October 17., 2001 •Volume 93, Number 20
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`1
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`AustraliaruReport Urges Nationwide Radiation Therapy Plan, L. Newman
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`A
`Rapainycin's Resurrection: A New Way to Target the Cancer CeU Cycle, 'K. Garber
`The Age of Breast Can~r Awareness: What Is the 'Effect of Media Coverage? N. Gottlieb
`Stat ·Bite: ·Leading Causes of Death Among Females by .i{~e Group, 1998
`Ethnicity May Affect Alternative, Complementary Thera y Choices, J. Jones
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`'Y-R!di.ati~~ Sensitivjty and Risk of Glioma, M. L Bondy, L.~E. Wang, R. El-Z-ein, M de Andrade,
`1553-=/~
`!ef. ~· 'Sel~anf 'I!· M. Bruner, V. A. Levin, "'.- K. A. Yung, P: A~atto •• Q. Wei
`....__..-.--
`Night Shut :Wofk, Light at Night, and Risk of Breast Cance~, ·S. Davis, D. K. Miric~ (~>
`'Rotating Nigli~$hifts anil Risk of Breast Cancer in Women Pnr.ticipating in the Nurses' G ,;;.)
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`. R. G. S!Jfe.ns
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`· Health Study~ E. S. Schem!uunmer, F. lAllen,. F. E. Speil.er, W: -~ D. J. Hunter, I. Kawachi,
`., p .. A, <:JoldJtz
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`CORRESPONDENCE Breast Cancer Screening for Women Aged 40-49 Years:'~c~ning May Not Be.the Benign
`Process Usuaily altouW!,t, M. Retsky, R. Demicheli, W. l/rushesky
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`· Testing for...-CJ>lon N.£op}asia Susceptibility 'V aiiantS at the H.uman COX2 Locus, 'c. M. Ulrich,
`J. D. Po'tjer • Resp<>nsi:. G. L. Wiesner. P. Platzer, S. G. Buxbaum, S. Lewis, M .fvf acMillen,
`/ ,,Willi&;ii4.. Ohakrayarti, R. C. Elston, S.iI). MarkQwitz f
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`~--.~Jll..M£th~ .!g.Jg!1m~ve ~fficncy of Intrav~ic~ Mitomy~ C: Results of a Rruidomized
`Phase ID Trlal, J, R. Mqsters • Response, J. L-S. Au, M. G.~Wientjes
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`Re: Meia:b<?}it~ of a Tobacco-Specific Lung Carciiufgen in Nonsmoktng Womei.i ~xposed to
`Environmental,Tobacco Smoke, N. S. Chobanyan, l<\. K. Net$esyan • Response, K p. Anderson,
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`S. S .. JiechJ, ~· I.,, Qli~s. C. Le
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`E"iltum: Re: Re:-Role of the Inslilin-Like Growtll,Factol"S in 1Cancer Development itnd
`Progres~on, R. '/. Collier, D . E. Bauman
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`Cal~nda11 o(E;) n~ .
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`Information for Authors appears-in the Octo.ber 3, 2001, issue and on the Journal's Web site
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`• Visit the Journal's Web site at http://jnci.oupjournals.org/ •
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`West-Ward Exhibit 1059
`Garber 2001 - Page 001
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`

`

`"Whenever a new facility opens, it
`is immediately swamped," said Lester
`Peters, M .D., chair of radiation oncol(cid:173)
`ogy at Peter MacCallum Cancer Insti(cid:173)
`tute in East Melbourne, Victoria, Aus(cid:173)
`tralia, who was not involved in the
`report. He attributed the lack of ad(cid:173)
`equate facilities to the absence of a
`cohesive plan between federal and
`state government, with inadequacy of
`resources extending to staffing and
`training.
`The report also asserts that there is
`an unmet need for radiation therapists,
`physicists, and
`radiation
`oncologists
`and a dearth
`of training
`programs
`nationally.
`The analysis
`links the mun(cid:173)
`bers of staff
`needed to the
`population.
`High-nnmber'c--
`of unfilled positions for physicists and
`therapists mean that staffing is inad(cid:173)
`equate to meet current needs, accord(cid:173)
`ing to the report.
`Burton pointed out that Australia
`does not have a national cancer control
`pr9gram akin to what the World Health
`Organization recommends. He also
`noted that searches for qualified person(cid:173)
`nel in the United Kingdom and Canada
`will make it even more difficult to fill
`vacancies in Australia.
`
`Dr. Lester Peters
`
`Separate Government Inquiry
`
`A second, separate government in(cid:173)
`quiry also has infuriated some in the
`radiation oncology profession. It is
`eyeing the same issues that the profes(cid:173)
`sion did in its strategic report. Accord-
`
`ing to Burton, "the terms of reference of
`the second inquiry" are to review and
`make recommendations concerning
`workforce, training, funding, patient
`access, and national standards for ser(cid:173)
`vices and facility accreditation.
`The second panel will also be
`charged with making recommendations
`on how the Commonwealth, the states,
`and private industry can collaborate and
`implement a nationwide strategic plan.
`The inquiry will begin next month and
`report its f indings and recommenda(cid:173)
`tions to the federal government, prob(cid:173)
`ably in mid-to-late 2002.
`
`'A Very Clear Problem'
`
`Burton commended the reach of
`the profession 's strategic p lan, ac(cid:173)
`knowle dging
`that it put
`forward "a lot
`of evidence,
`predictions,
`useful
`lifespans of
`equipment,
`and it pressed
`the training
`issue." He too
`maintained
`that there is
`"a very clear problem in manpower
`planning." One weakness is that the
`profession's report "did not include
`health economists or research ana(cid:173)
`lysts, nor it spell out priorities or
`timelines."
`He was not surprised that the new
`government inquiries have eclipsed the
`profession's report. The government
`could not move on the profession 's
`report, observed Burton, because " they
`are inside the box.;'
`
`Dr. Liz Kenny
`
`- Laura Newman
`
`Rapamycin's
`Resurrection: A New
`Way to Target the
`Cancer Cell Cycle
`
`CCI-779, a close analogue ofrapa(cid:173)
`mycin, has shown activity against a wide
`range of cancers in preclinical models
`and in phase I trials, and seven different
`phase Il trials are under way. Some sug(cid:173)
`gest that it may be one of the most prom(cid:173)
`ising drugs in the anticancer pipeline.
`" I'm excited," said Charles Sawyers,
`M.D., of the University of California at
`Los Angeles Jonsson Comprehensive
`Cancer Center. "It's a safe drug, it's very
`precise in its action, it's definitely a
`targeted therapy."
`The cancer research community is
`only now becoming aware of CCI-779.
`But it is hardly new. The parent drug,
`rapamycin, was discovered 30 years
`ago, and its activity against cancer was
`revealed back in the mid- l 970s. All of
`the research on rapamycin, the very
`first "cytostatic" agent, nearly fell by
`the wayside, but it was resurrected by a
`single determined individual.
`Rapamycin is a natural compound
`produced by bacteria that were found in
`an Easter Island soil sample around
`1970. ("Rapamycin" comes from Rapa
`Nui, the native name for Easter Island.)
`"We had the notion we were dealing with
`something novel," recalled Suren Sehgal,
`Ph.D., then senior scientist at Ayerst
`Research Laboratories in Montreal,
`where rapamycin was isolated in 1972.
`Ayerst began developing raparnycin
`as an antifungal drug, but soon realized
`it also suppressed the immune system.
`That killed it as an antifungal, but
`Sehgal sent a sample of the dmg to the
`
`Journal of the National Cancer Institute, Vol. 93, No. 20, October 17, 200 I
`
`NEWS 15 17
`
`West-Ward Exhibit 1059
`Garber 2001 - Page 002
`
`(cid:173)
`

`

`News
`I News
`New
`
`--------------------------------------~
`
`/ _:..&; ________________________________________ __
`
`I
`- I
`
`National Cancer Institute for testing.
`"They found absolutely fantastic activ(cid:173)
`ity of the drug against almost all solid
`tumors," said· Sehgal. In combination
`with chemotherapy, "the anticancer
`effect was absolutely astonishing."
`Rapamycin was quickly designated a
`priority drug ·by the NCI. "It was a
`totally new class of anticancer agents
`we were looking at-cytostatic," said
`Sehgal. "To that point they were all
`cytotoxic agents."
`But disaster soon struck. As Ayerst
`researchers (and academic scienti'sts) were
`struggling to develop an intravenous
`formulation for
`• use in clinical
`trials, company
`management
`made a fateful
`decision. To
`consolidate
`research facili(cid:173)
`ties, in 1982 it
`shut down the
`Montreal labo(cid:173)
`ratories, laid
`off95% of the
`workforce, and sent the remnants to
`Princeton, NJ. The rapamycin program
`was aborted. At the time, the notion of
`blocking signal transduction was ~om­
`pletely novel and untested.
`"For all practical purposes,
`rapamycin was a lost cause," recalled
`Sehgal. "It was abandoned by Ayerst as
`a drug candidate." NCI, without a
`source for the drug, was helpless to
`proceed. AU work halted.
`For 6 years, rapamycin was forgot(cid:173)
`ten. But Sehgal never gave up hope. In
`1987 American Home Products merged
`its two drug subsidiaries, Wyeth and
`Ayerst, and new management took over.
`In May 1988, Sehgal sent a memo about
`-U\J1R~'CfiI' ..arul Nill§' cn\lsw<.,'\f ,tf :.~nf Uh;
`
`Dr. Suren Sehgal
`
`drug out for animal testing. Outstanding
`results convinced Wyeth-Ayerst to res(cid:173)
`urrect the drug as an immunosuppres(cid:173)
`sant. Sehgal contacted the NCI, and
`anticancer work resumed.
`Rapamycin gradually regained mo(cid:173)
`mentum. Wyeth-Ayerst synthesized and
`tested hundreds of rapamycin ana(cid:173)
`logues, both to stay ahead of competi-'----(cid:173)
`tors and to extend patent life. The best
`one was CCI-779. When it was run
`through the NCI's standard 60-cell line
`screen, "we found that it was broadly
`active against a wide variety of tUmor
`types," said Jay Gibbons, Ph.D., assis(cid:173)
`tant vice president for oncology re(cid:173)
`search for Wyeth-Ayerst.
`More importantly, it seemed to work
`by a completely novel mechanism. "It
`didn't really look like any other drug in
`the cell line screen," said Janet Dancey,
`M.D., a senior clinical investigator in
`the NCI's investigational drug branch.
`"Its pattern of activity was unique."
`Researchers in academia and indus(cid:173)
`try, in the meantime, were deciphering
`rapamycin 's effect on the cell. Working
`in yeast, Michael Hall, Ph.D., of the
`University of Basel in Switzerland,
`cloned rapamycin's molecular target,
`dubbing it TOR (''target of rapamy(cid:173)
`cin."). "A beautiful series of experi(cid:173)
`ments," commented Sawyers. Others
`found its mammalian homologue,
`mTOR. Meanwhile, Jon Clardy, Ph.D.,
`of Cornell University, Ithaca, N.Y.,
`described how rapamycin inhibits
`mTOR and blocks its phosphorylation
`of doWnstream proteins that control
`translation of key cell-cycle mRNAs.
`Then the last, crucial piece fell into
`place. In 1997, Ramon Parsons, M.D.,
`Ph.D., of Columbia University cloned
`PTEN-a new tumor suppressor gene.
`PTEN, which is mutated (and presum(cid:173)
`ao1Y,hacnvated)' ill aoout tiarr oforafu - -
`
`Dr. Charles Sawyers
`
`cancers and endometrial cancers and_ in
`perhaps 20% of metastatic prostate
`cancers, regulates a critical cell signal(cid:173)
`ing pathway involving a versatile pro(cid:173)
`tein called Akt.
`In the last few years, Sawyers, Par(cid:173)
`sons, and others have placed mTOR
`downstream of
`Akt, ·suggest(cid:173)
`ing mTOR's
`central impor(cid:173)
`tance and
`providing a
`convincing
`rationB.le for
`the activity of
`CCI-779
`against so
`many tumors.
`Finally, three
`groups showed last swnmer that muta(cid:173)
`tions in PTEN make tumors especially
`vulnerable to CCI-779.
`The PTEN link is a clear invitation to
`apply pharrnacogenetics, the much(cid:173)
`talked-about but seldom practiced tai(cid:173)
`loring of cancer therapy to patients'
`individual tumor genetics. Though
`tamoxifen is given to estrogen receptor(cid:173)
`positive breast cancer patients and
`Herceptin to those with breast tumors
`overexpressing the erbB2 receptor, no
`drug is yet linked to a gene that is mu(cid:173)
`tated in many cancers.
`"You want to at least test the hypoth(cid:173)
`esis that cancers that are 'PTEN null'
`should be the ones that respond the
`best," said Sawyers. "That's the next
`step." In most of the phase II trials,
`patients' tumors will be analyzed for
`PTEN mutations. It is possible that
`phase III might include only these pa(cid:173)
`tients. "If we see a strong predictive
`pattern, we could design phase III to
`limit enrollment," said Dancey. "It re(cid:173)
`ally depends on what the results are."
`
`1518 NEWS
`
`Journal of the National Cancer Institute, Vol. 93, No. 20, October .17, 200 l
`
`' I
`
`West-Ward Exhibit 1059
`Garber 2001 - Page 003
`
`

`

`Molecular profiling downstream is
`also crucial. In several trials, mTOR's
`two chief targets are being checked for
`phosphorylation status-
`the hallmark of
`biological activity-in patients' tumors.
`"If we just enroll 50 patients with what(cid:173)
`ever cancer, I would not be surprised if
`we see a response rate of maybe l 0% or
`20%," said Sawyers, who argues for the
`widest possible molecular profiling to
`learn bow to improve that percentage.
`Sawyers is planning a CCI-779
`prostate cancer trial monitoring Akt.
`"If your patient's tumor has a high
`level of Akt phosphorylation, then that
`[patient is] the perfect candidate for
`thi s kind of treatment, if the model is
`right," he said.
`Although labor-intensive and expen(cid:173)
`sive, this work is necessary to later
`select patients and dose, agreed Manuel
`Hidalgo, M.D., Ph.D., assistant profes(cid:173)
`sor at the University of Texas Health
`Science Center in San Antonio. "We
`
`need to be able to profile who is who in
`that mass of tumors," he said.
`In a phase I study ofCCI-779, Hidalgo
`reported several cases of tumor regres(cid:173)
`sion. "It was a surprise to everybody,"
`he com(cid:173)
`mented. "We
`were expect(cid:173)
`ing cytostasis ."
`But combi(cid:173)
`nation therapy
`seems to be
`the best use
`for. CCI-779,
`as for other
`cytostatics.
`"It's probably
`a little unreal-
`istic to expect a drug with this mecha(cid:173)
`nism of action to result in out-and-out
`cures or outright regression of tumors,"
`said Gibbons. The main side effect,
`immunbsuppression, is mostly avoided
`through intermittent dosing.
`
`Dr. Jay Gibbons
`
`Given the importance of the mTOR
`signaling pathway, why does CCI-779
`have so few other side effects? Perhaps
`normal cells find alternate signaling
`pathways, while cancer cells rely on this
`one. "There must be some redundancy
`of signaling [in a normal cell] that al(cid:173)
`lows it to tolerate no mTOR activity,"
`speculated Sawyers. But in cancer cells,
`"when you add the rapamycin, there's
`no backup. And- Boom!- You get a
`therapeutic effect."
`CCI-779's uniqueness is its biggest
`advantage. "To date, there has not been
`another drug that attacks this pathway,"
`said Gibbons. Now, after 30 years, that's
`changing. ''Novartis is trying to develop
`mTOR inhibitors," said Sawyers. "Ev(cid:173)
`ery major pharma and a lot of biotechs
`are going after Akt [and] PI3 kinase ...
`Everyone thinks this pathway is impor(cid:173)
`tant."
`
`-Ken Garber
`
`Rapam~iILMay Pre:renL.P.ost-Transplant Lymphoma
`
`-1
`
`I
`
`Non-Hodgkin's lymphoma is a dreaded complication of
`organ transplantation. For kidney transplant patients, the risk
`of lymphoma is 37 times higher than for the general popula(cid:173)
`tion in the first year after surgery, and for heart transplant
`patients, it is 155 times higher. Lymphoma is so common after
`transplants that a new disease term, Post-Transplant Lympho(cid:173)
`proliferative Disorder (PTLD), was coined to describe these
`virulent cancers, of which about 70% prove fatal despite treat(cid:173)
`ment- most within l year of diagnosis.
`The cause of PTLD is thought to be drug-induced immuno(cid:173)
`suppression, which allows activation oflatent Epstein-Barr vims,
`which immortalizes infected B cells and sets the stage for malig(cid:173)
`nancy. The widely used immunosuppressants cyclosporine and
`FK.506 are especially dangerous. But rapamycin, an immtmosup(cid:173)
`pressant approved in 1999 by the FDA for kidney transplantation,
`might help reverse the PTLD scourge.
`At the joint annual meeting of the American Society of
`Transplantation and the American Society of Transplant
`
`Surgeons last May, Manikkam Suthanthiran, M.D., of
`Cornell University, reported that cyclosporine and FK506
`increased the number of metastases in several mouse mod(cid:173)
`els of organ transplantation, but that rapamycin blocked
`metastases. " If that observation holds up statistically, I
`think it will argue very much in favor of more broad use of
`rapamycin in the transplant setting," said Jay Gibbons,
`Ph.D., assistant vice president for oncology research for
`Wyeth-Ayerst, which markets rapamycin. "That's a clear-cut
`advantage."
`Rapamycin is newly approved, so it will be many years
`before the drug's PTJ.,D-preventive effect (if any) becomes
`clear. But the National Cancer Institute is sponsoring a phase
`II lymphoma treatment trial of the rapamycin analogue CCI-
`779 (see main story) .. Success would imply that rapamycin
`indeed can prevent the devastation of PTLD.
`
`-Ken Garber
`
`Journal of the National Cancer fnstirure, Vol. 93 , No. 20, October 17, 200 1
`
`NEWS 15 19
`
`West-Ward Exhibit 1059
`Garber 2001 - Page 004
`
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