ca cx biological markers

8/12/2019 CA CX Biological Markers

1/38

PROGNOSTIC CELL BIOLOGICAL

MARKERS IN CARCINOMA

CERVIX PATIENTS PRIMARILY

TREATED BY CHEMORADIATION

Dr Mayur Mayank14.04.2011

JOURNAL CLUB


2/38

Ref :International Journal of Radiation Oncology Biology Physics Vol 79No 2 2011

Article : PROGNOSTIC CELL BIOLOGICAL MARKERS IN CERVICALCANCER PATIENTS PRIMARILY TREATED WITH ( CHEMO )

RADIATION : A SYSTEMIC REVIEW

Authors : Maartje G Noordhuis , Jasper J H Eijsink , Frank Roossink ,Pauline De Graeff , Elisabeth Pras , Ed Schuuring , G Bea A Wisman ,Geertruida H de Bock , Ate G J Van der Zee


3/38


4/38

TREATMENT

Early Stage Ca Cervix may be treated bySurgery alone followed by regular follow upto check for any recurrences.

Standard treatment modality of Locallyadvanced cases of Ca Cervix is concurrentPlatinum based Chemo radiation. Thismodality has a 5-yr survival rate of around66%.


5/38

Currently, the most important prognostic factors in advanced

stage cervical cancer primarily treated by chemo radiation are :

- Stage of the disease- Tumor Histology

Newer Biological markers have being linked to the survivaland/or response in patients who have primarily been treated bychemo radiation.

These biological markers are the ones which are involved intumorigenesis and tumor progression, like the genes involvedin apoptosis , angiogenesis , and cell growth.


6/38

Method used for the analysis

Publications from PubMed, Embase, and Cochranewere searched & relevant articles were analyzed.

PubMed 1590 articles

Embase

808 articlesCochrane 0 articles

400 articles were common in both PubMed &Embrase and so a total no of 1998 primary searchstudies were identified.


7/38

1998 studiesPrimary search

1291 studiesAbstract evaluation

73 studiesUsed for data extraction

42 studies ( 82 cell biological markers )Used for systematic review

Exclusion criteria:

1. Publication concerning other tumors

(n=564)2. Non- English Publications ( n=143 )

Exclusion criteria:

1. No relation b/w cell biological

marker & tumor (n=856)2. Patient count


8/38

Total of 82 cell biological markers were selected for the reviewof their prognostic significance in patients treated by chemo

radiation.

These markers were studied under the various Subgroups :

- Angiogenesis & hypoxia markers- Apoptosis markers- Cyclooxygenase 2

- EGFR pathway markers

- HPV markers- Proliferation markers

- Serum Tumor markers


9/38

Out of these markers, 34 cell biological markersshowed a relationship with survival in Univariate

analysis.

Another 26 cell biological markers were

independently associated with survival in

Multivariate analysis.


10/38

Angiogenesis & hypoxia markers

Angiogenesis is essential for the growth & progression of thetumor.

Adaptation of the tumor to hypoxia also leads to a moremalignant phenotype, or to poor response to treatment withradiotherapy.

Markers which were studied are :

Hypoxia Inducible Factor-1 a ( HIF-1a )

Hypoxia Inducible Factor-2 a/CD 68 ratio ( HIF-2a/CD68 )

Vascular endothelial growth factor ( VEGF )Thymidine phosphorylase

Nitric oxide synthase ( iNOS )

Carbonic anhydrase 9 ( CA 9 )

Carbonic anhydrase 12 ( CA 12 )


11/38

HIF-1a Poor PrognosisPoor Survival

HIF-2a/CD68 Poor DFS but not poor DSS

Thymidine phosphorylasePoor DSS & MFS butnot with local control

iNOS Poor Survival

CA 9 Poor DFS,DSS,MFS,OS

VEGFCA 12

No conclusive evidence ofrelation to prognosis

DFS- Disease Free Survival ; DSS- Disease specific survival ; MFS- Metastasis free survival ; OS- Overall Survival


12/38

Out of all the Angiogenesis andhypoxia markers studied, expression

of HIF

1a and CA 9 are especiallyassociated with a poor prognosis.


13/38

Apoptosis Markers

The markers studied in this aspect were :

Bcl-2 ( Inhibitor of apoptosis )

Bax ( Pro-apoptotic )

Bid ( Pro-apoptotic )TRAIL to its death receptors DR 4 , DR 5

p53 ( Pro-apoptotic )

( TRAIL - Tumor necrosis factor Related Apoptosis Inducing Ligant )


14/38

Bcl-2 Poor DFS

Bax Good DFS

TRAIL DR 4, DR 5

p53

No relation

There was no convincing evidence that apoptoticmarkers have prognostic significance in Ca Cervix


15/38

Cyclooxygenase-2

Involved in the conversion of Arachidonic acid toProstaglandins.

Involved in Inflammation

Also over expressed in Ca Cervix and associated withinhibition of apoptosis & promotion of angiogenesis.

COX-2 Inhibition enhances tumor response toradiotherapy.

Over expression was found to be related to poor survival.


16/38

EGFR pathway markers

EGFR pathway is related to carcinogenesis by inhibitionof apoptosis, cell growth, cell migration & angiogenesis. Italso confers resistance to radiation therapy.

The markers studied under this pathway were :

- Phosphorylated EGFR ( HER 1 )

- C erbB 2 ( HER 2 )

- Her3

- Her4

- AKT

- PTEN

PTEN : Phosphatase and Tensin Homologue on Chromosome Ten


17/38

Her1Her2

Coexpression of EGFR & Her2

Poor DFS & DSS

Her3 No relation to survival

Her4 Good DFS

pAKT No prognostic significance

PTENImmunostaining

Not asso with DSS & OS


18/38

Thus, among the EGFR pathway markers, highprotein expression of Phosphorylated EGFR(Her 1 ) and C-erbB-2( Her 2 ) are indicators ofpoor survival in patients of Ca Cervix primarilytreated by chemo radiation.


19/38

HPV markers

As almost all cervical cancers are HPV positive so

only HPV subtypes may be related to survival.

Many studies were performed with the variousHPV subtypes to get a correlation between HPVsubtype and its prognostic value.


20/38

Bachtiary et al.

Studied presence of HPV 16, 18, 31, 33, 45 & other HPVtypes ( 35, 56, 58, 76 )

1. HPV 33 was a poor prognostic factor2. Presence of more than one of the HPVsubtypes( 16, 18, 31, 33, 35, 45, 56, 58 &76) was related to poor DSS & DFS

Reported


21/38

Ishikawa et al.

Studied the presence of HPV subtypes 16, 18, 33

Found NO RELATION

Harima et al.

Studied presence oh HPV subtypes ( 6, 16, 18, 31, 33, 35, 52, 56, 58/59)

Found the presence to be related to Good OS & DFS


22/38

Because of thediscrepancies between the

various studies performed,the value of HPV as aprognostic marker is

DOUBTFUL


23/38

Proliferation Markers

The various tumor proliferation markers which

were studied were :

- Bromodeoxyuridine ( BrdU )

- MIB 1 ( Monoclonal Ab against KI 67 )

- Mitotic Index

- Apoptotic Index/Mitotic Index Ratio


24/38

BrdU LI

Poor DFS ( not with OS ) NO prognostic impact

Flow cytometry Histological assessment

MIB 1 LI

Not associated with OS

Tsang et al.


25/38

High Mitotic Index

Good OS(in one of the two studies)

By Morphological Criteria

Apoptotic Index / Mitotic Index Ratio

Poor OS


26/38

Overall, there was NO convincingevidencefor a prognostic role of tumor

proliferation markers in patients of Ca

Cervix primarily treated by Chemoradiation.


27/38

Serum Tumor Markers

The markers studied under this were :

- SCC Ag ( Sq Cell Carcinoma Ag )- CEA


28/38

High levels of SCC Ag

Poor Survival

CEA> 10 ng/ml

Poor Survival


29/38

Miscellaneous Cell Biological Markers


30/38


31/38

Independent prognostic cell

biological markers

In total, 36 biological markers were studied in themultivariate model, out of which, 26 showed anindependent association with survival.


32/38


33/38


34/38

Marker Method Treatment Univariate

Response

Multivariate

Response

HIF 1 a IHC RT Poor

HIF 2a/CD 68ratio

IHC RT/CRT Poor

P63 IHC CRT Poor

P53 Mutations PCR RT LDFS Poor

TRAIL IHC RT/CRT No relation Poor

COX 2 IHC CRT Poor Poor

EGFR/COX 2coexpression

IHC CRT Poor


35/38

Marker Method Treatment Univariate

Response

Multivariate

Response

C-erbB-2 IHC RT/CRT LDFS Poor

EGFR IHC RT/CRT LDFS Poor

EGFR/C-erbB-2coexpression

IHC RT/CRT LDFS Poor LDFS Poor

pEGFR ( Her 1 ) IHC RT/CRT LDFS Poor LDFS Poor

Adj brdUrd LI FC RT Response PoorLDFS Poor

Poor

TGF b1 ELISA RT LDFS Poor

b3- integrin IHC RT LDFS Poor LDFS Poor


36/38


37/38

There was no relationship found with the markers ofApoptosis, HPV subtypes, and Proliferation markers.

The new biological markers can be used as Targetpathways, and in combination with chemoradiation,may help in improvement of survival in advanced stageCa Cervix patients.


38/38

THANK YOU

ca cx biological markers

Documents