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“Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers associated with bladder cancer progression: a potential tool for individualized therapy?

“Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

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Page 1: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

“Regina Elena” National Cancer Institute

Michele Gallucci

Anna Cianciulli

Highlights in the management of

Urogenital Cancer

Rome, May 9-10 2008

Biomarkers associated with bladder cancer progression: a potential tool for

individualized therapy?

Page 2: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Multivariables Multivariables prognostic modelprognostic model

Pathological variablesPathological variables

Michele GallucciMichele Gallucci

Biological markersBiological markers

Anna CianciulliAnna Cianciulli

Page 3: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

70 % of Ta bladder tumours70 % of Ta bladder tumours

7% of these are G3 tumours (WHO 7% of these are G3 tumours (WHO 1973)1973)

CISCIS 5-10% 5-10%

R. J. SILVESTER TSW UROLOGY (2006) 1 (S2), 15-23

Pathological prognostic factorsPathological prognostic factors

Page 4: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Pathological prognostic Pathological prognostic factorsfactors

5 years follow up 5 years follow up

906 TURB Ta-T1 906 TURB Ta-T1

47% of the patients recurred47% of the patients recurred

9 % progressed to muscle invasive 9 % progressed to muscle invasive diseasedisease

1/3 of patients with 1/3 of patients with CISCIS died died

R. J. SILVESTER TSW UROLOGY (2006) 1 (S2), 15-23

Page 5: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CLINICAL CLINICAL PROGRESSIONPROGRESSION

Page 6: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers
Page 7: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers
Page 8: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

HYSTOLOGYHYSTOLOGY

UROTHELIUMUROTHELIUM

LAMINA PROPRIALAMINA PROPRIA MEAN DEEP 1.4 mm *MEAN DEEP 1.4 mm *

MUSCULARIS MUCOSAE/MUSCULARIS MUCOSAE/ VESSELSVESSELS

SUBMUCOSASUBMUCOSA

MUSCULARIS PROPRIAMUSCULARIS PROPRIA * * Cheng L. et al., Cancer 1999; 85: 2638 - 47Cheng L. et al., Cancer 1999; 85: 2638 - 47

Page 9: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

INVASIVE UROTHELIAL INVASIVE UROTHELIAL CARCINOMACARCINOMA

SUBSTAGING OF T1 DISEASESUBSTAGING OF T1 DISEASE

T1a: T1a: tumors above or into muscularis tumors above or into muscularis mucosaemucosae

(or large vessels).(or large vessels).

T1b: T1b: tumors below muscularis mucosaetumors below muscularis mucosae

(or large vessels). (or large vessels).

Page 10: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

T1T1 SUBSTAGINGSUBSTAGING

T1aT1a

MUSCULARIS MUCOSAEMUSCULARIS MUCOSAE

muscularis propriamuscularis propria----------------------------------------------------------------------------------------------------------------------------------------

T1bT1b MUSCULARIS MUCOSAEMUSCULARIS MUCOSAE

muscularis propriamuscularis propria

Page 11: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

INVASIVE UROTHELIAL INVASIVE UROTHELIAL CARCINOMACARCINOMA T1a T1a

Page 12: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

INVASIVE UROTHELIAL INVASIVE UROTHELIAL CARCINOMACARCINOMA T1b T1b

Page 13: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

INVASIVE UROTHELIAL INVASIVE UROTHELIAL CARCINOMACARCINOMA T2 T2

Page 14: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

INVASIVE UROTHELIAL INVASIVE UROTHELIAL CARCINOMACARCINOMA

TUMORS INVADING BEYOND TUMORS INVADING BEYOND THE MUSCULARIS MUCOSAE THE MUSCULARIS MUCOSAE

TEND TO BEHAVE LIKE TEND TO BEHAVE LIKE MUSCULARIS PROPRIA MUSCULARIS PROPRIA

INVASIVE (T2) TUMORS.INVASIVE (T2) TUMORS.

Epstein JI et al. in Bladdere biopsy interpretation. Ed. Lippincott Epstein JI et al. in Bladdere biopsy interpretation. Ed. Lippincott Williams & Wilkins, 2004, pag. 95. Williams & Wilkins, 2004, pag. 95.

Page 15: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

T1a and T1b as variables predictive of T1a and T1b as variables predictive of disease progressiondisease progression

staging number of cases progression staging number of cases progression raterate

1994 1994 Hasui et al. Hasui et al. T1a T1a 60 60 6.76.7 T1b T1b 28 28 53.553.5 1997 1997 Holmang et al. Holmang et al. T1a T1a 26 26 3636 T1b T1b 38 5838 58

1999 1999 Cheng et al. Cheng et al. T1a T1a 23 1123 11 T1b T1b 21 3221 32

2000 2000 Kondylis et al. Kondylis et al. T1a T1a 32 2232 22 T1b T1b 17 2917 29

2003 2003 Trias et al. Trias et al. T1a T1a 11 911 9 T1b T1b 13 13

30.730.7

2005 2005 Orsola et al. Orsola et al. T1a T1a 25 825 8 T1b T1b 34 3434 34

Page 16: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CARCINOMA IN SITUCARCINOMA IN SITU

CARCINOMA OF THE BLADDERCARCINOMA OF THE BLADDERINVADING THE MUSCULARISINVADING THE MUSCULARISMUCOSAE MUCOSAE (T1b)(T1b) ASSOCIATED ASSOCIATEDWITH WITH CISCIS HAVE AN INCREASED HAVE AN INCREASED RISK OF PROGRESSIONRISK OF PROGRESSION

Bernardini S et al., J Urol 2001; 165: 42 - 46Bernardini S et al., J Urol 2001; 165: 42 - 46

Page 17: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

T1 SUBSTAGINGT1 SUBSTAGING

SUBSTAGING OF T1 BLADDER SUBSTAGING OF T1 BLADDER CARCINOMA ACCORDING TO THE CARCINOMA ACCORDING TO THE DEPTH INVASION DEPTH INVASION (MEASURED BY (MEASURED BY

MICROMETER)MICROMETER) PROVIDES PROVIDES SIGNIFICANT PROGNOSTIC SIGNIFICANT PROGNOSTIC

INFORMATION, AND WE INFORMATION, AND WE RECOMMEND THAT IT BE RECOMMEND THAT IT BE

INCORPORATED INTO A FUTURE INCORPORATED INTO A FUTURE TNM SYSTEMTNM SYSTEM

Cheng L et al.: Substaging of T1 bladder carcinoma based on the depth of Cheng L et al.: Substaging of T1 bladder carcinoma based on the depth of invasion as measured by micrometer. Cancer 1999, vol. 15: 1036-1042invasion as measured by micrometer. Cancer 1999, vol. 15: 1036-1042

Page 18: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

IF THE BIOPSY ISIF THE BIOPSY IS SUPERFICIAL SUPERFICIAL ANDAND LACKS LACKS

MUSCULARIS PROPRIA, A SECOND MUSCULARIS PROPRIA, A SECOND BIOPSY BIOPSY

SHOULD BE CONSIDEREDSHOULD BE CONSIDERED

Epstein JI et al. in Bladder biopsy interpretation. Ed. Lippincott Epstein JI et al. in Bladder biopsy interpretation. Ed. Lippincott Williams & Wilkins, 2004, pag. 118 Williams & Wilkins, 2004, pag. 118

Page 19: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

UROTHELIAL CARCINOMA UROTHELIAL CARCINOMA

HISTOLOGICAL SUBTYPESHISTOLOGICAL SUBTYPES

UrotheliumUrothelium

Tubular variantTubular variant

Nested Nested

Page 20: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

MICROPAPILLARY CARCINOMAMICROPAPILLARY CARCINOMA

Ca in situCa in situ

Micropapillary Micropapillary carcinomacarcinoma

Page 21: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

‘‘SIGNET RING CELL TYPE’ UROTHELIAL SIGNET RING CELL TYPE’ UROTHELIAL CARCINOMACARCINOMA

Signet ring Signet ring cell cell

Page 22: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

SMALL CELL UROTHELIAL CARCINOMASMALL CELL UROTHELIAL CARCINOMA

Page 23: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers
Page 24: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Early vs. deferred cystectomy

Page 25: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Presence of CIS

Early cystectomy

Deferred cystectomy

Page 26: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Biological markersBiological markers

Page 27: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

To identify and monitor those

patients presenting with

superficial tumors who are likely to develop

recurrent or progressive

disease

To provide additional important

informations in patients with muscle invasive carcinomas

concerning their metastatic potential

and response to adjuvant regimens

BIOLOGICAL MARKERSBIOLOGICAL MARKERS

Page 28: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

PHENOTYPIC MARKERSPHENOTYPIC MARKERS

• Blood Group Antigens ( ABH antigens )

•Tumor Associated Antigens ( BTA, Nuclear Matrix Proteins)

•Proliferating Antigens ( Ki-67, Proliferating Cell Antigen)

•Cellular Adhesion Molecules (e-cadherin, integrin)

Page 29: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

GENOTYPIC MARKERSGENOTYPIC MARKERS

• CYTOGENETIC ALTERATIONS

•MOLECULAR ALTERATIONS OF ONCOGENES

•MOLECULAR ALTERATIONS OF TUMOR SUPPRESSOR GENES

Page 30: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers
Page 31: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

MOLECULAR ALTERATIONS OF ONCOGENES

MOLECULAR ALTERATIONS OF ONCOGENES

• H-ras

•c-myc

•mdm2

•c-erB-2

Page 32: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers
Page 33: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

MOLECULAR ALTERATIONS OF TUMOR SUPPRESSOR GENES

MOLECULAR ALTERATIONS OF TUMOR SUPPRESSOR GENES

Studies on loss of heterozygosity have identified specific allelic deletions in

many bladder cancer. The Rb gene(13q) and the p53 gene (17p) are the best studied tumor suppressor genes.

Page 34: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

RETINOBLASTOMA TUMOR SUPPRESSOR GENE

RETINOBLASTOMA TUMOR SUPPRESSOR GENE

“ Inactivation of the Rb gene is thought to be an important step in bladder

cancer progression “ ( Jung I et al, Cancer Control 2000 )

“ Patients with muscle invasive bladder tumors who had lost Rb expression had a

statistically significant shorter 5-year survival ( p=0.001) than those with

normal Rb protein expression “ ( Cordon-

Cardo et al., Scand J Urol Nephrol 2000)

Page 35: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

p53 TUMOR SUPPRESSOR GENEp53 TUMOR SUPPRESSOR GENE

“ Increased p53 immunoreactivity has been noted in higher grade and stage bladder cancers and is associated with disease progression, and decreased overall and disease specific survival

“ ( Chatterjee SJ et al, J. J Clin Oncol 2004 )

Page 36: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Richard J. Cote *, Ram H. Datar, 2006

Page 37: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

2007, BJU INT

Prospective evaluation of p53 as prognostic marker in T1 transitional cell carcinoma of the bladder

Page 38: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

p53 MUTATIONS: CHEMORESISTENCE VERSUS CHEMOSENSITIVITY

Gemcitabine is effective in TCC cell lines independent of p53 status. Urology 2003

Page 39: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers
Page 40: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Why are the results contradictory?

•One difference is methodological

•p53 affects a remarkable number of cellular processes. Perhaps defects in damage-induced checkpoints enhance chemosensitivity, whereas defects in apoptosis promote drug resistence

• Examination of p53 status alone cannot determine whether the p53 pathway is intact

Page 41: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

p21 TUMOR SUPPRESSOR GENEp21 TUMOR SUPPRESSOR GENE

“ Loss of p21 expression was strongly associated with an increased probability of

recurrence and decreased probability of survival in patients with lymphonode negative

organ confined and lymphonode negative extrabladder disease “

( Shariat SF, 2004)

Page 42: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Richard J. Cote *, Ram H. Datar, 2006

Page 43: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Normal Urotheliump53,EGF-R

Low-grade TCC

Ta

High-grade TCC

Ta

High-grade TCC

Superficial

Carcinoma in situ

Stage T1

Stage T2-4

Metastasis

9p-,9q- Rb-,p16, EGF-R, 17p,7

8p-,11p,erbb2

9p-,9q-

Rb-,8p-,3p

N+,M+

p53?

p53?

Page 44: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CHROMOSOME 9CHROMOSOME 9

The genes,p16 and p15, are found in tandem at p21

region.These genes encode members of

a new family of negative cell cycle regulators, which

product function as cyclin-dependent kinase inibitory

molecules

Page 45: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CHROMOSOME 7CHROMOSOME 7

Pycha et al reported that in patients with recurrence ,61% has

trisomy 7.

Other investigators have also shown that

increased copy number of

chromosome 7 is associated with

progression

Page 46: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CHROMOSOME 17CHROMOSOME 17

Cordon-Cardo et al, revealed that deletions of 17p occur only in invasive tumors and are involved in the progression of bladder cancer

Page 47: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Our experienceInterphase cytogenetics of bladder cancer progression ( Cianciulli et al., 2000)Genetic instability in superficial bladder cancer and adjacent mucosa

( Cianciulli et al., 2003)Genetic instability in advanced bladder cancer and adjacent mucosa

( Gallucci et al, 2005)

Adverse genetic prognostic profile identification ( Gallucci et al, 2007)

Page 48: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Interphase cytogenetics of bladder cancer progression: relationship between aneusomy, DNA ploidy pattern, histopathology and clinical outcome

Cianciulli et al.

Int J Clin Lab Res 2000

Interphase cytogenetics of bladder cancer progression: relationship between aneusomy, DNA ploidy pattern, histopathology and clinical outcome

Cianciulli et al.

Int J Clin Lab Res 2000

Page 49: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

The aims of this study were:

To gain more insight into genetic changes at the chromosomal level during

different histopathological stages

To compare the sensitivity of FISH and FCM for detection of disturbed DNA

content

To combine pathological variables with genetic markers in order to identify the

phenotypes likely to progress

Page 50: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Aneusomy(meanSD)

Chr.1 Chr.7 Chr.9 Chr.17

Diploid vs

Aneuploid

ns 0.012 ns 0.000

Ta vs T1 T1 vs T2-3

nsns

ns0.032

nsns

ns0.006

G1 vs G2G2 vs G3

nsns

ns0.052

nsns

0.051ns

Cystectomy

No vs Yes ns 0.024 ns 0.014

Recurrence

No vs Yes ns ns ns 0.001

p value; Mann-Whitney test70 patients

Page 51: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

p value

Chr.1 Chr.7 Chr.9 Chr.17

Loss ns ns ns ns

Poly ns 0.015 ns 0.051

Aneusomy ns 0.051 ns 0.005

Comparison between superficial (Ta-1) Comparison between superficial (Ta-1) and invasive (T2-3) bladder cancers and invasive (T2-3) bladder cancers

Comparison between superficial (Ta-1) Comparison between superficial (Ta-1) and invasive (T2-3) bladder cancers and invasive (T2-3) bladder cancers

p value Mann-Whitney test

Page 52: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

Occurrence and extent of numerical aberrations of chromosomes 7 and 17 may be associated with the evolution of

aggressive growth in bladder cancer and may be a useful indicator for survival. The presence or absence of markers of potential aggressiveness could

determine the course of treatment.

When we compared chromosome 1 and 9 aneusomy with pathological findings and clinical outcome, our results did not reveal statistically significant differences: this alteration is an

early event

Page 53: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

UROEPITHELIAL SUPERFICIAL CANCER

MultifocalityRecurrence

A B

Page 54: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

MULTIFOCALITY OF UROEPITHELIAL MULTIFOCALITY OF UROEPITHELIAL SUPERFICIAL CANCERSUPERFICIAL CANCER

“Field Cancerization“ Clonal Development

Page 55: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

GENETIC INSTABILITY IN SUPERFICIAL BLADDER CANCER AND ADJACENT MUCOSA: AN INTERPHASE

CYTOGENETIC STUDY

GENETIC INSTABILITY IN SUPERFICIAL BLADDER CANCER AND ADJACENT MUCOSA: AN INTERPHASE

CYTOGENETIC STUDY

Cianciulli et al., Human Pathology 2003

Page 56: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

The aim of this study was:

To evaluate genetic alterations as a possible reason for multifocality of

uroepithelial superficial cancer

To evaluate genetic alterations as a possible reason for multifocality of

uroepithelial superficial cancer

25 uroepithelial carcinomas

51 tissue samples taken from sites of macroscopically uninvolved urothelium (1cm and

controlateral wall)

Page 57: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CHROMOSOME 1 ANEUSOMY

0

20

40

60

80

BT NPM NDM

ME

AN

% SD

% MEAN

CHROMOSOME 7 ANEUSOMY

0

20

40

60

80

BT NPM NDM

ME

AN

% SD

% MEAN

CHROMOSOME 9 ANEUSOMY

0

20

40

60

80

100

BT NPM NDM

ME

AN

%

SD

% MEAN

CHROMOSOME 17 ANEUSOMY

0

20

40

60

80

BT NPM NDM

ME

AN

%

SD

% MEAN

BT vs NPM:p<0.050

BT vs NDM: p<0.016

BT vs NPM:p<0.050

BT vs NDM: p<0.006

BT vs NPM:p<0.032

BT vs NDM: p<0.004

BT vs NPM:p<0.032

BT vs NDM: p<0.001

Page 58: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CHROMOSOME 1 ANEUSOMY

0

20

40

60

80

100

BT PPM PDM

ME

AN

% SD

% MEAN

CHROMOSOME 7 ANEUSOMY

0

20

40

60

80

BT PPM PDM

ME

AN

% SD

% MEAN

CHROMOSOME 9 ANEUSOMY

0

20

40

60

80

100

BT PPM PDM

ME

AN

%

SD

% MEAN

CHROMOSOME 17 ANEUSOMY

0

20

40

60

80

100

BT PPM PDM

ME

AN

%

SD

% MEAN

BT vs PPM:p<0.033

BT vs PDM: p<0.042

BT vs PPM:p=ns

BT vs PDM: p=ns

BT vs PPM:p=ns

BT vs PDM: p=ns

BT vs PPM:p<0.041

BT vs PDM: p<0.047

Page 59: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

CONCLUSIONS

Our results demonstrate a close genetic relationship between all examined tumors and normal-appearing

mucosa

General genetic instability already present in the entire transitional epithelium at the time

of tumor occurrence is a reason for multifocality

Aneusomy of evaluated chromosomes, especially of chromosomes 7 and 9, may represent an intermediate

biomarker of bladder tumorigenesis and could be potentially useful in identifying patients prone to

metachronous or synchronous

Page 60: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

BA C

CASE 3

A: T1 G2Chr.1=50Chr.7=18Chr.9=58Chr.17=40

B: Normal UrotheliumChr.1=5Chr.7=18Chr.9=9Chr.17=20

C: Normal UrotheliumChr.1=6Chr.7=1Chr.9=16Chr.17=16

AB

C

CASE 17

A: TaG2Chr.1=40Chr.7=62Chr.9=6Chr.17=38

B: TaG1Chr.1=26Chr.7=52Chr.9=6Chr.17=3

C: FlogosisChr.1=7Chr.7=30Chr.9=5Chr.17=30

Correlation between mean percentage of aneusomic cells and histological classification (p=0.000,r=0.6)

A

B

C

A

B

C

Page 61: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

AB

CASE 18

A: T1 G3Chr.1=98Chr.7=9Chr.9=58Chr.17=95

B: CISChr.1=46Chr.7=48Chr.9=47Chr.17=62

C BA

CASE 24

A: T1G3Chr.1=40Chr.7=50Chr.9=42Chr.17=88

B: TaG3Chr.1=20Chr.7=46Chr.9=30Chr.17=36

C: FlogosisChr.1=50Chr.7=82Chr.9=80Chr.17=64

Correlation between mean percentage of aneusomic cells and histological classification (p=0.000,r=0.6)

AB

ABC

Page 62: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

48 tumors + 20 non –malignant tissue samples

•Evaluation of genetic characteristics and differences between malignant and no-malignant urothelium

•Evaluation of chromosomal and gene characteristics by stage and lymphonodal status

•The potential role of a panel of genetic markers in patients with advanced tumors that will accurately predict not only the course but also the response to therapy

Page 63: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

HISTOLOGICAL DIAGNOSIS

*14 with concomitant

Ca in situ

N°N° TUMORS*TUMORS* N° Distal N° Distal MucosaeMucosae

66 T1 G3 N0T1 G3 N0

T2a G3 N0 (n=5)T2a G3 N0 (n=5) 33

T2b G3 N0 (n=6)T2b G3 N0 (n=6) 22

1313 T2b G3 N2 (n=1)T2b G3 N2 (n=1) 22

T2b G3 N1 (n=1)T2b G3 N1 (n=1) 22

T3a G3 N0 (n=5)T3a G3 N0 (n=5) 55

T3a G3 N2 (n=3)T3a G3 N2 (n=3) 22

1818 T3b G3 N0 (n=5)T3b G3 N0 (n=5)

T3b G3 N1 (n=2)T3b G3 N1 (n=2)

T3b G3 N2 (n=3)T3b G3 N2 (n=3) 22

T4a G3 N0 (n=3)T4a G3 N0 (n=3) 22

T4a G3 N1 (n=3)T4a G3 N1 (n=3)

1111 T4a G3 N2 (n=3)T4a G3 N2 (n=3)

T4a G3 N3 (n=2)T4a G3 N3 (n=2)

Cianciulli et al.

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9p21(p16)

Cr.9

Cr. 13

13q14(RB)

Cr. 17

17p13.1(p53)

Cr.3 Cr.7

17q11.2-q12(HER2)

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Table 1

Cianciulli et al.

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TUMOR WITH CONCOMITANT CIS

(n=14)

TUMOR WITHOUT CONCOMITANT

CIS(n=34)

Chr.17 polysomy

(p= .042)

HER-2 amplification

(p= .040)

Tumor CIS

versus

TumorCIS

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*= median value

% DFS1-yr

*<=18 81,5 18>18 76,2 ns 15

*<=22 86,5 19>22 78 ns 15

*<=22 83,8 20>22 72,2 ns 17

*<=38 83,8 21>38 72,9 ns 16

*<=18 91,9 18>18 68 0,05 18

*<=26 80,2 18>26 73,3 22no 79,4 21yes 73,3 19no 100 10yes 71 24no 78,5 20yes 76,2 10

Chromosome 17 monosomy

RB heterozygous deletion

Paz tot

Chromosome 7 polysomy

Chromosome 9 monosomy

Chromosome 9 aneusomy

Chromosome 3 polysomy

p

p53 homozygous deletion ns

9p21 homozygous deletion

ns

ns

0,02

RB homozygous deletion

Disease -free Survival According to the Analysis of Genetic Markers

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TAKE HOME MESSAGES TAKE HOME MESSAGES

Chromosome 3, 7, 17 Chromosome 3, 7, 17 aneusomy and RB1 aneusomy and RB1

heterozygous deletion heterozygous deletion and 9p21 homozygous and 9p21 homozygous

deletion might be deletion might be potentially useful potentially useful

intermediate intermediate biomarkers to detect biomarkers to detect those patients at high those patients at high

risk of progression who risk of progression who may benefit from may benefit from

particular and particular and innovative therapeutic innovative therapeutic

interventionsinterventions

Larger , longterm with Larger , longterm with follow up are needed follow up are needed to assess the validy to assess the validy and clinical relevance and clinical relevance of these genetic of these genetic findingsfindings

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Predictors of good prognosis

Predictors of poor prognosis

MCA plot showing the projections of the five identified biological variable ( active information) and death ( passive information)

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Prognostic factors based model: the presence of two

variables significantly

impair overall survival!

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Page 77: “Regina Elena” National Cancer Institute Michele Gallucci Anna Cianciulli Highlights in the management of Urogenital Cancer Rome, May 9-10 2008 Biomarkers

New genetic information must be incorporated intocurrent schema to gain a better understanding of

tumorigenesis, biologic pathways and ultimate treatment outcomes.

Hopefully, it will soon be possible to use a panel of markers to identify patients at greatest risk for progression: that will significantly

improve the clinical management of cancer.