lung cancer 2006

1

LUNG CANCER 2006LUNG CANCER 2006

Epidemiology :Epidemiology : Women and lung cancer Women and lung cancer Restaging after neoadjuvant Restaging after neoadjuvant

treatment treatment

of patients in stage IIIA cN2 NSCLC :of patients in stage IIIA cN2 NSCLC : Non-invasive restaging: CT or PET ? Non-invasive restaging: CT or PET ? Invasive restaging: Remediastinoscopy or EUS-Invasive restaging: Remediastinoscopy or EUS-

FNA ?FNA ?

Customizing ChemotherapyCustomizing Chemotherapy

2


Epidemiology :Epidemiology : Women and lung Women and lung cancer cancer

3

Women and Lung Cancer : Women and Lung Cancer : Epidemiology, tumor biology, and Epidemiology, tumor biology, and

emerging trends emerging trends in clinical researchin clinical research

ChandraChandra P.BelaniP.Belani, , SherrySherry MartsMarts, , JoanJoan SchillerSchiller, , MarkMark A.SocinskiA.SocinskiLung Cancer 2007; 55: 15-23Lung Cancer 2007; 55: 15-23 Sex chromosomes: Sex chromosomes:

In men : The presence of the SRY-g ene on the Y In men : The presence of the SRY-g ene on the Y chromosome chromosome

Expression of differences in physiology and endocrine Expression of differences in physiology and endocrine function,function,

(childhood,adolescence, adulthood and post (childhood,adolescence, adulthood and post menopause)menopause)

Higher percentage of body fat in women than in Higher percentage of body fat in women than in men,smaller muscle mass, lower blood pressure, higher men,smaller muscle mass, lower blood pressure, higher levels of estrogens and progestins and lower levels of levels of estrogens and progestins and lower levels of androgen ,androgen ,

4

Women and Lung Cancer : Women and Lung Cancer : Epidemiology, tumor biology, and Epidemiology, tumor biology, and

emerging trends emerging trends in clinical researchin clinical research

Hormonal fluctuations associated with Hormonal fluctuations associated with reproduction (mensturation and pregnancy) reproduction (mensturation and pregnancy) influence numerous body systems.influence numerous body systems.

Reduced estrogen levels in menopause not only Reduced estrogen levels in menopause not only affect ovaries, uterus and breast but also other affect ovaries, uterus and breast but also other tissues (Brain,skin,cardiovascular tissue and tissues (Brain,skin,cardiovascular tissue and bones)bones)

Sex: an important variable in research design.Sex: an important variable in research design. Gandhi M et al. Annu Rev Pharmacol Toxicol 2004, Turgeon JL et al. Gandhi M et al. Annu Rev Pharmacol Toxicol 2004, Turgeon JL et al.

Science 2004Science 2004

5

Lung Cancer: Lung Cancer: Epidemiology and Risk FactorsEpidemiology and Risk Factors

Male gender is a poor prognostic factor in metastatic Male gender is a poor prognostic factor in metastatic diseasedisease

Duration of smoking before diagnosis and smoking habit Duration of smoking before diagnosis and smoking habit

in women : determines surveyin women : determines survey

Risk of death: higher in former smoker or smoker women Risk of death: higher in former smoker or smoker women in comparison with non-smokers in comparison with non-smokers

Women with lung cancer have similar features with non-Women with lung cancer have similar features with non-smoker male patients and they are youngersmoker male patients and they are younger

Fu JB Chest 2005O’Connell JP JCO 1986Ferguson MK JCO 1990Shinkai T Can Chemoth Phar 1992Albain KS JCO 1991

Paesmans M JCO 1995Johnson BE AJM 1988Ebbert JO Lung Cancer 2005Goodman MT Cancer 1990

De Perrot M JTh Card Surg 2000Visbal AL Ann Th Surg 2004Nordquist LT Chest 2004Ringer G Cl Lung Cancer 2005

6


While male patients used to be more than females previously ( 1975 While male patients used to be more than females previously ( 1975 M/F= 3.65), currently they are lower (in1999, M/F= 1.99) M/F= 3.65), currently they are lower (in1999, M/F= 1.99)

While insidence is decreasing in men, the increase in women is While insidence is decreasing in men, the increase in women is going on, and this is primarily parallel to the increase in smokinggoing on, and this is primarily parallel to the increase in smoking

Lung cancer deaths in women :1960 Lung cancer deaths in women :1960 ( 5/100.000 ) , 2000 (40/100.000 ) are increasing( 5/100.000 ) , 2000 (40/100.000 ) are increasing

Today, the most frequent cause of death due to cancer in women is Today, the most frequent cause of death due to cancer in women is (27 %) lung cancer.(27 %) lung cancer.

Fu JB Chest 2005O’Connell JP JCO 1986Ferguson MK JCO 1990Shinkai T Can Chemoth Phar 1992Albain KS JCO 1991

Paesmans M JCO 1995 Johnson BE AJM 1988 Ebbert JO Lung Cancer 2005 Goodman MT Cancer 1990

De Perrot M JTh Card Surg 2000Visbal AL Ann Th Surg 2004Nordquist LT Chest 2004Ringer G Cl Lung Cancer 2005

7


Rates of smoking in women have been decreased since 1960Rates of smoking in women have been decreased since 1960

In 2004In 2004 19 % of women aged > 18 currently smoking19 % of women aged > 18 currently smoking In men aged > 18 the same rate is 23 %In men aged > 18 the same rate is 23 %

Smoking in adolescence : M=FSmoking in adolescence : M=F

Depression and weight gain affect smoking in young womenDepression and weight gain affect smoking in young women

CDC 28 May 2006,Warren CW Lancet 2006Simantov E Arch Pediat Adolesc Med 2000,Saules KK Addict Behav 2004

8

NSCLCNSCLC SCLCSCLCMen Men (%)(%) Women (%)Women (%) Men Men (%)(%) WWomeome

n n (%)(%)

All stagesAll stages 14.914.9 19.619.6 5.65.6 7.27.2

Local Local diseasedisease

46.646.6 56.056.0 20.720.7 21.621.6

Regional Regional diseasedisease

15.915.9 18.518.5 9.99.9 11.711.7

Metastatic Metastatic diseasedisease

2.02.0 2.32.3 1.81.8 2.22.2

Table 1A Rates of 5-years survival according to stages in

men and women with SCLC and NSCLC

9

Table 2A Distribution of patients with squamous

cell Ca and adenocarcinoma

AdenocarcinAdenocarcinomomaaSquamousSquamouscell carcinomacell carcinoma

Men (%)Men (%) Women Women (%)(%)

Men Men (%)(%) Women (%)Women (%)

Moore Moore etal. etal.

4040 5050 3030 2020

Fu et al. Fu et al. 3333 4545 3030 2121

Visbal et Visbal et al. al.

4848 5959 3232 2222

Chen et al. Chen et al. 4242 7373 4141 1616

Ringer et Ringer et al. al.

3838 4747 3838 2424

10

Table 2B Distribution of gender, histologycal type and smoking status of patients with lung cancer

( Muscat and Wynder)

MenMen WomenWomen

CurrentCurrentsmokers smokers (%)(%)

FormerFormersmokersmokers (%)s (%)

Never-Never-smokersmokerss(%)(%)

CurrentCurrentsmokers smokers (%)(%)

FormerFormersmokersmokers s (%)(%)

Never-Never-smokerssmokers(*)(*)

AdenoAdenocarcinomacarcinoma

3232 3434 5858 4242 4444 5959

Squamous Squamous cell cell carcinomacarcinoma

3535 3737 1919 2020 2020 1212

Small cell Small cell carcinomacarcinoma

1515 1111 00 1919 1212 33

OtherOther 1818 1818 2323 1919 2424 2626

11

Lung Cancer : Lung Cancer : Epidemiology and Risk FactorsEpidemiology and Risk Factors

Smoking is major risk factor , only a minority of smokers Smoking is major risk factor , only a minority of smokers develop lung cancer.develop lung cancer.

Approximately 10-15% of patients diagnosed are non-Approximately 10-15% of patients diagnosed are non-smokers.smokers.

The ratio of women to men in patients with lung cancer The ratio of women to men in patients with lung cancer who have never smoked is approximately 3:1.who have never smoked is approximately 3:1.

Increased risk of lung cancer in smokers and non-smokers Increased risk of lung cancer in smokers and non-smokers are related to certain carcinogenic polymorphisms in are related to certain carcinogenic polymorphisms in genes involved in the metabolism of carcinogens.genes involved in the metabolism of carcinogens.

Genetic susceptibility comes from studies on family history Genetic susceptibility comes from studies on family history of lung cancer.of lung cancer.

12

Lung Cancer : Lung Cancer : Epidemiology and Risk FactorsEpidemiology and Risk Factors

A positive family history has been defined as a risk factor in non-A positive family history has been defined as a risk factor in non-smokers; particularly in the development of adenocarcinoma, in smokers; particularly in the development of adenocarcinoma, in younger women.younger women.

An epidemiologic link between estrogen exposure and incidence An epidemiologic link between estrogen exposure and incidence of NSCLC has been suggested in Japanese non-smoking women .of NSCLC has been suggested in Japanese non-smoking women .

Younger, presumably pre-menopausal women appear to have Younger, presumably pre-menopausal women appear to have

shorter survival than older women:(assumed to be shorter survival than older women:(assumed to be premenopausal) have lower 1-year survival rates than older premenopausal) have lower 1-year survival rates than older women : in a analysis of patients with advanced NSCLC enrolled women : in a analysis of patients with advanced NSCLC enrolled in SWOG trials, women over 70 had a 34% 1 year survival in SWOG trials, women over 70 had a 34% 1 year survival compared with 11% for those under 45 .compared with 11% for those under 45 .

Visbal AL Ann Th Surg 2004, Gorlova OY Int J Cancer 2006, Thun MJ JNC Inst Visbal AL Ann Th Surg 2004, Gorlova OY Int J Cancer 2006, Thun MJ JNC Inst

1997, Stellman SD Cancer 1997, Wenzlaff AS Carsinogenesis 2005, Miller DP İnt J 1997, Stellman SD Cancer 1997, Wenzlaff AS Carsinogenesis 2005, Miller DP İnt J Cancer 2003, Wu AH Am J Epid 1996, Schwartz AG Am J Epid 1996, Matakidou A Cancer 2003, Wu AH Am J Epid 1996, Schwartz AG Am J Epid 1996, Matakidou A Br J Cancer 2005, Li X Lung Cancer 2005, Liu Y İnt J Cancer 2005, Xu H Hum Br J Cancer 2005, Li X Lung Cancer 2005, Liu Y İnt J Cancer 2005, Xu H Hum Genet 2005, Schwartz AG AJRCCM 2006Genet 2005, Schwartz AG AJRCCM 2006

13

Sex Differences inSex Differences inLung Tumor BiologyLung Tumor Biology

Smoking-related lung cancer is induced by the formation of Smoking-related lung cancer is induced by the formation of DNA adducts in lung epitheliel cells.DNA adducts in lung epitheliel cells.

Processing of these adducts by the cellular DNA repair Processing of these adducts by the cellular DNA repair

machinery may lead to mutations in genes that initiate or machinery may lead to mutations in genes that initiate or facilitate tumor growth, such as the tumor suppressor gene facilitate tumor growth, such as the tumor suppressor gene p53. p53.

PAH activation is catalyzed by the cytochrome P450 PAH activation is catalyzed by the cytochrome P450 enzymes CYP1A1 and CYP1B1, and inactivated by enzymes CYP1A1 and CYP1B1, and inactivated by glutathione S-transferases (GSTs). glutathione S-transferases (GSTs).

The expression of CYP1A1 and CYP1B1 in lung tissue is The expression of CYP1A1 and CYP1B1 in lung tissue is significantly higher in current smokers compared to former significantly higher in current smokers compared to former and never-smokers.than in non- and never-smokers .and never-smokers.than in non- and never-smokers .

14

Sex Differences inSex Differences inLung Tumor BiologyLung Tumor Biology

Levels of lung DNA adducts correlate with the level of Levels of lung DNA adducts correlate with the level of CYP1A1 expression .CYP1A1 expression .

Among smokers, female patients had a 3.9-fold higher Among smokers, female patients had a 3.9-fold higher median level of CYP1A1 compared to males.median level of CYP1A1 compared to males.

In non-smokers, CYP1A1 polymorphisms are associated In non-smokers, CYP1A1 polymorphisms are associated with an increased lung cancer risk.with an increased lung cancer risk.

A variant genotype of CYP1A1 and GSTM1 contribute to an A variant genotype of CYP1A1 and GSTM1 contribute to an increased risk of lung cancer in women (6.54) compared to increased risk of lung cancer in women (6.54) compared to men (2.36) .men (2.36) .

DeMarini DM Mutat Res 2004, Smith LE J Natl Cancer Inst 2000, DeMarini DM Mutat Res 2004, Smith LE J Natl Cancer Inst 2000, Mollerup S İnt J Cancer 2006,Mollerup S İnt J Cancer 2006,

Ng DP Cancer Causes Control 2005, Hung RJ Carcinogenesis 2003, Ng DP Cancer Causes Control 2005, Hung RJ Carcinogenesis 2003, Dresler CM Lung Can 2000 Dresler CM Lung Can 2000

15

Sex Differences in Sex Differences in Lung Tumor BiologyLung Tumor Biology

In lung cancers, these activating EGFR mutations are more common in In lung cancers, these activating EGFR mutations are more common in women and non-smokers.women and non-smokers.

Mutations in K-RAS, a downstream signaling molecule in the EGFR Mutations in K-RAS, a downstream signaling molecule in the EGFR pathway, may also be more common in women, but are significantly pathway, may also be more common in women, but are significantly associated with smoking and levels of DNA adduct formation.associated with smoking and levels of DNA adduct formation.

In hormone-dependent tissues, such as breast and ovary, estrogen In hormone-dependent tissues, such as breast and ovary, estrogen regulates the transcription of target genes through interaction with regulates the transcription of target genes through interaction with estrogen receptors (ERs) alpha or beta.estrogen receptors (ERs) alpha or beta.

While important for normal tissue physiology, estrogen receptor-While important for normal tissue physiology, estrogen receptor-mediated signaling also promotes tumorigenesis.mediated signaling also promotes tumorigenesis.

Estrogen plays a role in both normal pulmonary physiology and in the Estrogen plays a role in both normal pulmonary physiology and in the biology of NSCLC. In vitro studies confirm that NSCLC cells respond to biology of NSCLC. In vitro studies confirm that NSCLC cells respond to estrogens and anti-estrogens by altering endogenous gene expression.estrogens and anti-estrogens by altering endogenous gene expression.

Expression of ER-beta is associated with improved survival, while Expression of ER-beta is associated with improved survival, while expression of ER-alpha is a poor prognostic factor. Among non-expression of ER-alpha is a poor prognostic factor. Among non-smokers,higher ER-beta expression was observed significantly more smokers,higher ER-beta expression was observed significantly more frequently in female patients (58.3%) than in male patients (40.9%).frequently in female patients (58.3%) than in male patients (40.9%).

Lynch TJ NEJM 2004, Hsieh RK Chest 2005, Paez JG Science 2004, Sugio K BJC 2006,Lynch TJ NEJM 2004, Hsieh RK Chest 2005, Paez JG Science 2004, Sugio K BJC 2006, Nelson HH J Natl Can İnst 1999, Soung YH Virchows Arch 2005, Levin ER Mol Endoc 2005,Nelson HH J Natl Can İnst 1999, Soung YH Virchows Arch 2005, Levin ER Mol Endoc 2005, Pietras RJ Steroids 2005, Stabile LP Cancer Res 2005, Razandi M J Biol Chem 2003, Bunone G EMBO 1996, Massaro D Am JPhys Lung Cell Mol Pietras RJ Steroids 2005, Stabile LP Cancer Res 2005, Razandi M J Biol Chem 2003, Bunone G EMBO 1996, Massaro D Am JPhys Lung Cell Mol

Physiol 2005, Wu CT JTCardiovas Surg 2005, Physiol 2005, Wu CT JTCardiovas Surg 2005,

16

Current Therapy OptionsCurrent Therapy Options

Initial treatment for patients with localized, early-stage NSCLC Initial treatment for patients with localized, early-stage NSCLC typically includes surgical resection. typically includes surgical resection.

Patients with limited pulmonary reserve are candidates for Patients with limited pulmonary reserve are candidates for radiotherapy. radiotherapy.

The treatment modality for early stage disease differs The treatment modality for early stage disease differs significantly between men and women.significantly between men and women.

Radiotherapy is more frequently administered to men. Radiotherapy is more frequently administered to men.

The lower frequency of surgical resection in men does not explain The lower frequency of surgical resection in men does not explain the observed survival benefit for women as a comparison of the observed survival benefit for women as a comparison of patients who received surgery as their initial treatment showed patients who received surgery as their initial treatment showed that women have better survival than men.that women have better survival than men.

Schiller JH NEJM 2002, Fossella F JCO 2003, Smit EF JCO 2003, Georgoulias V Lancet 2001, Schiller JH NEJM 2002, Fossella F JCO 2003, Smit EF JCO 2003, Georgoulias V Lancet 2001, Gridelli C JCO 2003, Hoang T JCO 2005. Gridelli C JCO 2003, Hoang T JCO 2005.

17

Surgery onlySurgery only WomeWomen n (%)(%)

Men Men (%)(%)

P-P-valuevalue

SurvivalSurvival

Moore et al. Moore et al. 27.427.4 24.724.7 .031.031 MediaMedian:n:

: 55.4 months vs. 37.2 : 55.4 months vs. 37.2 months (P< .001)months (P< .001)

Radzikowska et al. Radzikowska et al. 23.323.3 18.818.8 .0001.0001 NANA

Fu et al. Fu et al.

Local RegionalLocal Regional 63.7 63.7 23.423.4

56.4 56.4 22.222.2 <.0001<.0001 2 -2 -

year:year:74.3% vs. 66.0%74.3% vs. 66.0%(P<.0001)(P<.0001)

Radiotherapy onlyRadiotherapy only

Moore et al. Moore et al. 17.717.7 19.619.6 .031.031 MediaMedian:n:

: 10.1 months vs. 8.0 : 10.1 months vs. 8.0 months (P= .004)months (P= .004)

Radzikowska et al. Radzikowska et al. 14.514.5 14.614.6 NSNS NANA

Fu et al. Fu et al.

Local RegionalLocal Regional 18.2 18.2 39.439.4

23.4 23.4 42.542.5 <.0001<.0001 2-year:2-year: 12. 2% vs. 15.5%12. 2% vs. 15.5%

(P<.0001)(P<.0001)

TablTablee 3 3Differences in treatment modalities related with genderDifferences in treatment modalities related with gender

18

TREATMENTTREATMENT The role of angiogenesis in tumour progression in lung cancer The role of angiogenesis in tumour progression in lung cancer

has been well understood.has been well understood. Release of VEGF proangiogenic factor and high microvascular Release of VEGF proangiogenic factor and high microvascular

density is associated with metastasis and poor survival.density is associated with metastasis and poor survival. VEGF inhibitionVEGF inhibition (Bevacizumab) inhibits new tumour (Bevacizumab) inhibits new tumour

revitalisation.revitalisation. In ECOG E4599 study, metastatic or recurrent NSCLC In ECOG E4599 study, metastatic or recurrent NSCLC

(besides squamous cell) (besides squamous cell) Signicant increase in response in Beva+Carbo+Paklitax Signicant increase in response in Beva+Carbo+Paklitax

group (27%) compared with Beva (-) group (10%) (p<0.001)group (27%) compared with Beva (-) group (10%) (p<0.001) Increase in progression – free and overall survivalIncrease in progression – free and overall survival,, In male cases with + Beva treatment : 11.7 months, with In male cases with + Beva treatment : 11.7 months, with

Beva(-) 8.7 months, (p=0.001)Beva(-) 8.7 months, (p=0.001) Similar survival rates in both arms in womenSimilar survival rates in both arms in women

Fontanini G Cl Can Res 1997, O’Byrne KJ BJC 2000, Willett CG Nat Med 2004, Fontanini G Cl Can Res 1997, O’Byrne KJ BJC 2000, Willett CG Nat Med 2004, Sandler AB ASCO 2005 JCO 2005, Brahmer JR ECOG 4599 ASCO 2006 JCO 2006,Sandler AB ASCO 2005 JCO 2005, Brahmer JR ECOG 4599 ASCO 2006 JCO 2006, Thatcher N Lancet 2005, Herbst RS INTACT 2 JCO 2004, Giaccone G INTACT 1 JCO 2004,Thatcher N Lancet 2005, Herbst RS INTACT 2 JCO 2004, Giaccone G INTACT 1 JCO 2004, Shepherd FA NEJM 2005, Herbst RS TRIBUTE JCO 2005, Bell DW IDEAL/INTACT JCO 2005Shepherd FA NEJM 2005, Herbst RS TRIBUTE JCO 2005, Bell DW IDEAL/INTACT JCO 2005

19

TREATMENTTREATMENT

EGFR inhibitors EGFR inhibitors (Erlotinib/gefitinib)(Erlotinib/gefitinib) They increase the survival alone or with 2. They increase the survival alone or with 2.

or 3.series of CT, (primarily in female, or 3.series of CT, (primarily in female, Japanese, non-smoker cases and in Japanese, non-smoker cases and in patients with adenocarcinoma)patients with adenocarcinoma)

Association of EGFR mutations with Association of EGFR mutations with sensitivity to Gefitinib has been shown in sensitivity to Gefitinib has been shown in studies and mutations have been found in studies and mutations have been found in 20 % of female cases, and in only 9% of 20 % of female cases, and in only 9% of malesmales

Fontanini G Cl Can Res 1997, O’Byrne KJ BJC 2000, Willett CG Nat Med 2004, Fontanini G Cl Can Res 1997, O’Byrne KJ BJC 2000, Willett CG Nat Med 2004, Sandler AB ASCO 2005 JCO 2005, Brahmer JR ECOG 4599 ASCO 2006 JCO 2006,Sandler AB ASCO 2005 JCO 2005, Brahmer JR ECOG 4599 ASCO 2006 JCO 2006, Thatcher N Lancet 2005, Herbst RS INTACT 2 JCO 2004, Giaccone G INTACT 1 JCO 2004,Thatcher N Lancet 2005, Herbst RS INTACT 2 JCO 2004, Giaccone G INTACT 1 JCO 2004, Shepherd FA NEJM 2005, Herbst RS TRIBUTE JCO 2005, Bell DW IDEAL/INTACT JCO 2005Shepherd FA NEJM 2005, Herbst RS TRIBUTE JCO 2005, Bell DW IDEAL/INTACT JCO 2005

20

TREATMENTTREATMENT Paclitaxel poliglumexPaclitaxel poliglumex (PPX) (PPX)

A macromolecular taxaneA macromolecular taxane Stabile in systemic circulationStabile in systemic circulation Accumulates in tumor tissueAccumulates in tumor tissue Changes lymphatic clearence and permeabilityChanges lymphatic clearence and permeability

In NSCLC metastatic disease and in cases with PS 2 , and In NSCLC metastatic disease and in cases with PS 2 , and without previous CT, the efficiency with Carboplatin or as without previous CT, the efficiency with Carboplatin or as a single agent in 800 cases, Phase III a single agent in 800 cases, Phase III 2 2 study, survival study, survival was evaluated, in women treated with PPX survival was was evaluated, in women treated with PPX survival was better while it was similar in menbetter while it was similar in men,,

Oestrogen provides the efficiency of PPX by increasing Oestrogen provides the efficiency of PPX by increasing the distribution to the tissues with ER-b release.the distribution to the tissues with ER-b release.

Singer JW J Control Release 2005, O’Byrne K EurJCan 2005, Langer CJ ASCO 2005 JCO 2005

21

DISCUSSIONDISCUSSION Lung cancer tumor histology and biology can Lung cancer tumor histology and biology can

change with the inhalation of cigarette smoke change with the inhalation of cigarette smoke and gender.and gender.

Female gender and genetic susceptibility are Female gender and genetic susceptibility are risk factors for the development of lung cancer in risk factors for the development of lung cancer in both smokers and non-smokers. both smokers and non-smokers.

In regard of differences due to gender in lung In regard of differences due to gender in lung tumor biology ,some treatments may be more tumor biology ,some treatments may be more effective in women than men.effective in women than men.

Singer JW J Control Release 2005, O’Byrne K EurJCan 2005, Langer CJ ASCO 2005 JCO 2005

22


Restaging after neoadjuvant Restaging after neoadjuvant treatment of patients in stage treatment of patients in stage IIIA cN2 NSCLC:IIIA cN2 NSCLC:

non-invasive restaging: CT or PET ?non-invasive restaging: CT or PET ?

24

NACT/ NACRTNACT/ NACRT

In NSCLC, N2 NACT and surgery : In NSCLC, N2 NACT and surgery :

5 -year survival 20-40 % 5 -year survival 20-40 % Without induction CT : 5 - 20 % Without induction CT : 5 - 20 % Operable IIIA cN2:Operable IIIA cN2:

Induction( NACRT> NAKT) Induction( NACRT> NAKT) Evaluation of response following Evaluation of response following

neoadjuvan therapy: how should be done neoadjuvan therapy: how should be done and surgery for whom ??and surgery for whom ??

25


Non-invasive restaging: Non-invasive restaging: CTCT or or PET ? PET ?

26

StagingStaging Standard approach is the detection of LAP >1cm on Standard approach is the detection of LAP >1cm on

olanlar CT, pathological examination of samples obtained olanlar CT, pathological examination of samples obtained with invasive techniques and establishment of diagnosis;with invasive techniques and establishment of diagnosis;

CT is standard, but without sufficient sensitivity,CT is standard, but without sufficient sensitivity, Dimension is a poor determinant for malignancy, Dimension is a poor determinant for malignancy, Accuracy 60-80 %, Accuracy 60-80 %, Misdiagnose of mediastinal malignant lymph nodes on Misdiagnose of mediastinal malignant lymph nodes on

CT: 21-33 %, in locally advanced disease : 11 % pN2CT: 21-33 %, in locally advanced disease : 11 % pN2 However, CT can’t determine mediastinal metastatic However, CT can’t determine mediastinal metastatic

lymph nodes in nearly 13 % (false negative),lymph nodes in nearly 13 % (false negative), In %50 of the cases : (false positive).In %50 of the cases : (false positive).

Wang KP et al. Chest 1983, Line BR et al Curr Treat Options Oncol 2004Wang KP et al. Chest 1983, Line BR et al Curr Treat Options Oncol 2004Herth F et al. Chest 2004, Yasafuku K et al. Chest 2004Herth F et al. Chest 2004, Yasafuku K et al. Chest 2004Rintoul RC et al. Eur Respir J 2006., Eloubeidi MA et al. Ann Thorac Surg 2005 Rintoul RC et al. Eur Respir J 2006., Eloubeidi MA et al. Ann Thorac Surg 2005 De Leyn et al J Clin Oncol 2006, Stamatis G et al Pneumologie 2005De Leyn et al J Clin Oncol 2006, Stamatis G et al Pneumologie 2005Goldstraw P J Clin Oncol 2006, Bruzzi JF Lung Cancer 2006, Yamamoto Y Eur J Nucl Med Imagıng 2006Goldstraw P J Clin Oncol 2006, Bruzzi JF Lung Cancer 2006, Yamamoto Y Eur J Nucl Med Imagıng 2006

27

RESTAGİNG IN SHORT TERM FOLLOWING RESTAGİNG IN SHORT TERM FOLLOWING NEOADJUVANT THERAPY-1NEOADJUVANT THERAPY-1

Aim:Aim: Are CT measurements in the first Are CT measurements in the first month of therapy useful in the evaluation of month of therapy useful in the evaluation of treatment response in patients with treatment response in patients with NSCLC ?NSCLC ?

Patients and Method:Patients and Method: Aprik 2001-June 2005Aprik 2001-June 2005 CT within 31 days following only one CT within 31 days following only one

cyclus of CT (mean 24, range 9-31 cyclus of CT (mean 24, range 9-31 days) days)

Consensus of 2 radiologists in Consensus of 2 radiologists in measurements,treatment response is measurements,treatment response is evaluated according to evaluated according to RECİSTRECİST criteriaecriteriae

30 male/ 27 female (57 patients) mean 30 male/ 27 female (57 patients) mean age 63 (37-85), Adeno(30),Squa (17) age 63 (37-85), Adeno(30),Squa (17) and others (10), stage: II(2), III(11) and and others (10), stage: II(2), III(11) and IV(44)IV(44)

John F Bruzzi, Mylene Truong, Ralph Zinner et al. J Thorac John F Bruzzi, Mylene Truong, Ralph Zinner et al. J Thorac Oncol 2006; 1: 425-29Oncol 2006; 1: 425-29

28

RESTAGİNG IN SHORT TERM FOLLOWING RESTAGİNG IN SHORT TERM FOLLOWING NEOADJUVANT THERAPY-2NEOADJUVANT THERAPY-2

Results :Results : A significant change in tumor size 14 % (8)A significant change in tumor size 14 % (8) Regression of > 30 % in total tumor size 3 % (2)Regression of > 30 % in total tumor size 3 % (2) Progression of > 20 % in total tumor size 11 % (6)Progression of > 20 % in total tumor size 11 % (6) Early insensitivity / resistance to CT in patients with Early insensitivity / resistance to CT in patients with

progression or discontinuance of CT / a different protocolprogression or discontinuance of CT / a different protocol

Partial responsePartial response Change in total tumor Change in total tumor size(« = 57)size(« = 57)

Magnitude of tumorMagnitude of tumor response (%)response (%)

>30% reduction in size>30% reduction in size 2(3)2(3) 36 (32-40)36 (32-40)

Stable diseaseStable disease

20 - 30% reduction in size20 - 30% reduction in size 1(2)1(2) 2828

10 - 19% reduction in size10 - 19% reduction in size 6(11)6(11) 13(10-18)13(10-18)

<10% change in size<10% change in size 34 (59)34 (59) 2 (-9-6)2 (-9-6)

1 0 - 20% increase in size1 0 - 20% increase in size 8(14)8(14) 13 (10-15)13 (10-15)

Tumor progressionTumor progression

> 20% increase in size> 20% increase in size 6(11)6(11) 26(21-33)26(21-33)

Values are «(%) or rc(range).Values are «(%) or rc(range).

30

DISCUSSIONDISCUSSION

Early restaging CT in NSCLCEarly restaging CT in NSCLC In the evaluation of response to therapy in early In the evaluation of response to therapy in early

stage stage Useful in arrangement of more suitable Useful in arrangement of more suitable

treatments (2. or 3. series). treatments (2. or 3. series).

(With a different CT rapid-early/ late (With a different CT rapid-early/ late response?, in different types ? Small size: response?, in different types ? Small size: metastasis?, large size: infection or scar metastasis?, large size: infection or scar tissue?)tissue?)

31


Non-invasive restaging: CT or Non-invasive restaging: CT or PETPET ? ?

32

PET/ PET-CT RESTAGİNG FOLLOWING PET/ PET-CT RESTAGİNG FOLLOWING NEOADJUVANT THERAPYNEOADJUVANT THERAPY

Ryu JS Lung Cancer 2002; 35(2): 179-87Ryu JS Lung Cancer 2002; 35(2): 179-87 26 pts, stage III26 pts, stage III FDG PET: KRT pre and postFDG PET: KRT pre and post SUV: when it is 3, residue tumor or complete response: SUV: when it is 3, residue tumor or complete response: Sen: 88 %, Spec:67% Sen: 88 %, Spec:67% Mediastinal lymph node: sen 58 %, spec 93 % , accuracy 85 %Mediastinal lymph node: sen 58 %, spec 93 % , accuracy 85 %

Weber WA J Clin Oncol 2003; 21(14): 2651-2657Weber WA J Clin Oncol 2003; 21(14): 2651-2657 Stage IIIB-IV 57 ptsStage IIIB-IV 57 pts FDG PET (Pretreatment and 21st day of the first KT cycle )FDG PET (Pretreatment and 21st day of the first KT cycle ) Metabolic response: SUVs pre and post treatment difference 20%> Metabolic response: SUVs pre and post treatment difference 20%>

decreasedecrease Sen 96 %, Spec 84 % Sen 96 %, Spec 84 %

1 year survival: ın metabolic responders 44 %, in nonresponders 10 %1 year survival: ın metabolic responders 44 %, in nonresponders 10 % PET response: % change = SUV(post—pre)X 100/ SUV prePET response: % change = SUV(post—pre)X 100/ SUV pre

33

FDG PET

The higher the post treatment The higher the post treatment PET (+) or max SUV , PET (+) or max SUV , prognosis is so poor : prognosis is so poor :

If 2 years survival= PET(+) is If 2 years survival= PET(+) is 23 %, or max SUV is 16.6> 23 %, or max SUV is 16.6> 37 %, if it is negative, 67 % or 37 %, if it is negative, 67 % or

if max SUV is 0.4-6.4 61%if max SUV is 0.4-6.4 61%

Post treatment prognostic valuePost treatment prognostic value

Pandit N 2003, Davies A Lung Cancer 2007

34

Repeat FDG-PET for neoadjuvant CT monitorization in Repeat FDG-PET for neoadjuvant CT monitorization in patients with stage III NSCLC-1patients with stage III NSCLC-1

MethodMethod Stage III NSCLC 65 ptsStage III NSCLC 65 pts 3 times FDG PET ( initial 3 times FDG PET ( initial

staging , after the 1st CT, staging , after the 1st CT, pre RT after 15 days and pre RT after 15 days and RCT 15 days later )RCT 15 days later )

FDG uptake changes in FDG uptake changes in primary tumourprimary tumour

Eschmann SM, G.Friedel, F.Paulsen et al. Eschmann SM, G.Friedel, F.Paulsen et al. Lung Cancer 2007; 55: 165-171Lung Cancer 2007; 55: 165-171

35

Repeat FDG-PET for neoadjuvant CT monitorization in Repeat FDG-PET for neoadjuvant CT monitorization in patients with stage III NSCLC-2patients with stage III NSCLC-2

During NARCT significantly decreased During NARCT significantly decreased mean maximum FDG uptake (standard mean maximum FDG uptake (standard uptake value, SUVmax), initial SUVmax uptake value, SUVmax), initial SUVmax PET1: 14.9+-4.0, induction CT 2 weeks later PET1: 14.9+-4.0, induction CT 2 weeks later PET2: 8.7+-4.8 and 15 days after RCT PET3: PET2: 8.7+-4.8 and 15 days after RCT PET3: 5.5+-2.45.5+-2.4

FDG PET SUVmax FDG PET SUVmax If (PET1-PET2) decrease is >60 % , If (PET1-PET2) decrease is >60 % ,

survival is long (5 years 60 %)survival is long (5 years 60 %) If < 60 % it is short 15 % (p=0.0007)If < 60 % it is short 15 % (p=0.0007) If the decrease is <25 %, survival is If the decrease is <25 %, survival is

shorter <5 %shorter <5 %

36

DİSCUSSİONDİSCUSSİON

FDG PET is useful in treatment FDG PET is useful in treatment monitorization of stage lll patientsmonitorization of stage lll patients

FDG uptake decrease during FDG uptake decrease during induction therapy has a major role in induction therapy has a major role in determining and deciding treatmentdetermining and deciding treatment

37

FDG PET (Results)FDG PET (Results)

T stage: sensitivity 90 %, specifity 67 %, T stage: sensitivity 90 %, specifity 67 %, N stage: sensitivity 67 %, specifity 93 % , N stage: sensitivity 67 %, specifity 93 % , M stage: sensitivity 100 % , specifity100 % M stage: sensitivity 100 % , specifity100 %

For mediastinal lymph nodes, the rate of accuracy is low for For mediastinal lymph nodes, the rate of accuracy is low for restaging in patients who haven’t been treated previouslyrestaging in patients who haven’t been treated previously

PET/PET-CTPET/PET-CT (=functional imaging, metabolic response evaluation)(=functional imaging, metabolic response evaluation) in the evaluation of treatment response determination of survival in the evaluation of treatment response determination of survival earlier and better than CTearlier and better than CT (anatomic imaging)(anatomic imaging) (p<0.0001)(p<0.0001)

Post NACTPost NACT Tm Tm central, N1 positivecentral, N1 positive : :RemediastinoscopyRemediastinoscopy Tm Tm periferal, N1 negativeperiferal, N1 negative: : Remediastinoscopy is not required !!Remediastinoscopy is not required !!

Eschmann SM Eur J Nucl Med Mol Imaging 2006, Akhurst T Ann Thorac Surg 2005 , Vansteenkiste J Lancet Oncology 2004Eschmann SM Eur J Nucl Med Mol Imaging 2006, Akhurst T Ann Thorac Surg 2005 , Vansteenkiste J Lancet Oncology 2004

38


İnvasive restaging: İnvasive restaging: RemediastinoscopyRemediastinoscopy or EUS-FNA ? or EUS-FNA ?

39

Nodal status at repeat mediastinoscopy determines Nodal status at repeat mediastinoscopy determines survival in non-small lung cancer with mediastinal survival in non-small lung cancer with mediastinal

nodal involvement, treated by induction therapynodal involvement, treated by induction therapy

De Waele M, J Hendriks, P Lauwers et al. De Waele M, J Hendriks, P Lauwers et al. European Journal of Cardio-thoracic Sur 2006;29: 240-43European Journal of Cardio-thoracic Sur 2006;29: 240-43

Aim:Aim: Remediastinoscopy (reMS) is a useful procedure Remediastinoscopy (reMS) is a useful procedure for the determination of the spread of mediastinal lymph for the determination of the spread of mediastinal lymph nodes and pathological response to therapy following nodes and pathological response to therapy following induction therapy , restaging and patient selection for induction therapy , restaging and patient selection for thoracotomy in NSCLC. However, long term survival thoracotomy in NSCLC. However, long term survival data following reMS are minimal.data following reMS are minimal.

Method:Method: November1994-April 2003 , a total of 32 November1994-April 2003 , a total of 32 (29 male, 3 female), locally advanced NSCLC, reMS (29 male, 3 female), locally advanced NSCLC, reMS

following induction CT, mean age 67.8 (47-83),following induction CT, mean age 67.8 (47-83), 26 pts:NACT, 6 pts: CRT, followed till January 2005. 26 pts:NACT, 6 pts: CRT, followed till January 2005.

40

REMEDİASTİNOSCOPYREMEDİASTİNOSCOPYResultsResults 5 false negative reMS5 false negative reMS Sensitivity 71 %, specifity Sensitivity 71 %, specifity

100 %, accuracy 84 % 100 %, accuracy 84 % Mean survivalMean survival : 21 months : 21 months ReMS positivity : 7 months, ReMS positivity : 7 months,

negativity: 41 months negativity: 41 months (p=0.003)(p=0.003)

False negative reMS : 24 False negative reMS : 24 monthsmonths

Positive and false negative Positive and false negative reMS : 8 monthsreMS : 8 months

PrognosisPrognosis : age,gender, : age,gender, histology and lymph node histology and lymph node status,status,

lymph node statuslymph node status is an is an important factor (p=0.015)important factor (p=0.015)

41

ReMS DiscussionReMS Discussion

ReMS is a valuable “restaging” procedure ReMS is a valuable “restaging” procedure following induction therapy.following induction therapy.

Prognosis is poor in patients with Prognosis is poor in patients with persistant widespread mediastinal persistant widespread mediastinal lymph nodes detected in ReMSlymph nodes detected in ReMS

42


Invasive restaging: Invasive restaging: EUS-FNA ?EUS-FNA ?

43

Transoesophageal US-guided fine needle aspiration Transoesophageal US-guided fine needle aspiration improves mediastinal staging in NSCLC patients with a improves mediastinal staging in NSCLC patients with a

normal mediastinum on CTnormal mediastinum on CT

Fernandez-Esparrach G, A.Gines, J.Belda et al.Fernandez-Esparrach G, A.Gines, J.Belda et al.

Lung Cancer 2006; 54: 35-40Lung Cancer 2006; 54: 35-40

In NSCLC patients with negative mediastinal lymph nodes on CT In NSCLC patients with negative mediastinal lymph nodes on CT EUS-FNA in mediastinal staging, EUS-FNA in mediastinal staging,

sen. 50%,spe. 100 %, sen. 50%,spe. 100 %,

PPV 100 %, NPV 88 %, accuracy 89 %,PPV 100 %, NPV 88 %, accuracy 89 %, EUS-FNA mediastinoscopy is more “cost-effective” than more EUS-FNA mediastinoscopy is more “cost-effective” than more

invasive methods like surgery.invasive methods like surgery. It should be known that lymph nodes can be small matastatic foci or It should be known that lymph nodes can be small matastatic foci or

micrometastases in NSCLC ( false negativity ) , and further new micrometastases in NSCLC ( false negativity ) , and further new techniques are required to determine them!!techniques are required to determine them!!

Wallace MB et al. Ann Thorac Surg 2004, Leblanc JK et al. Am J Respir Crit Care Med 2005, Toloza EM et al. Chest 2003 Eloubeidi MA et al. Ann Thorac Surg 2005

44

Molecular diagnostics of NSCLC using on mediastinal lymph Molecular diagnostics of NSCLC using on mediastinal lymph nodes sampled by endoscopic US - guided needle nodes sampled by endoscopic US - guided needle

aspirationaspiration

M.Al-Haddad and M.B.WallaceM.Al-Haddad and M.B.Wallace

Cytopathology 2006;17:3-9Cytopathology 2006;17:3-9

On the follow-up period after curative surgical resection, 5-On the follow-up period after curative surgical resection, 5-year survival in stage l disease (No) is only 62 % , and in year survival in stage l disease (No) is only 62 % , and in stage ll (N1), it is 42 %.stage ll (N1), it is 42 %.

Metastatic disease in the majority of patients with NSCLC Metastatic disease in the majority of patients with NSCLC can be overlooked in spite of histologic examinations .can be overlooked in spite of histologic examinations .

Recent studies have shown that serial sections and Recent studies have shown that serial sections and immunohistochemical stains increase sensitivity in the immunohistochemical stains increase sensitivity in the detection of metastatic disease. These techniques are time detection of metastatic disease. These techniques are time consuming, expensive and can’t be used routinely yet!!consuming, expensive and can’t be used routinely yet!!

45

Molecular StagingMolecular Staging Molecular characterization of lymph node tissue is a new Molecular characterization of lymph node tissue is a new

research field. research field. Early micrometastases in lymph nodes can’t be detected by Early micrometastases in lymph nodes can’t be detected by

standard cytologic or histologic methods. standard cytologic or histologic methods. The majority of tumour cells can be detected by the presence of The majority of tumour cells can be detected by the presence of

proteins specific to pulmonary epithelium cell or mRNA analyses proteins specific to pulmonary epithelium cell or mRNA analyses in lymph nodes.in lymph nodes.

Micrometastases are detected by the molecular techniques: Micrometastases are detected by the molecular techniques: “immunohistochemistry or reverse transcriptase-polymerase “immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR) ”. Various “markers’’ like telomeraz, and chain reaction (RT-PCR) ”. Various “markers’’ like telomeraz, and KS ¼ showing metastatic disease in cytopathologically negative KS ¼ showing metastatic disease in cytopathologically negative lymph nodes using this method. lymph nodes using this method.

Micrometastases have been detected by molecular techniques in Micrometastases have been detected by molecular techniques in over 50 % of patients with histologically normal lymph nodes in over 50 % of patients with histologically normal lymph nodes in this study. this study. Presence of micrometastases in patients with Presence of micrometastases in patients with histopathologically normal lymph nodes has significant histopathologically normal lymph nodes has significant effect on long term survival.effect on long term survival.

Mori M et al. Cancer Res 1995 Wallace MB et al. Am J Respir Crit Care Mori M et al. Cancer Res 1995 Wallace MB et al. Am J Respir Crit Care Med 2003 Wallace MB et al. Chest 2005Med 2003 Wallace MB et al. Chest 2005

46

Molecular StagingMolecular Staging

RT-PCR and gene marker expressionRT-PCR and gene marker expression Presence of malignant cells with epithelial derived Presence of malignant cells with epithelial derived

mRNA transcripts in lymphoid cells which are mRNA transcripts in lymphoid cells which are normally absent in lymph nodes , for example : normally absent in lymph nodes , for example : cytokeratine , mucopolysaccaride (MUC1 transcript), cytokeratine , mucopolysaccaride (MUC1 transcript), lunx, KS ¼ (Ber-EP4), EGFR and hTERT genes, p53 lunx, KS ¼ (Ber-EP4), EGFR and hTERT genes, p53 and K-rasand K-ras positivity: Metastatic cells origined from the positivity: Metastatic cells origined from the epithelium are present in lymph nodes and is epithelium are present in lymph nodes and is associated with poor survival.associated with poor survival.

Presence of these markers is important for Presence of these markers is important for recurrence and survival!!recurrence and survival!!

Salerno CT et al. Chest 1998, Hashimoto T et al. Cancer Res 2000, Iwao K et al. Int J Cancer 2001, Perez MS et al. J Immunol 1989,Latza U et al. J Clin Pathol 1990. Saretzki G et al. Cancer Lett 2002. Han S-W et al. J Clin Oncol 2005

47


Customizing Customizing

““IndividualIndividual”Chemotherapy”Chemotherapy

48

PhPharmaarmaccogenomiogenomicscs : : A reality or A reality or still a promise ?still a promise ?

Gerold BeplerGerold Bepler. . Lung Cancer 2006: 54 Lung Cancer 2006: 54 ((suppl 2suppl 2):): 3-7 3-7

49

Genomic abnormalities in lung cancerGenomic abnormalities in lung cancer

The most important types of genetic disorders in cancer : Structural The most important types of genetic disorders in cancer : Structural disorders of the chromosomes formed during the repair of DNA disorders of the chromosomes formed during the repair of DNA double helical hybrid damage like “deletion, substitution and double helical hybrid damage like “deletion, substitution and additions”.additions”.

Loss of Loss of HeteroHeterozyzygogositysity (LOH) anal (LOH) analysis, is the most common used ysis, is the most common used technique to measure technique to measure geneti genetic disorders.c disorders.

Several chromosome (Several chromosome ( 3, 5, 8, 9, 11 ve 17 3, 5, 8, 9, 11 ve 17.. chromosomeschromosomes ) loci with ) loci with frequent LOH were determined by molecularfrequent LOH were determined by molecular geneti geneticc studiesstudies..

Frequent allele loss at chromosome 11p15.5 in NSCLC, increased Frequent allele loss at chromosome 11p15.5 in NSCLC, increased the investigations determining and characterizing the tumour the investigations determining and characterizing the tumour suppressor genes associated with the development and progression suppressor genes associated with the development and progression of this disease.of this disease.

Loss of Loss of HeteroHeterozyzygogositysity in this area in NSCLC affected the prognosis in this area in NSCLC affected the prognosis of the patient and was a highly effective determinant of poor of the patient and was a highly effective determinant of poor

survival.survival.

50

RRM1RRM1 RRM1 is a tumour suppressor gene at 11p15.5 locus.RRM1 is a tumour suppressor gene at 11p15.5 locus. RRM1 (RRM1 (=ribonu=ribonuccleotidleotidee redu reducctatasese M1 M1) gene was shown) gene was shown

to inhibit the formation, migration and invasion of to inhibit the formation, migration and invasion of metastasis metastasis

to be a good prognostic factor in prediction of survival in to be a good prognostic factor in prediction of survival in NSCLC in invivo and invitro studies.NSCLC in invivo and invitro studies.

This This h hypothesis was investigated in ypothesis was investigated in re resectedsected NSCLC NSCLC patientspatients withwith retros retrospectivepective/prospe/prospectivective data and low data and low RRM1RRM1 levels were found to be a significant biological levels were found to be a significant biological and clinical determinator of and clinical determinator of malign malignantant behaviourbehaviour ..

O’Briant K O’Briant K et alet al, Anticancer Res 1997;17:3243-52, Anticancer Res 1997;17:3243-52, , Gautam A Gautam A et alet al, Oncogene 2003; 22: 2135-42, Oncogene 2003; 22: 2135-42Gautam A Gautam A et alet al, Cancer Res 2006; 66: 6497-502, Cancer Res 2006; 66: 6497-502,, Bepler G Bepler G et alet al, J Clin Oncol 2004; 22: 1878-85, J Clin Oncol 2004; 22: 1878-85

52

RRM1 RRM1 andand Gem Gemccitabinitabinee Congenital or acquired resistance of tumours against cyCongenital or acquired resistance of tumours against cytostatitostaticc

agents is an important agents is an important clinical problemclinical problem. .

Currently, several studies have lightened the probable Currently, several studies have lightened the probable association between association between RRM1 RRM1 expression and increasing resistance expression and increasing resistance to antimetabolite to antimetabolite GemGemccitabinitabine in NSCLCe in NSCLC

RR (ribonuRR (ribonuccleotidleotidee redu reducctatasese) ) is an enzyme which plays a role in is an enzyme which plays a role in DNA DNA synthesissynthesis andand which reverses which reverses ribonuribonuccleotidleotides required for es required for DNA DNA synthesis and repairsynthesis and repair. . 2 subgroups are 2 subgroups are RRM1 RRM1 and and RRM2RRM2..

The main determinator of Gemcitabine resistance is the increased The main determinator of Gemcitabine resistance is the increased expression of RRM1 . (Davidson et al. 2004).expression of RRM1 . (Davidson et al. 2004).

Bergman et al. , first showed gemcitabine resistance in in vivo Bergman et al. , first showed gemcitabine resistance in in vivo model in 2005 .model in 2005 .

RRM1 has been reported to play a significant role in determining RRM1 has been reported to play a significant role in determining the patient outcome (in improving the survival and treatment the patient outcome (in improving the survival and treatment response ) . response ) .

Bergman AM Bergman AM et alet al, Drug Resist Updat , Drug Resist Updat 2002;5:19-332002;5:19-33Davidson JD Davidson JD et alet al, Cancer Res , Cancer Res 2004;64: 3761-62004;64: 3761-6Bergman A Bergman A et alet al, Cancer Res , Cancer Res 2005;65: 9510-62005;65: 9510-6Bepler G Bepler G et alet al, J Clin Oncol , J Clin Oncol 20062006

54

RRM1-and ERCC1-based chemotherapy RRM1-and ERCC1-based chemotherapy selectionselection

If RRM1 is highly expressed, gemcitabine resistance increases, and if it If RRM1 is highly expressed, gemcitabine resistance increases, and if it is low, ıt becomes sensitive to gemcitabine.is low, ıt becomes sensitive to gemcitabine.

Increased RRM1 levels make the cells more sensitive to carboplatine .Increased RRM1 levels make the cells more sensitive to carboplatine . These data are important for combined treatments with platine !! These data are important for combined treatments with platine !! 2 retrospective studies2 retrospective studies

1. study: stage IV NSCLC, Gem+ Cis treatment, RRM1 mRNA 1. study: stage IV NSCLC, Gem+ Cis treatment, RRM1 mRNA expression is measuredexpression is measured

2. study ERCC1 (=excision-repair cross-complementing grup 1) 2. study ERCC1 (=excision-repair cross-complementing grup 1)

cisplatine activity related gene wascisplatine activity related gene was measuredmeasured

Bepler JCO 2006, Rosell R Oncogene 2003 , Rosell R Clin Can Res 2004Bepler JCO 2006, Rosell R Oncogene 2003 , Rosell R Clin Can Res 2004Reed E C Can Res 2005, Lord RV C Can Res 2002, Soria J JCO 2006Reed E C Can Res 2005, Lord RV C Can Res 2002, Soria J JCO 2006

55

The relation of extended survival following The relation of extended survival following cisplatin+gemcitabin CT with low ERCC1 cisplatin+gemcitabin CT with low ERCC1

expression in NSCLCexpression in NSCLC

R.V.N Lord, J Brabender, D Gandara et al.R.V.N Lord, J Brabender, D Gandara et al. Clinical Cancer Research, 2002; 8: 2286-2291Clinical Cancer Research, 2002; 8: 2286-2291 ERCC1ERCC1mRNAmRNA expression levels in metastatic NSCLC following expression levels in metastatic NSCLC following

Gem+Cisp CTGem+Cisp CT Stage IIIB-IV NSCLC 56 ptsStage IIIB-IV NSCLC 56 pts ERCC1 expression in all patientsERCC1 expression in all patients No relation between ERCC 1 levels and age, gender, PS, weight No relation between ERCC 1 levels and age, gender, PS, weight

loss and stageloss and stage Mean survival is 44.7 % in patients with low ERCC1Mean survival is 44.7 % in patients with low ERCC1 Mean survivalMean survival

If ERCC1 is low, mean survival is longer ( 61,6 weeks)If ERCC1 is low, mean survival is longer ( 61,6 weeks) If it is high, shorter ( 20.4 weeks )If it is high, shorter ( 20.4 weeks )

DISCUSSIONDISCUSSION ERCC1 expression is the characteristic factor in survival following ERCC1 expression is the characteristic factor in survival following

Cis+Gem therapy in metastatic NSCLCCis+Gem therapy in metastatic NSCLC

57

Treatment of non-small –cell lung cancer andTreatment of non-small –cell lung cancer and

pharmacogenomics:Where we are and where we are going pharmacogenomics:Where we are and where we are going R.Rosell, Cuello M, Cecere F et al.R.Rosell, Cuello M, Cecere F et al.

Current Opinion in Oncology. 2006;18: 136-43Current Opinion in Oncology. 2006;18: 136-43 1993-99, 1436 pts, stage IIIB-IV , platine based paclitaxel,1993-99, 1436 pts, stage IIIB-IV , platine based paclitaxel, Docetaxel, Vinorelbine or Gemcitabine combined therapyDocetaxel, Vinorelbine or Gemcitabine combined therapy Response rates: 20 %, mean survival 8.2 months, Response rates: 20 %, mean survival 8.2 months,

1-2 year survival 33 % - 11%1-2 year survival 33 % - 11% Low PS 0 is the most important prognostic factorLow PS 0 is the most important prognostic factor Cisplatine resistance is associated with increased expression of ERCC1 Cisplatine resistance is associated with increased expression of ERCC1

gene.gene. Investigation of the role of ERCC1 mRNA levels in patients with Investigation of the role of ERCC1 mRNA levels in patients with

metastatic NSCLC treated with Gem+Cis : response rate in patients with metastatic NSCLC treated with Gem+Cis : response rate in patients with low ERCC1 mRNA is 52 %, and 36 % in cases with higher ERCC1 and low ERCC1 mRNA is 52 %, and 36 % in cases with higher ERCC1 and the difference is not significant.the difference is not significant.

If cut-off value for ERCC1 expression is 5.8 , survival is 15 months for If cut-off value for ERCC1 expression is 5.8 , survival is 15 months for low levels and it is only 5 months for high levels (p< 0.001).low levels and it is only 5 months for high levels (p< 0.001).

58

CUSTOMİZİNG CHEMOTHERAPYCUSTOMİZİNG CHEMOTHERAPY More than 400 pts, 2 armsMore than 400 pts, 2 arms Control: Docetaxel+CisplatineControl: Docetaxel+Cisplatine ExperimentalExperimental

For low ERCC1 mRNA: Doce+ CisFor low ERCC1 mRNA: Doce+ Cis For high levels: Doce+ GemcitabineFor high levels: Doce+ Gemcitabine

Control response rates: 56.6 %, other 40.4 %Control response rates: 56.6 %, other 40.4 %

BRCA1 levelsBRCA1 levels and cisplatin resistance : If DNA repair gene levels are and cisplatin resistance : If DNA repair gene levels are high, survival is poor and there is resistance to cisplatine.high, survival is poor and there is resistance to cisplatine.

K-ras mutationsK-ras mutations Adjuvant therapy in Stage II (vino+cis) increase in survival, follow-Adjuvant therapy in Stage II (vino+cis) increase in survival, follow-

up group 41months, CT group 80 months, if ras mutations are up group 41months, CT group 80 months, if ras mutations are positive, there is no advantage for survival with Adj.CT positive, there is no advantage for survival with Adj.CT

In 20 % of NSCLC, primarily correlated with Adeno Ca and poor In 20 % of NSCLC, primarily correlated with Adeno Ca and poor prognosis.prognosis.

60

CUSTOMİZİNG CHEMOTHERAPYCUSTOMİZİNG CHEMOTHERAPY

Detection of molecular Detection of molecular markers is helpful in markers is helpful in prediction of treatment prediction of treatment response, and this response, and this leads to widespread leads to widespread use of personalized “ use of personalized “ Individual” CT which is Individual” CT which is a new approacha new approach

R.Rosell et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic NSLC. R.Rosell et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic NSLC. Oncogene 2003;22:3548-53.Oncogene 2003;22:3548-53.

61

CUSTOMİZİNG CHEMOTHERAPYCUSTOMİZİNG CHEMOTHERAPY

Genetic markers which determine the response to Genetic markers which determine the response to chemotherapeutic agents chemotherapeutic agents Beta-tubulin IIIBeta-tubulin III ( Paclitaxel resistance ) ( Paclitaxel resistance ) Stathmin Stathmin (sensitive to vindesine)(sensitive to vindesine) RRM1RRM1 (Gemcitabine resistance) low levels : longer (Gemcitabine resistance) low levels : longer

survivalsurvival COX-2 and GSTP1 expression has no COX-2 and GSTP1 expression has no

association with survival.association with survival.

R.Rosell et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic NSLC. R.Rosell et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic NSLC. Oncogene 2003;22:3548-53.Oncogene 2003;22:3548-53.

63

NSCLC - TargetsNSCLC - Targets

Response to CT ve RT shows a plateauResponse to CT ve RT shows a plateau

Toxicity problemsToxicity problems

Agressive nature of the diseaseAgressive nature of the disease

Targeted therapiesTargeted therapies

64

Targets in NSCLCTargets in NSCLC

65

Targets in NSCLCTargets in NSCLC

66

INTACT 1-2 INTACT 1-2

(Result)(Result)

The addition of Gefitinib The addition of Gefitinib to CT has no effect on to CT has no effect on response rate and response rate and survivalsurvival

It provides a survival It provides a survival advantage in subtype of advantage in subtype of adenocarcinomaadenocarcinoma

It doesn’t increase the It doesn’t increase the toxicity of CTtoxicity of CT

TALENT ve TRIBUTETALENT ve TRIBUTE

(Result)(Result)

The addition of Erlotinib to The addition of Erlotinib to CT has no effect on CT has no effect on response rate and survivalresponse rate and survival

In subgroup analysis, it In subgroup analysis, it provides a survival provides a survival advantage in non-smokers advantage in non-smokers and in cases with EGFR and in cases with EGFR mutationmutation

It doesn’t increase the It doesn’t increase the toxicity of CTtoxicity of CT

67

Non-smokers (% 50.8)Non-smokers (% 50.8) Former or current smokers (Former or current smokers (99 %) %)

Women (Women (37.537.5 %) %)

Men (Men (113 %)3 %)

AdenoAdenoccararccinominomaa ((31.331.3 %) %)

Non-adeno Non-adeno ((2.32.3 %) %)

In AsiansIn Asians ((29.129.1%)%)

In Non-Asians (In Non-Asians (7.97.9 % ) % )

EGFR TK Mutations (Fenotip)EGFR TK Mutations (Fenotip)

Pao W, Miller VA. J Clin Oncol. 2005, 10:2556-68. Shepherd, F. et al. N Engl J Med 2005;353:123-132

68

Anti-EGFR Therapy:Anti-EGFR Therapy:Predictive factorsPredictive factors

Gender (F>M)Gender (F>M) Asian raceAsian race AdenocarcinomaAdenocarcinoma Development of rash Development of rash Non-smokerNon-smoker Mutation at Exon 19-21Mutation at Exon 19-21 EGFR gene amplificationEGFR gene amplification

69

EGFR MutationEGFR Mutation

Takano T, et al. J Clin Oncol. 2005;23:6829-6837.

70

EGFR MutationsEGFR Mutations

TRIBUTE TRIBUTE (Pacli+Carbo+/- Erlotinib):+ (Pacli+Carbo+/- Erlotinib):+ Better response (53 % / 21 %, progression time 12.5/ 6.6 Better response (53 % / 21 %, progression time 12.5/ 6.6

months)months) K-ras mutationsK-ras mutations: +: +

Response in Erlotinib group: 8 %, in CT group 23%Response in Erlotinib group: 8 %, in CT group 23% Oestrogen and progesteron receptorsOestrogen and progesteron receptors

EGFR protein expression is related with decreased response EGFR protein expression is related with decreased response to to oestrogen oestrogen (poor response)(poor response)

Progestrone receptor immune reactivity is associated with Progestrone receptor immune reactivity is associated with better clinic.better clinic.

71

Anti-EGFR treatment: ResistanceAnti-EGFR treatment: Resistance

72

Anti-angiogenic therapiesAnti-angiogenic therapies

Monoclonal antibodiesMonoclonal antibodies Bevacizumab (Avastin, RhuMAb VEGF)Bevacizumab (Avastin, RhuMAb VEGF)

Small moleculesSmall molecules SunitinibSunitinib

SorafenibSorafenib

ZD6474ZD6474

73

NSCLC ConclusıonNSCLC Conclusıon

TreatmentTreatment

PeriodPeriod

Survival resultsSurvival results

MedMediianan Surv.Surv.

(months)(months)

11 year surv. year surv.((%%))

2 2 year surv.year surv. ((%%))

1980s1980s 4-64-6 1010 ----

20002000 88 30-3530-35 10-1510-15

20052005 1212 5050 2020

20102010 ?? ?? ??

74

NSCLC Conclusıon NSCLC Conclusıon (Slow, but stabil development)(Slow, but stabil development)

Treatment Treatment

PeriodPeriod

Survival resultsSurvival results

MedMediianan surv.surv.

(months)(months)

1 1 year surv.year surv.

((%%))2 2 year surv.year surv.

((%%))

1980s1980s 4-64-6 1010 ----

20002000 88 30-3530-35 10-1510-15

20052005 1212 5050 2020

20102010Personalized therapy andPersonalized therapy and

Combined Targeted TherapyCombined Targeted Therapy

75

Advanced stage NSCLC Treatment Algorythm Advanced stage NSCLC Treatment Algorythm (Genotype Based Treatment)(Genotype Based Treatment)

PSPS

3-43-4

0-20-2

( - )( - )

TreatmentTreatment

Non-smoker

EGFR mut. (+)

High Gene Copy

Non-smoker

EGFR mut. (+)

High Gene Copy

( + )( + ) EGFR InhibitorEGFR

Inhibitor

BSCBSC

ERCC-1ERCC-1

HighHigh

LowLow CT with cisCT with cis

CT without cisCT without cis

BRCA-1 ↑BRCA-1 ↑Anti-microtubulePaclit/Doce/vinor

Anti-microtubulePaclit/Doce/vinor

14-3-3 gen del14-3-3 gen del GemcitabineGemcitabine

Timidylate Synthase Timidylate Synthase PemetrexedPemetrexed

Anti-angiogenic therapyAnti-angiogenic therapy

↓

lung cancer 2006

Documents

lung cancer women

lung cancer restaging

smoking lung cancer

socinskilung cancer

ebbert jo lung cancer

goodman mt cancer

smoker women

nonsmokers women