Thirty-Seventh
`
`Annual Meeting of the
`
`American Society of Clinical Oncology
`
`May 12—15, 2001
`
`San Francisco, California
`
`Program/Proceedings
`
`ASC®'"
`
`The abstracts contained in the Pfi‘lgrum/PI‘IM‘L’t’dlngS of the American Society of Clinical Oncology (ASCO) are
`embargoed. No public announcements of the infornnttion or data contained in these abstracts may be made by any
`individual. organization, institution. or media outlet before the date and time of the scheduled scientific presentation.
`Those studies selected For inclusion in the official ASCO Annual Meeting Press Program (less than 1% of all
`abstracts) will have their embargocs lifted at the time of the news briefing. or the time of the scientific presentation.
`whichever comes first. Abstracts that are not scheduled for presentalinn—"publish-only" abstracts—are embargocd
`until the official start ot‘the Annual Meeting. scheduled for 8:00 am. (PDT) on Saturday. May l2. 2001.
`
`In the unlikely event that ASCO makes an exception to this Embargo Policy. infomtatiou regarding the exception will
`be publicly announced on ASCO OnLinc {www.ascgoig}. the official website of the. Society.
`
`Copyright 2001 American Society of Clinical Oncology
`
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`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00905
`
`

`

`Editor: Steven M. Grunberg, MD
`
`ASCD Education, Science, and Publications Department:
`
`Senior Director: Deborah Whippen
`
`Managing Editor and Deputy Director, Publications: Lisa Greaves
`
`Program Assistant: Pamela Jones
`
`The American Society of Clinical Oncology Program/Proceedings (ISBN 0-9664495-3-3) is
`published by the American Society of Clinical Oncology, Alexandria, VA 22314. The 2001
`issue is produced and printed by Lippincott Williams & Wilkins, 351 West Camden Street,
`Baltimore, MD 21201-2436.
`
`Editorial correspondence and production questions should be addressed to American
`Society of Clinical Oncology Program/Proceedings, American Society of Clinical Oncology
`Publications Department, 1900 Duke Street, Suite 200, Alexandria, VA 22314. Telephone:
`L703) 797-1910. Fax: (703) 299-1044. E-mail: ascopubs©asco.org.
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`Prices are subject to change. Back volumes exist and are available at previous published
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`Copyright (C) 2001, American Society of Clinical Oncology. All rights reserved. No part of
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`without written permission by the Society.
`
`The American Society of Clinical Oncology assumes no responsibility for errors or
`omissions in this document. The reader is advised to check the appropriate medical literature
`and the product information currently provided by the manufacturer of each drug to be
`administered to verify the dosage, the method and duration of administration, or
`contraindications. It is the responsibility of the treating physician or other health-care
`professional, relying on independent experience and knowledge of the patient, to determine
`drug, disease, and the best treatment for the patient.
`
`Abstract management and indexing provided by Medical Support Systems, Cambridge,
`MA. Composition services and print production provided by Lippincott Williams 8: Wilkins,
`Baltimore, MD, and Cadmus Professional Services, Linthicum, MD.
`
`Copyright 2001 American Society of' Clinical Oncology.
`
`AstraZeneca Exhibit 2108 p. 2
`
`

`

`
`
`Breast Cancer
`
`45::
`
`
`
`This material may be protected by Copyrlgqi law (Title no.5 Dede)
`
`Ptooeedings of ASCO VolUme 20 2001
`
`WE
`
`GENERAL POSTER. SUN. 3:00 AM - 12:00 PM
`
`110
`
`GENERAL POSTER. SUN. 8:00 AM - 12:00 PM
`
`Role of 81mm in Response to Therapeutic DNA-Danica!“ Agents in Human
`lroaat Dancer Calls. DLLLMEFESCQ, P. Arnold. F. Bogamaimy. L. Norton. P.
`Sargon. J. BoydrMem’onai Siben-Keffering Cancer Canfer. New York, NY
`introduction: ERCAI. a tumor suppressor of breast and ovarian cancer.
`functions in the repair of DNA damage. in mouse cells. BRCAl has been
`shown to repair doublestrencl DNA breaks.
`In human cells. BRCAI
`associates with numerous DNA repair proteins. Furthermore, the human
`breast cancer cell line HCCIQ37. which contains a mutant BRCAl.
`is
`hypersensitive torediaiion and to the DNA-damaging agent methyl methane
`sulfonate. In an effort to better design therapeutic regimens for BR‘CAl—
`associated cancers. we sought
`to determine whether BRCM‘deficient
`cancer cells are more sensitive to therapeutic agents that cause double—
`strand breaks than are cancer cells with wild-type BRCAl. Methods: We
`tested the cytotoxic effect of a broad panel of therapeutic agents. using the
`HCC1937 cell
`line,
`two breast cancer cell
`lines wild'type for BRCAI
`(SKfiR—S and MCF'I'). and an MCF7 BRCAI antisense clone. Both cell
`proliferation and colony-fanning
`were used. Results: As expected.
`HCCI937 cel ls were not hypersensitive‘to paclltaxel, which does not cause
`DNA damage. and were hypersensitive to ionizing radiation. Unexpectedly,
`H901937 cells were not hypersensitive to two chemotherapeutic agents
`that
`induce double-strand DNA breaks idoxorubicin and etoposide).
`HCC1937 cells were. however. significantly hypersensitive to Mitomycin C
`and. as others have recently shown in rodents. to cisplatin. both of which
`induce intrastrand and interstrand DNA crosslinks. The MCF? BRCAI
`antisense clone was markedly more sensitive to cisplatin than MCF7
`parental cells. Conclusion: These data suggest that human BRCAI—
`deficient breast cancer cells are hypersensitive to therapeutic agents that
`cause DNA crossiinks but not to agents that cause double—strand DNA
`breaks or to paclitaxel. Additionally. our finding that an MCF7 BRCAI
`antisense clone has increased sensitive to cisplatin more strongly corre-
`lates BRCAl with sensitivity of breast cancer cells to DNA crosslinlring
`agents. These findings provide insight into the roie of BRCA1 in DNA repair
`by linking SHEA; to a specific type of DNA damage repair and may lead to
`the development of better chemotherapeutic regimens for BRCA’I-
`associated cancers.
`
`Analysis of HE!“ and: “£512 in the Heart to clarin the Cardiotoxicity of
`Romantic.
`l. B. Fuchs, S. Landt, H. Boomer. K. livers, A. KleineeTebbe, W.
`Lichtensggmhafler’; Charite Campus Vircholeinikum, Berlin,
`Germany: Benjamin Franklin Medical Center, Berlin. Gennany
`Powerful combination therapy applying the HERZ antibody Herceptin‘“
`with anthracyclines in the management of HlERZ—overexpressing meta—
`static breast cancer is limited by severe cardiotoxic side effects. HERZ is
`one of four members of the epidermal growth factor receptor family. which
`elicit its intracellular response by dimerization with HERI or other family
`members.
`in vivo experiments in rodents indicate that HERZ plays an
`essential role in cardiogenesis and myocardial protection. To clarify.
`if
`direct antibody interaction with heart tissue contributes to the cardiotoxic-
`ity of Herceptinm we analyzed pathologically altered myocardium for the
`presence of HER 1 and HERZ. Sixty heart biopsies from patients with
`cardiac dysfunction revealed histological alterationsranging from myocar-
`ditis to severe myocardial hypertrophy. Moreover myocardium of 25 breast
`cancer patients with or without previous anthracycline treatment was
`assessed. Immunohistochernical analyses were performed using the pri-
`mary antibody ABJD (NeoMarkers) for HER 1 expression and the HercepT-
`est (DAKO) for HERE expression. In specimens showing a faint HERZ
`signal staining was repeated using an amplifying fluorescent Cya detection.
`HERZ gene amplification was analyzed by fluorescence in situ hybridisa-
`tion (FISH) (inform-Kit. Ventana). Neither in the heart biopsies of the
`cardiac patients nor in the myocardium of the breast cancer patients H£R1
`expression was noticed. lmmunohistochemical detection of HERZ expres-
`sion revealed a faint discontinuous membrane staining in a few biopsies.
`which resulted in a distinct spottet staining of total membranes with the
`intensified fluorescent Cy3 labelling. A strong staining typical for HERZ’
`overexpressing breast cancer was not found. There was no HERZ gene
`amplification detected by F lSH. Since we could not detect a strong
`expression of HERl and HERZ in the myocardium. a direct interaction of
`the HERB antibody Herceptinm with the myocardium seems unlikely to be
`responslble tor the cardiotoxlcity of Herceptinm. Indirect mechanisms as
`like a Herceptinm-induced increase of cytokines should.
`therefore. be
`taken in consideration.
`
`POSTER. SUN, 8:00 AM - 12:00 PM
`in
`Misfit” Stenosis is die Mechanical for Excessive Tar-in: in Patients on
`M Emma. B. Esmaelr', D. Booser, M. Ahmadi, V. Valera. N.
`ibrafiim. G. Hortobagyl. R. Erbuckle. E. Delpassand. F. Esteva; Univ. of
`Tees MD. Anderson Cancer Center. Houston, TX
`Domiaxel is a widely used antineoplastic agent for advanced breast cancer
`andlother malignancies. The toxicity profits for weekly docetaxel is different
`from every-three‘weeks docetaxel. In particular, the symptom of epiphora
`[excessive tearing) has been reported in a higher percentage of patients
`receiving weekly docetaxel (50%) compared with the every‘three—weeks
`rep’men (10%). However. the mechanism for epiphora has not been
`predatisly described. We reported 14 patients on weekly docetaxel who had
`caraficular stemsis as the underlying mechanism for epiphora. Three
`‘M’ents received weekly docetaxel as a single agent; the rest received
`docetaxel and herceptin or adriamycin. The length of time to development
`dlaziphora ranged from 4-16 weeks (mean =7 weeks). Bicenalicular
`silicone intonation or dacryocystorhinostomy (OCR)
`to overcome the
`littoral outflow blockage was recommended in all 14 patients. Complete
`or near complete resolution of epiphora was accomplished in 11 patients
`wiwunderwent surgery. To determine the relative frequency of canalicular
`we evaluated 19 additional patients enrolled in a weekly do—
`cetaiie‘l and Herceptin protocol and 18 patients enrolled in an every-three
`geometrical and adriamycin protocol. Ten patients in the weekly
`domel/Herceptin protocol had significant canalicular stenosis and
`required singles] intervention. Although many patients on everyethree—
`misdocetaxelmdriamycin had transient epiphora. none had significant
`anatomic narrowing of the canaliculi. In summary. we describe canalicular
`anemic as a newly recognized mechanism for excessive tearing secondary
`to docetaxel. Canalicular stenosis is much more common with weekly
`dooelaxel than with the everyethree-weeks regimen and can persist after
`bastion of therapy. Timely diagnosis of canalicular stenosis can prevent
`mutate closure of the canaliculi by allowing for bicanalicular silicone
`early in the course of weekly docetaxel administration. Prospec-
`tivestudies are under way to confirm our observations and to identify the
`incidencecf canalicular stenosis in patients receiving weekly dooetaxel.
`
`
`
`EENERM. POSTER, SUN, 8:00 AM - 12:00 PM
`178
`Prelimina Results cl a Randomized Double-unlind Phase II Study of the
`Selective ,
`, on Receptor Modulator (SEMI) Napalm: (A2) in Patterns
`(Pt!) with Local y Advanced‘orMstactatie Breast Cancer (MIG). A. U. fiuzdar.
`J. O‘Shau hnessy. C. Hudis, D. Booser, J. Pi
`an. S. Jones. WW.
`Enos, A.
`eiemed, E. Winer. A. Stomiolo;
`.D. Anderson Cancer Center,
`Houston. TX; US Oncol
`. Dallas, TX.- Memoriai Sloan-Ketterin Cancer
`Center, New York, NY.-
`” Lilly and Company, Indianapolis.
`i
`.- Dana—
`Fanber Cancer institute. Boston. MA
`AZ is a new selective estrogen receptor modulator (SERM) shown to be
`antagonistic in preclinical breast and endometrial models while agonistic
`on bone and lipids. Phase 1 testing identified an active dose ran
`and a
`multi-institutional randomized, phase ii trial was conducted to eva cats the
`safety. toxicity. and efficacy in two dose levels (20 mg or 50 mg daily) of A2
`in pts with advanced or MBC. Pts had either tamoxifen item) sensit ve (T8)
`or refractory (TR) disease. T3 was no prior tam or relapsed 12 months since
`adjuvant tam; all other pts were TR; A total 119 pts were randomized. 63
`were TR and 49 T3. For 63 Tigdpts, the median (med) age was 58 years.
`83% were postmenopausal; in
`time from diagnosis to study entry was 4
`yrs (ran e 1—25). 57% of pie had prior aoiuvant chemotherapy. 46% and
`54% 0 pts had received prior adiuvant/palliative hormonal
`therapy.
`respectively. Among the 49 T5 ptS. med age was 56 years. 84% were ER 4-,
`and 84% were postmenopausal; med time from diagnosis to study entry
`was 6 years [range 0—34 . 29% of patients had received rior ram, and
`50% had received adiuvant chemotherapy. The combined RH for the TR
`cohort was 7%, and 12% of patients had clinical benefit
`(CB)
`lCR+PR +8026 mo). The combined ORR for the TS cohort was 16%. with
`a GB of 33% lSee Table-intent to treat analysis for each cohort). There were
`no significant differences in. response rates. time-to—progression. or toxic-
`ity. between the 20 and 50 mg subgroups. Overall. hot flashes and nausea
`were reported in 43% and 2 ‘36 of patients. AZ was well tolerated and
`effective in tam—sensitive pts in this mum-institutional phase ll study. Less
`activity was seen in the TR pts. in a multinational phase Ill study effican
`and safety of AZ 20 mg/day is being compared with tamoxifen in T
`patients.
`TING.
`,
`Collar!
`11150
`T3
`55min
`T5
`3.1 mo
`17!
`2.7m
`TR
`2.8m
`
`Dd“
`20 my
`50 mg
`20 mg
`50 m
`
`EC
`24
`25
`31
`32
`
`PRC
`IE
`2
`2
`2
`
`505
`2
`6
`1
`2
`
`26%
`8%
`6%
`6%
`
`03
`33%
`32%
`10%
`137a
`
`AstraZeneca Exhibit 2108 p. 3 i
`
`