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Program and Abstracts
20th Bristol-Myers Squibb
Nagoya International
Cancer Treatment Symposium
New Concept of Treatment Strategies
for Hormone-Related Cancer
March 11.12, 2005
Aichi Cancer Center
Access to the Symposium Site
Subway
Meijyo Line
Subway
Higashiyama Line
Aichi Cancer Center
1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681
Phone: (052) 762-6111 / Fax:(052) 764-2963
ii
Aichi
Cancer Center
Organizing Committee
President
Hidehiko Saito
(Nagoya Medical Center)
Scientific Chief
Ryuzo Ueda
(Nagoya City University Medical School)
Advisory Board
Tatsuo Abe
Hiroshi Fujita
Susumu Hibino
Masami Hirano
Yukio Inuyama
Toshihiko Kotake
Hisanobu Niitani
Makoto Ogawa
Tatsuo Saito
Yoshio Sakurai
Masanori Shimoyama
Tetsuo Taguchi
Shigeru Tsukagoshi
Scientific Committee
Yutaka Ariyoshi
Hirotaka Iwase
Tetsuya Mitsudomi
Tomoki Naoe
Ryuzo Ohno
Kaoru Shimokata
(Keihoku Hospital)
(Tsurumi University)
(Nagoya Medical Center)
(Meijo University)
(Hokkaido University)
(Osaka Medical Center for Cancer and Cardiovascular
Diseases)
(Tokyo Cooperative Oncology Group)
(Aichi Cancer Center Hospital)
(Sendai Kosei Hospital)
(The Cancer Institute, Japanese Foundation for Cancer
Research)
(National Cancer Center Hospital)
(Japanese Society for Cancer Chemotherapy)
(Tokyo Cooperative Oncology Group)
(Marumo Hospital)
(Kumamoto University)
(Aichi Cancer Center Hospital)
(Nagoya University School of Medicine)
(Aichi Cancer Center Hospital)
(Nagoya University School of Medicine)
iii
Advisory Committee
Hideyuki Akaza
Shigetaka Asano
Kenji Eguchi
Masahiro Fukuoka
Tomomitsu Hotta
Ryunosuke Kanamaru
Michihiko Kuwano
Akimasa Nakao
Yoshiro Niitsu
Yuji Nimura
Shiro Nozawa
Nagahiro Saijo
Yuh Sakata
Tsuneo Sasaki
Yasutsuna Sasaki
Hiroshi Shiku
Tomoo Tajima
Toshitada Takahashi
Mamoru Tsukuda
Takashi Tsuruo
Jun Yoshida
Hiroyuki Yoshikawa
Scientific Program Committee
Keisuke Aiba
Yasuhiro Fujiwara
Masanori Hatae
Kiyohiko Hatake
Shinsuke Iida
Hironobu Minami
Kazuhiko Nakagawa
Yoichi Nakanishi
Kazuto Nishio
Atsushi Ohtsu
Toshiaki Saeki
Hideo Saka
Kazuhito Yamamoto
iv
(University of Tsukuba)
(The University of Tokyo)
(Tokai University School of Medicine)
(Kinki University School of Medicine)
(Tokai University School of Medicine)
(Funada Hospital)
(Kurume University, Research Center for Innovative Cancer
Therapy)
(Nagoya University School of Medicine)
(Sapporo Medical University)
(Nagoya University School of Medicine)
(Keio University School of Medicine)
(National Cancer Center Hospital)
(Misawa City Hospital)
(Tokyo Metropolitan Komagome Hospital)
(Saitama Medical School)
(Mie University School of Medicine)
(Tokai University Hospital)
(Aichi Cancer Center Research Institute)
(Yokohama City University School of Medicine)
(The University of Tokyo)
(Nagoya University School of Medicine)
(University of Tsukuba)
(The Jikei University School of Medicine)
(National Cancer Center Hospital)
(Kagoshima City Hospital)
(Cancer Institute Hospital, Japanese Foundation for Cancer
Research)
(Nagoya City University Medical School)
(National Cancer Center Hospital East)
(Kinki University School of Medicine)
(Kyushu University Faculty of Medicine)
(Tokyo Metropolitan Komagome Hospital)
(National Cancer Center Hospital East)
(Saitama Medical School)
(Nagoya Medical Center)
(Nagoya University School of Medicine)
DAILY PROGRAM
Friday, March 11
Saturday, March 12
8:30
9:00
9:30
10:00
Special Lecture
(10)
Presidential Opening Address(1)
Keynote Address
(2)(3)
10:30
Session 4 : Chemotherapy (Including New Drug)
(11)(12)(13)
11:00
11:30
12:00
Lunch
12:30
13:00
13:30
Lunch
BMS Award in 2005
Session 1 : Gane Tip, Prognosis Factor, SNP
(4)(5)
Session 5 : Chemotherapy (Including New Drug)
(14)(15)
14:00
14:30
15:00
15:30
Kimura Memorial Lecture
(16)
Session 2 : Hormone Treatment
(Including Aromatase Inhibitor)
(6)(7)
Closing Address
16:00
16:30
Session 3 : Hormone Treatment for Prostate
Cancer
(8)(9)
17:00
17:40
v
Friday, March 11, 2005
9:50-10:00
(1)
10:00-12:00
Presidential Opening Address
Hidehiko Saito (Nagoya Medical Center)
Keynote Address
Chairperson : Ryuzo Ueda
(2)
(3)
"Function of Nuclear Sex Hormone Receptors in Gene Regulation"
Shigeaki Kato (The University of Tokyo)
Chairperson : Yutaka Ariyoshi
"The Role of Estrogen Receptor and Growth Factor Signaling Cross-Talk in
Breast Cancer"
Rachel Schiff (Baylor College of Medicine, U.S.A.)
12:00-13:00
Lunch Time
13:00-13:30
BMS Award in 2005
Chairperson : Hidehiko Saito
"Clinical Significance of Estrogen Receptor β in Breast Cancer"
Shigehira Saji (Tokyo Metropolitan Komagome Hospital)
13:30-15:00
15:00-16:20
16:20-17:40
Session 1 : Gene Tip, Prognosis Factor, SNP
Chairpersons : Dennis C. Sgroi & Takashi Takahashi
(4)
"A Novel Two-Gene Expression Ratio That Predicts Clinical Outcome in
Breast Cancer Patients Treated with Tamoxifen"
Dennis C. Sgroi (Massachusetts General Hospital, U.S.A.)
(5)
"Estrogen Signaling and Prediction of Endocrine-Therapy"
Shin-ichi Hayashi (Tohoku University)
Session 2 : Hormone Treatment (Including Aromatase Inhibitor)
Chairpersons : Rachel Schiff & Hirotaka Iwase
(6)
"The Use of Aromatase Inhibitors in Adjuvant Therapy for Early Breast
Cancer"
Walter Jonat (University of Kiel, Germany)
(7)
"Resistance to Endocrine Therapy in Breast Cancer"
Junichi Kurebayashi (Kawasaki Medical University)
Session 3 : Hormone Treatment for Prostate Cancer
Chairpersons : Maha Hussain & Hironobu Minami
(8)
vi
"Improving Chemo-and Hormonal Therapies by Targeting Cell Survival Genes
Using Antisense Oligonucleotides"
Martin E. Gleave (Vancouver General Hospital, Canada)
(9)
"Hormone Treatment for Prostate Cancer : Current Issues and Future
Directions"
Tomohiko Ichikawa (Chiba University)
Saturday, March 12, 2005
9:30-10:30
Special Lecture
Chairperson : Tomoki Naoe
(10) "Self-Renewal and Cancer"
Michael F. Clarke (University of Michigan, U.S.A.)
10:30-12:30
Session 4 : Chemotherapy (Including New Drug)
Chairpersons : Andrew D. Seidman & Hiroji Iwata
(11) "The Role of Chemotherapy in Advanced Prostate Cancer"
Maha Hussain (University of Michigan, U.S.A.)
(12) "Current Status of Dose-Dense Chemotherapy for Breast Cancer"
Andrew D. Seidman (Memorial Sloan-Kettering Cancer Center,U.S.A.)
(13) "Drug Resistance in the Chemotherapy for Breast Cancer"
Toshiaki Saeki (Saitama Medical School)
12:30-13:30
Lunch Time
13:30-14:30
Session 5 : Chemotherapy (Including New Drug)
Chairperson : Tetsuya Mitsudomi
(14) "Preclinical and Molecular Correlative Study for EGFR-Specific Tyrosine
Kinase Inhibitors in Japan"
Kazuto Nishio (National Cancer Center Research Institute)
(15) "Trastuzumab : Updates and Issues"
Masakazu Toi (Tokyo Metropolitan Komagome Hospital)
14:30-15:30
Kimura Memorial Lecture
Chairperson : Ryuzo Ohno
(16)
Moshe Talpaz (MD Anderson Cancer Center, U.S.A.)
15:30-15:40
Closing Address
vii
viii
Abstracts
Hidehiko Saito, M.D.
1963
1968-1971
1971-1981
1982-1984
1984-2001
1991-1995
1998-2000
2001-
M.D., Nagoya University School of Medicine
Research Fellow, Children's Cancer Research Foundation,
Boston, U.S.A.
Instructor, Assistant and Associate Professor of Medicine,
Department of Medicine, Case Western Reserve
University, Cleveland, U.S.A.
Professor of Medicine, Department of Medicine, Saga
Medical School
Chairman and Professor of Medicine,First Department of
Medicine, Nagoya University School of Medicine
Dean, Nagoya University School of Medicine
Director, Nagoya University Hospital
President, Nagoya National Hospital
(Nagoya Midical Center)
Specialty and Research Field of Interest
Hematology and Medical Oncology, Stem cell tranplantation, Chemotherapy,
Thrombosis and Hemostasis.
Recent Selected Publications
1.
2.
3.
4.
5.
6.
7.
8.
9.
1
Kuno, Y., Abe, A., Emi, N., Iida, M., Yokozawa, T., Towatari, M., Tanimoto, M. and Saito, H: Constitutive kinase
activation of the TEL-Syk fusion in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 97: 1050-1055, 2001.
Yamamoto, Y., Kiyoi, H., Nakano, Y., Suzuki, R., Kodera, Y. Miyawaki S., Asou, N., Kuriyama, K.,
Yagasaki, F., Shimazaki, C., Akiyama, H., Saito, K., Nishimura, M., Motoji, T., Shinagawa, K., Takeshita, A.,
Saito, H., Ueda, R., Ohno, R. and Naoe, T.: Activating mutation of D835 within the activation loop of FLT3 in
human hematologic malignancies. Blood 97: 2434-2439, 2001.
Kiyoi, H., Ohno, R., Ueda, R., Saito, H., Naoe, T.: Mechanism of constitutive activation of FLT3 with internal
tandem duplication in the juxtamembrane domain. Oncogene 21: 2555-2563, 2002.
Li Y., Nagai, H., Ohno, T., Yuge, M., Hatano, S., Ito, E., Mori, N., Saito, H., Kinoshita, T.: Abberrant DNA
methylation of p57KIP2 gene in the promoter region in lymphoid malignancies of B-cell phenotype. Blood
100: 2572-2577, 2002.
Murate, T., Suzuki, M., Hattori, M., Takagi, A., Kojima, T., Tanizawa, T., Asano, H., Hotta, T., Saito, H.,
Yoshida, S., Tamiya-Koizumi, K.: Up-regulation of acid sphingomyelinase during retinoic acid-induced myeloid
differentiation of NB4, a human acute promyelocytic leukemia cell line. J Biol Chem 277: 9936-9943, 2002.
Nishihira, H., Kato, K., Isoyama, K., Takahashi, TA., Kai, S., Kato, S., Takanashi, M., Sato, N., Sato, H.,
Kitajima, K., Naoe, T., Saito, H.: The Japanese cord blood bank network experience with cord blood
transplantation from unrelated donors for haematological malignancies: an evaluation of graft-versus-host
disease prophylaxis. Br J Haematol 120:516-522, 2003.
Ozawa, Y., Towatari, M., Tsuzuki, S., Hayakawa, F., Maeda, T., Miyata, Y., Tanimoto, M., Saito, H.: Histone
deacetylase 3 associates with and represses the transcription factor GATA-2. Blood 98: 2116-2123, 2001
Yazaki M, Takahashi T, Mizutani K, Ito Y, Wakiguchi H, Inoue M, Kawa K, Kato T, Saito H, Togari H.:
Human leucocyte antigen-Cw-specific cytotoxic T lymphocytes generated from naive cord blood used for cord
blood stem cell transplantation. Br J Haematol 117:893-898, 2002.
Nishihira H, Kato K, Isoyama K, Takahashi TA, Kai S, Kato S, Takanashi M, Sato N, Sato H, Kitajima K,
Naoe T, Saito H: The Japanese cord blood bank network experience with cord blood transplantation from
unrelated donors for haematological malignancies: an evaluation of graft-versus-host disease prophylaxis. Br J
Haematol 120(3):516-522, 2003.
(1) Presidential Opening Address
Hidehiko Saito, M.D.
Nagoya Medical Center
On behalf of the Organizing Committee, I am pleased to welcome you to the
20th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium.
First of all, I would like to thank the speakers and audiences who came a long
distance to join us in Nagoya. It is your active participation that makes the meeting
exiting and valuable.
Since 1986 the Nagoya Symposium has been providing an important, annual,
international forum for exchange of the most up-to-data information regarding
cancer chemotherapy. The meetings, supported by an educational grant of BristolMyers Squibb Company, are a recognized opportunity for updating clinical
oncologists and basic scientists on various topics. During the past 20 years we have
seen remarkable changes in cancer chemotherapy. Our symposium has been
responding to the rapid progress every year by addressing new timely topics.
Internationally well known speakers from abroad and Japan are invited to give the
State of the Art Lecture, which is followed by discussion from the audience. The
program is designed to promote free discussion among participants and speakers,
and every year the numbers of attending physicians and scientists exceeded 400.
The Proceedings of the meeting have been published as a supplement to the Journal
"Cancer Chemotherapy and Pharmacology", and we believe that the proceedings
have been useful in disseminate the information generated at the meeting to a wider
audience.
The main theme of this year's symposium is "New concept of treatment
strategies for hormone-related cancer". We will have 15 invited speakers who will
discuss the basic and clinical aspects of hormone treatment for breast cancer and
prostate cancer. We also have "Meet The Expert" session to enhance informal
discussion in small groups. We believe that the meeting will be an excellent
opportunity to grasp current status and future perspectives of hormone-related
cancer.
Finally, but least, on behalf of the organizing committee I would like to express
our sincere gratitude to Bristol-Myers Squib Company for their warm, continuous
support. I hope that you will enjoy the meeting.
2
Shigeaki Kato, Ph.D.
1988
1988-1992
Ph.D. University of Tokyo, Bunkyo-ku, Tokyo
Assistant Professor, Department of Agricultural Chemistry,
Tokyo university of Agriculture
1992-1996
Associate Professor, Department of Agricultural
Chemistry,
Tokyo university of Agriculture
1996-1998
Associate Professor, Institute of Molecular and Cellular
Biosciences, University of Tokyo
1998-Present Professor, Institute of Molecular and Cellular
Biosciences, University of Tokyo
2002-2004
Research Director, Solution Oriented Research for Science
and Technology (SORST), Japan Science and Technology
Agency (JST)
2004-Present Research Director, KATO Nuclear Complex Project,
Exploratory Research for Advanced Technology
(ERATO), Japan Science and Technology Agency (JST)
Specialty and Research Field of Interest
Transcriptional controls by nuclear receptors, and histone modifying/chromatin
remodeling complexes. The in vivo function of nuclear receptors.
Recent Selected Publications
1.
2.
3.
4.
5.
3
Modulation of oestrogen receptor signaling by association with the activated dioxin receptor.
Nature, 423, 545-550, 2003
The chromatin remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in
Williams Syndrome.
Cell, 113, 905-917, 2003
Nuclear receptor function requires a TFTC-type histone acetyl transferase comples.
Mol. Cell, 9, 553-562, 2002
Brain masculinization requires androgen receptor function.
Proc. Natl. Acad. Sci. USA, 101, 1673-1678, 2004
Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching.
EMBO J., 23, 1598-1608, 2004
(2) Function of Nnclear Sex Hormone Receptors in Gene
Regulation
Shigeaki Kato, Ph.D.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi-Cho, Bunkyo-Ku,
Tokyo, 113-0032, and ERATO, Japan Science and Technology Corporation, Japan
Sex steroids exhibit a wide variety of biological actions in physiological and
pathological events. Development of reproductive organ tumors often depends on
the sex hormone actions, but the molecular basis remains totally unknown. Nuclear
sex hormone receptors (androgen receptor, AR; estrogen receptors, ER) belong to
the members of the nuclear hormone receptor superfamily and act as ligandinducible transcription factors. Nuclear receptors are considered to directly interact
with a number of nuclear co-regulatory complexes involving in chromatin
remodeling and histone modification.
We have studied the functions of sex hormone receptors in two lines. One of the
two is to search of novel co-regulators/ complexes for estrogen receptor (ER).
Based our previous findings on the cross-talk with MAP kinase-mediated growth
factor signalings (Kato et al., Science, 270, 1491, 1995), we extended the study by
cloning hERαAF-1 co-activators p68/72 (Watanabe et al., EMBO J., 20, 1341,
2001), and biochemically identification of a GCN5 HAT co-activator complex from
HeLa cell nuclear extracts (Yanagisawa et al., Mol. Cell., 9, 553, 2002). Moreover,
the other cross-talk of dioxin signalings was found by the association with the
heterodimer of dioxin receptor (Ohtake et al., Nature, 423, 545, 2003). Thus, the
ER-meditated estrogen singnalings in breast cancer development are presumed to
couple with a number of nuclear co-regulators/ complexes.
To study the function of the AR mutants found in prostate cancer patients in
prostatic cancer development, a human AR mutation (T877A) was introduced into
the AR gene floxed mice (Kawano et al., PNAS, 100, 9416, 2003;Sato et al.,
PNAS, 101, 1673, 2004) by replacing the mouse AR ligand binding domain with a
hAR mutated LBD. The mice expressing the mouse-human hybrid AR mutant
protein (T877A) mice looked normal in external sexual organs and reproduction.
However, the prostate development in the AR (T877A/Y) mice observed at age of
17 weeks was clearly advanced. No antagonistic action of a clinically used
androgen antagonist (hydroxyflutamide) in the prostate development was observed.
Thus, these findings suggest that hypersensitivity of AR mutants to antagonists and
endogenous steroid hormones may potentiate hormone-dependency in prostate
cancer development.
4
Rachel Schiff, Ph.D.
1986-1991
Graduate Teaching/Research Assistant
The Hebrew University, Hadassah Medical School
1993
Postdoctoral Fellow
Department of Experimental Medicine and Cancer
Research
The Hebrew University, Hadassah Medical School
Jerusalem, Israel
1994-1999
Postdoctoral Fellow
Department of Medicine, Division of Medical Oncology
University of Texas Health Science Center at San Antonio,
San Antonio, Texas
1999-2002
Instructor
Breast Center, Department of Medicine, Baylor College of
Medicine, Houston, Texas
2002-present Assistant Professor
Breast Center, Department of Medicine, Baylor College of
Medicine, Houston, Texas
Membership in Scientific Society
American Association of Cancer Research
Recent Selected Publications
1.
2.
3.
4.
5.
5
Oesterreich S, Deng W, Jiang S, Cui X, Ivanova M, Schiff R, Kang K, Hadsell DL, Behrens J, Lee AV:
Estrogen-mediated down-regulation of E-cadherin in breast cancer cells. Cancer Res 63(17):5203-8, 2003.
Osborne CK, Schiff R: Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen
resistance in breast cancer. Breast 12(6):362-7, 2003.
Come SE, Buzdar AU, Arteaga CL, Bissell MJ, Brown MA, Ellis MJ, Goss PE, Green JE, Ingle JN, Lee AV,
Medina D, Nicholson RI, Santen RJ, Schiff R, Hart CS: Proceedings of the Third International Conference on
Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer: conference summary
statement. Clin Cancer Res 10(1 Pt 2):327S-330S, 2004
Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK: Cross-talk between estrogen receptor
and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 10(1
Pt 2):331S-6S, 2004.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R: Mechanisms of tamoxifen
resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl
Cancer Inst 96(12):926-35, 2004.
(3) The Role of Estrogen Receptor and Growth Factor Signaling CrossTalk in Breast Cancer Endocrine Resistance
Rachel Schiff, Ph.D., Jiang Shou, Suleiman Massarweh, Grazia
Arpino, Lavina Bharwani, Mothaffar Rimawi, and C Kent Osborne.
The Breast Center at Baylor College of Medicine and The Methodist Hospital, Houston, TX, 77030,
U.S.A.
Endocrine therapy, and especially tamoxifen, is the most important systemic treatment
of estrogen receptor (ER)-positive breast cancer at all stages, but resistance, both de novo
and acquired, is a major problem, and therefore novel strategies to reverse or prevent this
resistance are needed. Compelling evidence suggests that cross-talk between the estrogen
receptor (ER) and the epidermal growth factor (EGF)/HER2 receptor pathway contributes
to endocrine resistance. Indeed, we have shown, using an experimental in vivo model, that
MCF-7/HER2-overexpressing xenografts are growth-stimulated by tamoxifen as a
mechanism of de novo resistance. Molecular cross-talk between ER and HER2 pathways,
involving rapid nongenomic ER activities, is increased in the HER2-overexpressing tumor
cells, with cross-phosphorylation and activation of both receptors and downstream
signaling molecules. This causes tamoxifen to act as an agonist for ER-mediated
transcription and for tumor growth. In contrast to tamoxifen, estrogen deprivation (ED) or
the pure antagonist fulvestrant strikingly inhibit MCF-7/HER2 tumor growth, but resistance
develops rapidly and tumors regrow in 2-3 months. This resistance to ED and fulvestrant is
associated with a significant increase in HER2 expression and signaling.
We have previously shown that in these HER2-overexpressing breast tumors, antiEGFR/HER2 treatment with either the tyrosine kinase inhibitor (TKI) gefitinib or the
monoclonal antibody trastuzumab eliminates the ER-EGFR/HER2 cross-talk, restores
tamoxifen growth inhibition and delays resistance to ED and fulvestrant. However, this
effect is only temporary and resistance develops in 2-3 months and tumor growth resumes
even when gefitinib and trastuzumab are combined. Pertuzumab is a new potent humanized
monoclonal antibody against HER2 that can inhibit dimerization of HER-2 with all other
HER family members. We evaluated pertuzumab activity as a single agent and in various
combinations with tamoxifen, gefitinib, and trastuzumab. As a monotherapy, pertuzumab
only minimally inhibited the growth of E2-stimulated tumors but, like gefitinib and
trastuzumab, it completely blocked tamoxifen-stimulated tumor growth. Again, however,
like the other two inhibitors, resistance to pertuzumab developed in 2-3 months. Since these
three agents inhibit HER2 signaling in a slightly different way, combination therapy was
investigated. In mice given tamoxifen, combinations of pertuzumab with trastuzumab, and,
especially, pertuzumab with both trastuzumab and gefitinib, had remarkably greater
antitumor effects. Complete regression of all tumors was observed in tamoxifen-treated
mice only when all three inhibitors were added in combination. In contrast, in estrogentreated mice, these three growth factor inhibitors induced only a brief period of tumor
growth inhibition. Our results suggest that these inhibitory agents modulate the growth of
HER2-overexpressing breast tumors through distinct, yet complementary, mechanisms,
cooperating to convey a remarkably potent HER2 signaling blockade.
Finally, we further show in our xenograft model of breast cancer that in non-HER2
overexpressing breast tumors, acquired resistance to tamoxifen is also caused by tamoxifenstimulated growth and is associated with EGFR and HER2 overexpression. Again,
targeting the EGFR/HER2 pathway improves the anti-tumor effect of tamoxifen and delays
acquired resistance. Overall, our data suggest that combined ER-targeted therapy with
various growth factor pathway inhibitors may be a highly effective treatment for ERpositive breast cancer. We and others are now conducting clinical trials to see if this new
strategy is effective in patients.
6
Dennis C. Sgroi, M.D.
1989-1991
Resident, Clinical Pathology, Massachusetts General
Hospital
1991-1992
Chief Resident, Anatomic Pathology, Massachusetts
General Hospital
1992-1994
Research Fellow, Massachusetts General Hospital, Harvard
Medical School
1994-1995
Graduate Assistant in Pathology, Harvard Medical School,
Massachusetts General Hospital
1995-2003
Assistant Professor of Pathology, Harvard Medical School,
Assistant in Pathology,
Massachusetts General Hospital
2003-Present Director of Breast Pathology, Massachusetts General
Hospital
Associate Professor of Pathology, Harvard Medical
School, Associate in Pathology,
Massachusetts General Hospital
Licensure and Certification
1992 Massachusetts Medical License.
1993 American Board of Pathology (Anatomic Pathology).
Recent Selected Publications
1.
2.
3.
4.
5.
7
Reynolds PA, Smolen GA, Palmer RE, Sgroi D, Yajnik V, Gerald WL and Haber DA. Identification of a
DNA-binding site and transcriptional target for the EWS-WT1 (+KTS) oncoprotein. Genes and Dev. 2003; 17:
2094-2107.
Michaelson JS, Silverstein M, Sgroi D, Cheongsiatomy JA, Taghian A, Powell S, Hughes K, Comegno A,
Tanabe K and Smith B. The effect of tumor size and nodal status on the lethality of breast cancer. Cancer
2003; 98: 2133-2143.
Hogemann-Savellano D, Bos E, Blondet C, Sato F, Josephson L, Weissleder R, Gaudet J, Sgroi D, Basilion
JP. The Transferrin receptor: A potential molecular imaging marker for human cancer. Neoplasia 2003; 5: 112.
Zang L, Palmer-Toy D, Hancock WS, Sgroi DC, and Karger BL. Proteomic analysis of 10,000 cells from laser
capture microdissected breast cancer tumor tissue using LC-MS and 16O/18O isotopic labeling. Journal of
Proteomic Research, 2004; 3: 604-612.
Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A, Muir B, Mohapatra G, Salunga R, Tuggle JT,
Tran Y, Tran D, Tassin A, Amon P, Wang W, Wang W, Enright E, Stecker K, Estepa-Sabal E, Smith B,
Younger J, Balis U, Michaelson J, Bhan A, Habin K, Baer TM, Brugge J, Haber DA, Erlander MG and
Sgroi DC. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with
tamoxifen. Cancer Cell, 2004; 5: 607-616.
(4) A Novel Two-Gene Expression Ratio That Predicts Clinical
Outcome in Breast Cancer Patients Treated with Tamoxifen
Dennis C. Sgroi, M.D.
Massachusetts General Hospital and Harvard Madical School, U.S.A.
Tamoxifen is the antiestrogen agent most frequently prescribed in women with
early stage and hormone receptor-positive breast cancer and significantly reduces
tumor recurrence in such patients. Currently, tumor expression of ER and PR are
the most useful markers predictive of treatment outcome. However, approximately
30-40% of patients with hormone receptor positive breast cancer fail to respond or
develop resistance to tamoxifen through mechanisms that remain largely unclear.
Current clinicopathological features including tumor stage, tumor grade, and Her-1
and Her-2 expression fail to accurately identify individuals who are at risk for
tumor recurrence. Using a case-control study design, we performed microarray
gene expression analysis of tumors from 60 women uniformly treated with
adjuvant tamoxifen monotherapy and identified a novel two gene expression ratio
(HOXB13/IL17BR) that outperformed existing biomarkers in predicted treatment
outcome. The predictive power of this two-gene expression ratio was validated in
two independent cohorts of breast cancer patients treated with tamoxifen alone.
Ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances
motility and invasion in vitro and its expression is increased in both pre-invasive
and invasive primary breast cancer. Taken together our results demonstrate the
potential of a simple two-gene expression-based test for selecting breast cancer
patients for tamoxifen treatment and may provide new insight into the mechanisms
of tamoxifen resistance.
8
Shin-ichi Hayashi, Ph.D.
1988,
1981-1989,
1988-1989,
1990-1995,
1995-2004,
2004-
Ph.D., Kyushu Univ. Faculty of Science
Research Associate, Hiroshima Univ.
Dept. of Biochemistry, Sch. of Dentistry
Guest Researcher, Dept of Medical Nutrition,
Karolinska Institute, Sweden
Researcher, Dept. of Biochemistry, Saitama
Cancer Center Research Institute
Senior Researcher, Dept. of Biochemistry,
Saitama Cancer Center Research Institute
Prof. of Tohoku Univ. Faculty of Medicine,
Sch. of Health Science
Specialty and Research Field of Interest
Hormone-dependent cancer, such as breast, endometrial and prostate cancer.
Nuclear receptors, particularly estrogen receptor.
Development of diagnostic tools for hormone-dependent cancer.
Recent Selected Publications
1.
2.
3.
4.
5.
9
Prediction of prognosis of estrogen receptor-positive breast cancer with combination of selected estrogenregulated genes. Cancer Science, 95: 496-502, 2004.
Transcription factor EGR3 is involved in the estrogen-signaling pathway in breast cancer cells. J. Mo.
Endocrin., 32: 649-661, 2004.
Prediction of hormone sensitivity by DNA microarray. Biomedicine & Pharmacotherapy, 58: 1-9, 2004.
Estrogen receptor (ER)β1 and ERβcx /β2 inhibit ERα function differently in breast cancer cell line MCF7. Oncogene, 22: 5011-5020, 2003.
The expression and function of ERα and β in human breast cancer and its clinical application. EndocrineRelated Cancer, 10: 193-202, 2003.
(5) Estrogen Signaling and Prediction of Endocrine-Therapy
Shin-ichi Hayashi, Ph.D.
Department of Medical Technology, School of Health Sciences, Faculty of Medicine, Tohoku
University, Sendai 980-8575, Japan
Estrogen plays an important role in growth and progression of human breast
cancer. To understand the whole figure of estrogen signaling is very important to
clarify the biology of breast cancer. On the other hand, the hormone therapy for
breast cancer has recently been progressing rapidly, using drugs such as SERMs
and aromatase inhibitors. Then, the prediction of individual response to these
hormone therapies is becoming very important for treatment of breast cancer
patients. In order to address these basic and clinical issues, we are developing a
several new tools such as focused microarray and GFP-reporter cell system. We
first carried out expression profiling of approximately 10000 genes in estrogen
receptor (ER)-positive breast cancer cells. Based on the results, estrogen-responsive
genes were selected and produced a custom-made cDNA microarray. Using this
microarray consisting of 200 genes of narrowed-down subset, we studied several
basic researches about estrogen signaling such as the effect of estrogen-antagonists
on estrogen-responsive gene expression profile, function of ERβ, and the
expression profiles among twelve ER-positive cancer cell lines derived from
various organs. Furthermore, expression levels of several candidate genes selected
from the contents of custom-array were also analyzed by real-time RT-PCR and by
immunohistochemical technique using breast cancer tissues, in order to find the
new predictive factors for responsiveness to hormone therapy of primary breast
cancer patients. We found that the expression of several genes such as HDAC6
significantly correlated with disease-free and overall survival of patients treated
with adjuvant tamoxifen therapy. Furthermore, we are developing a new tool for
analyzing the effect of new aromatase inhibitors on individual breast cancer
patients using ERE-GFP-indicator cells. We hope that these approaches could
provide not only new clues for elucidation of estrogen-dependent growth
mechanisms of cancer, but also clinical benefits to patients by assessment of
individual response to endocrine therapy.
10
Walter Jonat, M.D.
1971-1983
1975-1976
1976
1976-1985
1985-1995
1995-Present
University of Hamburg
Sonderforschungsbereich 34
(SFB 34) Endocrinology
University of Hamburg
Amalie-Sieveking Hospital
Department of Anaesthesia
and Intensive Medicine,
Amalie-Sieveking-Hospital,
Hamburg (Intern)
Women Hospital
Zentral-Krankenhaus
St. Jürgen-Strasse, Bremen
Senior Physician, Provisionally in Charge of the hospital
University of Hamburg Department of Gynecology and Obstetrics
Hamburg-Eppendorf
Senior Physician in Charge
Assistant Professor
Christian-Albrechts-University
of Kiel - Department of Gynecology and Obstetrics
Director
Major Professional Societies
ASCO - American Society of Clinical Oncology
AACR - American Association for Cancer Research
DKG - Deutsche Krebsgesellschaft
DKH - Deutsche Krebshilfe
DGGG - Deutsche Gesellschaft für Gynäkologie und Geburtshilfe
DGS - Deutsche Gesellschaft für Senologie
FIGO - Fédération Internationale de Gynécologie et d’Obstétrique
LEOPOLDINA
Member Editorial Board Scientific Journals
American Journal of Cancer
Achieves of Gynecology and Obstetrics
Geburtshilfe und Frauenheilkunde
GynSpectrum
Journal of Pharmacology and Therapy
Labormedizin
Der Onkologe
Senologie
Gynäkologische Praxis
Breast Cancer Online
Awards
1985 - Staude-Pfannenstiel-Award
1992 - German Cancer Award
Publications
153
753
15
11
reviewed full papers listed in PubMed
invited oral presentations
books
(6) The Use of Aromatase Inhibitors in Adjuvant Therapy for Early
Breast Cancer
Walter Jonat, M.D.
University of Kiei, Germany
The clinical evidence supporting the use of aromatase inhibitors (AIs) in adjuvant
therapy for hormone-sensitive early breast cancer (EBC) has been growing over the past
few years. Five years' tamoxifen has been the standard adjuvant endocrine treatment for
almost 30 years, but better-tolerated alternatives with improved efficacy have been sought
in order to improve the prognosis for postmenopausal women diagnosed with EBC.
Although adjuvant tamoxifen decreases the risk of recurrence for postmenopausal women
by around 50% (Early Breast Cancer Trialists' Collaborative Group 1998), long-term
tamoxifen use also increases the risk of endometrial cancer by up to four-fold over this
time, with no additional benefit gained from extending treatment beyond five years.
The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial compared the nonsteroidal AI anastrozole with tamoxifen as initial adjuvant treatment in 9366
postmenopausal women with hormone receptor-positive EBC. Data covering the entire
five-year adjuvant period (median follow-up 68 months) confirmed the improved efficacy
and superior tolerability of anastrozole compared with tamoxifen. Patients receiving
anastrozole had significantly prolonged disease-free survival (DFS; hazard ratio [HR] 0.87;
95% confidence interval [CI] 0.78, 0.97; p=0.01) and time to recurrence (TTR; HR 0.79;
95% CI 0.70, 0.90; p<0.001). There were also significant reductions in the incidence of
endometrial cancer and thromboembolic events in the anastrozole group compared with the
tamoxifen group. The ATAC trial results provide the largest safety database for any of the
third-generation AIs and highlight anastrozole as having a consistently beneficial
risk:benefit ratio compared with tamoxifen as initial adjuvant treatment. Early efficacy data
from the BIG 1-98 study, which compares the non-steroidal AI letrozole with tamoxifen as
adjuvant therapy, has further strengthened the clinical evidence supporting the initial use of
AIs in this setting.
Further studies have investigated the option of switching therapy to an AI as a strategy
to improve outcomes for women already receiving adjuvant tamoxifen. The Italian
Tamoxifen Anastrozole ITA trial and the ABCSG 8/ARNO 95 combined analysis both
investigated switching postmenopausal women with hormone-sensitive EBC to anastrozole
after 2-3 years' adjuvant tamoxifen, compared with continuing tamoxifen treatment. Both
trials found significant benefits associated with switching adjuvant therapy from tamoxifen
to anastrozole. The ITA trial reported a significant increase in event-free survival (EFS) in
the anastrozole group at a median follow-up of 36 months (HR 0.35; 95% CI 0.20-0.63;
p_0.0002). The larger ABCSG 8 /ARNO 95 combined analysis confirmed these findings,
with EFS significantly increased in the group switched to anastrozole therapy at a median
follow-up of 28 months (HR 0.60; 95% CI 0.44, 0.81; p=0.0009). The switching approach
has also been investigated with the steroidal AI exemestane in the International Exemestane
Study (IES). This study found that switching to exemestane after 2-3 years' adjuvant
tamoxifen significantly improved DFS compared with continuing tamoxifen therapy (HR
0.68; CI 0.56, 0.82; p<0.001).
In conjunction, these trials indicate that tamoxifen is no longer the most appropriate
initial choice for adjuvant therapy in postmenopausal women with hormone-sensitive EBC,
and that better options exist for women already receiving adjuvant tamoxifen. This
conclusion has been recognised in the most recent Technology Assessment from ASCO,
which recommends that adjuvant endocrine therapy for postmenopausal women with
hormone-sensitive EBC includes an AI either initially, or after 2-5 years, in order to lower
the risk of tumour recurrence.
12
Junichi Kurebayashi, M.D., Ph.D.
1981
1988
1990-1992
M.D., Gunma University School of Medicine
Ph.D, Gunma University
Postdoctoral Fellow, Lombardi Cancer Research Center,
Georgetown University Medical Center
1992-2001
Assistant Professor, Department of Breast & Thyroid
Surgery
Kawasaki Medical School
2001-present Associate Professor, Department of Breast & Thyroid
Surgery
Kawasaki Medical School
Specialty and Research Field of Interest
Endocrine therapy for breast cancer. Endocrine resistance in breast cancer.
Hormonal regulation of growth factors and cytokines in breast and thyroid cancers. Biomarkers
in breast and thyroid cancers. Establishment of breast cancer and thyroid cancer cell lines.
Recent Selected Publications
1.
2.
3.
4.
5.
13
Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic
therapy: a prospective study. Breast Cancer, 11(4): 389-395, 2004
Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer. Breast
Cancer, 11(1): 38-41, 2004
Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa,
ZD1839) and the antiestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells. British Journal of
Cancer, 90(1): 236-244, 2004
Endocrine-resistant breast cancer: underlying mechanisms and strategies for overcoming resistance. Breast
Cancer, 10(2): 112-119, 2003
Medroxyprogesterone acetate decreases secretion of interleukin-6 and parathyroid hormone-related protein in
a new anaplastic thyroid cancer cell line, KTC-2. Thyroid, 13: 251-260, 2003
(7) Resistance to Endocrine Therapy in Breast Cancer
Junichi Kurebayashi, M.D., Ph.D.
Department of Breast & Thyroid Surgery, Kawasaki Medical School,
Kurashiki, Okayama, Japan
Endocrine therapy is a treatment of choice for patients with breast cancer
expressing estrogen receptor (ER) and/or progesterone receptor. Efficacy of
endocrine therapy is well-established in the prevention, adjuvant and metastatic
settings. However, de novo or acquired resistance to endocrine therapy is frequently
observed in clinics.
A large amount of effort has been made to elucidate action mechanisms
underlying resistance to endocrine therapy in breast cancer, and several possible
mechanisms responsible for this resistance have been reported. Two of them,
ligand-independent ER activation medicated by growth factor signaling pathway
and loss of ER expression mediated by hypoxia have been investigated in our
laboratory.
Our previous studies have indicated that a combined treatment with an
antiestrogen, fulvestrant, and an inhibitor of HER2 signaling pathway, trastuzumab
or that of HER1 signaling pathway, gefitinib, resulted in an additive antitumor
effect in breast cancer cells expressing ER and HER2 or HER1, respectively. In
addition, it has been suggested that HER1 and/or HER2 signaling pathway is
activated during the development of antiestrogen-resistant growth in breast cancer
cells. These findings suggest that signal transduction inhibitors are effective for the
treatment of antiestrogen-resistant breast cancer.
Hypoxic microenvironment in cancer tissues has been indicated to promote
malignant progression of cancer cells. Our previous study and others have
suggested that hypoxia post-transcriptionally reduces ER protein expression and
decreases sensitivity to hormonal agents in breast cancer cells. Additionally, our
preliminary study has revealed that a hypoxic cytotoxin, tirapazamine, which is
specifically toxic to hypoxic cells, increases ER expression in breast cancer
xenografts. Differential antitumor activity of tirapazamine on tumor cells under a
normoxic or hypoxic condition inside xenografts may cause this interesting
phenomenon. These findings suggest that hypoxic cytotoxins may retard the
development of endocrine-resistance induced by hypoxia.
Molecular mechanisms responsible for endocrine-resistance in breast cancer are
reviewed and possible therapeutic strategies against this resistance are discussed.
14
Martin E. Gleave, M.D., FRCSC, FACS
1984
1989
1992
1998
M.D. - University of British Columbia,
Fellow of the Royal College of Surgeons of Canada
(FRCSC) ,
Urologic Oncology Fellow, University of Texas MD
Anderson Cancer Center
Fellow of the American College of Surgeons (FACS)
Academic Appointments
Distinguished Professor, Department of Surgery, University of British Columbia
Co-Director, The Prostate Centre, Division of Urology, Vancouver General Hospital;
Consultant Urologist, Department of Urology, University of Washington.
Honours and Awards
UBC Male Athlete of the Year, 1983
American Urologic Association Research Award, 1991
American College of Surgeons HA Clowes Career Development Award, 1997-2002
Capcure Award, American Urologic Association 1998
Joseph F. McCarthy/Circon ACMI Essay Award, Western Section, AUA - 1999
AUA Research Award, First Prize, Clinical Research, 2000
NCI Canada - William E. Rawls Prize, 2001
Distinguished University Scholar, UBC, 2003
Ernst and Young Entrepreneur of the Year, Finalist 2004
Don Coffey Physician Scientist Award 2004, Prostate Cancer Foundation (Capcure)
Recent Selected Publications
1.
2.
3.
4.
5.
6.
15
M. Gleave, et al. Interferon gamma-1b compared with placebo in metastatic renal cell carcinoma. NEJM 338:1265-1271, 1998
Gleave ME, Tolcher A, Miyake H, Beraldi E, and Goldie J. Progression to Androgen-Independence is Delayed by Antisense Bcl-2
Oligodeoxynucleotides After Castration in the LNCaP Prostate Tumor Model. Clinical Cancer Res 5:2891-2898, 1999
Miyake H, Rennie P, Nelson C, Gleave ME. Acquisition of Chemoresistant Phenotype by Overexpression of the Antiapoptotic Gene,
Testosterone-Repressed Prostate Message-2 (TRPM-2), in Prostate Cancer Xenograft Models Cancer Res 60:2547-54, 2000.
Gleave ME, et al: Phase III randomized comparative study of 3 vs 8 months of neoadjuvant hormone therapy prior to radical prostatectomy:
Biochemical and Pathologic endpoints. J Urol. 166(2):500-6, 2001
Gleave M, Miyake H, Zangemeister-Wittke U, and Jansen B. Antisense therapy: Current status in prostate cancer and other malignancies.
Cancer and Metastases Review 21: 79-92, 2002.
Kiyama S, Morrison K, Zellweger T, Akbari M, Cox M, Yu D, Miyake M, and Gleave M. Castration-Induced Increases in Insulin-Like
Growth Factor-Binding Protein-2 Promotes Proliferation of Androgen-Independent Human Prostate LNCaP Tumors. Cancer Research 2003
1;63:3575-3584
Rocchi P, So A, Kojima S. Beraldi E, Fazli L and Gleave ME. Heat Shock Protein 27 Increases after Androgen Ablation and Plays a
Cytoprotective Role in Hormone Refractory Prostate Cancer. Cancer Research, 2004 Sep 15;64(18):6595-602
(8) Improving Chemo-and Hormonal Therapies by Targeting Cell
Survival Genes Using Antisense Oligonucleotides
Martin E. Gleave, M.D., FRCSC, FACS
Distinguished Professor of Surgery
Division of Urology, Vancouver General Hospital, University of British Columbia, Vancouver,
Canada
One strategy to improve therapies in advanced prostate cancer involves targeting genes
that are activated by either androgen withdrawal or chemotherapy to delay or prevent the
emergence of the resistant of the AI phenotype. The strategy used in our laboratory is
based on the hypothesis that changes in apoptosis-associated gene expression after certain
apoptotic triggers alter the balance between cell death and survival and play critical roles in
tumor progression and drug resistance. Targeted inhibition of stress-associated increases in
gene expression precipitated by androgen withdrawal or chemotherapy may enhance
treatment-induced apoptosis and delay progression of HRPC. Proteins fulfilling these
criteria include antiapoptotic members of the Bcl-2 protein family, clusterin, Hsp27, and
IGFBP-2 and IGFBP-5. The purpose of this presentation is to review the rationale and
progress in using targeted gene therapies to enhance tumour cell death after androgen
withdrawal or taxane chemotherapy. Antisense oligonucleotides offer one approach to
target genes involved in cancer progression, especially those not amenable to small
molecule or antibody inhibition. Improved chemical modifications of the phosphorthioate
backbone enhance resistance to nuclease digestion, prolong tissue half-lives, and improve
scheduling. The current status and future directions of several ASO’s that have potential
clinical use in cancer will be reviewed. In particular, we will focus on the rationale, preclinical proof-of-principle and early clinical results of a second generation antisense
targeting the cytoprotcetive molecule, clusterin.
Also known as TRPM-2, or SGP-2, clusterin is associated with numerous tumors. In
human prostate cancer, clusterin levels are low or absent in most untreated hormone-naive
tissues, but increase significantly within weeks after hormone therapy. Because clusterin
binds to a wide variety of biological ligands, and is regulated by transcription factor HSF1
(heat shock factor 1), an emerging view suggests that clusterin functions similarly to heat
shock protein to chaperone and stabilize conformations of proteins at time of cell stress.
Indeed, clusterin is more potent than other HSP’s at inhibiting stress-induced protein
precipitation.
OGX-011 (OncoGeneX Technologies Inc.) is an ASO complementary to the clusterin
mRNA. OGX-011 incorporates a phosphorothioate backbone with 2nd-generation
chemistry in the form of 2’-O-Methoxytheyl modifications to the 4 bases on either end of
the 21-mer molecule. Such “gap-mer” modifications maintain the improved tissue
pharmacokinetic profile of the 2nd-generation chemistry but preserves high affinity for
target mRNA and recruitment of RNase H necessary for activity. In pre-clinical models,
OGX-011 improves the efficacy of chemotherapy, radiation, and androgen withdrawal by
inhibiting expression of clusterin and enhancing the apoptotic response and has a tissue half
life of > 1 week. OGX-011 recently completed two phase I trials given weekly as a single
agent or in combination with docetaxel. The single agent study has a unique design in that
patients with localized prostate cancer are treated with the OGX-011 prior to radical
prostatectomy. This permits assessment of clusterin expression and tissue concentrations in
prostate tumors from all patients, allowing determination of an optimal biologically
effective dose and tissue drug levels in addition to the usual parameters of toxicity. OGX011 was given by IV infusion over 2 hrs at a starting dose of 40mg on days 1, 3, 5, 8, 15,
22, and 29. Buserelin and flutamide were started on day 1. Prostatectomy was performed
16
day 30-36. 25 patients were enrolled to 6 cohorts with doses of OGX-011 up to 640mg
delivered. Toxicity was limited to grade 1 or 2, including fevers, rigors, fatigue and
transient AST and ALT elevations. Plasma PK analysis showed linear increases in AUC
and Cmax with a t1/2 of ~2 hrs. Prostate tissue concentrations of OGX-011 increased with
dose, and tissue concentrations associated with preclinical effect could be achieved. Dose
dependent decreases in prostate cancer cell clusterin expression were observed. At 640mg
dosing, clusterin mRNA was decreased to a mean of 8% (SD=4%) compared with lower
dose levels and historical controls as assessed by reverse transcription PCR of
microdissected cancer cells. By immuno-histochemistry, mean % cancer cells staining with
zero intensity for clusterin protein at 640mg dosing was 54% (SD=24%) compared with 215% for lower dose levels and historical controls. Clusterin levels were also suppressed
significantly in regional lymph tissues. This Phase I trial demonstrates that OGX-011 is
well tolerated and inhibits clusterin expression in prostate cancers. The phase II dose for
OGX-011 is 640mg based on pharmacokinetic parameters and target regulation results.
Phase II studies of OGX-011 in combination with hormone and chemotherapy are planned
in patients with prostate, breast and lung cancers.
Selected References.
Chi K, Gleave M, Klasa R, Bryce C, Murray N, D’Aloisio S, Lopes de Menezes D,
Tolcher A. A Phase I Dose Finding Study of Combined Treatment with an Antisense Bcl-2
Oligonucleotide (Genasense) and Mitoxantrone in Patients with Metastatic Androgen
Independent Prostate Cancer. Clin Cancer Res. 2001 Dec;7(12):3920-3927.
Gleave ME, Tolcher A, Miyake H, Beraldi E, and Goldie J. Progression to androgenindependence is delayed by antisense Bcl-2 oligodeoxynucleotides after castration in the
LNCaP prostate tumor model. Clin Cancer Res 5:2891-2898, 1999.
Gleave ME, Miyake H, Goldie J, Tolcher A. Use of antisense oligonucleotides to target
anti-apoptotic genes to enhance androgen- and chemo-sensitivity and delay androgenindependent progression in prostate cancer. Urology 54:36-46, 1999.
Kiyama S, Morrison K, Zellweger T, Akbari M, Cox M, Yu D, Miyake M, and Gleave
M. Castration-Induced Increases in Insulin-Like Growth Factor-Binding Protein-2
Promotes Proliferation of Androgen-Independent Human Prostate LNCaP Tumors. Cancer
Research 2003 1;63:3575-3584
Leung S, Miyake H, Jackson J, Burt H, And Gleave M. Polymeric micellar paclitaxel
phosphorylates Bcl-2 and induces apoptotic regression of androgen-independent LNCaP
prostate tumors. The Prostate 44: 156-63, 2000.
Miyake H, Tolcher A, Gleave ME. Antisense Bcl-2 oligodeoxynucleotides delay
progression to androgen-independence after castration in the androgen dependent Shionogi
tumor model. Cancer Res 59: 4030-4034, 1999.
Miyake H, Tolcher A, Gleave ME. Antisense Bcl-2 Oligodeoxynucleotides enhance
Taxol chemosensitivity and synergistically delays progression to androgen-independence
after castration in the androgen dependent Shionogi tumor model. J Natl Cancer Inst 92:3441, 2000.
17
Miyake H, Rennie P, Nelson C, Gleave ME. Testosterone-repressed prostate message-2
(TRPM-2) is an antiapoptotic gene that confers resistance to androgen ablation in prostate
cancer xenograft models. Cancer Res 60:170-76, 2000.
Miyake H, Chi K, Gleave ME. Antisense TRPM-2 oligodeoxynucleotides
chemosensitize human androgen-independent PC-3 prostate cancer cells both in vitro and in
vivo. Clinical Cancer Res 6:1655-63, 2000.
Miyake H, Rennie P, Nelson C, Gleave ME. Acquisition of chemoresistant phenotype
by overexpression of the antiapoptotic gene, testosterone-repressed prostate message-2
(TRPM-2), in prostate cancer xenograft models. Cancer Res 60:2547-54, 2000.
Miyake H, Pollak M, Nelson C, Gleave ME: Antisense insulin-like growth factor
binding protein-5 oligodeoxynucleotides inhibit progression to androgen-independence
after castration in the Shionogi tumor model via negative modulation of insulin-like growth
factor-I action. Cancer Research 60: 3058-64, 2000.
Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and Estramustine Compared
with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer. NEJM
351:1513-1520
Rocchi P, So A, Kojima S. Beraldi E, Fazli L Gleave ME. Heat Shock Protein 27
Increases after Androgen Ablation and Plays a Cytoprotective Role in Hormone Refractory
Prostate Cancer. Cancer Research, 2004 Sep 15;64(18):6595-602
So AI, Bowden M, Gleave M. Effect of time of castration and tumour volume on time
to androgen-independent recurrence in Shionogi tumours. BJU Int. 2004 Apr;93(6):845-50
Trougakos I, So A, Jansen B, Gleave M and Gonos ES. Silencing expression of the
Clusterin/Apolipoprotein J gene in human cancer cells using small interfering RNA induces
spontaneous apoptosis, reduced growth ability and cell sensitization to genotoxic and
oxidative stress. Cancer Research, 64:1834-42, 2004
Zellweger T, Miyake H, Monia B, Cooper S, Gleave M. Efficacy of antisense clusterin
oligonucleotides is improved in vitro and in vivo by incorporation of 2’-o-(2-methoxy)
ethyl chemistry. J Pharmacol Exp Ther. 298:934-40, 2001
18
Tomohiko Ichikawa, M.D., Ph.D.
1984
1989
1989-1991
1992-1997
2001-2004
2004-
M.D., School of Med. Chiba Univ.
Ph.D., School of Med. Chiba Univ.
Postdoctoral Fellow, Johns Hopkins Oncology Center
Assist. Prof. of Urol., School of Med., Chiba Univ.
Assoc. Prof. of Urol., Grad. Sch. of Med., Chiba University
Prof. and Chairman of Urol., Grad. Sch. of Med.,
Chiba Univ.
Specialty and Research Field of Interest
Basic research of prostate cancer, Molecular cytogenetics, Androgen receptor, Tumor
suppressor genes, Metastasis, Metastasis suppressor genes
Recent Selected Publications
1.
2.
3.
4.
5.
19
Kojima, S., Suzuki, H., Akakura, K., Shimbo, M., Ichikawa, T., Ito, H. (2004) Alternative antiandrogens to
treat prostate cancer relapse after initial hormone therapy. J. Urol., 171(2): 679-683.
Suzuki, H., Ueda, T., Ichikawa, T., Ito, H. Androgen receptor involvement in the progression of prostate
cancer. (2003) Endocr Relat Cancer, 10(2): 209-216.
Nihei, N., Kouprina, N., Larionov, V., Oshima, J., Martin, G.M., Ichikawa, T., Barrett, J.C. (2002)
Functional evidence for a metastasis suppressor gene for rat prostate cancer within a 60-kilobase region on
human chromosome 8p21-p12. Cancer Res., 62(2): 367-370.
Luu, H. H., Zagaja, G. P., Dubauskas, Z., Chen, S. L., Smith, R. C., Watabe, K., Ichikawa, Y., Ichikawa, T.,
Davis, E. M., Le Beau, M. M., and Rinker-Schaeffer, C. W. (1998) Identification of a novel metastasissuppressor region on human chormosome 12. Cancer Res., 58(16): 3561-3565.
Dong, J.-T., Lamb, P. W., Rinker-Schaeffer, C. W., Vukanovic, J., Ichikawa, T., Isaacs, J. T., and Barrett, J. C.
(1995) KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science,
268(12 May): 884-886.
(9) Hormone Treatment for Prostate Cancer : Current Issues and
Future Directions
Tomohiko Ichikawa, M.D. Ph.D., Hiroyoshi Suzuki, Takeshi Ueda
Akira Komiya, Takashi Imamoto, Satoko Kojima
Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
Since the first observation by Huggins and Hodges in 1941, hormonal therapy has been
the main option for advanced prostate cancer. Most prostate cancers are androgendependent and essentially respond to androgen ablation therapy. However, these tumors
eventually become androgen-independent and grow despite androgen ablation. At this
point, the options are limited and most of them are palliative. Therefore, it has been a major
issue to clarify the mechanism of the development of androgen-refractory prostate cancer.
Since the androgen receptor sequence was determined, numerous studies have been
performed and have shown that the androgen receptor plays a critical role in the
development of androgen-refractory prostate cancer. Recently, Chen et al found that an
increase in androgen receptor mRNA was the only change consistently associated with the
development of resistance to antiandrogen therapy. They have concluded that increased
levels of androgen receptor confer resistance to antiandrogens by amplifying signal output
from low levels of residual ligand, and by altering the normal response to antagonists.
According to the immunohistochemical analysis, most androgen-independent prostate
cancers still express androgen receptor protein, suggesting that androgen receptordependent signaling is important for the development of androgen-refractory prostate
cancer. As Debes and Tindall have shown recently, we divide mechanisms of the
development of androgen-refractory prostate cancer into two pathways, androgen receptordependent and -independent ones.
Table Mechanisms of androgen-refractory prostate cancer.
-------------------------------------------------------------------------------------Androgen receptor (AR)-dependent pathway
Amplification of AR
Mutations of AR
Deregulation of growth factors or cytokines (e.g., IGF1, IL-6)
AR coactivators
AR-independent pathway
Neuropeptides secreted by neuroendocrine cells
Overexpression of Bcl-2
Unknown mechanisms related with down-regulation of AR
(e.g., methylation of the promoter region of AR)
-------------------------------------------------------------------------------------Androgen-refractory prostate cancers with the androgen receptor-dependent pathway
could be treated by suppressing the androgen receptor activity, whereas those with the
androgen receptor-independent one would be no longer controlled by the same way. As
shown in the table, several possible mechanisms have been identified for the androgen
receptor-independent pathways. When more cell-survival pathways are defined, an
improvement in survival for patients could be achieved by developing the specific genetargeting therapies to interfere with those pathways.
References
1. Chen CD, et al. Nat Med 10: 33-39, 2004.
2. Debes JD and Tindall DJ. N Engl J Med 351: 1488-1490, 2004.
3. Suzuki H, et al. Endocr Relat Cancer, 10: 209-216, 2003.
20
Michael F. Clarke, M.D.
1977
M.D. Indiana University; Indianapolis, Indiana
1980
Clinical Associate, Medicine Branch, National
Cancer Institute, National Institutes of Health
1986
Assistant Professor, Internal Medicine, University of
Michigan
1992
Associate Professor, Internal Medicine, University of
Michigan
1998
Professor, Internal Medicine,University of Michigan
2003
Professor of Cell and Development Biology,
University of Michigan
Specialty and Research Field of Interest
Medical Oncology, Bone Marrow Transplantation. Stem Cell Biology, Cancer
Biology. Regulation of Self-Renewal, Cancer Stem Cells.
Recent Selected Publications
21
1.
Park, I, Klug, C., Kaijun, L., Jerabek, L., Linheng, Li, Nanamori, M., Neubig, R.R., Hood, L., Weissman, I.L.,
Clarke, M.F.. Molecular Cloning and Characterization of a Novel Regulator of G-Protein Signaling from
Mouse Hematopoietic stem Cells. J. Biol. Chem. 276: 915-928, 2001.
2.
Al-Hajj, M., Wicha, M, Morrison, S.J., Clarke, M.F. Prospective identification and characterization of a
tumorigenic breast cancer cell. PNAS 7:3983-8, April 1, 2003.
3.
Park, I, Qian, D., Kiel, M, Becker, M.W., Pihalja, M., Weissman, IL, Morrison, I.L. and Clarke, M.F. Bmi1 is
required for adult hematopoietic stem cell self renewal. Nature. 43:302-5, May 15, 2003.
4.
Molofsky A.V., Pardal R., Iwashita T., Park I-K., Clarke, M.D., Morrison S.J. Bmi-1 dependence
distinguishes neural stem cell self-renewal from restricted progenitor proliferation. Nature, 425(6961) 962-7,
Oct 2003.
5.
Al-Hajj M., Becker M.W., Wicha M., Weissman I., Clarke M.F. Therapeutic implications of cancer stem
cells. Current Opinion in Genetics & Development, 14:43-47, 2004.
(10) Self-Renewal and Cancer
Michael F. Clarke, M. D.
Professor of Medicine and Professor of Cell and Developmental Biology,
University of Michigan Medical School, Ann Arbor, MI 48109-0936, U.S.A.
Several aspects of stem cell biology are relevant to cancer. Common Cancers
arise in tissues that contain a large sub-population of proliferating cells that are
responsible for replenishing the short-lived mature cells. In such organs, cell
maturation is arranged in a hierarchy in which a rare population of stem cells give
rise to the mature cells. To do this, stem cells have 2 functions. First, they need to
self-renew in order to maintain the stem cell pool whose size is under strict genetic
regulation. Second, they must undergo differentiation to maintain a constant pool
of mature cells in normal conditions and to produce increased numbers of a
particular lineage in response to stresses.
By contrast, cancer cells have escaped this homeostatic regulation and the
number of cells within a tumor that have the ability to self renew is constantly
expanding, resulting in the inevitable growth of the tumor. Self-renewal is a cell
division in which one or both of the daughter cells remain undifferentiated and
retain the ability to give rise to another stem cell that has the same capacity to
proliferate as the parental cell. Proliferation does not require either daughter cell to
be a stem cell nor retain the ability to give rise to a differentiated progeny. A single
HSC can restore the blood system for life, but a progenitor cell is destined to
eventually stop proliferating. Thus, normal stem cells share with at least some of
the cancer cells within a tumor the ability to replicate without losing the capacity to
proliferate. Recently, tumorigenic and non-tumorigenic subsets of cancer cells have
been isolated from human breast cancer tumors, providing the first direct evidence
for cancer stem cells in solid tumors. To assay the tumorigenic cancer cells, a
xenograft model for human breast cancer was developed that allowed breast cancer
tumors isolated directly from patients to be passaged reliably in vivo. In this
model, only a subset of the breast cancer cells had the ability to form new tumors.
In cancer cells isolated from most patients' tumors, tumorigenic cells could be
distinguished from non-tumorigenic cancer cells based upon surface marker
expression. In eight out of nine patients, tumorigenic cells could be prospectively
identified and isolated by flow cytometry as CD44+CD24-/lowLineage- cells.
Limiting-dilution assays demonstrated that as few as one hundred tumorigenic
cancer cells were able to form tumors, while tens of thousands of the other
populations of cancer cells failed to form tumors in NOD/SCID mice. These
tumorigenic cells have been serially passaged, and each time cells within this
population generated new tumors containing additional CD44+CD24-/lowLineagetumorigenic cells as well as the phenotypically mixed populations of nontumorigenic cancer cells. Importantly, the phenotypic distribution of cells closely
resembled that of the original tumor. These data demonstrate the presence of a
hierarchy of cells within a breast cancer tumor in which only a fraction of the cells
have the ability to generate a new tumor which contains similar populations of
tumorigenic and non-tumorigenic cancer cells, suggesting that the tumorigenic
cells can both generate both populations of cells. Thus, tumorigenic breast cancer
cells from most tumors appear to exhibit the properties of cancer stem cells. Not
surprisingly, some oncogenes function to promote stem cell self-renewal.
Differences in self-renewal pathways between cancer stem cells and normal stem
cells might be exploited to more effectively treat cancer.
22
Maha Hussain, M.D., F.A.C.P.
1980
1983
1984
1986
1989
M.D., Baghdad University School of Medicine.
Int/Med and General Surgery training, United Kingdom.
Intern, Wayne State University, Dept of Int/Med, Detroit, Michigan.
Resident, Wayne State University, Dept of Int/Med, Detroit, Michigan.
Fellow, Dept of Int/Med, Div of Hem/Onc, Wayne State University School of
Medicine, Detroit, Michigan
Academic Appointments
1989
Assistant Professor, Dept of Int/Med, Division of Hematology/Oncology, Wayne State
University School of Medicine, Detroit, MI.
1996
Associate Professor of Medicine, Dept of Int/Med, Division of Hematology/Oncology,
Wayne State University.
1997
Joint Associate Professor of Oncology, Barbara Ann Karmanos Cancer Institute.
2001
Professor of Medicine and Oncology, Dept of Int/Med, Division of
Hematology/Oncology, Wayne State University and Barbara Ann Karmanos Cancer
Institute, Detroit, MI.
2002
Professor, Depts of Int/Med and Urology, Div of Hem/Onc, University of Michigan,
Ann Arbor, MI.
Hospital Appointments
1989
Staff Physician, Section of Hematology/Oncology, VA Medical Center, Detroit, MI.
1993
Chief, Section of Hematology/Oncology, VA Medical Center, Detroit, MI.
1997
Team Leader, Multidisciplinary GU Clinical Program, Barbara Ann Karmanos Cancer
Institute (KCI)
2002
Professor, Dept of Int/Med and Urology, University of Michigan, Ann Arbor,
Michigan
Specialty and Research Field of Interest
GU oncology particularly in the areas of Prostate, Bladder and Renal cancers.
Recent Selected Publications
23
1.
Vaishampayan U, Fontana J, Du W, Hussain M: An active regimen of weekly paclitaxel and estramustine in
metastatic androgen independent prostate cancer. Urology 69:1050-1054, 2002.
2.
Hussain M, Smith DC, El-Rayes BF, Du W, Vaishampayan U, Fontana Joseph, Sakr W, Wood D:
Neoadjuvant docetaxel and estramustine chemotherapy in high-risk/locally advanced prostate cancer. Urology
61:774-780, 2003.
3.
Tangen CM, Faulkner JR, Crawford ED, Hirano D, Thompson IM, Eisenberger M, Hussain M: Ten-years
survival in patients with metastatic prostate cancer. Clinical Prostate Cancer, (1):41-45, 2003.
4.
Barnholtz-Sloan JS, Severson RK, Vaishampayan U, Hussain M: Survival analysis of distant prostate cancer
by decade (1973-1997) in the Detroit Metropolitan Surveillance, Epidemiology and End Results (SEER)
Program registry: has outcome improved?. Cancer Causes Control. 2003 Sep;14(7):681-5.
5.
Petrylak DP, Tangen CM, Hussain M, Jones J, Taplin ME, Burch PA, Berry DL, Crawford ED: Docetaxel
and estramustine versus mitoxantrone and prednisone: Results of SWOG intergroup protocol 9916. N Engl J
Med ,351(15):1513-20, 2004.
(11) The Role of Chemotherapy in Advanced Prostate Cancer
Maha Hussain, M. D., F.A.C.P.
Professor, Medicine and Urology,
University of Michigan Comprehensive Cancer Center, U.S.A.
Prostate cancer is a heterogeneous disease characterized by a long natural history
relative to other tumors. It is the second leading cause of cancer death in the United
States. The primary cause of mortality is metastatic hormone refractory disease.
The role of systemic therapy, historically, for this stage of the disease has been only
palliative. However, recently newer chemotherapy agents, particularly docetaxel
based therapy has been shown via large, well conducted clinical trials to impact
survival, thus heralding a new chapter in the treatment of this disease.
Over the last decade various newer agents have emerged from the laboratory
based on a deeper understanding of the biology of hormone refractory prostate
cancer. The list of these agents is expanding. It includes cytotoxic chemotherapy
targeting the microtubules such as the epothilones, anti-angiogenesis agents
(bevacizumab, cilengitide, among others), anti-sense therapy (bcl-2 antisense
oligonucleotide, Genasense), endothelin receptor antagonists (atrasentan), and
vaccine therapies. Several of these agents are in phase II and pivotal phase III
trials.
While real progress has been made over the past decade, more effective
therapies are urgently needed in the clinic. Key to the continued progress is the
enrollment of prostate cancer patients worldwide to clinical trials.
24
Andrew D. Seidman, M.D.
1992-1995
1992-1995
1995-2000
1995-2000
1996-2001
2000-present
2001-present
Clinical Assistant Physician, Department of Medicine, Memorial
Hospital for Cancer and Allied Diseases, New York, New York
Clinical Assistant, Memorial Sloan-Kettering Cancer Center, New
York, New York 10021
Assistant Attending Physician, Breast Cancer Medicine Service,
Division of Solid Tumor Oncology, Department of Medicine,
Memorial Hospital for Cancer & Allied Diseases
Assistant Member, Memorial Sloan-Kettering Cancer Center, New
York, New York
Assistant Professor of Medicine, Cornell University Medical College,
New York, New York
Associate Attending Physician, Division of Solid Tumor
Oncology,Breast Cancer Medicine Service, Department of Medicine,
Memorial Hospital for Cancer and Allied Diseases
Associate Professor of Medicine, Department of Medicine, Joan and
Sanford I. Weill Medical College of Cornell University New York,
New York
Honors and Awards
Gay Stoddard Clark Memorial Award for Excellence and Compassionate Breast Cancer
Care, from the Susan G. Komen Breast Cancer Foundation, 2003
Outstanding Service Award, Cancer Care, Inc., 2003
Recent Selected Publications
25
1.
Dang CT, Dannenberg AJ, Subbaramaiah K, Dickler MN, Moasser MM, Seidman
AD, D'Andrea GM,
Theodoulou M, Panageas KS, Norton L, Hudis CA. Phase II study of celecoxib and trastuzumab in metastatic
breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin Cancer Res
10:4062-4067, 2004.
2.
Dang CT, D'Andrea G, Moynahan M, Dickler M, Seidman A, Fornier M, Robson M, Theodoulou M, Lake D,
Currie V, Hurria A, Panageas K, Norton L, Hudis C. Phase II study of dose-dense 5-flourouracil, epirubicin,
and cyclophosphamide (FEC) followed by alternating weekly paclitaxel and docetaxel in high-risk, 4 or more
node-positive breast cancer: Feasibility. Clin Cancer Res 10(17):5754-5761, 2004.
3.
Modi S, Seidman AD, Dickler M, Moasser M, D'Andrea GD, Moynahan ME, Menell J, Panageas KS, Tan L,
Norton L, Hudis CA. A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast
cancer. J Clin Oncol 2004 (submitted)
4.
Tripathy D, Seidman A, Hudis C, Keefe D, Pierri MK, Paton V, Lieberman G. Effect of cardiac dysfunction
on treatment outcomes in women receiving trastuzumab for HER2 overexpressing metastatic breast cancer.
Clin Breast Cancer 5(4): 293-298, 2004.
5.
Modi S, DiGiovanna MP, Lu Z, Moskowitz C, Panageas KS, Van Poznak C, Hudis CA, Norton L, Tan L,
Stern DF, Carter D, Seidman AD. Phosphorylated/activated HER2 as a marker of clinical resistance to single
agent taxane chemotherapy for metastatic breast cancer. Cancer Investigation 23(8): 2004 (accepted).
(12) Current Status of Dose-Dense Chemotherapy for Breast Cancer
Andrew D. Seidman, M.D.
Breast Cancer Medicine Service, Division of Solid Tumor Oncology, Department of Medicine,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, U.S.A.
Despite the judicious use of “state of the art” adjuvant chemotherapy regimens for early stage breast cancer,
the prognosis for patients presenting with extensive axillary lymph node involvement remains poor 1,2.
Nevertheless, systemic adjuvant chemotherapy remains a critical component in the eradication of occult
micrometastases, and cure. In an attempt to improve upon the efficacy of existing chemotherapy, a phase III
Intergroup trial led by the Cancer and Leukemia Group B (CALGB 9741) 3 was designed , which tested a
mathematical model of tumor growth based on the Norton-Simon hypothesis 4. This hypothesis, developed about
three decades ago, and the kinetic model derived from it, formed the basis for the concept of dose-density and
sequential therapy, both tested in CALGB 9741. This large, prospective, randomized study convincingly
demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose
size resulted in a significant improvement in disease-free and overall survival in patients with node-positive breast
cancer without increasing toxicity. This result is highly relevant, has immediate practical implication, and changes
the standard practice of breast cancer treatment in the adjuvant setting. Should we be surprised?
Growth Kinetics of Human Cancers
In considering the role of dose density, it is useful to revisit the concept of dose-intensity. Dose-intensity
describes body-size adjusted dose (mg/m2) divided by time (per week) 5. The most widely used method of
increasing dose-intensity is dose escalation (increase in dose size), which has been shown to be modestly
successful for certain drugs, in selected diseases, over some dose ranges 6. The total impact of therapy relates to
the log cell kill for each dose, the periodicity of drug administration and the rate of tumor re-growth between each
treatment. Thus, a fixed cell kill achieved at shorter time intervals should improve the overall impact of therapy, as
it would allow less time and opportunity for the emergence and proliferation of surviving, drug resistant cell
clones. This concept is termed dose-density 4.
Another strategy to improve upon the efficacy of chemotherapy employs sequential non-cross-resistant
regimens to optimize cytotoxicity in a heterogeneous group of tumor cells. An understanding of the importance of
sequential therapy requires revisitation of tumor cell growth kinetics. Human solid tumors do not exhibit an
exponential, but rather a Gompertzian growth pattern in which the doubling time is not constant but rather
increases with increasing tumor size, up to a certain mass/volume 7. Thus, surviving tumor cell re-growth after
sub-optimal therapy may be quite rapid after each cycle of therapy and therefore complete eradication of disease
may be difficult 8. The Skipper-Schabel-Wilcox model, also termed the log-kill model, was the first significant
proliferation model in clinical oncology 9. By this model, enough cycles of enough drugs at high enough
individual doses should be able to kill a high percentage, if not all, of the cells. Unfortunately, this has not been
clinically proven to be true for breast cancer. Since most tumors possess significant cellular heterogeneity, some
are likely to be slowly growing clones that are resistant to drugs used. An alternative model, the Norton-Simon
model, predicts that the best way to cure this heterogeneous mix of cells is to eradicate the numerically dominant,
faster-growing cells first, followed by eradication of the more slowly-growing, resistant cells 4. This is termed
sequential therapy, which has been proven to be clinically superior to alternating therapy 10.
Lessons from Adjuvant Chemotherapy Trial CALGB 9741 / INT C9741
CALGB 9741 was constructed to examine the concepts of dose-density and sequential therapy. In this trial
which enrolled 2005 women with node-positive breast cancer, patients were randomized to one of 4 treatment
arms: (I) sequential doxorubicin (A) x 4 → paclitaxel (P) x 4 → cyclophosphamide (C) x 4 conventionally every 3
weeks, (II) sequential A x 4 → P x 4 → C x 4 every 2 weeks with filgrastim, (III) AC x 4 → P x 4 every 3 weeks,
(IV) AC x 4 → P x 4 every 2 weeks with filgrastim. This trial used a 2 x 2 factorial design to answer 2 questions:
1) Is dose-dense superior to conventional chemotherapy? , and 2) Is sequential superior to concurrent combination
chemotherapy? This study was powered to detect a 33% difference in either disease-free (DFS) or overall survival
(OS). At a median follow-up of 36 months, 351 patients had relapsed or died, compared with 515 expected
treatment failures. The DFS was significantly prolonged for the dose-dense arms (II and IV) compared to the
conventional arms (I and III; risk ratio {RR}=0.74, p=0.010), and OS (RR=0.69, p=0.013). The 4-year DFS was
82% for dose-dense regimens and 75% for conventional regimens (95% CI, 73.7% to 76.2%). The 3-year OS was
92% (95% CI, 91.7% to 92.3%) in dose-dense arms and 90% in conventional arms (95% CI, 89.6% to 90.4%).
The differences between dose-dense and conventional regimens are expected to increase over time. There was no
difference in either DFS or OS between sequential and concurrent chemotherapy schedules. There was no
interaction between dose-density and sequence.
There was less frequent severe grade 4 granulocytopenia in those patients on dose-dense regimens vs
conventional regimens (6% vs 33%; p<0.0001). Overall only 3% of patients were hospitalized for febrile
neutropenia. Grade 3/4 emesis was more frequent in concurrent regimens than for sequential regimens (7 % vs 3
%, p=0.0002). About 13% of patients on dose-dense AC → P had at least one red blood cell transfusion vs none
in conventional, sequential A → P → C vs < 4% in other two arms (p=0.0002). Only a small percentage of the
26
patients required dose delay or reductions. The 3-year incidence of acute myelogenous leukemia or
myelodysplasia was 0.18%, and the incidence of leukemia was not influenced by filgrastim. A provocative
unexpected finding is that the dose-dense regimens were associated with a significantly reduced incidence of
contralateral breast cancer (0.3% vs 1.5%; p=0.0004). Overall, all treatment arms were well-tolerated 3.
The design of this trial allows one to draw strong conceptual conclusions. All patients received same number
of drugs at the same cumulative dose for each arm of the trial. The results are consistent with the mathematical
predictions that dose-dense chemotherapy would result in superior survival over conventional regimens. Also,
sequential therapy that preserves dose density maintains efficacy; there was no adverse impact of uncoupling A
from C (nor any benefit). This trial does not stand alone in support of the notion that dose-dense therapy is “ready
for prime time”.
Evidence from Other Trials Examining Dose Density
Green at al recently reported on the comparative efficacy of dose-dense weekly vs every 3-weekly paclitaxel
as neoadjuvant therapy in operable breast cancer at the M.D. Anderson Cancer Center ( followed by fluorouracil
/doxorubicin / cyclophosphamide, post-operatively). In this study the rate of pathologic complete response (pCR)
of weekly dose-dense paclitaxel was more than double that of 3-weekly paclitaxel (28.8% vs 13.6%; p<0.01) 11.
Untch et al demonstrated the superiority of neoadjuvant dose-dense, sequential epirubicin (E) → T every 2 weeks
with filgrastim to conventional 3-weekly ET in terms of pCR and breast conservation rate. However, in this trial
the concept of dose intensity and dose-density were blurred, as the dose-dense arm received higher cumulative
doses of chemotherapy than the 3-weekly arm 12. Thus, it is not clear that the biweekly treatment is this study is
purely superior based on dose-density alone.
Not all “dose-dense trials” have been viewed as confirmatory; however, upon closer inspection, not all trials
often cited as “dose-dense trials” are indeed “clean” tests of the concept of dose-density. Therasse et al reported
results of randomized phase III trial by European Organization for Research and Treatment of Cancer (EORTC) /
National Cancer Institute of Canada / Swiss Group for Clinical and Epidemiological Cancer Research comparing
standard CEF x 6 (oral cyclophosphamide days 1-14, E and F on days 1 and 8, every 28 days) to dose-intensified
biweekly EC x 6 with filgrastim (without 5-fluororuacil) as primary chemotherapy in locally advanced breast
cancer. This trial did not show therapeutic benefit of dose-dense EC over conventional CEF 13. However, the
interpretability of this trial as a dose of dose intensity or density is confounded by the design, in that the 2 arms
were not equal in terms of number of different drugs given (fluorouracil in one arm, not the other), or even
schedule and route of drug administration (cyclophosphamide). One can view this study with optimism in that
similar efficacy was achieved with both treatments but duration of treatment was half as long with dose-dense EC
without additional significant toxicity. Jackisch et al reported results of the Geparduo study of preoperative
chemotherapy comparing sequential 3-weekly AC x 4 → docetaxel (D) x 4 vs biweekly AD x 4. In this trial AC
→ D was superior to dose-dense AD in terms of clinical response rate, pCR, pathologic node-negativity rate, and
breast conservation rate. This again is not a pure test of dose density, given that patients in AC → D received an
additional drug (cyclophosphamide) and that the cumulative doses of A and D were higher than that of AD arm 14.
We await the results of multiple ongoing trials currently testing the concept of dose-density. The Eastern
Cooperative Group adjuvant trial 1199 is a large 4-arm, phase III study of 3-weekly AC x 4 → 3-weekly P x 4 vs
weekly P x 12, AC x 4 → 3-weekly D x 4 vs weekly D x 12. This study completed accrual in January 2002, and
will answer the question as to whether dose-dense weekly taxane is superior to conventionally administered
taxane. CALGB 9840 (n=585), which completed accrual in November 2003, and which will be reported upon at
the American Society of Clinical Oncology Meeting in 2004, has addressed this question as well for paclitaxel in
patients with metastatic disease. Of note, in this trial the weekly arms are both more dense and intense, though the
results of CALGB 9342 would suggest no advantage for paclitaxel dose intensity, at least with every 3 week
dosing). Finally, the National Cancer Institute of Canada MA.21 is currently comparing standard CEF x 6 vs AC x
4 → P x 4 vs biweekly EC x 6 → 3-weekly P x 4 15. Interestingly, only EC is dose-dense and results will reveal
whether there is any therapeutic benefit in accelerating part of a regimen.
Future Directions
Dose-dense trials have demonstrated that filgrastim-facilitated biweekly chemotherapy is feasible 16-18. Based
on the landmark results of C9741, many have adopted this strategy as a new standard of care. However,
appropriate caution should be applied in extrapolating this data to any / all regimens outside of a clinical trial
setting, as unanticipated toxicities may emerge. At Memorial Sloan-Kettering Cancer Center, and elsewhere,
feasibility trials are either planned or underway exploring dose-dense regimens examining other agents, for
example, docetaxel.
Instinctively, it is intuitive that patients would be willing to endure the minor inconvenience of filgrastim
administration to shorten duration of treatment and to gain therapeutically. Cost-effectiveness analysis for the
addition of filgrastim would be useful. With the availability of pegylated filgrastim (Neulasta, Amgen, Inc.,
Thousand Oaks, CA), a novel formulation that provides once-per-cycle dosing, as opposed to daily injection, it
will be important to explore its usage in biweekly regimens. At Memorial Sloan-Kettering Cancer Center, we
evaluated a regimen of dose-dense biweekly FEC100 x 6 → weekly alternating D and P x 18 high-risk (4 or more
positive-node) breast cancer patients, and found this particular approach to be not feasible, due to non-hematologic
toxicity21. We currently are exploring the feasibility of recycling optimal doses of EC and P at 10-11 day
("denser") intervals with filgrastim support.
In the current era of emerging rationally targeted therapeutics, combinations of “biologic therapy” with dosedense regimens to further improve on efficacy of adjuvant treatment are ongoing (e.g. NCCTG 9831) or planned.
It would seem prudent to allow the dose-dense use of AC in these trials (vide supra), given the survival benefit
27
observed in C9741.
Is dose-dense application of chemotherapy “ready for prime time”? Clearly the answer is yes. For all drugs in
all diseases? No. Does “the buck stop here”? Hardly. There is every expectation that integration of targeted
biologic therapies with optimally dosed and scheduled cytotoxic chemotherapy will lead to further incremental
improvement in the adjuvant therapy of breast cancer. Most immediately, ongoing trials offer promise that this
may be realized with agents such as trastuzumab and bevacizumab (Genentech, Inc., So. San Francisco, CA). A
new chapter has begun, one that seems to hold greater promise than the chapter of dose-intensity in breast cancer.
Ultimately, both the discovery of new agents, and the clarification of optimal scheduling and dosing will serve the
interests of patients with breast cancer maximally.
References:
1. Fisher B, Foster R, Gardner B, et al. Relation of positive axillary nodes to the prognosis of patients with
primary breast cancer. Cancer 52:1551-1557, 1983.
2. Saez RA, McGuire WL, Clark GM, et al. Prognostic factors in breast cancer. Sem Surg Oncol 5:102-110,
1989.
3. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled
and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of nodepositive primary breast cancer: first report of intergroup trial C9741/Cancer and Leukemia Group B Trial
9741. J Clin Oncol 2003.
4. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Res 70:163-169, 1986.
5. Hryniuk W, Levine MN. Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer.
J Clin Oncol 4:1162-1170, 1986 (abstract).
6. Wood W, Budman D, Korzun A, et al. Dose and dose intensity trial of adjuvant chemotherapy for stage II,
node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994.
7. Norton L. A Gompertzian model of human breast cancer growth. Cancer Res 48:7067-7071, 1988.
8. Gilewski T, Surbone A, Dang CT, Norton L. Cytokinetics, In Cancer Medicine 5th edition, Holland JF, Frei E,
Bast RC, et al, eds., Williams and Wilkins, Baltimore, 2000, p.491-519.
9. Skipper HE. Laboratory models: the historical perspective. Cancer Treat Rep 70:3, 1986.
10. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast
cancer with more tan three positive nodes. JAMA 273:542-547, 1995.
11. Green MC, Buzdar AU, Smith S, et al. Weekly paclitaxel followed by FAC as primary systemic
chemotherapy of operable breast cancer improves pathologic complete remission rates when compared to
every 3-week P therapy followed by FAC: Final results of a prospective phase III randomized trial. Proc Am
Soc Clin Oncol 21:35a, 2002 (abstr 135).
12. Untch M, Konecny G, Ditsch N, et al. Dose-dense sequential epirubicin-paclitaxel as preoperative treatment
of breast cancer: results of a randomized trial AGO study. Proc Am Clin Oncol 21:34a, 2002 (abstr 133).
13. Therasse P, Mauriac L, Jassem J, et al. Final results of a randomized phase III trial comparing
cyclophosphamide, epirubicin, and fluorouracil with dose-intensified epirubicin and cyclophosphamide plus
filgrastim in locally advanced breast cancer. A EORTC-NCIC-SAKK multicenter study. J Clin Oncol
21:843-850, 2003.
14. Jackisch C, Von Minckwitz G, Rabb G, et al. Primary endpoint analysis of the Geparduo-study-preoperative
chemotherapy (PCT) comparing dose-dense versus sequential Adriamycin/docetaxel combination in operable
breast cancer. Breast Cancer Res Treat 76:s50, 2002 (suppl, abstr 152).
15. Trudeau ME: Optimizing adjuvant breast cancer chemotherapy: Rationale for MA.21 study. Oncology 15:713, 2001 (suppl 7).
16. Hudis C, Seidman A, Baselga J, et al. Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide
for resectable high-risk breast cancer: feasibility and efficacy. J Clin Oncol 17:93-100, 1999.
17. Hudis C, Fornier M, Riccio L, et al. 5-year results of dose-intensive sequential adjuvant chemotherapy for
women with high-risk node-positive breast cancer: a phase II study. J Clin Oncol 17:1118-1126, 1999.
18. Fornier MN, Seidman AD, Theodoulou M, et al. Doxorubicin followed by sequential paclitaxel and
cyclophosphamide versus concurrent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized
trial of adjuvant dose-dense chemotherapy for women with node-positive primary breast cancer. Clin Cancer
Res 7:3934-3941, 2001.
19. Dang CT, Moynahan ME, Dickler MN, et al. Phase II study of dose-dense (DD) 5-fluorouracil, epirubicin, and
cyclophosphamide followed by alternating weekly paclitaxel (P) and docetaxel (D) in high-risk node-positive
(N+) breast cancer: Feasibility and efficacy. Proc Am Soc Clin Oncol 22:12a, 2003 (abstract 46).
28
Toshiaki Saeki, M.D., Ph.D.
1982
1988-1990
1989-1991:
M.D, Hiroshima Univ. School of Med.
Research associate, Hiroshima Univ.
Visiting Fellow National Cancer Institutes, Bethesda, MD,
and USA
1992-1993: Research associate, Hiroshima Univ.
1993-1999: Chief of Breast Unit, National Shikoku Cancer Center
1999-2001: Chief of Breast Unit, National Cancer Center Hospital
EAST
2001- 2003: Director, Department of Clinical Research, National
Shikoku Cancer Center
2003-present: Professor and Chairman, Department of Breast Oncology,
Saitama Medical School
Specialty and Research Field of Interest
Chemotherapy and endocrine therapy for breast cancer
Translational Research
Growth factors , Clinical Trials
Recent Selected Publications
29
1.
Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal
tumors.
Cancer Res 52:3467-3473, 1992.
2.
Localization of Estrone Sulfatase in Human Breast Carcinomas,
Breast Cancer 6:331-337, 1999
3.
A phase II study of S-1 in patients with metastatic breast cancer-Japanese trial by the S-1 Cooperative Study
Group, Breast Cancer Working Group.
Breast Cancer 11:194-202, 2004
4.
Phase I and pharmacokinetic study of KW-2170, a novel pyrazoloacridone compaund, in patients with
malignant tumors.Cancer Chemother Pharmacolo 54:459-468, 2004
5.
A Japanese phase I study of continuous oral capecitabine in patients with malignant solid tumors
Int. J. Clin Oncol (in press)
(13) Drug Resistance in the Chemotherapy for Breast Cancer
Toshiaki Saeki, M.D., Ph.D.,1) Takashi Tsuruo2)
1) Department of Breast Oncology, Saitama Medical School: 38 Morohongo, Moroyama-machi,
Iruma-gun, Saitama 350-0495, Japan
2) Institute of Molecular and Cellular Biosciences, The University of Tokyo
Multidrug resistance (MDR) is a big problem in the chemotherapy against to
various human malignancies. P-gp, encoded by MDR1 gene on the cell membrane
can bind and transport the antitumor drugs in an ATP-dependent manner. The
expression of MDR1 mRNA in tumors was associated with certain clinical drug
resistance. Since P-gp appeared to be involved in both acquired and intrinsic
(congenital) MDR in human cancers, P-gp could be an important target to improve
efficacy of chemotherapy. Recently we focused on a therapeutic approach to
reduce the drug resistance in the chemotherapy for breast cancer.
Tamoxifen(TAM) and toremifene(TOR), anti-estrogens, may possible moderate
the P-gp related drug resistance in vitro. Toremifene demonstrated synergistic
effect in combination with paclitaxel on various human breast cancer cell lines.
Furthermore synergistic effect was observed on a multi-drug resistant cell line.
This synergistic effect was more potent in combination with TOR than that was
TAM. Some cases, which demonstrated clinical benefits in the patients with
recurrent breast cancer, were reported. We conducted a pharmacokinetic study of
TOR and paclitaxel combination treatment for the patients who already received
paclitaxel monotherapy. Preliminary data will be presented.
Dofequidar fumarate (Dof) is a novel, orally active quinoline derivative that
reverses multidrug resistance. In the clinical study, we compared the efficacy and
tolerability of Dof plus cyclophosphamide (C), doxorubicin (A) and 5-FU therapy
(F) with CAF alone, in patients with advanced or recurrent breast cancer. In this
randomised, double-blind, placebo-controlled trial, all patients were treated with 6
cycles of CAF therapy. Patients received Dof (900 mg po) 30 minutes before A.
Primary endpoint was overall response rate (partial or complete response). In total,
221 patients were evaluable. Overall response rate was 42.6% for CAF alone vs.
53.1% for Dof + CAF. More than 10% response rate improved in the combination
of Dof + CAF, but was not statistically significant. However, Dof significantly
improved PFS in patients who were premenopausal (p=0.046), who had no prior
therapy (p<0.01) or patients with advanced (stage IV) primary tumour (p=0.017).
Treatment with Dof did not affect plasma concentration of A in patients. These
clinical studies indicate that Dof was well tolerated and displayed promising
efficacy in patients who had not received prior therapy.
30
Kazuto Nishio, M.D.
19861988-1990
1990-1992
1992-1996
199620022004-
M.D. Wakayama Medical School
Staff, Wakayama Medical School Hospital
Research Resident, Foundation for Promotion of Cancer
Research
Staff, National Cancer Center Research Institute
Head, Pharmacol Div, National Cancer Center
Research Institute
Head, Shien-Lab, National Cancer Center Hospital
Invited Professor, Proteome Center, Tokyo Medical
University
Specialty and Research Field of Interest
Molecular pharmacology, Molecular correlative study
MOA of anticancer drugs, Drug resistance, Molecular target drugs
Recent Selected Publications
31
1.
The role of DNA-microarray in translational cancer research. Curr. Pharmacogenomics in press
2.
Establishment of a human non-small cell lung cancer cell line resistant to gefitinib. Int. J. Cancer in press
3.
Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474.
Cancer Res. 64:9101-9104, 2004
4.
The translational study for lung cancer.
Lung Cancer 45:S16-S17, 2004
5.
Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib ('Iressa') and the DNA
topoisomeraseÖü inhibitor CPT-11 (Irinotecan) in human colorectal cancer cells.
Int. J. Cancer 108:464-472, 2004
(14) Preclinical and Molecular Correlative Study for EGFR-Specific
Tyrosine Kinase Inhibitors in Japan
Kazuto Nishio, M.D.
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan
The modes of action of tyrosine kinase inhibitors have been biologically
investigated, and the target molecules responsible for tumor growth and
angiogenesis have been clarified. Recently, mutations in EGFR tyrosine kinase in
human non-small cell lung carcinoma (NSCLC) and the hyper-responsiveness of
NSCLCs with this mutation to gefitinib were reported. A short, in-frame deletional
mutant (E746_A750del) is one of the major mutant forms of epidermal growth
factor receptor (EGFR) in Japan, and is a determinant for EGFR-specific tyrosine
kinase inhibitors like gefitinib and ZD6474. We investigated the biological and
pharmacological functions of this mutated EGFR to determine whether tumors with
a deletional-EGFR status are responsive to ligand stimulation, whether the mutated
EGFR is constitutively active, and whether the downstream intracellular signaling
pathway is altered. We concluded that the deletional EGFR (E746_A750del) is
constitutively active and that its downstream events are shifted to the AKT
pathway. In addition, a cell-free kinetic assay using mutant EGFR proteins
demonstrated a differential affinity to tyrosine kinase inhibitors among different
EGFR mutants. .
To demonstrate the proof-of-principle of cancer therapeutics based on tyrosine
kinase inhibitors, molecular correlative studies have been conducted using
established potential surrogate markers for tumor response and adverse events. The
main signaling pathway for anticancer agents including these tyrosine kinase
inhibitors was identified by pathway analysis of gene expression profiles and other
methods. These approaches could be used to identify the biomarkers for sensitivity
and resistance to target-based drugs.
32
Masakazu Toi, M.D., Ph.D.
1982
1988
1994
1996
199820032004-
M.D. Hiroshima University
Ph.D. Hiroshima University Hospital
Associate Director, Tokyo Metropolitan Komagome
Hospital, Cancer and
Infectious Diseases Center (TMCICK)
Director, Clinical Biochemistry Laboratory
Director, Director, Department of Surgery, TMCICK
Director, Department of Clinical Trials and Research,
TMCICK
Professor, Drug Delivery System Center, School of
Pharmacy,
Tokyo University of Science
Field of Interest
Breast Cancer, Angiogenesis, Molecular-targeting therapy
Recent Selected Publications
33
1.
Role of thymidine phosphorylase/PD-ECGF in cancer biology and treatment
Lancet Oncology (2005)
2.
Targeting of Nuclear Factor {kappa}B Pathways by
Dehydroxymethylepoxyquinomicin, a novel Inhibitor of breast carcinomas:
antitumor and antiangiogenic potential In vivo. Clinical Cancer Research (2005)
3.
Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2
and prognosis in breast cancer. British journal of Cancer (2005)
4.
Her2/neu Expression Predicts the Response to Anti-Aromatase Neoadjuvant Therapy
in Advanced Breast Cancer: Subgroup Analysis from CAAN Trial.
Clinical Cancer Research (2004)
5.
Dynamism of tumour vasculature in the early phase of cancer progression:
Outcomes from oesophageal cancer research. Lancet Oncology (2003)
(15) Trastuzumab : Updates and Issues
Masakazu Toi, M.D., Ph.D.
Division of Clinical Trials and Research, Komagome Hospital, Tokyo Metropolitan Cancer and
Infectious Disease Center, Tokyo, Japan
Trastuzumab has changed practice of breast cancer. It is considered as first-line
therapy in common for Her-2 positive metastatic breast cancer patients with lifethreatening diseases, and with hormone-refractory or -insensitive non-lifethreatening diseases. Since trastuzumab has been incorporated in common practice,
three-year survival rate of Her-2 positive metastatic breast cancer patients has
increased to 50%, which is a dramatic improvement as compared with the survival
outcome prior to trastuzumab. In addition, it was also turned out that trastuzumabcontaining treatment, in most of cases, combined with chemotherapy can drive the
survival advantage not only for the patients with non-life-threatening diseases but
also for those with life-threatening diseases. One common feature emerged from
clinical experiences is that response to trastuzumab is diverse and duration of
response is heterogeneous in the responders. Few clinical markers are available to
predict tumor response. Therefore, it is warranted to study about mechanisms of
therapeutic response and to develop novel biomarkers for prediction. Among many
approaches, we have focused upon protein-based assays, such as eTag technology,
that detect and quantitiate homo- and hetero-dimers of Her families as well as its
down-stream phosphoproteins. Preliminarily, the protein signature was able to
correctly differentiate patients with progressive vs. non-progressive disease on
trastuzumab-containing treatments. These novel diagnostics are validated currently
in clinical trials. For hormone-sensitive Her-2 positive cancers, trastuzumab might
be indicated with hormone therapy. In fact, in most of adjuvant clinical trials,
trastuzumab is used in combined with hormone therapies if tumor hormone
receptor status is positive. According to a translational research using primary
breast tumor samples treated by aromatase inhibitors in preoperative setting, it was
observed that Her-2 expression tended to be down-regulated by aromatase
inhibition, presumably through estrogen blockade, in Her-2 over-expressing
tumors, particularly in responders to the treatment. It was indicated therefore that
Her-2 status is never stable, even in gene-amplified cases, and it seems frequently
occur that Her-2 expression is changed by disease regression by treatments such as
hormone therapy. Recent updates and current issues on trastuzumab therapy will be
discussed.
34
Moshe Talpaz, M.D.
35
(16) Kimura Memorial Lecture
Moshe Talpaz, M.D.
36
37
BMS Award in 2005
‘BMS Award’ was first organized in 2005 in commemoration of the 20th
Anniversary of the Bristol-Myers Squibb Nagoya International Cancer Treatment
Symposium.
We are honored through this Award to support young novel researchers who bring
about a great advance in the progress of science that lead to the advanced cancer
treatments in the 21st century.
Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium
38
Shigehira Saji, M.D., Ph.D.
1992
1992-97
1997-99
1999
1999-01
20012003
2004-
M.D., Gifu Univ. School of Med.
Resident, Fellow, Tokyo Metropolitan Komagome Hp.
Depts. Biochemistry, Surgery II, Gifu Univ. School of
Med.
Div. Endocrinology, Saitama Cancer Center Research Inst.
Ph.D. Gifu Univ. Graduate School of Med.
Post-doc. Dept. Bioscience, Karolinska Institute.
(Stockholm, Sweden)
Assist. Director, Dept. Breast Surgery, Tokyo Metropolitan
Komagome Hp.
Medical Exchange Program, M.D. Anderson Cancer
Center, Breast Medical Oncology. (Houston, TX)
Assoc. Director, Depts. Clinical Trial and Research, Breast
Surgery, Tokyo Metropolitan Komagome Hp.
Specialty and Research Field of Interest
Development of novel endocrine therapy for breast cancer.
Biology of estrogen signaling in breast and other related organs. Steroid receptor
biology
Recent Selected Publications
The expression of oestrogen receptor (ER)-b and its variants, but not ERa, in adult human mammary fibroblasts.
J Mol Endocrinol. 33(1):35-50, 2004.
Estrogen receptor b in breast cancer.
Endocr Relat Cancer, 9(1):1-13, 2002.
Expression of Estrogen Receptor (ER) bcx Protein in ERa-positive Breast Cancer; Specific Correlation with
Progesterone Receptor
Cancer Res, 62(17):4849-4853, 2002.
Estrogen receptors and proliferation markers in primary and recurrent breast cancer.
Proc. Natl. Acad. Sci. USA, 98(26): 15197-15202, 2001.
Estrogen receptors a and b in the rodent mammary gland.
Proc. Natl. Acad. Sci. USA, 97 (1) : 337-342, 2000
39
BMS Award in 2005
Clinical Significance of Estrogen Receptor β in Breast Cancer
Shigehira Saji, M.D., Ph.D.
Associate Director, Departments of Clinical Trial and Research, Breast Surgery,
Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
Since the first evidence of the existence of protein binding to estradiol (E2) in
rat uterus discovered by E.V. Jensen in 1964, and cloning of estrogen receptor (ER)
in 1986, it has been thought that actions of estrogens are mediated through only
one estrogen receptor. Therefore, until the finding of second ER named ERβ from
rat prostate in 1996, we have been evaluated only first one, now called ERα, for
deciding the application of endocrine therapy to breast cancer patients. As a
consequence of accumulated data defining its specific function against ERα and
implication for breast cancer treatment, we are now trying to involve this newcomer
to clinical application.
Against ERα, ERβ has almost identical affinity for estradiol, and favorable
binding profile for genistein, one of the major phytoestrogens in soy. ERβ has
lesser transactivation function as compared with ERα, due to the difference in AF-1
domain. When ERβ acts as heterodimer partner of ERα, ERβ repress E2-depedent
transactivation function of ERα. Tethered to AP-1 or Sp1, ERα monomer exhibits
E2-dependent activation of transcription at AP-1 site, whereas ERβ monomer
quenches the activation by these factors.
From our studies and recent reports on breast cancer archive, we have gradually
understood the character of ERβ in the breast. ERβ has wide-distribution in
healthy mammary gland from pre-puberty to adult. In addition, although expression
of ERα is restricted to epithelial cells, ERβ is seen in stromal fibroblast,
endothelial and immuno related cells. During the carcinogenesis step from
hyperplasia to invasive cancer, expression of ERβ is generally decreased probably
due to silencing of promoter region by methylation. Still data is not conclusive,
expression of ERβ seems to positively correlate with expression of ERα, PR, and
moreover, with better prognosis.
From epidemiologic aspect, it would be important to note the data about
consumption of soy, where it has high impact on the prevention of breast and
colonic cancer incidence. Since expression of ERβ has been reported in widerange of normal mammary gland and intestinal tract, and ERβ has high affinity for
genistein, further research on the molecular basis of this observation should be first
priority subject.
40
Speakers & Chairpersons
Organizers
Scientific Program Committee
42
Speakers & Chairpersons
Yutaka Ariyoshi
Marumo Hospital
2-124-1 Hongo, Meitou-ku
Nagoya 465-0024, Japan
[email protected]
Hiroji Iwata
Aichi Cancer Center Hospital
1-1 Kanokoden, Chikusa-ku
Nagoya 464-8681, Japan
[email protected]
Michael F. Clarke
Associate Professor of Internal Medicine,
U-M Comprehensive Cancer Center
1500 E. Medical Center Drive
CCGC 6-303
Ann Arbor, MI 48109-0944, U.S.A.
[email protected]
Walter Jonat
Klinik fur Gynakologie und Geburtshilfe,
University of Kiel,
D-24105 Kiel, Germany
[email protected]
Martin E. Gleave
Vancouver Hospital and Health Sciences Centre
D9, 2733 Heather Street,
Vancouver, B.C.,
Canada V5Z 3J5
[email protected]
Shin-ichi Hayashi
Department of Molecular Medical Technology
School of Health Science, Faculty of Medicine,
Tohoku University,
Sendai 980-8575, Japan
[email protected]
Maha Hussain
University of Michigan
7314 CCGC
Cancer Center and Geriatrics Center
1500 East Medical Center Drive,
Ann Arbor, MI 48109-0946, U.S.A.
[email protected]
Tomohiko Ichikawa
Department of Urology
Graduate School of Medicine, Chiba University
1-8-1 Inohana, Chuo-ku,
Chiba 260-8670, Japan
[email protected]
Hirotaka Iwase
Kumamoto University
1-1-1 Honjo, Kumamoto City
Kumamoto 860-8556, Japan
[email protected]
43
Shigeaki Kato
Institute of Molecular and Cellular Biosciences,
The University of Tokyo,
Yayoi-cho, Bunkyo-ku,
Tokyo 113-0032, Japan
[email protected]
Junichi Kurebayashi
Department of Breast & Thyroid Surgery,
Kawasaki Medical School,
575 Matsushima, Kurashiki,
Okayama 701-0192, Japan
[email protected]
Hironobu Minami
National Cancer Center Hospital East
6-5-1 Kashiwanoha, Kashiwa
Chiba 277-8577, Japan
[email protected]
Tetsuya Mitsudomi
Department of Thoracic Surgery
Aichi Cancer Center Hospital
1-1 Kanokoden, Chikusa-ku
Nagoya 464-8681, Japan
[email protected]
Tomoki Naoe
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Hidehiko Saito
Nagoya Medical Center
4-1-1 Sannomaru, Naka-ku
Nagoya 460-0001, Japan
[email protected]
Shigehira Saji
Departments of Clinical Trial and Research,
Breast Surgery
Tokyo Metropolitan Komagome Hospital,
3-18-22 Honkomagome, Bunkyo-ku,
Tokyo 113-8677, Japan
[email protected]
Rachael Schiff
Baylor college of Medicine,
One Baylor Plaza,
Houston, TX 77030, U.S.A.
[email protected]
Andrew D. Seidman
Breast Cancer Medicine Service,
Memorial Sloan-Kettering Cancer Center,
1275 York Avenue, New York
New York, 10021, U.S.A.
[email protected]
Dennis C. Sgroi
Associate Professor of Pathology
Mass General Hospital
Building 149, 13th Street
Mol. Pathology Lab-7th fl.
Charlestown, MA 02129, U.S.A.
[email protected]
Takashi Takahashi
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Masakazu Toi
Division of Clinical Trials and Research,
Tokyo Metropolitan Komagome Hospital,
3-18-22 Honkomagome, Bunkyo-ku,
Tokyo 113-8677, Japan
[email protected]
Ryuzo Ueda
Department of Internal Medicine 2
Nagoya City University Medical School
1 Kawasumi, Kizuho-co, Mizuho-ku
Nagoya 467-8602, Japan
[email protected]
44
Organizers
Tatsuo Abe
Keihoku Hospital
Keihoku-cho,
Kyoto 601-0533, Japan
[email protected]
Masami Hirano
Faculty of Pharmacy
Meijo University
1-501 Shiogamaguchi, Tempaku-ku,
Nagoya 468-8502, Japan
Hideyuki Akaza
Department of Urology Institute of Clinical
Medicine, University of Tsukuba
1-1-1 Tennoudai, Tsukuba City
Ibaraki 305-8575, Japan
[email protected]
Tomomitsu Hotta
Tokai University School of Medicine
Bouseidai, Isehara City
Kanagawa 259-1193, Japan
[email protected]
Yutaka Ariyoshi
Marumo Hospital
2-124-1 Hongo, Meitou-ku,
Nagoya 465-0024, Japan
[email protected]
Shigetaka Asano
The Institute of Medical Science
The University of Tokyo
4-6-1 Shirokanedai, Minato-ku
Tokyo 108-8639, Japan
[email protected]
Kenji Eguchi
Tokai University School of Medicine
Bouseidai, Isehara City
Kanagawa 259-1193, Japan
[email protected]
Hiroshi Fujita
Tsurumi University School of Dental Medicine
2-1-3 Tsurumi, Tsurumi-ku
Yokohama 230-8501, Japan
Masahiro Fukuoka
Department of Internal Medicine 4
Kinki University School of Medicine
377-2 Ohno-Higashi
Osaka-Sayama 589-8511, Japan
[email protected]
Susumu Hibino
Nagoya Medical Center
4-1-1 Sannomaru, Naka-ku
Nagoya 460-0001, Japan
45
Yukio Inuyama
Department of Otorhinolaryngology
Hokkaido University School of Medicine
Nishi-5-chome, Kita-14-jyo, Kita-ku
Sapporo 060-8638, Japan
Hirotaka Iwase
Kumamoto University
1-1-1 Honjo, Kumamoto City
Kumamoto 860-8556, Japan
[email protected]
Ryunosuke Kanamaru
Funada Hospital
4 Hachiken Kohji, Minamikoizumi
Wakabayashi-ku, Sendai City
Sendai 984-0827, Japan
Toshihiko Kotake
Department of Urology
Osaka Medical Center for Cancer and
Cardiovascular Diseases
1-3-3 Nakamichi, Higashinari-ku
Osaka 537-8511, Japan
Michihiko Kuwano
Kurume University,
Research Center for
Innovative Cancer Therapy
67 Asahimachi, Kurume City
Fukuoka 830-0011, Japan
[email protected]
Tetsuya Mitsudomi
Department of Thoracic Surgery
Aichi Cancer Center Hospital
1-1 Kanokoden, Chikusa-ku
Nagoya 464-8681, Japan
[email protected]
Akimasa Nakao
Department of Surgery 2
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Nagahiro Saijo
Medical Oncology Division
National Cancer Center Hospital
5-1-1 Tsukiji, Chuo-ku
Tokyo 104-0045, Japan
[email protected]
Tomoki Naoe
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Hidehiko Saito
Nagoya Medical Center
4-1-1 Sannomaru, Naka-ku
Nagoya 460-0001, Japan
[email protected]
Hisanobu Niitani
Tokyo Cooperative Oncology Group
3-5-6 Kamiikedai, Ohta-ku
Tokyo 145-0064, Japan
[email protected]
Tatsuo Saito
Kyoundo Hospital
1-8 Kanda-Surugadai, Chiyoda-ku
Tokyo 101-0062, Japan
Yoshiro Niitsu
4th Department of Internal Medicine
Sapporo Medical University
Minami-1-chome, Nishi-17-jyo, Chuo-ku
Sapporo 060-8556, Japan
[email protected]
Yuh Sakata
Misawa City Hospital
4-1-2 Chuou-cho, Misawa City
Aomori 033-0001, Japan
[email protected]
Yuji Nimura
Department of Surgery 1
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Shiro Nozawa
Department of Obstetrics and Gynecology
Keio University School of Medicine
35 Shinano-machi,Shinjuku-ku
Tokyo 160-8582, Japan
[email protected]
Makoto Ogawa
Aichi Cancer Center Hospital
1-1 Kanokoden, Chikusa-ku
Nagoya 464-8681, Japan
Ryuzo Ohno
Aichi Cancer Center Hospital
1-1 Kanokoden, Chikusa-ku
Nagoya 464-8681, Japan
[email protected]
Yoshio Sakurai
Cancer Institute
Japanese Foundation for Cancer Research
1-37-1 Kami-Ikebukuro, Toshima-ku
Tokyo 170-0012, Japan
Tsuneo Sasaki
Department of Chemotherapy
Tokyo Metropolitan Komagome Hospital
3-18-2 Honkomagome, Bunkyo-ku
Tokyo 113-8677, Japan
[email protected]
Yasutsuna Sasaki
Saitama Medical School
38 Morohongo, Moroyama-machi, Iruma-gun
Saitama 350-0495, Japan
[email protected]
Hiroshi Shiku
Department of Internal Medicine 2
Mie University School of Medicine
2-174 Edobashi
Tsu 514-8507, Japan
[email protected]
46
Kaoru Shimokata
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Masanori Shimoyama
National Cancer Center Hospital
5-1-1 Tsukiji, Chuo-ku
Tokyo 104-0045, Japan
[email protected]
Tetsuo Taguchi
Japan Society for Cancer Chemotherapy
#505 Higobashi IP Building
1-18-35 Edobori, Nishi-ku
Osaka 550-0002, Japan
[email protected]
Tomoo Tajima
Department of Surgery
Tokai University Hospital
Bohseidai, Isehara
Kanagawa 259-1193, Japan
Toshitada Takahashi
Aichi Cancer Center Research Institute
1-1 Kanokoden, Chikusa-ku
Nagoya 464-8681, Japan
[email protected]
Shigeru Tsukagoshi
Tokyo Cooperative Oncology Group
Japanese Foundation for Cancer Research
Bancho-Heim 337, 2-bancho, Chiyoda-ku
Tokyo 102-0084, Japan
[email protected]
Mamoru Tsukuda
Yokohama City University
3-9 Fukuura, Kanazawa-ku
Yokohama 236-0004, Japan
[email protected]
47
Takashi Tsuruo
Institute of Molecular and Cellular Biosciences
The University of Tokyo
1-1-1 Yayoi, Bunkyo-ku
Tokyo 113-0032, Japan
[email protected]
Ryuzo Ueda
Department of Internal Medicine 2
Nagoya City University Medical School
1 Kawasumi, Mizuho-cho, Mizuho-ku
Nagoya 467-8602, Japan
[email protected]
Jun Yoshida
Department of Neurosurgery
Nagoya University Graduate School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Hiroyuki Yoshikawa
Institution of Obstetrios & Gynecology in Clinical
Medicine, University of Tsukuba
2-1-1 Amakubo, Tsukuba City
Ibaraki 305-8576, Japan
[email protected]
Scientific Program Committee
Keisuke Aiba
The Jikei University School of Medicine
3-25-8 Nishishinbashi, Minato-ku
Tokyo 105-8461, Japan
[email protected]
Yasuhiro Fujiwara
Section of Medical Oncology, National Cancer
Center Hospital
5-1-1 Tsukiji, Chuoh-ku
Tokyo 104-0045, Japan
[email protected]
Masanori Hatae
Kagoshima City Hospital
20-17 Kajiya-cho, Kagoshima City
Kagoshima 892-8580, Japan
[email protected]
Kiyohiko Hatake
Division of Clinical Chemotherapy, Department
of Internal Medicine, Cancer Institute Hospital,
Japanese Foundation for Cancer Research
1-37 Kamiikebukuro, Toshima-ku
Tokyo 170-8455, Japan
[email protected]
Shinsuke Iida
Nagoya City University Medical School
1 Kawasumi, Mizuho-cho, Mizuho-ku
Nagoya 467-8602, Japan
[email protected]
Kazuto Nishio
Pharmacology Division
National Cancer Center Research Institute
5-1-1 Tsukiji, Chuo-ku
Tokyo 104-0045, Japan
[email protected]
Atsushi Ohtsu
Division of Gastrointestinal
Oncology/Digestive Endoscopy
National Cancer Center Hospital East
6-5-1 Kashiwanoha, Kashiwa
Chiba 277-8577, Japan
[email protected]
Toshiaki Saeki
Saitama Medical School
38 Morohongo, Moroyama-machi, Iruma-gun
Saitama 350-0495, Japan
[email protected]
Hideo Saka
Nagoya Medical Hospital
4-1-1 Sannomaru, Naka-ku
Nagoya 460-0001, Japan
[email protected]
Kazuhito Yamamoto
Nagoya University School of Medicine
65 Tsuruma-cho, Showa-ku
Nagoya 466-8550, Japan
[email protected]
Hironobu Minami
National Cancer Center Hospital East
6-5-1 Kashiwanoha, Kashiwa
Chiba 277-8577, Japan
[email protected]
Kazuhiko Nakagawa
4th department of Internal Medicine
Kinki University School of Medicine
377-2 Ohno-Higashi, Osakasayama
Osaka 589-8511, Japan
[email protected]
Yoichi Nakanishi
Research Institute for Diseases of the Chest,
Graduate School of Medical Sciences
Kyushu University
3-1-1 Maidashi, Higashi-ku
Fukuoka 812-8582, Japan
[email protected]
48