Download Era of molecular targeted therapy for lung cancer: The

INTRODUCTION
• Lung cancer was considered a rare entity
until the mid 1930s when its incidence has
increased mainly due to the habit of
smoking
Lung Cancer
Mortality (male
population) in the USA
FEINSTEIN et al.
Epidemiology of lung
cancer. Chest Surg. Clin. N
Am., v. 10, n. 4, p. 653-661,
2000.
Câncer de Pulmão
Mortality rate (female
population) in the U.S.A
FEINSTEIN et al.
Epidemiology of lung cancer.
Chest Surg. Clin. N Am., v.
10, n. 4, p. 653-661, 2000.
Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of Economic Development, 2008. Source:
:
GLOBOCAN2008.Global Cancer Statistics72 CA
Airway - Organization
Fishman’s Pulmonary Diseases and Disorders 3rd e pp 24
Airway - Histology
Fishman’s Pulmonary Diseases and Disorders 3rd ed pp 25
Alveolar septum – M.E.
O2
CO2
From Weibel ER. In Fishman’s Pulmonary Diseases and Disorders 3rd e pp 25
Neoplasia
• Impact of molecular genetic alterations in the
cell cycle
– neoplasia = phenotypic expression=
accumulation of genetic changes over time in
cells
– Genetic Changes = uncontrolled cellular
proliferation by interfering with the cell cycle or
inhibition of programmed cell death (apoptosis).
Mutation Pro-growth
E
E
E
Inhalation of airway irritants
• Acute Changes
– Aggression covering
epithelium.
– Mucus secretion by
submucosal glands and
goblet cells
• Chronic Changes
– Squamous metaplasia
of the bronchial
columnar epithelium
– Acinar gland
hyperplasia
Smoking: Irritating, alteration of ciliary beating and mutagenic
Occupational agents and exposure
circumstances
WHO 2004
Chronic Bronchitis
Squamous metaplasia
Normal epithelium to cancer “in situ”
progression
Classification
• Even with advances in surgical treatment,
chemotherapy and radiotherapy, the
prognosis is considered bleak.
• In general, less than 15% of the patients
remain alive at 5 years.
Classification (WHO 2004)
-Non Small Cell Lung Carcinoma(*)
-Squamous Cell Carcinoma
Variants: Papillary, Clear Cell, Small cell, Basaloid
- Small cell carcinoma
Variants: Combined Small Cell Carcinoma
-Adenocarcinoma
Variants: Mixed Subtype, Acinar, Papillary, Solid, Fetal, Mucinosous (Colloid), Signet ring,
Cistadenocarcinoma Mucinoso, Clear cell
- Large Cell Carcinoma
Subtype: Combined Large Cell Carcinoma Neuroendocrine, Combined Large Cell
Carcinoma Neuroendocrine, Basaloid carcinoma, Clear cell carcinoma, Carcinoma
linfoepithelioma like carcinoma, Large cel carcinomna with rhabdoid fenotype.
- Bronquioloalveolar Adenocarinoma
Variants: Mucinous , Nonmucinous.
- Adenosquamous carcinoma
- Typical Carcinoid
- Atypical Carcinoid
- Sarcomatoid carcinoma
- Adenóid cystic carcinoma
- Mucoepidermoid carcinoma
-Others (Lymphomas, Metastatic tumors, Rare neoplasia)
Classification (IASLAC/ATS 2009)
-Non Small Cell Lung Carcinoma(*) avoid this term
-Squamous Cell Carcinoma
Variants: Papillary, Clear Cell, Small cell, Basaloid
- Small cell carcinoma
Variants: Combined Small Cell Carcinoma
-Adenocarcinoma
Variants: Mixed Subtype, Acinar, Papillary, Solid, Fetal, Mucinosous (Colloid), Signet ring,
Cistadenocarcinoma Mucinoso, Clear cell
- Large Cell Carcinoma
Subtype: Combined Large Cell Carcinoma Neuroendocrine, Combined Large Cell
Carcinoma Neuroendocrine, Basaloid carcinoma, Clear cell carcinoma, Carcinoma
linfoepithelioma like carcinoma, Large cel carcinomna with rhabdoid fenotype.
- Adenocarcinoma “in situ” (≤ 3,0cm) (AIS-formerly known as BAC)
Variants: Mucinous , Nonmucinous.
-MINIMALLY INVASIVE ADENOCARCINOMA (≤0.5cm)(MIA)
- Adenosquamous carcinoma
- Typical Carcinoid
- Atypical Carcinoid
- Sarcomatoid carcinoma
- Adenóid cystic carcinoma
- Mucoepidermoid carcinoma
-Others (Lymphomas, Metastatic tumors, Rare neoplasias)
• Because of this poor prognosis, the WHO used to
separates the two groups most comprehensive lung
cancer:
– 1) Small Cell Lung Carcinoma (SCLC) - 20%
– 2) Non Small Cell Lung Carcinoma (NSCLC) - 80%
• This has been established by different prognosis
and treatment among these entities and the
prognosis group SCLC worse than NSCLC.
Classification
• Currently we avoid using the term NSCLC
even in small biopsies.
• Due to improvements in treatment target
with specific drugs and the advent of
specific molecular markers, try define
ADENOCARCINOMA or SQCC even in
small specimens.
66yo, right upper
lobe mass,
Core biopsy
Negative IHQ for p63
Positive IHQ for TTF-1
Adenocarcinoma
74yo, left lower lobe
lobe mass,
Core biopsy
Positive IHQ for p63
Negative for TTF-1
Squamous Cell carcinoma
• http://cancergrace.org/lung/files/2010/08/his
tologybrhttp://cancergrace.org/lung/files/2010/08/
histology-breakdown-of-lungcancer.jpgeakdown-of-lung-cancer.jpg
ADENOCARCINOMAS
(40% of tumors)
• Adenocarcinoma is a cancer (malignant
neoplasm) that originates in glandular
tissue.
• To be classified as adenocarcinoma cells
need not necessarily be part of a gland, as
long as they have secretory patterns.
ATYPICAL ADENOMATOUS HIPERPLASIA (AAH)
SMALL AND LOCALIZED PROLIFERATION ≤ 0.5CM , NO INVASIVE COMPONENT
International Association for the Study of LungCancer/American Thoracic Society/EuropeanRespiratory Society International
Multidisciplinary Classification of Lung AdenocarcinomaWilliam D. Travis, MD, Elisabeth Brambilla, MD
ADENOCARCINOMA “ IN SITU” (AIS) NONMUCINOUS
FORMELY NONMUCINOUS BAC,AtYPICAL PROLIFERATION ≤3,0cm
ADENOCARCINOMA “ IN SITU” (AIS) MUCINOUS
FORMELY MUCINOUS BAC,AYPICAL PROLIFERATION ≤3,0cm
ADENOCARCINOMA MICROPAPILLARY
ADENOCARCINOMA MIXED SUBTYPE
ACINAR/LEIPDIC(AIS)
ADENOCARCINOMA SOLID
MOLECULAR FEATURES:
For adenocarcinomas:
1) EGFR MUTATIONS IS A PREDICTIVE FACTOR WITH
THE USE OF INHIBITORS EGFR (TKIs), FIRST LINETREATING EVEN IN AVANCED TUMORS
2) Tumors with EGFR mutation have a more indolent
course
3) EGFR and KRAS mutations are excludents.
The epidermal growth factor receptor (EGFR,
HER-1/ErbB1) is a receptor tyrosine kinase (TK)
EGFR mutation:
Women,
Never smokers
Asian
Non mucinosos
EGFR Mutation Is a Better Predictor of Response to
Tyrosine Kinase Inhibitors in Non–Small Cell Lung
Carcinoma Than FISH,
CISH, and Immunohistochemistry
PCR IS A GOLD STANDAERD
The PCR method is designed to detect the most
frequent EGFR mutations (exon 19
deletions and exon 21 L858R substitutions),
which account for 85% to 90% of reported
EGFR mutations.
Lung adenocarcinoma: guiding EGFR-targetedtherapy and beyond Marc Ladanyi and William Pao
Departments of Pathology and Medicine, and Human Oncology and Pathogenesis Program, Memorial
Sloan-Kettering Cancer Center, New York, NY, USA
ADENOCARCINOMA
EGFR mutation
positive
Treatment with anti
EGFR, gefitinib
Kras mutation
negative
ADENOCARCINOMA
EGFR mutation
negative
Traditional
chemotherapy
Kras mutation
Positive
or
Negative
ADENOCARCINOMA
EGFR mutation
Negative
EML4/ALK (5%)
Kras mutation
Negative
ADENOCARCINOMA
EML4/ALK
negative
EML4/ALK
Positive
Traditional
chemotherapy
ALK inhibitor therapy
crizotinib
FISH IS A GOLD STANDARD
Squamous cell carcinoma.
(30% of tumors)
Squamous cell carcinoma.
•
•
•
•
p63 gene is amplified in some cases
SOX2 gene is amplified
Seen in lung and esophagus
SOX2 expression is observed in progression
from dysplasia to carcinoma
Squamous cell carcinoma.
Sox 2
•Transcription factor important for large airway development
•Invitro SOX2 amplification upregulates p63
•May help maintain pluripotency, may allow for squamous
differentiation.
These discoveries have ushered in a new era of targeted
therapeutic agents for patients with Squamous Cell
Carcinoma.
Lung cancer genomics –Gene expression profiling and lung cancer classificationAlain Borczuk, MDColumbia University
Medical Center
Small Cell Carcinoma
(15% of tmors)
Tumores Neuroendócrinos
• Small Cell Carcinoma (SCLC)
• Large Cell Neuroendocrine Carcinoma (LCNEC).
• Atypical carcinoid (AT)
• Typic carcinoid
(TC)
TC 99% sobrevida
AC 75% sobrevida
AFIP, 1995
Histogenesis of Neuroendocrine
Tumors
• There are normal neuroendocrine cells in
the airways.
• Various stimuli can occur for Ne cell
hyperplasia.
• Diffuse neuroendocrine cell hyperplasia is a
rare entity and recognized as a preneoplastic lesions.
Tumores neuroendócrinos
histogênese
• Under-representation of chromosome 11q
(MEN1 gene) by 50% and 70% of TC CA..
• P53 shows no mutation in TC
• Aberrant p53 is present in rare cases of AC.
• Other tumor suppressor genes are rare in
TCs.
Classification of neuroendocrine tumors
Feyter
1938
Órgão Epitelial Endócrino Difuso
Fröhlich
1949
Células Claras- na Mucosa Brônquica
Hamperl
1952
Células K-Kulschitsky
Bench
1968
Grânulos Ne-ME
Corrin
1968
TC, SCLC
Arrigone
1972
TC, AC, SCLC
WHO
1982
TC,AC,SCLC, GCelAnaplas
Capelozzi
1986
TC, AC, SCLC, LCC com
Diferenciação NE-IHQ e ME
Travis
1991
TC,AC,SCLC,LCC,LCNEC
WHO
1999/
2004
TC,AC,SCLC,LCC,LCNEC,
(LCCNM*)
Carcinoma Pequenas Células
Capelozzi VL & Sheppard MN. Morphometric characterization of typical carcinoid, atypical carcinoid, large cell NE
carcinoma and small cell carcinoma based on ultrastructural and sterological procedure. Chest 106: 90S, 1994
Carcinóide Atípico
Capelozzi VL & Sheppard MN. Morphometric characterization of typical carcinoid, atypical carcinoid, large cell NE
carcinoma and small cell carcinoma based on ultrastructural and sterological procedure. Chest 106: 90S, 1994
Carcinoma Grandes Células Neuroendócrino
Capelozzi VL & Sheppard MN. Morphometric characterization of typical carcinoid, atypical carcinoid, large cell NE
carcinoma and small cell carcinoma based on ultrastructural and sterological procedure. Chest 106: 90S, 1994
Classificação dos Carcinomas de Grandes
Células (LCC)
• 1.3.4-Large Cell Carcinoma (LCC)
– 1.3.4.1-Large Cell Neuroendocrine Carcinoma
– 1.3.4.1.1-Combined Large Cell Neuroendocrine
Carcinoma.
– 1.3.4.2 -Basaloid Carcinoma
– 1.3.4.3-Lymphoepithelioma like Carcinoma.
– 1.3.4.4-Clear Cell Carcinoma
– 1.3.4.5-Large Cell Carcinoma with Rhabdoid
Phenotype.
WHO ,4th Ed,Geneva ,Switzerland,2004.
HE 200X
LCNEC HE 400X
Imunohistoquímica Cromogranina 200X
Molecular profile of LCC
• •Large cell carcinoma –EGFR mutation
6%–KRAS mutations 16%
• TrkB and its ligand brain-derived neurotrophic factor (BDNF) in
clinical specimens and their influences on phenotypes of invasiveness
and tumorigenicity for LCNEC.
• In particular, LCNEC, a subtype of NET, exhibited significantly higher
TrkB and BDNF expressions than another NET type: small cell lung
cancer (SCLC).
• Significant correlation between TrkB and BDNF expressions was
noted in LCNEC but not in SCLC.
Odate S, Nakamura K, Onishi H, Kojima M, Uchiyama A, Nakano K, Kato M, Tanaka
M, Katano M. TrkB/BDNF signaling pathway is a potential therapeutic target for
pulmonary large cell neuroendocrine carcinoma. Lung Cancer. 2013
Mar;79(3):205-14. doi: 10.1016/j.lungcan.2012.12.004. Epub 2013 Jan 9. PubMed
PMID: 23312550.
Survival
IPX DIAGNOSTIC
Small biopsy
Sclc
Cromogranin A
Positive 50%
Adenocarcinomas
Squamos Ceell
Rare Positive
Negative
5%
TTF-1
Positive 94%
Positive 63%
Rare Positive (10%)
CEA-monoclonal
Positive 39%
Positive 86%
Negative
P63
Negative
Negative
Positive 98%
Mucicarmin
Negative
Positive
Negative
IPX DIAGNOSTIC
AE1 / E3
TTF-1
Ber-EP4
p63
34BE12
(Ck alto
PM)
35BH11
(Ck baixo
PM)
Cromogra
nina A
Mucicarmi
m*
LCC
96%
75%
9%
0
17%
23%
0
-
Adenocarci
noma
100%
73%
92%
0
57%
99%
5%
+
Squamous
Cell
100%
4%
3%
90%
96%
7%
0
-
LCNEC
96%
75%
9%
0
15%
23%
67%
-
NATURAL HISTORY