Case 1:18-cv-01363-CFC Document 82-10 Filed 03/22/19 Page 1 of 10 PageID #:
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`EXHIBIT 10
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`Case 1:18-cv-01363-CFC Document 82-10 Filed 03/22/19 Page 2 of 10 PageID #:
`9897
`
`_ CAP today (HST AR)
`v. 13, no. 3 (Mar. 1999)
`General Collection
`W1 CA709
`Received: 03-23-1999
`
`\_
`
`. --~MWll=IWtiHftdtiliPM~l@l;IIRil/llhiff·PWIIIW•-•mm
`March 1999 /j\
`Pathology/Laboratory Medicine/Laboratory Management
`
`I ' /
`
`'Moie than on way to look for t/ER2,
`On Sept. 25, 1998 the Food and Drug
`
`l
`Williamfcheck, PhD
`
`Administration approved the ge(cid:173)
`netically engineered monoclonal an(cid:173)
`tibody trastuzurnab (Herceptin) for
`
`the treatment of patients with
`metastatic breast cancer whose tu-
`mors overexpress the HER2 protein.
`On the same day, the FDA approved
`Dako's irnrnunohistochernical assay,
`HercepTest, for the detection of HER2
`
`protein, the target of the antibody.
`Says Mehrdad Nadji, MD, professor
`of pathology at the University of Mi-
`arni School of Medicine, "For the first
`time FDA simultaneously approved
`a treatment and a test that identifies
`
`.,,;.,.-,. '""'"'"'1 en
`
`patients who ~a~da;;·for thaf)
`treatment."
`Between the a pproxima tel y
`181,000 women who are diagnosed
`annually with breast cancer and the
`thousands who have a recurrence,
`there is a large market for assays to
`qualify patients for trastuzumab ther-
`apy. (Even among newly diagnosed
`patients who do not have metastat(cid:173)
`ic disease, HER2 status is often de(cid:173)
`termined to guide chemotherapy.)
`Michael Samoszuk, MD, medical
`and scientific director of oncology
`for Quest Diagnostics Inc., and clin(cid:173)
`ical associate professor of pathology
`at UC Irvine, savs Quest's facilitv in
`,
`,
`San Juan Capistrano is running three
`autostainers up to six days per week
`to keep up with demand. "Growth
`was exponential," Dr. Samoszuk
`says. "It doubled or tripled every
`month." Since many tests are from
`archival cases, Dr. Samoszuk has
`now seen demand plateau.
`But some patients are not stop(cid:173)
`ping at one test. "There is some ten(cid:173)
`dency now for samples
`to be shopped _ around
`because people want to
`qualify for Herceptin,"
`says Ivlichael Press, MD,
`PhD, professor of pa(cid:173)
`thology at the Univer(cid:173)
`sity of Southern California Medical
`continued on page 40
`
`_,,
`
`;
`iii"
`3
`tu
`FJ
`..,
`tu
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`~ tu
`Ill
`r"I
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`rb
`0..
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`l
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`I
`
`I
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`\ l
`
`Two steps forward,
`one back on Medicare
`tt,Hterage policies
`Carl Graziano
`in late January, a committee of
`representatives from the federal
`government, the College, and oth(cid:173)
`er private groups ended more than
`six months of intense negotiations
`,vith a tentative agreement on 23
`national coverage policies and oth-
`er uniform documentation and
`claims processing requirements for
`clinical laboratory services under
`Me:licare.
`-- - -- ·- ··dut by mid-February, barely two
`v,:eeks later, proposed changes to
`the package threatened to undo
`· ~:l-~ich of the committee's work.
`Under the process establisl}_ed
`for the negotiated rulemaking com(cid:173)
`mittee, each member group had
`until Feb. 15 to review the Janu(cid:173)
`ary agreement and suggest changes
`to it. Any single group's changes
`vrnuld require unanimous ap(cid:173)
`proval from the other negotiation
`parties.
`Some of the proposed changes
`submitted during the two-week
`review period appeared unlikely at
`t
`An P
`ne ax on
`press time to win unanimous sup(cid:173)
`Ttiroughout this decade, the biotechnology industry has re-
`port of the committee, which in(cid:173)
`1 · liably produced front-page news vvith a stream of star-
`cluded representatives from the
`tling discoveries, potential treatment breakthroughs, and
`Health Care Financing Adminis(cid:173)
`phenomenal profit forecasts. The deciphering of the ge-
`tration, the College, and 16 other
`netic code continues to expand the menu of diagnostic tests
`groups. (See "Negotiated rule(cid:173)
`and promises to revolutionize disease detection, pre-
`making parties," page 16.) As a re(cid:173)
`vention, and treatment.
`sult, it seemed certain that a much
`But with at least 40 disease genes patented to date, and
`anticipated consensus on the pack-
`continued on page 16 many more filed and pending, the collision of science
`
`Melody Cohleigh, MD, director of Rush~Presbyterian-St. Luke's
`Comprehensive Breast Center; requests both IHC and FISH assays
`from the laboratory of KennethBloom;MD (shov,inabove), and
`treats with Herceptin If either testls-positiv1i:""That is as good as
`you can do in 1999," she says:~'·
`·
`
`rG~he patents push labs to their limits
`
`and commerce is having an unforeseen and unsettling ef-
`f
`1 b
`1
`·
`1·
`·
`f
`· Th
`ect on a oratories:
`e exc us1ve 1censmg o gene
`patents is starting to limit the tests laboratories are able to
`perform and preventing them from performing certain
`tests altogether.
`'The scope of these patents is unprecedented," says De-
`bra Leonard, MD, PhD, director of the molecular pathol-
`ogy laboratory at the University of Pennsylvania Health
`Care System, Philadelphia.
`Genetic testing patents are a small but rapidly grow-
`continued on page 30
`
`\.,.--;_,- ---ft:--i?-.:._~->¾~~~~""' •,v'.1.:/'.. .. /;.'f~e;r~!-·"f<f»:~~ :;v, .. ::1.:<>1~:-S-r,-,:x"' .. ~-s-J:•/_,> .-\ ·---·~ -~f .. '\·- -. ..-;:: ::<:.:,:_~::,.~
`ow one lab took an automation tack that went bevond a
`,
`· Page 24
`search for track.
`
`.
`
`-,
`
`CU>_
`
`Advancing Excellence
`
`~--.****************** 3-DIGIT
`I
`··,,7341 a 993
`4
`•· .. t·lATIOMAL LIBRARY OF MED
`SERIAL RECORDS SECTIOH
`8600 ROCKlJILLE PIKE
`
`L~" Mr, 20294-0001
`
`208
`
`0002~!
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`••r"'"•L1•111n.n-11o••uu11
`
`

`

`Case 1:18-cv-01363-CFC Document 82-10 Filed 03/22/19 Page 3 of 10 PageID #:
`9898
`
`March 1999
`
`CAP TODAY/ 5
`
`Clinton budget again.sets sights on laboratory fees
`
`tern. "Despite the slowdown in
`freeze hospital payments for a year.
`President Clinton's fiscal 2000 Medicare growth over recent years,
`budget, released last month, would
`there is still evidence to suggest
`reduce Medicare spending on
`that Medicare pays too much for
`provider payments by $7.5 billion
`some services and has not bene-
`over five years and impose nearly
`fited from cost-efficiencies that
`$195 million in new user fees.
`have occurred in the marketplace,"
`The reductions are not as drastic
`the Department of Health and Hu-
`for laboratories as those proposed in man Services reported in a bud-
`previous administration budgets.
`get summary.
`
`But the cuts would continue to chip
`The clinical laboratory fee sched-
`away at reimbursement levels that
`ule has been a frequent target of
`the CAP and other laboratory
`administration and congressional
`groups have said are already un-
`efforts to reduce Medicare spend-
`fairly low.
`ing, and the College always has
`
`icaYi:~~:~~;J~: :;:e~p o: clin-
`.·. s;ngly ~p-
`•.·· << / •> • •• /
`~~iJ;r;:~:~~~uif ;:~~
`\-• ___ ~- There_ is -still _evid~nce. > -__ --- 1 _
`- est that Med1car e.
`--
`. to sugg
`some
`pays too much for
`_--
`--
`and has not ben.
`. -- .- -- -
`•
`services
`-
`. . -
`..
`-• ef ited fr om cost-ef flcien •
`th t have occur red
`-
`-
`-
`ij -.
`. c1es
`a
`\ Jn the marketpl-ace .
`
`/
`
`\.
`
`and other provider payments.
`The College will monitor the
`budget process closely and, as in
`years past, vigorously oppose
`spending reductions that target lab(cid:173)
`oratory services and physician pay(cid:173)
`ments.
`The administration's budget pro(cid:173)
`posal also calls for Health and Hu(cid:173)
`man Services to receive authority to
`levy o_n providers $194.5 million in
`new user fees, including charges
`for claims not submitted electroni(cid:173)
`cally and for duplicate claims or
`those that cannot be processed. Oth(cid:173)
`er proposed fees include an
`idtial charge to physicians,
`providers, and suppliers to
`enroll in Medicare and sub(cid:173)
`sequent renewal fees.
`The Department of
`Health and Human Ser(cid:173)
`vices reported that it in(cid:173)
`tends to save $2.9 billion
`over five years with new
`initiatives to reduce fraud,
`waste, and abuse. Those -
`initiatives include elimi(cid:173)
`nating physician mark(cid:173)
`ups for outpatient drugs
`and imposing civil mon(cid:173)
`etary penalties when a
`physician falsely certifies the need
`for partial hospitalization services
`in certain settings. -
`On the upside, the administra(cid:173)
`tion's budget plan would provide
`$15.9 billion for the National Insti(cid:173)
`tutes of Health, $320 million more ·
`than was budgeted for fiscal 1999.
`Of the total, $8.8 billion would go to
`support grants for basic medical
`research.
`The budget proposaI also seeks
`to raise the rate of Pap smears per(cid:173)
`formed annually for women served
`by the Indian Health Service. The
`plan endeavors to increase the per~
`centage of women who have Pap
`smears to 55 percent from a 1997
`baseline of 43 percent. The Indian
`Health Service provides care to 1.4
`million American Indians and
`Alaska natives. Details of the pro-
`continued on page 8
`
`-.
`--
`...m· ent of Health a nd.
`oeparL
`-
`marY -
`. --
`an services budget sum
`-
`---
`\ Hum
`- _ - ___ .-----.
`-•-__
`-· _
`_.
`.
`
`-_
`
`cent of the national med1-
`an for all Medicare Carri-
`ers, savi~g ~edicare ab?ut
`$550 million over five
`years.
`The administration wants
`to return to "that old well,
`which we all know is_ more
`than dry," laborato1:Y md~s-
`try observer Denms Weiss-
`.
`.
`man said dunng a speech last
`month at the annual meet-
`ing of the American Clinical
`Laboratory Association, held
`in Washington; DC.
`Weissman, president and pub-
`. lisher of Washington G-2 Reports,
`said data show the cost of providing
`laboratory services rose 30 percent
`from 1994 to 1997, but federal
`_ spending on such services dropped
`10 percent during the same period.
`"Now that doesn't even indicate
`what happened prior to 1994, when
`there were other severe cuts that
`go all the way back to the 1980s,"
`Weissman stated in his speech. "So,
`we're talking about billions of dol(cid:173)
`lars that have been cut out of this in(cid:173)
`dustry."
`The administration argues that
`clinical laboratory fee schedule re(cid:173)
`ductions and other provider cuts
`are necessary to allow the federal
`government to reap the benefits of
`a more efficient health care sys-
`
`posed Con(cid:173)
`gress' tactic. Two years ago, Con(cid:173)
`gress considered proposals that, at
`best, would have reduced the fee
`schedule cap from 76 percent to 74
`percent and trimmed annual up(cid:173)
`dates. At worst, the plans would
`have reduced the cap to 72 percent
`and frozen updates for five years.
`Although Congress eventually de(cid:173)
`cided to impose the update freeze,
`lobbying by the College and oth(cid:173)
`ers prompted lawmakers to choose
`the higher of the two proposed
`caps-74 percent.
`At press time, Republicans had
`not yet completed their spending
`plan for fiscal 2000. While the GOP(cid:173)
`controlled Congress almost certainly
`will reject Clinton's proposed bud(cid:173)
`get in favor of its own, it could adopt
`elements of the administration plan
`or make similar cuts in laboratory
`
`In this issue
`
`56 Managing information
`70 Anatomic pathology
`computer systems
`89 laboratory Accreditation News
`Departments
`
`Bridging information technologies and bringing people
`together are the needs of the next few years.
`
`CAP TODA Y's 11th annual survey of anatomic
`pathology systems profiles 22 products from 19 vendors.
`
`Your Laboratory Accreditation Program link.
`
`Special
`Section
`
`c=:::J
`
`Abstracts
`93
`107 Capitol Scan
`Classifieds
`113
`Firsthand Views
`122
`
`121
`Index to Advertisers
`110
`Innovations
`Letters
`11
`114 New Products
`
`112 Newsbytes
`President's Desk
`11
`108 Q&A
`-Webwatch
`118
`
`Carl Graziano
`The Clinton administration has
`again targeted the clinical labora(cid:173)
`tory fee schedule in its latest bid to
`shave dollars from Medicare spend(cid:173)
`ing. It has also revived attempts to
`impose user fees on providers and
`
`I
`
`I
`
`-~
`
`March 1999
`Vol.13 No. 3
`
`Copyright © 1999 by the College of American
`Pathologists. Views and opinions expressed in CAP
`TODAY are not necessarily endorsed by the CAP.
`President: Thomas P. Wood, MD
`President-Elect: Paul Bachner, MD
`Secretary-Treasurer: Paul A. Raslavicus, MD
`Inirnediate Past President Raymond C. Zastrow, MD
`Governors: William R. Dito, MD; Daniel J. Hanson,
`MD; Richard J. Hausner, MD; John Bernard Henry,
`MD; Gene N. Herbek, MD; Victor Hinrichs, MD;
`Richard E. Horowitz, MD; Mary E. Kass, MD;
`Margaret S. Skinner, MD; Thomas D. Trainer, MD;
`Henry Travers, MD; Harry J. Zemel, MD
`Speaker, House of Delegates: Joseph P.
`Leverone, MD
`Vice Speaker: Mary L. Nielsen, MD
`Residents Forum Chair: James L. Caruso, r-.m
`Executive Vice President: Lee VanBremen, PhD
`Medical Editorial Board to CAP TODAY: Donald
`A. Senhauser, MD, chair; Howard M. Rawnsley,
`MD; Frederick L. Kiechle, MD, PhD; Seth L. Haber,
`MD; P.R. Gilmer Jr., MD; Rebecca L. Johnson, MD;
`Stanley Burrows, MD; Henry Homburger, MD;
`William R. Dito, MD; William W. Mclendon, MD;
`Richard A. Savage, MD; David Alter, MD
`Contributing Editors: Raymond D. Aller, MD; Ann
`Marie Blenc, MD; Stanley B. Burrows, MD; Robert P.
`De Cresce, MD, MBA; P.R. Gilmer Jr., MD; Seth L.
`Haber, MD; Gene N. Herbek, MD; Theodore Krouse,
`MD; Mark S. Lifshitz, MD; Raouf E. Nakhleh, MD;
`Richard A. Savage, MD; Michael Weiler!, MD
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`laboratory medicine worldwide.
`
`

`

`Case 1:18-cv-01363-CFC Document 82-10 Filed 03/22/19 Page 4 of 10 PageID #:
`9899
`
`40 I CAP TODAY
`
`HER2
`
`conti1111ed from page 1
`
`Dr. Pauletti
`
`Center. "In the last year we have
`seen a substantial increase in vol(cid:173)
`ume." Dr. Press gets samples that
`have been tested in one or two oth(cid:173)
`er laboratories. Gio(cid:173)
`vanni Pauletti, PhD,
`assistant research
`scientist in the divi(cid:173)
`sion of hematolo(cid:173)
`gy/ oncology at the
`University of Cali(cid:173)
`fornia, Los Angeles,
`also gets calls from
`patients who are
`negative for HER2 by immunohis(cid:173)
`tochemistry (IHC) and want to be
`tested for HER2 by an alternative
`method, fluorescence in situ hy(cid:173)
`bridization (FISH), that both he and
`Dr. Press perform.
`Tumors that are candidates for
`trastuzumab therapy can in principle
`be detected at the DNA level by FISH
`because there is a high correlation
`between overexpression of the HER2
`protein and amplification of the gene
`
`that codes for it, HER2, both of which
`are found in 25 percent to 30 percent
`of breast cancers. Two FISH kits for
`HER2 are available, Path Vysion from
`Vysis and Inform, developed by On(cid:173)
`cor and now marketed by Ventana.
`FISH and IHC each have advantages
`and disadvantages, but they share
`one desirable feature, Dr. Nadji says:
`"Both techniques are easily applica(cid:173)
`ble to formalin-fixed paraffin-em(cid:173)
`bedded material. Therefore, they can
`both be used on archival tumor ma(cid:173)
`terial from patients whose original
`biopsy was taken many years ago
`and who now have a recurrence that
`may benefit from Herceptin treat(cid:173)
`ment." (See "The value of Herceptin,"
`page54.)
`Each method-IHC and FISH(cid:173)
`has its advocates. Says Dr. Press, "I
`think IHC is a great method and we
`use it routinely. But if a laboratory is
`doing this test for first time, I would
`strongly recommend the FISH assay.
`It is more complicated to do, but eas(cid:173)
`ier to interpret."
`Allen M. Gown, MD, director and
`chief pathologist at PhenoPath Lab-
`
`(cid:141) For in vitro diagnostic use
`
`l. Koll1oniemi, 0., et al; Int J Cancer 49:650-655
`[1991).
`2. Press, M.F., et cl; Cancer l?es. 54·2771-2777
`[1994).
`3. Penoult-Uorca, F., el cl; J Pothol. 173(1): 65-75 (1994).
`
`Dr. Gown
`
`oratories in Seattle,
`acknowledges that
`both assays will get
`you the same infor(cid:173)
`mation. "But," he
`says, "FISH is much
`more labor-inten-
`sive. And its cost to
`the patient and the laboratory is much
`higher."
`One complication is that, while
`HercepTest is approved for selecting
`patients with metastatic breast cancer
`for trastuzumab therapy, the FISH
`assays are not. Path Vysion is indi(cid:173)
`cated as a prognostic indicator and to
`predict response to standard chemo(cid:173)
`therapy in stage II patients. More im(cid:173)
`portant, results from FISH have not
`yet been correlated with response to
`trastuzumab therapy. In the Her(cid:173)
`ceptin trials, patient selection was
`with an IHC method, on which Her(cid:173)
`cepTest is based.
`As a result, says Kenneth Bloom,
`MD, director of laboratory opera(cid:173)
`tions in the Department of Pathology
`at Rush-Presbyterian-St. Luke's Med(cid:173)
`ical Center, Chicago, "Before our on(cid:173)
`cologists will give Herceptin, they
`want to know if there is HER2/ neu
`protein overexpression by IHC, be(cid:173)
`cause that is what
`has been correlated
`with treatment suc(cid:173)
`cess." Dr. Bloom
`calls treating with
`trastuzumab on the
`basis of gene am(cid:173)
`plification alone
`"more controver- Dr. Masood
`sial. No clinical data
`have been published on that yet," he
`notes.
`Shahla Masood, MD, associate
`chair in the Department of Pathology
`at the University of Florida College of
`Medicine, Jacksonville, and chief of
`pathology and laboratory medicine at
`University Medical Center, says,
`"Clinicians who want to use Her(cid:173)
`ceptin have to look at IHC, because all
`of the studies have been done with
`that and the answers are in the liter(cid:173)
`ature."
`As for clinicians using the FISH
`assay for therapeutic guidance, Dr.
`Samoszuk says, 'Tm sure that is hap(cid:173)
`pening and will continue to happen.
`There is a tremendous amount of
`confusion. We don't encourage or
`promote that, but we are aware that
`it happens." Because trastuzumab is
`directed against the HER2 protein,
`Dr. Samoszuk says, "To me it seems
`more likely that HER2 overexpres(cid:173)
`sion will predict response to drug
`than gene amplification. We need to
`wait until additional data answer
`this question."
`Predictive value is especially im(cid:173)
`portant because of the price differ(cid:173)
`ential between the two assays: Her(cid:173)
`cepTest costs about $35 per sample,
`Path Vysion about $75. Reimburse(cid:173)
`ment is about equal for the two tests.
`John Bishop, president and CEO of
`Vysis, defends the higher price of the
`FISH assay by saying, "Studies have
`
`March 1999
`
`shown that the most accurate and
`reliable determination of HER2 status
`is critical in selecting the most ap(cid:173)
`propriate therapy for breast cancer
`patients. Path Vysion and the under(cid:173)
`lying FISH technology address these
`needs, providing higher medical val(cid:173)
`ue than competing technologies."
`But many persons working in this
`area believe evidence for this claim is
`lacking in regard to trastuzumab
`therapy. For exam(cid:173)
`ple, Susan Gam(cid:173)
`mon, PhD, MBA,
`vice president of
`product develop(cid:173)
`ment at IMPATH
`Inc., says, "Those
`clinical trials are still
`underway, so the Dr. Gammon
`jury is still out."
`And Dr. Gown says, because of
`the higher price of FISH, "In order for
`me to recommend FISH, it would
`have to be demonstrated that it is
`significantly better than immuno(cid:173)
`histochemistry. To me that is still an
`open question."
`Dr. Pauletti says a clinical trial is
`now getting underway in which pa(cid:173)
`tients will be screened by IHC and
`FISH for treatment with trastuzum(cid:173)
`ab, so the relative predictive value
`of the two tests should become clear
`in the near future.
`In the meantime, in principle either
`assay should give the same result
`most of the time, since HER2 gene
`amplification and HER2 protein
`overexpression are closely correlated,
`which is supported by ample data
`in the literature. IHC has a long track
`record with pathologists and could
`therefore be the assay of choice. On(cid:173)
`cologists, on the other hand, would be
`familiar with the work of the princi(cid:173)
`pal discoverer of the prognostic val(cid:173)
`ue of HER2, oncologist Dennis Sla(cid:173)
`mon, MD, of UCLA's Janssen Com(cid:173)
`prehensive Cancer Center, a major
`force behind the clinical validation
`of trastuzumab. Dr. Slamon's group,
`with whom Dr. Press collaborates,
`favors the FISH assay.
`Specialty differences can drive
`marketing strategies, Dr. Nadji points
`out. "If a company is not successful
`with pathologists, it can bypass them
`and market directly to clinicians," he
`says. ''Right now, oncologists are sold
`on FISH because they think it is more
`sensitive. But we pathologists need to
`ask what is the clinical value of this in(cid:173)
`creased sensitivity."
`Dr. Gown is seeing a similar phe(cid:173)
`nomenon. "I occasionally get a phone
`call from an oncologist who knows
`about the FISH test from marketing
`information," he says. "But they don't
`always know that we can get the
`same information with immunohis(cid:173)
`tochemistry."
`Dr. Masood notes that coopera(cid:173)
`tive action between clinicians and
`pathologists will be necessary to de(cid:173)
`cide which one of the tests-or
`both-is going to be used. "I think
`that the indications for this testing
`continued 011 page 42
`
`

`

`Case 1:18-cv-01363-CFC Document 82-10 Filed 03/22/19 Page 5 of 10 PageID #:
`9900
`
`42 I CAP TODAY
`
`HER2
`
`co11ti11lled from page 40
`
`have to come from mutual agree(cid:173)
`ment between oncologists and pa(cid:173)
`thologists in an institution," she says.
`"Ultimately a test has to be embraced
`by oncologists, since they are the ones
`who are going to be utilizing the re(cid:173)
`sults to treat patients."
`
`As experience and data accumulate
`
`with the two methods-several
`laboratories are offering both IHC
`and FISH assays-apparent defi(cid:173)
`ciencies have been identified with
`each product. Both false-negative and
`false-positive results have been ob-
`
`served with the Dako kit. In 15 per(cid:173)
`cent to 20 percent of cases that are
`negative by IHC, FISH will detect
`. gene amplification. Whether this dis(cid:173)
`crepancy has clinical relevance is a
`topic of debate.
`As for false-positives, Dr. Paulet(cid:173)
`ti cites a meeting abstract in which
`investigators from the Mayo Clinic
`using HercepTest found among 1,142
`patients a 57 percent rate of positiv(cid:173)
`ity for clear (2+/3+) HER2 overex(cid:173)
`pression, much higher than the ac(cid:173)
`cepted 25 percent to 30 percent rate.
`Other reference laboratories, hmv(cid:173)
`ever, are not seeing such a strange re(cid:173)
`sult. Dr. Gown believes these data
`simply indicate the need to adapt
`
`assay conditions and antigen re(cid:173)
`trieval to different fixatives (ex(cid:173)
`plained later).
`(To see whether selection bias
`might explain the Mayo Clinic re(cid:173)
`sults, Dr. Pauletti checked his own
`data from a large breast cancer co(cid:173)
`hort. "Even selecting only for node(cid:173)
`positive patients with grade 3 infil(cid:173)
`trating carcinomas," he told CAP TO(cid:173)
`DAY, "the amplification/ overex(cid:173)
`pression frequency ,vas no higher
`than 32 percent. If there really was a
`bias in the Mayo Clinic population,
`it must have been that a good num(cid:173)
`ber of these people were sent to
`Mayo for a confirmation of their
`HER2 status.")
`
`Cdtl(tfi
`
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`
`Dr. Samoszuk
`
`With FISH, so far the chief problem
`is its technical difficulty. Says Dr.
`Samoszuk, "In my
`opinion, the FISH
`assay may be more
`difficult to perform
`and interpret. It re(cid:173)
`quires the ability to
`identify tumor cells
`under fluorescent
`light and the ability
`to count fluorescent
`signals for individual HER2 genes,
`which is sometimes more difficult
`than pictures would suggest. Our ex(cid:173)
`perience over the past month," Dr.
`Samoszuk continues, "is that a sig(cid:173)
`nificant minority of cases do lead to
`difficulty in interpretation. FISH prob(cid:173)
`ably does require more expertise to
`interpret."
`Dr. Gammon agrees. "FISH is not
`always easy to read," she says.
`But Mark Pegram, MD, assistant
`professor in the division of hematol(cid:173)
`ogy/ oncology at the UCLA Janssen
`Comprehensive Cancer Center, be(cid:173)
`lieves the required expertise can be
`learned. "FISH is too good an assay
`to dismiss because it is too complex,"
`he says.
`Although FISH is used frequently
`in cytogenetics cases, the accuracy
`of this particular application is in
`somewhat of a "honeymoon" period,
`since it has not been used widely
`enough outside of experienced hands
`to determine its reliability in general
`use, Dr. Gammon points out. "These
`are early days for HER2 by FISH
`analysis, and the industry is waiting
`to understand its robustness and in(cid:173)
`terlaboratory variability," she says.
`"Outside of our lab and a handful of
`others, the HER2 FISH assay has not
`been performed routinely in quanti(cid:173)
`ty. What will happen when 150 lab(cid:173)
`oratories with less experience start
`to try to perform this test?"
`(A question has been raised about
`a 10 percent to 15 percent rate of false(cid:173)
`negative results with DNA-based
`tests-protein overexpression with(cid:173)
`out gene amplification-in some of
`Dr. Slamon' s early work. Dr. Pegram
`explains that these results occurred
`when Southern blotting was used to
`detect gene amplification. "These
`data suggested single-gene copy
`overexpression," Dr. Pegram says.
`"But FISH testing showed that this
`was mostly a dilutional artifact." Sin(cid:173)
`gle-copy overexpression actually oc(cid:173)
`curs in only about four percent of
`cases, Dr. Pegram estimates.)
`A survey of which laboratories
`are using which test(s)-and why(cid:173)
`and their experience may prove help(cid:173)
`ful for those nmv trying to choose.
`Melody Cobleigh, MD, director of
`the Comprehensive Breast Center at
`Rush-Presbyterian-St. Luke's Medical
`Center, Chicago, was one of the in(cid:173)
`vestigators in the trastuzumab tri(cid:173)
`als. She requests both assays on all
`samples and treats with trastuzum(cid:173)
`ab on the basis of either test being
`positive. "That is as good as you can
`co11ti1111ed 011 page 46
`
`

`

`Case 1:18-cv-01363-CFC Document 82-10 Filed 03/22/19 Page 6 of 10 PageID #:
`9901
`
`46 I CAP TODAY
`
`HER2
`
`c01Itinucd fro111 pngc 42
`
`do in 1999," she says. Asked whether
`this route isn't quite expensive, she
`replies, "Yes, but so is Herceptin."
`(Herceptin costs about $250 per
`weekly dose.) Comparing the two
`tests shows about a six percent rate
`of overexpression without gene am(cid:173)
`plification. Over the next year, it
`should become apparent if such cas(cid:173)
`es have a different response to
`trastuzumab than cases that are pos(cid:173)
`itive in both assays.
`Dr. Bloom's laboratory performs
`assays for Dr. Cobleigh. Asked
`·whether he has seen an abnormally
`
`high positive rate with HercepTest
`like that reported from the Mayo
`Clinic, he replies, "We have no ex(cid:173)
`perience with that at all. Our posi(cid:173)
`tivity rate is sitting at about 25 per(cid:173)
`cent and the stain has been incredi(cid:173)
`bly clean. Our true-positive cases
`have looked like pictures in a journal
`article."
`As for false-negative results on
`fixed specimens with IHC, Dr. Bloom
`attributes them to variations in
`reagents, tissue processing, and stor(cid:173)
`age. He notes that false-negatives
`can occur on fresh frozen tissue as
`well. All processing in his laborato(cid:173)
`ry is done uniformly, so conditions
`can be adjusted for optimal results.
`
`Dr. Bloom calls this "critically im(cid:173)
`portant. I think that's our huge ad(cid:173)
`vantage over reference laboratories,"
`he says. "Controlling fixation and
`tissue processing is vital to getting
`good staining."
`At the request of the oncologists,
`Dr. Bloom is now setting up FISH,
`which will be performed on the 70
`percent or so of samples negative by
`IHC. He chose to do IHC as a screen
`and FISH second because of cost and
`time. "Our issue is the time it takes to
`actually count cells," Dr. Bloom says.
`"It is fairly time-consuming." Be(cid:173)
`cause this is the first FISH test being
`performed in the laboratory, there
`were no trained technologists. So the
`
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