Table Of ContentCurrent Human Cell Research and Applications
Series Editors: Nariyoshi Shinomiya · Hiroaki Kataoka
Yutaka Shimada
Yutaka Shimada
Katsuhiko Yanaga Editors
Molecular
Diagnosis and
Targeting for
Thoracic and
Gastrointestinal
Malignancy
Current Human Cell Research and Applications
Series Editors:
Nariyoshi Shinomiya
Department of Integrative Physiology and Bio-Nano Medicine
National Defense Medical College
Tokorozawa, Saitama
Japan
Hiroaki Kataoka
Department of Pathology
University of Miyazaki
Miyazaki, Japan
Yutaka Shimada
Department of Nanobio Drug Discovery
Kyoto University
Sakyo-ku, Kyoto
Japan
This series covers basic and clinical research on human cells, including molecular
diagnostics/targeted therapy, cell therapy, cancer stem cells, regenerative medicine,
etc., and provides an up-to-date review of human-cell research. All volumes are
contributed by leading experts in the field, and offer valuable resources for both cell
biologists and clinical researchers in the areas of oncology, stem cell biology,
regenerative medicine, and clinical medicine including gynecology, gastroenterology,
etc.
Current Human Cell Research and Applications will be published in partnership
with the Japan Human Cell Society.
More information about this series at http://www.springer.com/series/15107
Yutaka Shimada • Katsuhiko Yanaga
Editors
Molecular Diagnosis and
Targeting for Thoracic and
Gastrointestinal Malignancy
Editors
Yutaka Shimada Katsuhiko Yanaga
Department of Nanobio Drug Discovery Department of Surgery
Kyoto University Jikei University School of Medicine
Sakyo-ku, Kyoto Minato-ku, Tokyo
Japan Japan
ISSN 2522-073X ISSN 2522-0748 (electronic)
Current Human Cell Research and Applications
ISBN 978-981-10-6468-5 ISBN 978-981-10-6469-2 (eBook)
https://doi.org/10.1007/978-981-10-6469-2
Library of Congress Control Number: 2017960825
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Preface
Recent advances in molecular biology have resulted in the mechanisms responsible
for cancer progression being elucidated in detail, and molecular targeted drugs are
now used in the treatment of various malignant diseases. Analyses of the molecular
backgrounds of tumors are indispensable for the diagnosis and precise treatment of
cancer. However, tumor-specific and comprehensive mechanisms are involved in
these processes.
This book focuses on these issues and provides information from the viewpoint
of molecular biology and its clinical applications. The molecular mechanisms of
thoracic and gastrointestinal malignancies and their clinical applications are also
outlined. This book is primarily for clinical oncologists but is also relevant to basic
oncologists. It may also attract clinicians who have an interest in this field and are
considering the initiation of molecular diagnoses and targeted therapies.
Although several good textbooks are currently available on molecular diagnoses
and targeted therapies, our book places a strong emphasis on clinical applications
from the viewpoint of oncologists specializing in specific organs. Furthermore, we
focus on the role of molecular diagnoses and targeted therapies in the course of
surgical treatment.
We hope this book will provide timely and useful information to clinicians.
Kyoto, Japan Yutaka Shimada
Tokyo, Japan Katsuhiko Yanaga
v
Contents
1 Molecular Diagnosis and Targeting for Lung Cancer . . . . . . . . . . . . . 1
Kazue Yoneda and Fumihiro Tanaka
2 Molecular Diagnosis and Targeting Therapy
for Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Akira Tangoku, Takahiro Yoshida, Hirokazu Takechi, Masakazu
Okumua, Misako Nakagawa, Masami Morimoto, Takeshi Nishino,
Seiya Inoue, Toru Sawada, Mariko Aoyama, Naoki Miyamoto,
Kohei Nishioka, Keisuke Fujimoto, and Hiroaki Toba
3 Clinical Application of Stem Cell Biology
in Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Tomoyuki Okumura, Hirohumi Kojima, Tetsuji Yamaguchi, and
Yutaka Shimada
4 Molecular Diagnosis and Targeted Therapy for Gastric Cancer . . . . 63
Nobuhisa Matsuhashi, Kazuhiro Yoshida, Kazuya Yamaguchi, and
Toshiyuki Tanahashi
5 Colorectal Cancers Developed from Proximal and
Distal Tumor Location Belong to the Distinct Genetic
Entity and Show Different Oncologic Behavior . . . . . . . . . . . . . . . . . . 81
Nagahide Matsubara
6 Evolving Immunotherapy Approaches
for Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Ken Takahashi and Hiroyuki Marusawa
7 Molecular Diagnosis and Targeting of Biliary Tract Cancer . . . . . . . 111
Kazuhiro Hanazaki, Masaya Munekage, Hiroyuki Kitagawa,
Takuhiro Kosaki, Toshiji Saibara, and Tsutomu Namikawa
vii
viii Contents
8 Molecular Analysis for Therapeutic Targets of Pancreatic Cancer . . 127
Shinji Tanaka
9 Molecular Targeted Therapy for Gastroenteropancreatic
Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Izumi Komoto, Yohei Hosoda, and Masayuki Imamura
Chapter 1
Molecular Diagnosis and Targeting
for Lung Cancer
Kazue Yoneda and Fumihiro Tanaka
Abstract Lung cancer is the leading cause of cancer deaths associated with poor
prognosis. Patients with advanced lung cancer had been “uniformly” treated with
platinum-based cytotoxic chemotherapy, which had provided an only modest clini-
cal benefit. However, recent advances in molecular diagnosis and systemic treat-
ment targeting cancer hallmarks such as angiogenesis, oncogenic gene alteration,
and evasion from cancer immunity have dramatically changed treatment strategies
associated with a tremendous improvement in outcomes of lung cancer patients.
Here, we review current status and future perspectives of molecular diagnosis and
personalized “precision” medicine for lung cancer.
Keywords Angiogenesis • Oncogenic alteration • EGFR (epidermal growth factor
receptor) • ALK (anaplastic lymphoma kinase) • Immune checkpoint inhibitor
1.1 Introduction
Lung cancer is the leading cause of cancer-related death worldwide [1, 2]. Lung
cancer is classified into several histologic categories including four major subtypes
as follows: small cell lung cancer (SCLC, ~15%), squamous cell carcinoma (~25%),
adenocarcinoma (~50%), and large cell carcinoma (~10%). SCLC is biologically
and clinically distinct from other subtypes, as characterized by early lymphatic and
K. Yoneda • F. Tanaka (*)
Second Department of Surgery, University of Occupational and Environmental Health,
Fukuoka 807-0804, Japan
e-mail: [email protected]
© Springer Nature Singapore Pte Ltd. 2018 1
Y. Shimada, K. Yanaga (eds.), Molecular Diagnosis and Targeting for Thoracic
and Gastrointestinal Malignancy, Current Human Cell Research and
Applications, https://doi.org/10.1007/978-981-10-6469-2_1
2 K. Yoneda and F. Tanaka
distant metastatic spread as well as by higher responsiveness to cytotoxic chemo-
therapeutic agents [1, 3, 4]. The other histologic subtypes have been clinically cat-
egorized as a whole into non-small cell lung cancer (NSCLC), for which cytotoxic
agents provided an only modest clinical benefit [1].
The optimal treatment for the cure of cancer patients is surgical removal, but less
than 20% of lung cancer patients present with localized disease for which surgery
may be indicated. The majority of patients present with metastatic disease and are
treated with systemic treatment. During the last few decades, systemic chemother-
apy using cytotoxic agents, especially platinum-doublet chemotherapy consisting a
platinum agent (cisplatin or carboplatin) plus one non-platinum agent, has been
employed as the “standard care of treatment” and has provided an only modest sur-
vival benefit with the median overall survival (OS) of less than 2 years [1, 5–7].
However, recent discoveries of molecular hallmarks of cancer have changed our
understanding of lung cancer, especially NSCLC, as a single disease to a disease
comprising a variety of molecularly distinct subtypes, and novel agents targeting
various cancer hallmarks have provided a tremendous improvement in treatment out-
comes for NSCLC carrying specific targets [1, 8–13] (Table 1.1). Among them, the
Table 1.1 Overview of molecular targets and targeting agents for lung cancer
Agent
Name Target Class Approved indicationa
Angiogenesis inhibitors
Bevacizumab VEGF Humanized Non-squamous NSCLC
MoAb (IgG1) In combination with cytotoxic agents
Ramucirumab VEGFR-2 Fully human Previously treated NSCLC
MoAb (IgG1) In combination with DOC
Nintedanib VEGFR-1, TKI Adenocarcinoma, after first-line
VEGFR-2, chemotherapy
VEGFR-3
FGFR-1, In combination with DOC
FGFR-2,
FGFR-3
PDGFR-α, # approved only by EMA
PDGFR-β
Inhibitors for driver oncogenic alterations
Gefitinib EGFR TKI EGFR-mutated NSCLC
Erlotinib EGFR TKI EGFR-mutated NSCLC
Afatinib EGFR TKI EGFR-mutated NSCLC
Osimertinib EGFR TKI T790M-positive, EGFR-mutated
NSCLC, after treatment with
EGFR-TKI (gefitinib, erlotinib,
or afatinib)
Crizotinib ALK TKI ALK-rearranged NSCLC
Alectinib ALK TKI ALK-rearranged NSCLC
Ceritinib ALK TKI ALK-rearranged NSCLC, after
treatment with crizotinib
