant forms of p53

found in cancer cells prevent p63 from acti-

vating two genes that curtail metastasis. And

last fall, in a study inNature, Flores and col-

leagues showed that the TA isoforms of p63

curb metastasis through another mechanism:

boosting levels of microRNAs, RNA snip-

pets that turn down gene activity. The teamdiscovered that p63s TA isoforms increase

production of Dicer, an enzyme that snips

and activates inert microRNAs. The isoforms

also raise levels of a specific microRNA,

miR-130b, that prevents cells from mov-

ing on. p63 may be the master regulator of

metastasis, says Flores, and activating it

might increase levels of several metastasis-

halting microRNAs by flipping on Dicer.

The big question is whether drug design-

ers can capture p63s and p73s cancer-

quelling talents. The research directed at

this goal isnt as intense or advanced as the

work on p53, but scientists can claim someencouraging findings.

One therapeutic strategy attempts to

reduce sibling rivalry in the p53 fam-

ily. The mutant p53s found in cancer cells

often latch onto and neutralize p63 and p73.

Three years ago, a research group from the

Cleveland Clinic in Ohio screened more

than 46,000 compounds and pinpointed

one, named RETRA, that in test tubes

breaks mutant p53s embrace of p73. To

test whether freeing p73 destroys tumors,

the researchers then transplanted human

cancer cells into mice and

administered RETRA. The

treatment cut the number

of tumors that sprouted in

the animals, the scientists

revealed in the Proceed-

ings of the National Acad-

emy of Sciences.

To liberate p73 from a

different inhibitor that is

abundant in cancer cells,

one known as iASPP, Ryan

and colleagues ironically

turned to p53 for inspi-

ration. They developed a

snippet of p53, just 37 of

its nearly 400 amino acids, that in the test

tube separates p73 from iASPP. Dosing can-

cer-ridden mice with the snippet, known as37AA, shrank the rodents tumors, the team

reported in The Journal of Clinical Investi-

gationin 2007.

RETRAs effects were fairly weak, and

37AA was fragile, so neither is likely to

become a drug. But the importance of stud-

ies like these, says El-Deiry, is that they

show its possible to uncover compounds that

rouse p53s siblings to attack cancer cells.

Scientists are hunting for other molecules

that might spur p73 and p63 into action and

that could make effective drugs. El-Deirys

group, for example, is in the middle of a proj-

ect to screen thousands of small moleculestheyve assessed more than 70,000 so farin

hopes of finding ones that switch on genes in

the p53 pathway. Some of the candidates, he

says, appear to work by activating p73.

At least one group has started clini-

cal trials. Medical oncologist Ingrid Mayer

and cancer biologist Jennifer Pietenpol

of VUMC are targeting a form of breast

cancerknown as triple-negative because

the tumor cells lack three key receptor pro-

teinsthat defies standard treatments such

as tamoxifen and Herceptin. The tumor cells

harbor large quantities of the N isoforms of

p63, which the researchers suspect preventp73 from killing the cells. Along with stan-

dard chemotherapy, patients will receive an

existing drug, everolimus, that boosts p73

levels by inhibiting a p73 blocker called

mTOR. The goal is to overcome p63s inter-

ference and enable p73 to kill the tumor cells.

Its too late for Erasmus Darwin to match

his brothers fame. But these clinical trials

and the surge of research on p63 and p73

suggest that the proteins are finally stepping

out of the shadow of their famous sibling.

MITCH LESLIE

On the attack.Researchers are testing antitumor compounds that rely

on p73.

TARGETING P73

Drug candidate Mechanism Results

37AA Disengages p73 Shrinks tumorsfrom inhibitor in mice

NSC176327 Boosts p73 Kills cancer cellsproduction in culture

Antisense Curtailsproduction Curbs growth ofgapmers of p73sN isoforms melanoma tumors

in mice

Everolimus Increases p73 levels Trials in progress

RETRA Separates p73 from Impedes tumormutant p53 formation in mice



16/35

REVIEW

Exploring the Genomes of Cancer

Cells: Progress and PromiseMichael R. Stratton*

The description and interpretation of genomic abnormalities in cancer cells have been at the

heart of cancer research for more than a century. With exhaustive sequencing of cancer genomes

across a wide range of human tumors well under way, we are now entering the end game of this

mission. In the forthcoming decade, essentially complete catalogs of somatic mutations will be

generated for tens of thousands of human cancers. Here, I provide an overview of what these

efforts have revealed to date about the origin and behavioral features of cancer cells and how

this genomic information is being exploited to improve diagnosis and therapy of the disease.

Much of our current understanding of

cancer is based on the central tenet thatit is a genetic disease, arising as a clone

of cells that expands in an unregulated fashion

because of somatically acquired mutations (1).

These somatic mutations include base substitu-

tions, insertions and deletions (indels) of bases,

rearrangements caused by breakage and abnor-

mal rejoining of DNA, and changes in the copy

numberof DNAsegments. They also often include

epigenetic changes that are stably inherited over

mitotic DNA replication, for example, alterations

in methylation of cytosine residues (2).

Whether a mature cancer clone emerges in an

individual person is influenced by environmental

and life-style factors, as well as by the set of ge-

nomic sequence variants present in the fertilizedegg from which the individual develops and that

are therefore found in all somatic cells. These so-

called constitutional orgermlinemutations can

influence cancer susceptibility in a number of ways,

including directly altering growth of the cancer

clone, altering the mutation rate in somatic cells,

or modulating the metabolism of carcinogens.

Somatic mutations are thought to occur in the

genomes of all normal cells as they proceed

through the rounds of cell division that take place

during development in utero and during replen-

ishment of body tissues in postnatal life. Addi-

tional somatic mutations continue to accumulate

in cancer cells as they divide. The rate of acqui-sition and the types of somatic mutation that accrue

can be increased by exogenous and endogenous

exposures that cause DNA damage and are miti-

gated by DNA repair processes. Indeed, in the

event that DNA repair fails, the somatic mutation

rate may also increase.

Somatic mutations are more or less randomly

distributed throughout the genome. However, in

the cell thatundergoesclonalexpansion to become

a cancer, a subsettermed driver mutations

have by chance fallen in a set of key genes, calledcancer genes, and have thus subverted normal

control of cell proliferation, differentiation, death,

and other homeostatic interactions with the tissue

microenvironment (3). Driver mutations confer

growth advantage upon the neoplastic clone, allow-

ing it to expand more than normal cells from the

same tissue, invade into surrounding tissue, and,

in many cases, metastasize. The number of driver

mutations in a cancer cell reflects the number of

mutated cancer genes and thus the deregulation

of cell biological processes required to convert a

normal cell into a symptomatic cancer clone. The

remainingand often the large majority of

mutations are passengers, which, by definition,

do not confer growth advantage. The number ofpassenger mutations in a cancer genome primar-

ily reflects the number of mitotic cell divisions

between the fertilized egg and the cancer cell and

the mutation rate at each of these cell divisions.

Thus, the catalog of somatic mutations in the ge-

nome of a cancer cell represents genomic changes

that usually accumulate over several decades. It

includes the mutations responsible for conferring

the various aspects of the neoplastic phenotype

and bears the imprints of the mutational processes

that caused the disease in the first place.

Cataloging Mutations in Human

Cancer Genomes

Over thepast half-century a seriesof technologies

have been deployed to characterize systematical-

ly, at ever-increasing levels of resolution, the state

of cancer genomes across the range of cancer

types (Fig. 1). The earliest, and still one of the

most influential in its impact on cancer science,

was cytogenetic studies of chromosomes from

cancer cells. These revealed abnormalities of chro-

mosome copy number and the presence of somat-

ically acquired rearrangements (chromosomal

translocations). They showed that some cancer

types had very disordered genomes whereas others

displayed few genomic abnormalities. They also

yielded evidence that certain positions in the

genome were recurrently rearranged in particular

cancer types, from which it was inferred that a

cancer gene resided at the rearrangement break-

points. After the widespread adoption of recom-

binant DNA technology in the 1980s, it became

possible to isolate and sequence the genome inthe vicinity of these recurrently rearranged regions,

leading to the identification of many rearranged

cancergenes, particularly in leukemias, lymphomas,

and sarcomas (4).

The next major suite of technologies primar-

ily provided evidence of copy number change in

cancer genomes, but at higher resolution than was

generally possible by cytogenetics. These ap-

proaches confirmed the variation in extent of copy

number change between individualcancer genomes

and highlighted regions showing recurrent in-

creases or reductions in copy number. Subsequent

studies focusing on these recurrently abnormal

regions provided a further harvest of new cancergenes (5, 6).

These technologies had their limitations. Most

obviously, they could not directly detect base

substitutions or small indels. The emergence of

the draft human genome sequence in 2000 em-

powered the study of cancer genomes in many

ways. In particular, it provided a template for the

design of polymerase chain reaction (PCR) primer

pairs to amplify and

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