Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Umrs 1138, Paris Descartes 5 University, Paris/France, 4 Department of Pathology,
Hopital Européen Georges-Pompidou AP-HP and Inserm U 970, Team 10, Paris
Descartes 5 University, Paris/France, 5 Department of Biopathology, Hôpital Bichat-
Claude Bernard, AP-HP, and Faculté de Médecine, Université Paris Diderot, Inserm
Umr 1152, Paris/France, 6 Biopathology, Cancer Institute Léon Bérard, Lyon/France,
7 Department of Biopathology, Centre Jean Perrin, Clermont-Ferrand, France, Ea
4677 “Ertica”, University of Auvergne, Clermont-Ferrand/France
This abstract is under embargo until December 7, 2016 at 07:00 CET.
SESSION PL05: CLOSING PLENARY SESSION: A LIFE IN THO-
RACIC ONCOLOGY - REFLECTIONS FROM GIANTS ON MILES-
TONES IN THE TREATMENT ADVANCES IN LUNG CANCER
WEDNESDAY, DECEMBER 7, 2016 - 16:00-18:00
PL05.01 PATHOLOGY
Adi Gazdar
Hamon Center for Therapeutic Oncology Research, University of Texas
Southwestern Medical Center, Dallas/TX/United States of America
While many regard a pathologist as a physician involved in laboratory
diagnosis, by definition Pathology is the science or the study of the origin,
nature and course of diseases. This broader definition of pathology, which
basically encompasses all of the study of medicine, is what first attracted me
to the field. After my residency I joined the NCI as a research pathologist
studying viral oncology in rodents. However a few years later John Minna gave
me the opportunity to return to the study of human cancer when he was
appointed the head of the NCI-VA Medical Oncology Branch in Washington,
DC, with a focus on lung cancer therapy. Our branch was fortunate to have an
outstanding lung pathologist, Mary Matthews who taught me most of what I
know about lung pathology. Mary also had a profound effect on the
understanding and treatment of lung cancer. In 1973 she established that
small cell lung cancer (SCLC) was almost always metastatic at the time of
diagnosis, and that surgery was unlikely to be curative. 1 These observations,
plus the finding that SCLC showed initial responses to the therapy then
currently available, helped establish the fundamental distinction of lung
cancers into SCLC and NSCLC categories. The Mary Matthew award for
Pathology and Translational Research is one of the distinguished awards of
the IASLC and I was fortunate and honored to be the fourth recipient in 2003.
John Minna assembled an outstanding group of physicians/scientist many of
whom became pioneers in the field of lung cancer. Of interest, all three past
and present Chief Executive Officers of the IASLC, Heine Hansen, Paul Bunn
and Fred Hirsch, spent time at the NCI-VA Medical Oncology Branch. John
preached that new approaches for the therapy of lung cancer were needed,
that this would require understanding biology, and to understand biology we
needed preclinical models. My job was to establish such models and help
“translate” them into clinical care. By the early 1980s we had established and
characterized large banks of SCLC cell lines and demonstrated that they
expressed the entire neuroendocrine (NE) cell program. 2 The cell lines were
widely distributed to the scientific community, and in the absence of reliable
tumor tissue sources, became the major source of biologic and molecular
knowledge of SCLC. Within that decade our group, largely from the use of cell
lines, described chromosome 3p loss, MYC family amplification, RB1 and TP53
loss as being characteristics of SCLC and also discovered the MYCL oncogene.
The NCI-VA Medical Oncology Branch later relocated to the Bethesda Naval
Hospital, MD. In 1991, John Minna accepted a position at the University of
Texas Southwestern Medical Center, Dallas, and I was his first recruitment.
Thus, during my long career I have only had two employers! I believe this
continuity has helped establish strong, long term collaborations and boosted
overall productivity. One of the interests of Mary Matthews and me was the
heterogeneity of SCLC. It became obvious to us that the so-called oat cell
variant was an ischemic artifact. However we were intrigued by the plasticity
of SCLC, with a substantial percentage of cases having abnormal (“variant”)
morphologies or combined with NSCLC elements, especially after therapy. 3
The variant morphology and its relationship to NEUROD1 as the driver
transcription factor (as opposed to ASCL1 as the driver in typical or “classic”
SCLC) has recently been highlighted. 4 By the mid 1980s, advances in SCLC
biology and therapy had hit a stonewall, and funding dried up. It was time to
move onto NSCLC! We established a large collection of NSCLC cell lines and
these also formed much of the basis of our understanding of this disease,
although tumor tissues were much more readily available. While cell lines have
their pluses and minuses, they are excellent for identifying driver mutations
and testing targeted therapies. They contributed to the identification of the
role of EGFR mutations in lung cancer. 5, 6 Soon after this discovery we used our
international fellows and contacts to perform the first large multinational
study of geographic and ethnic variations in mutation frequencies, and also
demonstrated that mutations were largely absent in tumors other than
NSCLC. 7 The advent of Precision Medicine has highlighted the crucial role of
the pathologist. Instead of the image of a pathologist looking at microscope
slides in isolation in a basement office, he or she plays a crucial role as an
integral part of the diagnostic and therapeutic team involved in every aspect
of patient management. The pathologist assumes further responsibilities
such as tissue procurement and optimal utilization, triaging scant resources
for clinical trial requirements, involvement in molecular testing, performing
requested or required immunostaining, establishing tissue repositories etc.
Previously clinical decision making required the pathologist only to make a
diagnosis of SCLC or NSCLC. Precision Medicine has highlighted the
importance of accurate classification of NSCLC. Classification is required for
mutation testing, therapy selection (or exclusion) and entry onto histology
dependent clinical trials. While the introduction of immunostains has greatly
facilitated the classification of poorly differentiated NSCLC, the SEER
database indicates that up to 14% of NSCLC may remain unclassified
throughout the USA. For these reasons we developed a molecular classifier for
NSCLC that can be applied to formalin fixed paraffin embedded (FFPE)
materials and small core biopsies. 8 The assay is highly accurate and
quantitative, and also provides information on grading and survival. While
SCLC languished for three decades, its recent designation as a recalcitrant
cancer by the US Congress has resulted in a dramatic resurrection of interest,
funding and achievement. 9 This has highlighted the importance of preclinical
models for SCLC. 10, 11 I feel very humbled and privileged to have lived through
and contributed to the seminal advances in our understanding of the biology
and therapy of lung cancer. This would not have been possible without the
many wonderful and talented people I have worked with. I am reminded of the
quote of Isaac Newton: “If I have seen further than others, it is because I have
stood on the shoulders of giants”.References
1. Matthews MJ, Kanhouwa S, Pickren J, et al. Frequency of residual and
metastatic tumor in patients undergoing curative surgical resection for lung
cancer. Cancer chemotherapy reports Part 3 1973;4:63-67.
2. Gazdar AF, Carney DN, Russell EK, et al. Establishment of continuous,
clonable cultures of small-cell carcinoma of lung which have amine precursor
uptake and decarboxylation cell properties. Cancer Res 1980;40:3502-3507.
3. Gazdar AF, Carney DN, Nau MM, et al. Characterization of variant subclasses
of cell lines derived from small cell lung cancer having distinctive biochemical,
morphological, and growth properties. Cancer Res 1985;45:2924-2930.
4. Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEUROD1 Reveal
Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct
Genetic Programs. Cell reports 2016;16:1259-1272.
5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation
with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
6. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor
mutations in lung cancer. Nat Rev Cancer 2007;7:169-181.
7. Shigematsu S, Lin L, Takahashi T, et al. Clinical and biological features
associated with Epidermal Growth Factor Receptor gene mutations in lung
cancers. J Natl Cancer Inst 2005;97:339-346.
8. Girard L, Rodriguez-Canales J, Behrens C, et al. An Expression Signature as
an Aid to the Histologic Classification of Non-Small Cell Lung Cancer. Clin
Cancer Res 2016.
9. Gazdar AF, Minna JD. Developing New, Rational Therapies for Recalcitrant
Small Cell Lung Cancer. J Natl Cancer Inst 2016;108.
10. Gazdar AF, Hirsch FR, Minna JD. From Mice to Men and Back: An
Assessment of Preclinical Model Systems for the Study of Lung Cancers. J
Thorac Oncol 2016;11:287-299.
11. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of
genetically engineered mouse models for neuroendocrine carcinomas of the
lung. J Thorac Oncol 2015;10:553-564.
Keywords: Molecular biology, Translational medicine, Pathology, lung cancer
PL05: CLOSING PLENARY SESSION: A LIFE IN THORACIC ONCOLOGY - REFLECTIONS FROM
GIANTS ON MILESTONES IN THE TREATMENT ADVANCES IN LUNG CANCER
WEDNESDAY, DECEMBER 7, 2016 - 16:00-18:00
PL05.02 SURGERY
Peter Goldstraw]
Academic Department of Thoracic Surgery, National Heart and Lung Institute,
Imperial College, Dartmouth/United Kingdom
The speaker began his training in Cardiothoracic surgery in 1973 and was
appointed as a Consultant in 1979. He will introduce this topic by describing
a typical case undergoing surgical treatment for lung cancer in the 1970s,
the patient journey and outcomes at that time. From that basis he will detail
the changes in the surgical treatment of lung cancer in the last 40 years. This
will include: · Changes in the epidemiology of lung cancer. · Improvements
in pre-operative selection. · Improvements in the staging process prior to
surgery, during surgery and post-surgery. · Differences in surgical approach
and the anatomical extent of resection. · Changes in the stage classification
over that period. · The establishment of effective adjuvant therapy. ·
Improved outcomes in morbidity, mortality and survivorship. None of these
improvements has been of itself a game changer but collectively they amount
Copyright © 2016 by the International Association for the Study of Lung Cancer
S5