V0122, No 14s
`
`_
`
`July 15, 2004
`
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`— SUPPLEMENT TO —
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`w 1
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`2004 ASCO Annual Meeting Proceedings
`(Post—Meeting Edition)
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`ONCOLOGY
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`OffICIal Journal of the American SOCIety of Cllnlcal Oncology
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`Ex. 1082-0001
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`

`

`40th
`
`'
`
`I
`
`Annual Meeting of the
`
`American Society of Clinical Oncology
`
`June 5-8, 2004
`
`Ernest N. Morial Convention Center
`New Orleans, Louisiana
`
`Annual Meeting Proceedings
`(Post-Meeting Edition)
`
`ASC
`
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`JUL 2 3 2004
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`Ex. 1082-0002
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`

`Proceedings Editor: Steven M. Grunberg, MD
`
`Proceedings Staff
`
`Publisher: Lisa Greaves
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`Managing Editor: Anthony Gary
`Administrative Assistant: Adel] Cokley
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`Director of Production: Victoria Vaughn
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`Executive Editor: Deborah Whippen
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`Requests for permission to reprint abstracts should be directed to Intellectual Property
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`Ex. 1082-0003
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`Ex. 1082-0003
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`SUPPLEMENT TO
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`
`JOURNAL OF CLINICAL ONCOLOGY
`Official Journal of the American Society of Clinical Oncology
`
`
`2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition)
`July 15, 2004
`Vol. 22, No.14S
`
`
`
`
`
`
`
`
`(continued on following page)
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`Journal ofClinical Oncology (ISSN 0732-183X) is published 24 times a year, twice monthly, by American Society of Clinical Oncology, 1900 Duke Street, Suite 200, Alexandria,
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`Eifi 082-0604
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`35
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`973
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`.. ..
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`..
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`
`Plenary Session (Abstracts ’1 —
`Breast Cancer
`Scheduled presentations (Abstracts 500 ~ 681)
`Published only (Abstracts 682 — 881)
`Cancer Prevention
`.
`Scheduled presentations (Abstracts 1000 — 1034) ..
`
`
`Published only (Abstracts 1035 — 1039) .
`..
`Central Nervous System Tumors
`Scheduled presentations (Abstracts 1500 ~ 1574) .
`Published only (Abstracts 1575 — 1579)
`Developmental Therapeutics: Cytotoxic Chemotherapy
`Scheduled presentations (Abstracts 2000 — 2085) ._
`Published only (Abstracts 2086 — 2141)......... .
`. . .
`Developmental Therapeutics: Immunotherapy
`Scheduled presentations (Abstracts 2500 — 2592)
`.. .
`Published only (Abstracts 2593 — 2625)
`. ..
`Developmental Therapeutics: Molecular Therapeutics
`195s
`.
`Scheduled presentations (Abstracts 3000 — 3089) .
`
`Published only (Abstracts 3090 — 3203)
`..
`..
`Gastrointestinal (Colorectal) Cancer
`..
`.
`Scheduled presentations (Abstracts 3500 — 3627)
` Published only (Abstracts 3628 — 3776) ...........
`Gastrointestinal (Noncolorectal) Cancer
`Scheduled presentations (Abstracts 4000 — 4126)
`Published only (Abstracts 4127 — —.275)
`Genitourinary Cancer
`Scheduled presentations (Abstracts 4500 — 4659) ..
`Published only (Abstracts 4660 — —-768) .. .
`Gynecologic Cancer
`Scheduled presentations (Abstracts 5000 — 5092)
`Published only (Abstracts 5093 — 5154)
`Head and Neck Cancer
`Scheduled presentations (Abstracts 5500 — 5588)
`Published only (Abstracts 5589 — 5620)
`
`245s
`.2765
`
`.. 3145
`., 345s
`
`
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`Ex. 1082-0004
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`

`

`
`
`Health Services Research
`
`
`Scheduled presentations (Abstrac s 6000 — 6091)
`V
`Published on y (Abstracts 6092 — 6156)
`..
`
`Leukemia, Lymphoma, and Transplantation (Adult)
`Scheduled presentations (Abstrac s 6500 — 6668)
`..
`
`
`Published on y (Abstracts 6669 — 6738) ..
`Lung Cancer
`Schedu ed presentations (Abstrac s 7000 — 7233)
`Pub (shed on y (Abstracts 7234 — 7373)
`Melanoma/Skin Cancer
`Schedu ed presentat'ons (Abstrac s 7500 — 7557) .......
`Pub ished on y (Abstracts 7558 ~ 7574)
`Patient Care
`
`..
`
`
`.,
`
`
`.5195
`5425
`
`5583
`.5995
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`.617s
`,. B745
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`,1 7103
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`. 7245
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`7715
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`.. 7995
`8155
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`.. 8185
`831$
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`
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`
`
`
`Schedu ed presentat‘ons (Abstrac s 8000 — 8168)
`Pub ished on y (Abstracts 8169 — 8281)
`Pediatric Cancer
`
`Schedu ed presentat'ons (Abstracts 8500 — 8564)
`Pub ished on y (Abstracts 8565 — 8574)
`Sarcoma
`
`Schedu ed presentat'ons (Abstracts 9000 — 9053)
`Pub (shed on y (Abstracts 9054 — 9066) ..
`Tumor Biology and Human Genetics
`Schedu ed presentat'ons (Abstracts 9500 ~ 9629A)
`
`Pub (shed on y (Abstracts 9630 — 9736)
`Indexes
`Disclosure Index .
`Author lndex ......,.
`Subject Index .......
`
`
`
`
`
`
`
`Ex. 1082-0005
`
`Ex. 1082-0005
`
`

`

`
`
`JOURNAL OF CLINICAL ONCOLOGY
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`

`Developmental Therapeutics: Molecular Therapeutics
`
`231 s
`
`Publish Dnly
`3146
`Study of vascular endothelial growth factor (VEGF) serial blood levels as
`predictor of
`response to chemotherapy. Llrigoyfl, J.-R. Delgado, P.
`Bal/esteros,
`/. Rodriguez, E. Gonzalez, R. Luque, V. Condo, P. Bee/0n, M.
`SanchezeMoreno, J. Belon; Hospital Virgen Nieves, Granada, Spain,- Sci-
`ence Faculty, University, Granada, Spain
`Background: The molecular profile of a cancer may give information
`pertinent to response to chemotherapeutic agents. Vascular endothelial
`growth factor is a endothelial mitogen, survival factor and permeability
`inducer produced by many types of tumor cells. A rational approach is to
`study the sequential expression in peripheral blood of biomarkers during
`the treatment in order to select an individualized therapy. Methods: From
`February 2002 we have determined the serial levels of VEGF in the serum
`of cancer patients , with a life expectancy superior to 12 weeks, with a
`Karnofsky index superior to 60, which have received chemotherapy. The
`VEGF expression has been measured before the starting of treatment, after
`2 courses, at the end of therapy, and when the disease progression was
`documented, using the enzymelinked inmunosorbent assay technique (
`Oncogene Research Products kits ). Until now 119 patients have com»
`pleted 2 extractions Results: We have observed 2 groups according to the
`levels of VEGF in peripheral blood: The first group includes non small cell
`lung and gastric cancer, in which we have observed concentrations in the
`rank of 500 to 2000 pg/ml, and the second group is made up of ovarian,
`breast, colorectal, head and neck cancer where the lowest values are found
`over 100 pg/ml and the maximum does not reach 500 pg/ml. in most cases
`of lung cancer there is a relationship between the VEGF evolution and the
`response to treatment. The more advanced is the disease stage the bigger
`are the VEGF values at the first extraction. The VEGF values have been
`predictive of the disease evolution during the treatment in patients with
`gastric and ovarian cancer. VEGF confirmed their predictive value in case of
`discrepancy with computed tomography. Conclusions: The determinations
`of VEGF levels in peripheral blood before the chemotherapy and after the
`second course could predict the individual response to treatment in non
`small cell lung, gastric and ovarian cancer
`
`Publish Only
`3149
`Effects of 5-fluorouracil on endothelial nitric oxide synthase in endothelial
`cells in different states of confluence.
`V. M. Caggdofcharren, C. Abare
`rategui, R. Alvarez, G. Rubia, A. Leon, M. Domino,
`I. Calvo, L. G. Este’vez,
`A. Lopez~Farré, F. Labo; Fundacion Jimenez Diaz, Madrid, Spain
`Background: Some studies suggest a direct effect of 5—fluoruracil (5-FU) on
`vascular endothelium. The enzyme endothelial nitricoxide synthase (eNOS)
`produces nitric oxide (NO) in the endothelium.
`It
`is known that NO has
`multiple physiological functions one of which is involved in the interaction
`of circulating tumour cells with the endothelium. On the other hand,
`endothelial cells (E.C) can be found in two different states of proliferation:
`confluence (quiescent) and subconfluence (proliferating). Our objetives are
`to study the effect of 5—FU on the eNOS expression and to analyse if there is
`a direct relationship between the effect of 5—FU and eNOs expression and
`the state of endothelial growth. Methods: Culture of bovine aortal endothe—
`lial cells (B.A.E.C). The dosage of 5-FU was 20 ugr/mL. The enzyme eNOS
`was measured using Western-blot method. Results: We observed an
`increase in eNOs expression in subconfluent BC with respect to confluent
`E.C (14.6 densitometric units as opposed 8.97 DU;p<0.003; t Student
`method).The presence of 5»FU reduces eNOs expression in subconfluent
`E.C with respect to control subconfluent endothelial cells (14.6 DU as
`opposed to 9.47; p< 0.023). Conclusions: 5—FU reduces eNOs expression
`in EC in subconfluence state. This finding suggests a direct effect of 5—FU
`on the proliferating endothelium and as well a possible effect on tumoral
`endothelium.
`
`Publish Only
`3147
`Gene expression changes during acquired resistance to tamoxifen: a preclini-
`cal model of post-menopausal breast cancer. N. Macgherson, S. Moore, A.
`Brodie, T. Olivotto, A. Thiantanawat, B. Long, D. Je/ovac, C. Nelson; BC
`Cancer Agency, Victoria, BC, Canada; The Prostate Centre, Vancouver, BC,
`Canada,- Deptof Pharmacology, University of Maryland, Baltimore, MD
`Background: Most metastatic breast cancers initially respond to hormonal
`treatment but all become resistant to these treatments over time. The
`genetic events that occur during acquired resistance are unknown. To
`examine the gene expression changes during acquired hormonal resis
`tance, we used a model that mimics ER positive breast cancers in the
`post-menopausal setting with the tumors responsive to both Tamoxifen
`(TAM) and aromatase inhibitors. Tumors were analyzed with high density
`cDNA microarrays to identify genes associated with TAM resistance.
`Methods: Aromatase—transfected MCF-7Ca human breast cancer cells were
`grown as tumor xenografts in female ovariectomized athymic nude mice in
`which an androstenedione supplement was converted to estrogen to
`stimulate tumor growth. When tumor volume was approximately 300 mm3,
`the animals were grouped (4 groups, each with n=20) for continued
`supplementation with androstenedione (A4A) only (control), Letrozole (an
`aromatase inhibitor) 10 rig/day + AAA, TAM 100 rug/day + A4A, or
`vehicle. Tumors were then retrieved at various time points during the
`development of hormone resistance. Tumor RNA samples were compared
`to reference RNA from Stratagene and incubated with 14K microarrays
`(Array—Ready Oligo Set, Qiagen). Expression results were analyzed with
`Genespring 6.1 (Silicon Genetics). Results: We have identified 15 TAM-
`resistant associated genes that are overeexpressed by at least 2-fold, after
`controlling for genes associated with housekeeping function (Vehiéle and
`short term control), proliferation (freely growing tumors without TAM), and
`TAM inducible genes. They include; cystatin A, TGFbetalainduced anti—
`apoptotic factor, cadherinl
`E—cadherin, Snf2-related CBP activator pro—
`tein, and chromatin—remodelling genes. At the meeting we will also present
`data on the expression changes seen in the Her-regulin family, cyclin family
`and MAP kinase genes during acquired TAM resistance. Patient biopsies
`are currently being collected and analyzed to validate these observations.
`Conclusions: Chromatin remodeling genes are over-expressed in acquired
`TAM—resistance.
`
`3150
`
`Publish Only
`
`A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly)
`in patients (pts) with refractory or advanced malignancies: A pharmacokinetic
`(PK) and pharmacodynamic (PD) analysis. A. A. Desai, L. Janisch, L. R. Berk,
`H. L. Know/es, V. M. Rivera, C. L. Bedrosian, M. J. Ratain; University of
`Chicago, Chicago,
`IL,- AR/AD Pharmaceuticals, Cambridge, MA; ARIAD
`Pharmaceuticals, lnc., Cambridge. MA
`Background:AP23573 is a non-prodrug rapamycin analog that potently
`inhibits mTOR, a downstream effector of
`the Pl3K/Akt and nutrient
`pathways. AP23573 demonstrated powerful antiproliferative activity in
`vitro and antitumor activity in mouse xenograft studies. Methods: This trial
`is utilizing an accelerated dose escalation scheme to determine safety and
`tolerability, establish a maximum tolerated dose, and characterize the PK
`and PD of AP23573. AP23573 is administered as 30-minute lV infusion
`wkly on 4-week cycles, and tumor responses are evaluated every 2 cycles.
`Potential PD markers are being assessed using western blot analysis of
`peripheral blood mononuclear cells. Results: As of 12/01/03: 9 pts
`(4M/5F), median age 55 yrs (range 27 — 79 yrs), have received doses
`ranging from 6.25 to 25 mg in 3 dose level cohorts (total cycles, 15;
`median cycles, 2/pt). No dose limiting toxicities or AP23573-related
`serious adverse events have been observed. Common reversible side effects
`for first cycle have been grade 1 chills, diarrhea, fatigue, rash, anorexia,
`mucositis, and one pt had grade 2 anemia. PK analyses (doses 6.25 and
`12.5 mg) suggest a mean AP23573 half—life of 46 — 52 hours, with
`AP23573 concentration levels generally remaining above in vitro antiprolif-
`eration lC50 levels until the next wkly dose. PD analyses (doses 12.5 and
`25 mg) show inhibition of mTOR activity until
`the next wkly dose as
`measured by decrease in phosphorylated 4EBP1 levels. One of 5 evaluable
`pts has stable medullary thyroid cancer for > 2 months. Conclusions:
`AP23573 can be administered safely using this schedule. There is
`evidence of a substantial PD effect at dose levels associated with minimal
`toxicity, and early evidence of antitumor activity. Given the promising PD
`findings,
`further dose escalation and new pt enrollment will
`include
`evaluation of maximum effective dose of AP23573 based on PK/PD
`relationship.
`If substantial
`interindividual PK variability is observed, the
`trial also is prospectively designed to evaluate the relevance of genetic
`variants in candidate drug metabolism genes.
`
`
`This material may be protected by Copyright law (Title 17 us. Code)
`
`
`
`—————
`EX. 1082-0007
`
`Ex. 1082-0007
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