Prognostic Factors of Ovarian Cancer

7/31/2019 Prognostic Factors of Ovarian Cancer

1/68

Prognostic Factors ofOvarian Cancers

Prof.Veena AgrawalM.D., MICOG, WHO Fellow USA,Diploma in USG

Dept of Obstetrics. & Gynaecology

G.R.Medical College

Gwalior, M.P. INDIA

Dr R. Gautam


2/68

Ovarian cancer accounts for 32% of allgynecologic malignancies.

causes 55% of all gynecologic cancer

deaths. Over 75% of Ovarian Cancers cases

are diagnosed at an advanced stage.

5-year overall survival is 20-30%.Aljoa MANDI ET AL 2001

J.M. CLASSE et al 2004


3/68

Initial surgery is primodial.

In Stage IA and IB patients with grade Itumors do not require adjuvanttreatment.

Patients with stage greater than aboveare at high risk for recurrence, due tomicrometastatic disease, and should

thus undergo chemotherapy.


4/68

There is a wide spectrum of clinicalbehaviours from an excellent prognosisand high likelihood of cure to those with

rapid progression and poor prognosisirrespective of clinical stage of thedisease, most probably reflecting differentbiological properties of the tumour.


5/68

Prognostic Factors

Ethnicity & Race

Age

Stage of Disease

Histology

Tumor grade Tumor markers

Site-specificsurgical

treatment. Size of residual

disease

Tumor response


6/68

Ethnicity & Race

African-American women have a 30% greaterrisk and are more likely to die earlier whencompared to Caucasian women David Greenberg2004, JillS. Barnholtz-Sloan,2002

Non-Hispanic white women had age-adjustedincidence rates that were slightly higher(13.3/100,000) than rates for American

Indians (11.4) and Hispanics (10.7) over the24-year period. Schiff M et al 1996


7/68

Age

Advanced age remains an adverseprognostic factor even after adjustment fortreatment and comorbidity factors. O'Malley Cd et al2003,Chan JK et al Obstet Gynecol. 2003

Young patients have survival rates as high as75% across all stages, compared with 40% inthe overall population Rodriguez M,et al 1994,Lee CK,et al 1999

A ten year increase in age induces a 1.6times greater risk of death. Balvert-Locht et al. 1991, Markmanet al. 1993, Baker et al. 1994, Curtin et al. 1997, Eisenkop et al. 1998).


8/68

One age-related reason for anincreased risk of cancer may be anaccumulation of somatic cell mutations.

Loss of heterozygosity on chromosome17 (deletion of a proportion of achromosome containing a putativetumor suppressor gene) increases withagePieretti & Turker 1997


9/68

Stage of disease FIGO staging is "surgicopathologic

stage".

Most powerful predictor of prognosis

In many studies the patients are dividedinto two groups: early (Stage I and II)and advanced stage (stage III and IV),

because the survival in early stagedisease is significantly better than thatin advanced disease.


10/68

Stage IA and IB patients with grade Itumors have a 5-year survival of over90%

Despite the high response rates of initialtreatments (i.e.,70-80%), the medianprogression-free survival of advanced

ovarian cancer is 16-22 months, and the5-year overall survival is20-30%.


11/68

Factors correlate with poorprognosis in same stage

In early stage are histopathological type(serous vs. non-serous), degree or grade ofdifferentiation, the presence of denseadhesions, large volume ascites andspontaneous rupture of a cyst (Malkasian et al. 1984, Demboet al. 1990, Vergote et al. 2001)

In advanced stage the amount of residualtumour, performance status, type of

chemotherapy, substage, age of the patient,grade and in some studies histologicaltype Malkasian et al. 1984, Einhorn et al. 1985, Hunter et al. 1992, Venesmaa 1994a,Makar et al. 1995, Munkarah et al. 1997, Eisenkop et al. 1998, Bristow et al. 1999, Naik etal. 2000, Akahira et al. 2001, Vergote et al. 2001.


12/68

Grade

No grading system available mainly becausethe same criteria are not applicable to allhistological types

Grading is clinically important only for stage1

No need of three grade systems usuallyproposed

Should be classified into either low or highgrade, because chemotherapy is withheld for

low grade stage I tumors in view of theiroutstanding prognosis when untreated Ovariancancer net


13/68

Histologic Subtype

The prognostic significance of the histologicaltype is limitedFriedlander 1998.

It determines the chemoresponsiveness oftumor.

Glutathione S-transferase-pi (GST-pi), MDR(multidrug resistance)-1, and p53 expression

pattern is closely related to histologic subtypeof ovarian cancer, although they are notsignificant predictors of survival. Ikeda K et al 03


14/68

Histopathological type Mucinous and endometrioid tumours are

more often diagnosed at early stages, whichcontributes to their more favourableprognosisMalkasian et al. 1984, Friedlander 1998.

Advanced stage mucinous tumours areknown to a have poor prognosis, probablydue to their chemoresistanceMakar et al. 1995.

Clear cell carcinomas are suggested to havea more aggressive biological naturecompared to the other typesMakar et al. 1995.


15/68

Tumors with a micropapillaryarchitecture be designated"micropapillary serous carcinomas," andthose lacking these features, "atypical

proliferative serous tumors.

Presence of a micropapillaryarchitecture in the primary ovarian

tumor is a strong predictor of invasiveimplants. Seidman JD, Kurman RJ.2000


16/68

Volume of Residual Disease

Standard therapy for advanced case consistof Optimal debulking - reducing tumor size to< 2 cm followed by platinum basedchemotherapy

Maximum cytoreduction is one of the mostpowerful determinants of cohort survival BristowRE et al 2002

Proponents point out that prognosis &survival correlate with residual disease.

Critics argue that survival advantage resultsfrom the biological inherent predisposition.


17/68

Peritoneal cytology

Presence of ascites at the time oflaparotomy for ovarian cancer has been

associated with poor prognosis Patients with normal peritoneal

cytological specimens had better

survival rates than patients withabnormal findings


18/68

Tumor rupture at surgery

Data are conflicting on tumor ruptureand capsular penetration at the time of

surgery. Findings warrants reassigning of stage I

or II tumor to IC or IIC , the prognostic

value of these features is unclear.


19/68

Systematic lymphadenectomy (LNX)might be of benefit in conjunction withprimary optimal cytoreductive surgery inadvanced epithelial ovarian cancer (OC)

patients who do not respond toplatinum-based chemotherapy

No survival benefit could be seen in

platinum-sensitive patients. Seiji Isonishi 2004


20/68

Platinum sensitivity

Patient relapsing 6 weeks after the endof cisplatin therapy are defined as beingPlatinum sensitive,whereas whosedisease progress in less than 6 weeksare considered Platinum resistance Loehreret al 88,Motzer et al 91,Gershenson 93

Interval from surgery to commencementof chemotherapy is not an independentprognostic factor for progression-freesurvival. Flyn nPM et al 03


21/68

Primary Site of Tumor

The primary site of tumor was the onlyindependent prognostic factor for survival

& event-free survival of Malignant germcell tumors in childhood - gonadal hadgood survival than extragonadal Study "TCG 91". 03


22/68

Tumor Markers No single biological tumor factor will

give accurate prognostic information forall ovarian cancer patients. On the other

hand, a combination of two or moreindependent factors may yield animproved overall prognostic index

In 1979 the significance of serum tumormarkers either before surgery orchemotherapy was studied.


23/68

Tissue Tumor Markers

Oncogenes

ERBB2

MYC Ets-1

Tumor suppressor

genes BRCA 1

P53

Cell cycleregulators

p21 p27

DNA ploidy(aneuploidy)


24/68

Markers of cellproliferation Ki67

AP2 Topoisomerase II

Growth factors PDGFR- fact de

crestere derivat dintromboocite

VEGF-fact de cersterea endoteliului vascular

CSF-fact de stimulareal coloniilor

Adhesion molecules CD44 -catenin


25/68

ProteolyticEnzyme

UPA

UPAI1 KLK-5

MMP2

Collagen IV

Steroid HormoneReceptors

E and/or p

receptors Others

Hyaluronan

Bax Bcl-2


26/68

Serum tumor markers

CA125

TATI

CEA CASA

Inhibin A

IAP VEGF

CSF-1

Soluble FAS

Interleukin 6 MAGE4

Tetranectin

HCG Progesterone /

estrogen


27/68

CA125

CA125, a small heavily glycosylatedglycosylphosphatidylinositol - linked cellsurface protein,with molecular mass from220-1000kDa, is the most widely used

prognostic factor tumor marker in Epihtelialovarian cancer management.

Localized in most serous, endometrioid, andclear cell; mucinous tumors express this

antigen less frequently CA125 is, nevertheless, not sensitive and

specific enough to be used for diagnosis orscreening.


28/68

Sensitivity is 69.8%,Specificiy 72.3%,

Positive Predictive value 49.2% &Negative Predictive value 86.2%Marinovic et al1997

Sensitivity may be improved by

measuring multiple complementarytumor markers such as OVX1, M-CSF(macrophage colony stimulating factor).

Normalisation in


29/68

Tumor Markers in Ovarian

Germ Cell TumorsTUMOR HCG AFP LDH CA-125

Mixed germ cell tumorEmbryonal carcinoma

Endodermal sinus tumor

Dysgerminoma

Immature teratoma

Choriocarcinoma

++

-

-

+

++

+

-

-

+

+

++

?

+

+

?


30/68

Continued:

Dosage of HCG, LDH and FP isinformative in follow-up of germ cell

tumors Its prognostic value not clearly

established

Increased value signals a tumor relapsebut clinical progression can occur inabsence of increased signals.


31/68

Presence of Progesterone

ReceptorsIn serous cancers presence ofprogesterone receptors is a favorablefactor of prognosis and, as a rule,associates with a high degree of tumourdifferentiation indicate the efficiency of

hormonotherapy and chemotherapy.Kolosov AE, Novichkov EV. 03


32/68

Androgenic State in Women

Heightened androgenicity is linked to thepathogenesis and tumor biology ofepithelial ovarian cancer.

Li AJ, 03


33/68

Patients' Psychological

Constitution Variables "genetic or hereditary risk",

"hormone replacement therapy" and "use oftobacco or alcohol" had no significant

influence on survival. "psychic disorders" and"parity" were found to be of strong prognosticinfluence,

Link between patients' psychologicalconstitution and course of disease suggestspsychotherapeutic support to be helpful forovarian carcinoma patients.

von Georgi R et al 02


34/68

New Researches


35/68

Loss of Heterozygosity on

theX Chromosome

Loss of heterozygosity (LOH) at micro-satellite markers DXS454 (Xq21-q23)appeared to be correlated with reducedsurvival

Hogdall EV et al 04 .


36/68

Angiogenesis

Progression of disease depends ondynamism of angiogenesis.

But acc Sonmezer M et al 04 angiogenesisdoes not appear as a prognostic factor inepithelial ovarian cancer

Gene expression of Angiopoietin-1 (Ang-1) &

Angiopoietin-2 (Ang-2), might present apertinent diagnostic tool to select a high-riskgroup of patients Hata K,et al 2004


37/68

Angiogenesis (CD 34 )

Endothelial marker CD 34 is a usefulmarker in determining tumourneovascularisation which might be ofprognostic relevance in patients with

ovarian cancer Heimburg S et al 99, Blok R et al 04


38/68

Angiostatin Expression

The presence of angiostatin expressionand absence of VEGF expression arefavorable prognostic factors with regard tosurvival in ovarian carcinoma patients.

Yabushita H et al 03


39/68

Vascular Endothelial

Growth Factor Vascular endothelial growth factor (VEFG) in

epithelial ovarian cancer did not affect patients'

survival but is an important mediator of ascitesformation Sonmezer M et al 04

Increased expression of VEGF-C, VEGF-D andVEGFR-3 was significantly associated with LN

and peritoneal mets outside the pelvis VEGF-D was found to be an independent

predictor of poor outcome Yokoyama Y et al 03


40/68

ETS-1 a Transcription Factor

ETS-1 might act as an angiogenicmediator in, and be a prognostic factorfor, ovarian cancers.

Khatun S et al 03


41/68

p53 Mutations

Abnormalities of p53 expression is an inducerof apoptosis. Expression of p53 wassignificantly associated with the tumor gradeand disease-free survival (DFS)

p53 status, and epidermal growth factorreceptor (EGFR) status were all independentand significant prognostic factors with regardto disease-free survival Berker B et al 02, Skirnisdottir I et al 2004

p53 mutations and over expression of K-rasaffect prognosis of ovarian endometrioidcancer but not clear cell cancer.Okuda T, et al 2003


42/68

p21 Expression

p21 is a direct p53 response gene. p21expression is closely related to

sequenced p53 mutations and positivep21 staining can be an independent poorprognostic factor in p53-null ovarian

cancer. Rose SL et al 03


43/68

Ki67 Antigen

Immunostaining (MIB 1Monoclonal Antibody)Proliferation index detected by Ki67 antigen

immunostaining may represent an indicator ofaggressiveness in serous ovarian tumors andan additionally useful prognostic factor incystoadenoma, probably independent of and

apparently more significant than the tumorarchitectural grade and the disease FIGO stage

G. Gioele Garzetti et al 02


44/68

AgNORs Count in

Cancer Cell Mean number of AgNORs per nucleus

correlates better than grading with the

effect of chemotherapy in serousovarian cancer.

The quantitative assessment ofAgNORs is better prognostic factor

when compared to grading for theeffectiveness of adjuvant chemotherapyin serous ovarian cancer.

Gottwald L et al 03


45/68

Cyclooxygenase-2 (COX-2) COX-2 over-expression is associated with

increased proliferation, reduced apoptosis,and angiogenesis.

Expression of COX-2 also was correlated withtumor angiogenesis but not with epidermalgrowth factor receptor (EGFR), Her-2/neu, orp53 expression.

COX-2 expression was correlatedsignificantly with survival in patients with high-grade, high-stage serous ovarian carcinoma

Ali-Fehmi R et al 03


46/68

Prostasin - A Potential serum marker forovarian cancer.It is a secretory proteinpresent in prostate that is overexpressed in

epihtelial ovarian cancer Mok SC et al 2001

Osteopontin A Potential serum marker. AnRNA spotoverproduced in ovarian cancer

Kim J-H etal 2002


47/68

Y Box-Binding Protein-1 andP-Glycoprotein

Co-expression of Y box-binding protein-1

and P-glycoprotein emerged as apromising relevant biomarker forunfavorable prognosis for survival in

epithelial ovarian cancer.Huang X, et al 2004


48/68

Polo-like Kinase Isoform

The Polo-like kinase (PLK) family comprisesthree serine/threonine kinases, functionallyinvolved in signal transduction pathways

essential for the accomplishment of mitosis inboth normal and malignant cells.

PLK1 is a novel independent prognosticmarker in ovarian carcinomas. Inhibition of

PLKs might represent an interesting newtargeted approach for chemotherapy ofepithelial ovarian cancer.

Weichert W, et al 2004


49/68

Lysosomal Aspartyl

Protease Cathepsin DStromal cathepsin D expression was anindependent prognostic factor for disease-

free survival (DFS) in patients withinvasive cancer, while cathepsin Dexpression missed to be of prognostic

value for overall survival (OS) in invasiveovarian cancerLosch A et al 04


50/68

Multidrug Resistance-1Protein

Expression of multidrug resistance-1protein inversely correlates with paclitaxelresponse and survival in ovarian cancerpatients

Penson RT et al 04


51/68

Type I & III CollagenMetabolites & Peritoneal Cells Malignant tissue growth induces marked

biochemical and structural changes in theextracellular matrix of the tumour and its

surrounding tissues. High preoperative serum type I collagendegradation (ICTP) & type III collagen (PIIINP)and a low type I collagen (PICP, PINP) ratio

correlate with poor prognosis Serum collagen metabolites, especially ICTP,

are important indicators of prognosis in epithelialovarian ca. Marja Simojoki2003


52/68

Thrombocytosis

Thrombocytosis is a frequent preoperativefinding in ovarian and peritoneal carcinomasand may be a marker of aggressive tumorbiology.

Li AJ et al 04


53/68

Fibronectin

Fibronectin is involved in tumourneovascularisation and metastasis, preventsapoptosis and is considered to be

immunosuppressive It is an important prognostic factor in ovarian

ca and may be central to tumour progression

Offer new treatment possibilities since several

agents may antagonize the mechanism offibronectin expression. Franke FE et al 03


54/68

DAX-1 (Nuclear Receptor)

DAX-1 is a member of the nuclear receptorsuperfamily and is thought to be involved inthe regulation of steroidogenesis

DAX-1 immunoreactivity is considered to be anew independent marker of poor prognosis oradverse clinical outcome in patients with

epithelial ovarian carcinoma, possibly throughaltering in situ steroids production.Abd-Elaziz et al 03


55/68

ERBB2 Gene Amplification

Increased copy number of ERBB2 was alsoassociated with high tumor grade, greaterpatient age, large residual tumor size, highproliferation index, aberrant p53 and negativeprogesterone receptor status.

A significant association was found betweenERBB2 amplification and ERBB2 protein overexpression.

Over-expression of ERBB2 protein wasassociated with poor overall survival, but theprognostic value was weaker than that ofERBB2 gene copy number status.

Lassus H et al 04


56/68

KLK15 ( Kallikrein Gene )

KLK15 is a newly cloned human kallikreingene

KLK15 is up-regulated mainly by androgensand to a lesser extent by progestins in cancercell lines.

KLK15 expression is an independent marker

of unfavorable prognosis for ovarian cancer.Yousef GM et al 03


57/68

Human Embryonic-Lethal

Abnormal Vision-LikeProtein HuR

Dysregulation of cellular distribution of themRNA stability factor HuR result in anincreased expression of COX-2, anincreased proliferative rate, and may lead

to a reduced survival time.Denkert C et al 04


58/68

Protein Kinase Ciota

Alteration of PKC isoform expression may beinvolved in progression of ovarian ca.

Univariate survival analysis showed that

amongst other yet k/n prognostic parameters(FIGO stage, histopathological grading,proliferation index) PKCiota expression in pri.ovarian ca correlated significantly (p=0.024)with a reduced median survival time, but wasnot an independent prognostic factor.

Weichert W et al 2003


59/68

YKL-40

YKL-40 (human cartilage glycoprotein-39), amember of family 18 glycosyl hydrolases, is agrowth factor and is secreted by cancer cells.

High plasma level in patients with ovarian

cancer stage III is related to shorter survival.Hogdall EV et al 2003

Proved to be an independent prognosticfactor in a multivariate Cox analysis including

serum CA-125 and clinical/histologicalparameters and is related to short survival inpatients with recurrent ovarian cancer.

Dehn H et al 03


60/68

Bikunin Gene Expression

Low bikunin mRNA expression by ovarianca cells may identify patients with ovariancarcinoma who are at high risk for earlydisease recurrence and a poor prognosis.

Tanaka Y et al 03


61/68

Skp2 Protein Expression

Skp2 expression might play an important rolein the development and progression of

ovarian adenocarcinomas, and Skp2 overexpression is an independent prognosticmarker of ovarian adenocarcinoma patients.

Skp2 protein expression is examined byimmuno-histochemistry

Shigemasa K et al 03

EMMPRIN


62/68

EMMPRIN(Extracellularmatrix

Metalloproteinase inducer) EMMPRIN is a member of the

immunoglobulin superfamily of adhesionmolecules and has a role in the activation ofseveral matrix metalloproteinases (MMP).

EMMPRIN is a novel marker of poor outcome

in serous ovarian ca and is co-expressed withother MMP-1, MMP-9 and the alphav andbeta1 integrin subunits.

Davidson B et al


63/68

PEA3 mRNA PEA3 mRNA expression is associated with

poor survival in advanced-stage ovarian ca.

Association b/n PEA3 mRNA expression andthe expression of the beta (1) integrinsubunit, basic fibroblast growth factor, andEMMPRIN, points to the central role of thistranscription factor in tumor progression inovarian ca.

Davidson B et al 03


64/68

Cyclin E Expression Cyclin E is a key regulator of the G(1)-S

transition its expression was not associatedwith age, race, stage, grade, cell type but

associated with advanced, sub-optimallydebulked ovarian cancer patients

High cyclin E expression was an independentpoor prognostic factor for patients with

advanced ovarian ca, and it was associatedwith amplification of the cyclin E gene.Farley J et al 03

Mit A ti t d P t i


65/68

Mitogen-Activated ProteinKinase Phosphatase-1

(MKP-1) MKP-1 (CL100) is involved in inactivation of

MAP-kinase pathways, regulation of stress-

responses and suppression of apoptosis. Immunohistochemical expression of MKP-1

protein was reduced in tissue from LMPtumors and invasive ovarian ca compared to

normal ovaries and cystadenomas and maybe associated with shorter progression-freesurvival times

Denkert C et al 02


66/68

Maspin

Maspin is a noninhibitory member of the

serpin family and over expression wassignificantly associated with a high tumorgrade and may serve as an adverse

prognostic factorSood AK et al 02


67/68

Conclusion

Significance of various prognostic factors areunclear and difficult to evaluatebecause of inconsistencies and confusion inthe literature.

But all ovarian tumors are independentlyeffected by stage at diagnosis, histologicalsubtype, tumor grade and vol. of residual

disease after surgery Of the three, the most important are stageand vol. of residual disease


68/68

THANKS

Prognostic Factors of Ovarian Cancer

Documents

Transcript of Prognostic Factors of Ovarian Cancer