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Adenocarcinoma of the lung: a molecular perspective. Rolf Stahel Zürich, Switzerland. Lugano, 8.7.07. Morpholgical classification of lung cancer. Small cell lung cancer (15%) Non-small cell lung cancer (85%) Squamous cell carcinoma Adenocarcinoma Bronchoalveolar carcinoma

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adenocarcinoma of the lung a molecular perspective

Adenocarcinoma of the lung:a molecular perspective

Rolf Stahel

Zürich, Switzerland

Lugano, 8.7.07

morpholgical classification of lung cancer
Morpholgical classification of lung cancer
  • Small cell lung cancer (15%)
  • Non-small cell lung cancer (85%)
    • Squamous cell carcinoma
    • Adenocarcinoma
      • Bronchoalveolar carcinoma
    • Large cell carcinoma
    • Rarer entities
changing distribution of lung cancer histology u texas galvaston
Changing distribution of lung cancer histology (U Texas Galvaston)

Mary Wahbah, Ann Dign Pathol, 2007

oncogene mutations lung adenocarcinoma
Oncogene mutations lung adenocarcinoma
  • About 50% of lung adenocarcinoma harbor somatic mutations of six genes that encode proteins in the EGFR signaling pathway:
    • KRAS mutations
    • EGFR mutations
    • Her-2 mutations
    • Her-4 mutations
    • BRAF mutations
    • Phosphatidylinositol 3-kinase (PI3K) mutations
egfr downstream signaling
EGFR: downstream signaling

EGFR, HER2

Cell membrane

SOS

EGFR-TK

RAS

ATP

ATP

PI3K

GRB2

RAF

P

MAPK

Akt

STAT

MEK

EGFR-TKpathways

Gene transcriptioncell-cycle progression

Nucleus

Proliferation

Resistance to

apoptosis

Invasion

Metastasis

Angiogenesis

ras mutations
Ras mutations
  • 1979-1981: Cloning of H-ras and K-ras
  • 1987: Rodenhuis, NEJM 1990: Slebos, NEJM: K-ras mutation in 30% of lung adenocarcinoma. Associaton with smoking. Poor prognostic factor in resected tumors
  • 1989-1990:Isoprenylation (farnesyl-tranferase) necessary for biological activity
ras mutation in nsclc
RAS mutation in NSCLC
  • Induction of lung adenocarcinoma in the mouse model by conditional activation of mutated KRAS (Meuwissen, Oncogene 2001)
  • Meta-analysis of 23 clinical studies with mutational data: HR 1.4 (CI 1.18-1.65)(Mascaux, Br J Cancer 2005)
  • Adjuvant cisplatin/vinorelbine subgroup analysis according to ras mutation: No apparent benefit in patients with ras mutated tumors (however not significant in interaction analysis)(Winton, NEJM 2005)
  • Lack of sensitivity of K-ras mutated tumors to gefitinib or erlotinib(Pao, PLoS 2005)
slide8

Gefitinib responders

Non-responders

EGFR mutations

8/9

0/7

case report
Case report

75 y/o man retired, held many jobs from working as driver, attendant at gasoline station to sexton. Hobby trumpet

  • 2/06 follow-up CT one year after TUR-P: solitary lesion L lower lobe. 3-months follow-up CT: Increasing seize
  • 6/06 thoracoscopic wedge resection abandoned because of non-small cell lung cancer with carcinomatosis of pleura: referral for palliative chemotherapy
  • Histology: adenocarcinoma
  • Smoking history: Never smoker
  • EGFR mutation analysis: deletion in exon 19 (delL747-E749, A750P)
case report10
Case report
  • 7/06: erlotinib and bevacizumab (SAKK 19/05)

10.7.06

29.8.06

22.6.07

egfr mutations in lung adenocarcinoma
EGFR mutations in lung adenocarcinoma

Sharma, Nat Rev Cancer, 2007

egfr mutations and adenocarcinoma histology
EGFR mutations and adenocarcinoma histology

Yatabe and Mitsudomi, Pathology International, 2007

Mucinous differentiation of adenocarcinoma with broncheoalveolar features correlates with absence of EGFR mutations and presence of KRAS mutations(Finberg, J Mol Diagn 2007)

slide13

11 ligands each with a common

EGF like structure

EGF

TGF-a

Amphiregulin

Betacellulin

Epiregulin

HB-EGF

Epigen

Neuregulin 1 (NRG1)

Neuregulin 2 (NRG2)

Neuregulin 3 (NRG3)

Neuregulin 4 (NRG4)

EGF

The ErbB family

4 types of erbB receptors

ErbB1 (HER1, EGFR)

ErbB2 (HER2, neu)

ErbB3 (HER3)

ErbB4 (HER4)

her2 and her4 mutations lung cancer
HER2 and HER4 mutations lung cancer
  • HER2 mutation in 10% of lung adenocarcinomas(Stephens, Nature 04)
  • HER2 mutations mainly in adenocarcinoma with broncheoalveolar features and mutually exclusive with KRAS and EGFR mutations(Buttitta, IJC 2006)
  • Cells transfected wit mutated HER2 remain sensitive to lapatinib, but become resistant to EGFR TKIs(Wang, Cancer Cell 2006)
  • HER4 mutations in 2.3% of lung cancers (adeno and squamous cell)(Soung, IJC 2006)
egfr downstream signaling15
EGFR: downstream signaling

EGFR, HER2, HER4

Cell membrane

SOS

EGFR-TK

RAS

ATP

ATP

PI3K

GRB2

RAF

P

MAPK

Akt

STAT

MEK

EGFR-TKpathways

Gene transcriptioncell-cycle progression

Nucleus

Proliferation

Resistance to

apoptosis

Invasion

Metastasis

Angiogenesis

braf mutations in nsclc
BRAF Mutations in NSCLC

V600E

Missense mutations in 4/35 lung adenocarcinoma cell lines and in 2/127 lung adenocarcinoma tissues (Davis, Nature 2002, Noaki, CR 2002 )

Lung-specific expression of mBRAF in mice induced MAPK pathway activation and development of lung adenocarcinomas, which were sensitive to a MEK inhibitor(Ji, Cancer Res 2007)

Expression of mBRAF induced lung adenomas in mice. For the development of adenocarcinomas additional TP53 mutation was needed. (Dankort, Genes and Development, 2007)

egfr downstream signaling17
EGFR: downstream signaling

EGFR, HER2, HER4

  • PI3K mutations:
  • 5% NSCLC cell lines
  • 1.2% NSCLC tumors

Cell membrane

SOS

EGFR-TK

RAS

ATP

ATP

PI3K

GRB2

RAF

P

MAPK

Akt

STAT

MEK

EGFR-TKpathways

Gene transcriptioncell-cycle progression

Nucleus

Proliferation

Resistance to

apoptosis

Invasion

Metastasis

Angiogenesis

slide18
Two mutually exclusive pathways to lung adenocarcinoma(pooled data from East Asian and western countries)

Tobacco

KRAS mutations (14%)

Smokers

Adenocarcinoma

Genetic factors ?

? Carcinogen

EGFR mutations (31%)

HER2 mutations (4%)

BRAF mutations (1%)HER4 mutations (rare)

Never

Smokers

Gazdar, IASLC Workshop 2006

mutational profiling of resected lung adenocarcinomas
Mutational profiling of resected lung adenocarcinomas

235 lung adenocarcinomas from MSKCC tissue bank, 39 kinases:

  • EGFR mutations: 6%
  • BRAF mutations: <1%
  • PI3K mutations: 2%
  • KRAS mutations: 12%
  • 1 not previously described mutation of the fibroblast growth factor receptor-4 (FGFR4)

Conclusion: The majority of gain of function mutations in lung adencocarcinoma have been identified

Marks, PLOS 2007

correlation between mutation status and tki sensitivity her2 overexpression confers sensitivity
Correlation between mutation status and TKI sensitivity: HER2 overexpression confers sensitivity

1000

100

T790M

10

PTEN absent

TKI IC50 (mM)

1

HER2 amplified

0.1

0.01

mEGFR

mKRAS

mBRAF

WT

Mutation status

Gazdar, IASLC Workshop 2006

met amplification leads to gefitinib resistance in lung cancer by activating erbb3s signaling
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3s signaling

Concurrent inhibition of MET by PHA665725 und EGFR suppresses growth of MET amplified, EGFR mutant adenocarcinoma cell line

Engelman, Science 2007

findings associated with resistance to egfr tki
Findings associated with resistance to EGFR TKI
  • Lack of activating activating mutations in EGFR exons 18–21
  • K-ras mutation: Screening of cell lines and introduction of mutated KRAS into EGFR mutated cell line(Pao, PLoS 2005, Uchida, Cancer Sci 2007)
  • Presence of T790M mutation: 50% of tissue samples from patients with acquired gefitinib resistance(Kosaka, Clin Cancer Res 2006)
  • ADAM17 mediated heregulin autocrine loop inducing ERBB2/3 signalling(Zhou, Cancer Cell, 2006)
  • Amplification of MET: 22% of patients with acquired gefitinib or erlotinib resistance(Engelman, Science 2007)
slide24
Molecular classification of lung cancer and morphology: Terminal respiratory unit (TRU) derived adenocarcinoma

TRU

Yatabe, Cancer Chemother Pharmacol 2006

proposed schema of molecular classification of lung cancer
Proposed schema of molecular classification of lung cancer

Yatabe and Mitsudomi, Pathology International, 2007

lung mutagene model potti nejm 2006
Lung mutagene model(Potti, NEJM 2006)

Identifying gene expression profiles predictive of recurrence after surgery

adenocarcinoma of the lung a molecular perspective 1
Adenocarcinoma of the lung:a molecular perspective (1)
  • 50% of tumors harbor somatic mutations of six genes encoding proteins in the EGFR signaling pathway: KRAS, EGFR, BRAF, PI3K, HER2 and HER4.
  • With the exception of PI3K mutations, they are mutually exclusive
  • The carcinogens of tumors with oncogenic mutations other than KRAS remain to be identified
  • The identification of an activating EGFR mutations has therapeutic implications today(USA 15’000 cases/y, CML and GIST 4500 cases/y each)
adenocarcinoma of the lung a molecular perspective 2
Adenocarcinoma of the lung:a molecular perspective (2)
  • The following genetic alterations confer resistance to EGFR TKIs: KRAS mutations, EGFR mutation T790M, MET amplification
  • The correlations between molecular and histologcial characteristics of lung tumors will lead to new proposals for the classification of lung adenocarcinoma
  • Gene expression arrays are likely to become an integral part of clinical decision making