Prognostic Factors of Ovarian Cancers

Prof. Veena Agrawal

M.D., MICOG, WHO Fellow USA,Diploma in USG Dept of Obstetrics. & Gynaecology G.R.Medical College Gwalior, M.P. INDIA

Dr R. Gautam

 Ovarian cancer accounts for 32% of all gynecologic 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

 Initial surgery is primodial. In Stage IA and IB patients with grade I tumors do not require adjuvant treatment. Patients with stage greater than above are at high risk for recurrence, due to micrometastatic disease, and should thus undergo chemotherapy.

There is a wide spectrum of clinical behaviours from an excellent prognosis and high likelihood of cure to those with rapid progression and poor prognosis irrespective of clinical stage of the disease, most probably reflecting different biological properties of the tumour.

Prognostic Factors
Ethnicity & Race Age Stage of Disease Histology Tumor grade Tumor markers Site-specific surgical treatment. Size of residual disease Tumor response

Ethnicity & Race

African-American women have a 30% greater risk and are more likely to die earlier when compared to Caucasian women David Greenberg2004, Jill
S. Barnholtz-Sloan,2002

Non-Hispanic white women had age-adjusted incidence rates that were slightly higher (13.3/100,000) than rates for American Indians (11.4) and Hispanics (10.7) over the 24-year period. Schiff M et al 1996

Age
Advanced age remains an adverse prognostic factor even after adjustment for treatment and comorbidity factors. O'Malley Cd et al
2003,Chan JK et al Obstet Gynecol. 2003

Young patients have survival rates as high as 75% across all stages, compared with 40% in the overall population Rodriguez M,et al 1994,Lee CK,et al 1999 A ten year increase in age induces a 1.6 times greater risk of death. Balvert-Locht et al. 1991, Markman
et al. 1993, Baker et al. 1994, Curtin et al. 1997, Eisenkop et al. 1998).

 One age-related reason for an increased risk of cancer may be an accumulation of somatic cell mutations. Loss of heterozygosity on chromosome 17 (deletion of a proportion of a chromosome containing a putative tumor suppressor gene) increases with age Pieretti & Turker 1997

Stage of disease
FIGO staging is "surgicopathologic stage". Most powerful predictor of prognosis In many studies the patients are divided into two groups: early (Stage I and II) and advanced stage (stage III and IV), because the survival in early stage disease is significantly better than that in advanced disease.

 Stage IA and IB patients with grade I tumors have a 5-year survival of over 90% Despite the high response rates of initial treatments (i.e.,70-80%), the median progression-free survival of advanced ovarian cancer is 16-22 months, and the 5-year overall survival is 20-30%.

Factors correlate with poor prognosis in same stage

In early stage are histopathological type (serous vs. non-serous), degree or grade of differentiation, the presence of dense adhesions, large volume ascites and spontaneous rupture of a cyst (Malkasian et al. 1984, Dembo
et al. 1990, Vergote et al. 2001)

In advanced stage the amount of residual tumour, performance status, type of chemotherapy, substage, age of the patient, grade and in some studies histological type 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 et al. 2000, Akahira et al. 2001, Vergote et al. 2001.

Grade
No grading system available mainly because the same criteria are not applicable to all histological types Grading is clinically important only for stage1 No need of three grade systems usually proposed Should be classified into either low or high grade, because chemotherapy is withheld for low grade stage I tumors in view of their outstanding prognosis when untreated Ovarian
cancer net

Histologic Subtype
The prognostic significance of the histological type is limited Friedlander 1998. It determines the chemoresponsiveness of tumor. Glutathione S-transferase-pi (GST-pi), MDR (multidrug resistance)-1, and p53 expression pattern is closely related to histologic subtype of ovarian cancer, although they are not significant predictors of survival. Ikeda K et al 03

Histopathological type
Mucinous and endometrioid tumours are more often diagnosed at early stages, which contributes to their more favourable prognosis Malkasian et al. 1984, Friedlander 1998. Advanced stage mucinous tumours are known to a have poor prognosis, probably due to their chemoresistance Makar et al. 1995. Clear cell carcinomas are suggested to have a more aggressive biological nature compared to the other types Makar et al. 1995.

 Tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors. Presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. Seidman JD, Kurman RJ.2000

Volume of Residual Disease

Standard therapy for advanced case consist of Optimal debulking - reducing tumor size to < 2 cm followed by platinum based chemotherapy Maximum cytoreduction is one of the most powerful determinants of cohort survival Bristow
RE et al 2002

Proponents point out that prognosis & survival correlate with residual disease. Critics argue that survival advantage results from the biological inherent predisposition.

Peritoneal cytology
Presence of ascites at the time of laparotomy for ovarian cancer has been associated with poor prognosis Patients with normal peritoneal cytological specimens had better survival rates than patients with abnormal findings

Tumor rupture at surgery

Data are conflicting on tumor rupture and 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.

 Systematic lymphadenectomy (LNX) might be of benefit in conjunction with primary optimal cytoreductive surgery in advanced epithelial ovarian cancer (OC) patients who do not respond to platinum-based chemotherapy No survival benefit could be seen in platinum-sensitive patients. Seiji Isonishi 2004

Platinum sensitivity
Patient relapsing 6 weeks after the end of cisplatin therapy are defined as being Platinum sensitive,whereas whose disease progress in less than 6 weeks are considered Platinum resistance Loehrer
et al 88,Motzer et al 91,Gershenson 93

Interval from surgery to commencement of chemotherapy is not an independent prognostic factor for progression-free survival. Flyn nPM et al 03

Primary Site of Tumor

The primary site of tumor was the only independent prognostic factor for survival & event-free survival of Malignant germ cell tumors in childhood - gonadal had good survival than extragonadal Study "TCG 91". 03

Tumor Markers
No single biological tumor factor will give accurate prognostic information for all ovarian cancer patients. On the other hand, a combination of two or more independent factors may yield an improved overall prognostic index In 1979 the significance of serum tumor markers either before surgery or chemotherapy was studied.

Tissue Tumor Markers

Oncogenes ERBB2 MYC Ets-1 Tumor suppressor genes BRCA 1 P53 Cell cycle regulators p21 p27 DNA ploidy (aneuploidy)

Markers of cell proliferation Ki67 AP2 Topoisomerase II

Growth factors PDGFR- fact de crestere derivat din tromboocite VEGF-fact de cerstere a endoteliului vascular CSF-fact de stimulare al coloniilor Adhesion molecules CD44 -catenin

 Proteolytic Enzyme UPA UPAI1 KLK-5 MMP2 Collagen IV

Steroid Hormone Receptors E and/or p receptors Others Hyaluronan Bax Bcl-2

Serum tumor markers

CA125 TATI CEA CASA Inhibin A IAP VEGF CSF-1 Soluble FAS Interleukin 6 MAGE4 Tetranectin HCG Progesterone / estrogen

CA125
CA125, a small heavily glycosylated glycosylphosphatidylinositol - linked cell surface protein,with molecular mass from 220-1000kDa, is the most widely used prognostic factor tumor marker in Epihtelial ovarian cancer management. Localized in most serous, endometrioid, and clear cell; mucinous tumors express this antigen less frequently CA125 is, nevertheless, not sensitive and specific enough to be used for diagnosis or screening.

 Sensitivity is 69.8%,Specificiy 72.3%, Positive Predictive value 49.2% & Negative Predictive value 86.2% Marinovic et al
1997

Sensitivity may be improved by measuring multiple complementary tumor markers such as OVX1, M-CSF (macrophage colony stimulating factor). Normalisation in <3 months & half life of <16 days has associated with median survival and disease free survival.

Tumor Markers in Ovarian Germ Cell Tumors

TUMOR Mixed germ cell tumor Embryonal carcinoma Endodermal sinus tumor Dysgerminoma Immature teratoma Choriocarcinoma HCG AFP LDH CA-125 + + + + + + + + + + ? + + ?

Continued:
Dosage of HCG, LDH and FP is informative in follow-up of germ cell tumors Its prognostic value not clearly established Increased value signals a tumor relapse but clinical progression can occur in absence of increased signals.

Presence of Progesterone Receptors

In serous cancers presence of progesterone receptors is a favorable factor of prognosis and, as a rule, associates with a high degree of tumour differentiation indicate the efficiency of hormonotherapy and chemotherapy.
Kolosov AE, Novichkov EV. 03

Androgenic State in Women

Heightened androgenicity is linked to the pathogenesis and tumor biology of epithelial ovarian cancer.
Li AJ, 03

Patients' Psychological Constitution

Variables "genetic or hereditary risk", "hormone replacement therapy" and "use of tobacco or alcohol" had no significant influence on survival. "psychic disorders" and "parity" were found to be of strong prognostic influence, Link between patients' psychological constitution and course of disease suggests psychotherapeutic support to be helpful for ovarian carcinoma patients.
von Georgi R et al 02

New Researches

Loss of Heterozygosity on the X Chromosome

Loss of heterozygosity (LOH) at microsatellite markers DXS454 (Xq21-q23) appeared to be correlated with reduced survival
Hogdall EV et al 04 .

Angiogenesis
Progression of disease depends on dynamism of angiogenesis. But acc Sonmezer M et al 04 angiogenesis does not appear as a prognostic factor in epithelial ovarian cancer Gene expression of Angiopoietin-1 (Ang-1) & Angiopoietin-2 (Ang-2), might present a pertinent diagnostic tool to select a high-risk group of patients Hata K,et al 2004

Angiogenesis (CD 34 )
Endothelial marker CD 34 is a useful marker in determining tumour neovascularisation which might be of prognostic relevance in patients with ovarian cancer Heimburg S et al 99, Blok R et al 04

Angiostatin Expression
The presence of angiostatin expression and absence of VEGF expression are favorable prognostic factors with regard to survival in ovarian carcinoma patients.
Yabushita H et al 03

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEFG) in epithelial ovarian cancer did not affect patients' survival but is an important mediator of ascites formation Sonmezer M et al 04 Increased expression of VEGF-C, VEGF-D and VEGFR-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

ETS-1 a Transcription Factor

ETS-1 might act as an angiogenic mediator in, and be a prognostic factor for, ovarian cancers.
Khatun S et al 03

p53 Mutations
Abnormalities of p53 expression is an inducer of apoptosis. Expression of p53 was significantly associated with the tumor grade and disease-free survival (DFS) p53 status, and epidermal growth factor receptor (EGFR) status were all independent and significant prognostic factors with regard to disease-free survival Berker B et al 02, Skirnisdottir I et al 2004 p53 mutations and over expression of K-ras affect prognosis of ovarian endometrioid cancer but not clear cell cancer. Okuda T, et al 2003

p21 Expression
p21 is a direct p53 response gene. p21 expression is closely related to sequenced p53 mutations and positive p21 staining can be an independent poor prognostic factor in p53-null ovarian cancer.
Rose SL et al 03

Ki67 Antigen Immunostaining (MIB 1 Monoclonal Antibody)

Proliferation index detected by Ki67 antigen immunostaining may represent an indicator of aggressiveness in serous ovarian tumors and an additionally useful prognostic factor in cystoadenoma, probably independent of and apparently more significant than the tumor architectural grade and the disease FIGO stage
G. Gioele Garzetti et al 02

AgNORs Count in Cancer Cell

Mean number of AgNORs per nucleus correlates better than grading with the effect of chemotherapy in serous ovarian cancer. The quantitative assessment of AgNORs is better prognostic factor when compared to grading for the effectiveness of adjuvant chemotherapy in serous ovarian cancer.
Gottwald L et al 03

Cyclooxygenase-2 (COX-2)
COX-2 over-expression is associated with increased proliferation, reduced apoptosis, and angiogenesis. Expression of COX-2 also was correlated with tumor angiogenesis but not with epidermal growth factor receptor (EGFR), Her-2/neu, or p53 expression. COX-2 expression was correlated significantly with survival in patients with highgrade, high-stage serous ovarian carcinoma
Ali-Fehmi R et al 03

 Prostasin - A Potential serum marker for ovarian cancer.It is a secretory protein present in prostate that is overexpressed in epihtelial ovarian cancer Mok SC et al 2001 Osteopontin A Potential serum marker. An RNA spotoverproduced in ovarian cancer
Kim J-H etal 2002

Y Box-Binding Protein-1 and P-Glycoprotein

Co-expression of Y box-binding protein-1 and P-glycoprotein emerged as a promising relevant biomarker for unfavorable prognosis for survival in epithelial ovarian cancer.
Huang X, et al 2004

Polo-like Kinase Isoform

The Polo-like kinase (PLK) family comprises three serine/threonine kinases, functionally involved in signal transduction pathways essential for the accomplishment of mitosis in both normal and malignant cells. PLK1 is a novel independent prognostic marker in ovarian carcinomas. Inhibition of PLKs might represent an interesting new targeted approach for chemotherapy of epithelial ovarian cancer.
Weichert W, et al 2004

Lysosomal Aspartyl Protease Cathepsin D

Stromal cathepsin D expression was an independent prognostic factor for diseasefree survival (DFS) in patients with invasive cancer, while cathepsin D expression missed to be of prognostic value for overall survival (OS) in invasive ovarian cancer
Losch A et al 04

Multidrug Resistance-1 Protein

Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients
Penson RT et al 04

Type I & III Collagen Metabolites & Peritoneal Cells

Malignant tissue growth induces marked biochemical and structural changes in the extracellular matrix of the tumour and its surrounding tissues. High preoperative serum type I collagen degradation (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 epithelial ovarian ca. Marja Simojoki2003

Thrombocytosis
Thrombocytosis is a frequent preoperative finding in ovarian and peritoneal carcinomas and may be a marker of aggressive tumor biology.
Li AJ et al 04

Fibronectin
Fibronectin is involved in tumour neovascularisation and metastasis, prevents apoptosis 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 of fibronectin expression. Franke FE et al 03

DAX-1 (Nuclear Receptor)

DAX-1 is a member of the nuclear receptor superfamily and is thought to be involved in the regulation of steroidogenesis DAX-1 immunoreactivity is considered to be a new independent marker of poor prognosis or adverse clinical outcome in patients with epithelial ovarian carcinoma, possibly through altering in situ steroids production.
Abd-Elaziz et al 03

ERBB2 Gene Amplification

Increased copy number of ERBB2 was also associated with high tumor grade, greater patient age, large residual tumor size, high proliferation index, aberrant p53 and negative progesterone receptor status. A significant association was found between ERBB2 amplification and ERBB2 protein over expression. Over-expression of ERBB2 protein was associated with poor overall survival, but the prognostic value was weaker than that of ERBB2 gene copy number status.
Lassus H et al 04

KLK15 ( Kallikrein Gene )

KLK15 is a newly cloned human kallikrein gene KLK15 is up-regulated mainly by androgens and to a lesser extent by progestins in cancer cell lines. KLK15 expression is an independent marker of unfavorable prognosis for ovarian cancer.
Yousef GM et al 03

Human Embryonic-Lethal Abnormal Vision-Like Protein HuR

Dysregulation of cellular distribution of the mRNA stability factor HuR result in an increased expression of COX-2, an increased proliferative rate, and may lead to a reduced survival time.
Denkert C et al 04

Protein Kinase Ciota

Alteration of PKC isoform expression may be involved 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 was not an independent prognostic factor.
Weichert W et al 2003

YKL-40
YKL-40 (human cartilage glycoprotein-39), a member of family 18 glycosyl hydrolases, is a growth 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 prognostic factor in a multivariate Cox analysis including serum CA-125 and clinical/histological parameters and is related to short survival in patients with recurrent ovarian cancer.
Dehn H et al 03

Bikunin Gene Expression

Low bikunin mRNA expression by ovarian ca cells may identify patients with ovarian carcinoma who are at high risk for early disease recurrence and a poor prognosis.
Tanaka Y et al 03

Skp2 Protein Expression

Skp2 expression might play an important role in the development and progression of ovarian adenocarcinomas, and Skp2 over expression is an independent prognostic marker of ovarian adenocarcinoma patients.

Skp2 protein expression is examined by immuno-histochemistry

Shigemasa K et al 03

EMMPRIN (Extracellularmatrix Metalloproteinase inducer)

EMMPRIN is a member of the immunoglobulin superfamily of adhesion molecules and has a role in the activation of several matrix metalloproteinases (MMP). EMMPRIN is a novel marker of poor outcome in serous ovarian ca and is co-expressed with other MMP-1, MMP-9 and the alphav and beta1 integrin subunits.
Davidson B et al

PEA3 mRNA
PEA3 mRNA expression is associated with poor survival in advanced-stage ovarian ca. Association b/n PEA3 mRNA expression and the expression of the beta (1) integrin subunit, basic fibroblast growth factor, and EMMPRIN, points to the central role of this transcription factor in tumor progression in ovarian ca.
Davidson B et al 03

Cyclin E Expression
Cyclin E is a key regulator of the G(1)-S transition its expression was not associated with age, race, stage, grade, cell type but associated with advanced, sub-optimally debulked ovarian cancer patients High cyclin E expression was an independent poor prognostic factor for patients with advanced ovarian ca, and it was associated with amplification of the cyclin E gene.
Farley J et al 03

Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1)

MKP-1 (CL100) is involved in inactivation of MAP-kinase pathways, regulation of stressresponses and suppression of apoptosis. Immunohistochemical expression of MKP-1 protein was reduced in tissue from LMP tumors and invasive ovarian ca compared to normal ovaries and cystadenomas and may be associated with shorter progression-free survival times
Denkert C et al 02

Maspin
Maspin is a noninhibitory member of the serpin family and over expression was significantly associated with a high tumor grade and may serve as an adverse prognostic factor
Sood AK et al 02

Conclusion
Significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. But all ovarian tumors are independently effected by stage at diagnosis, histological subtype, tumor grade and vol. of residual disease after surgery Of the three, the most important are stage and vol. of residual disease

THANKS