I tumori del corpo dell’utero: strategie

Fattori prognostici biologici nel carcinoma endometrioide dell’endometrio

Angiolo Gadducci

(Pisa)

Torino, 26 febbraio 2010

I tumori del corpo dell’utero: strategie

terapeutiche in evoluzione

P53

PTEN- PI3K-AKT–mTOR

Microsatellite instability (MSI)

Progesterone receptor (PR)

DNA ploidy

tumor-infiltrating lymphocytes

Serum CA 125 levels

Lee, 2010

Biological prognostic variables

in endometrial cancer (EC)

p53 and endometrial cancer (EC)

Study population: 131 pts with EC of any histological type p53 status assessed by PCR and/or IHC

39 (29.8%) had p53 alterations [p53+ pts]

P53+ pts: lower DSS and DFS than p53 – pts

Statistically significant correlations: p53+ status and non-endometrioid histology type, high grade tumours, and absence of PR

Multivariate analyses: p53 alteration and FIGO stage at diagnosis were adverse prognostic factors

p53+ pts had an 11.0 RR of death (95% CI: 1.008-120.765) vs p53– pts

Lee, 2010

p53 and endometrial cancer (EC)

Study population: 59 pts with endometrioid-type of EC [EEC]

p53 status assessed by PCR

20 (20.3%) had mutations and 9 had polymorfisms (7 codon SNP with an Arg/pro allelotype)

p53 with mutations/Arg/Pro SNP had lower OS than wild-type pts (p= 0.002)

Saffari, 2005

p53 and endometrial cancer (EC)

Pts with p53 alterations who had not RT had the lowest OS (P= 0.0005)

Among pts with p53 alterations, adjuvant RT increased OS (p= 0.035)

Multivariate analyses: pts with p53 alterations who did not receive RT had a RR of death of 5.9 (95% CI= 1.5-22.7) vs wild-type p53 pts who did not receive RT

Saffari, 2005

p53 and endometrial cancer (EC)

Study population: 315 pts with EEC p53 status assessed by IHC

P53 expression related to high stage (p= 0.006) and high grade (p< 0.0001)

p53 overexpression was independently related to the risk of death (OR: 3.0, 95% CI: 1.0-8.7, p= 0.04)

Jongen, 2009

Author Histology pts method univariate multivariate

p RR of death

Safari ²⁰⁰⁵ EEC 59 PCR 0.0029 5.9(1.5-22.7)*

Jongen ²⁰⁰⁹ EEC 315 ICH - 3.0 (1.0-8.7) Catsaus ²⁰⁰⁸ any 132 PCR 0.000 -

Lee ²⁰¹⁰ any 131 PCR, IHC - 11 (1.0008-120.765)

*for women with p53 alteration

P53 alteration and EC

PI3K

PTEN AKT

mTOR mTOR inhibitors: CCI-779, RAD001, AP-23573

translation of mRNAs for cyclin D1, c-myc, VEGF, and MMP

PTEN-PI3K-AKT–mTOR pathway

-

PI3K

PTEN PIP3

AKT translocation to plasma membrane

AKT activation

mTOR activation

PTEN-PI3K-AKT–mTOR pathway

-

PDK1 and PDK2

Inactivation of members

of apoptotic machinery TSC1 and TSC2 inactivation

4E-BP 1 phopshorylation S6K1 phosphorylation

eIF-4E

Ribosome biogenesis

Protein translation Cell cycle progression

Author Method cases PTEN status

Tashiro ¹⁹⁹⁷ PCR 32 16 (50%) mutations Risinger ¹⁹⁹⁸ PCR 136 44 (32%) mutations Lin ¹⁹⁹⁸ PCR 21 9 (43%) mutations Bussaglia ²⁰⁰⁰ PCR 38 17 (45%) mutations Mutter ²⁰⁰⁰ PCR 30 25 (83%) mutations An ²⁰⁰² IHC 61 40 (66%) weak or absent

PTEN expression

Terakawa ²⁰⁰³ IHC 103 37 (36%) absent PTEN expression

PTEN in endometrioid-type EC

Study population: 33 EEC tested for PIK3CA and RAS mutational status and PTEN inactivation status

PIK3CA mutations: 8 (24%) (7 in exon 20 and 1 in exon 9)

PTEN alterations: 19 (57%) (biallelic inactivation: 11, monoallelic inactivation: 1)

PIK3CA mutations coexisted with:

i) monoallelic PTEN alterations of PTEN in 4 cases ii) biallelic PTEN inactivation in 1 case

iii) wild-type PTEN in 3 cases

PIK3CA and K-RAS mutations (8 cases): mutually exclusive alterations

Velasco, 2006

Alterations in the PI3K-AKT signaling pathway

Concomitant PI3K-AKT and p53 alteration in EC

p53 alterations conferred a worse OS (p=0.000)

Alterations in the PI3K-AKT pathway alone did not influence OS

Pts with deregulated PI3K-AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter OS (p= 0.000) than pts with only p53 alterations

Catsaus, 2009

Concomitant PI3K-AKT and p53 alteration in EC

Study population: 132 pts with EC of any histological type P53 and PI3K-AKT status assessed by PCR

P53 mutations: 17% of high-grade EEC, 54% of non-EEC EC, 50%

mixed EC

PIK3CA mutations: 26% of low grade EEC, 34% of high-grade EEC, 21%

of non EEC* vs 44% of mixed EC

p53 and PIK3CA alterations sometimes coexisted, whereas they rarely coexisted with the PTEN mutations

PIK3CA mutations in exon 20: tumours frequently high-grade, deeply invasive EC, LVSI+

PIK3CA mutation in exon 9: tumours more likely low-grade EC

°plus 45% mRNA overexpresion

Catsaus, 2008, 2009

Study population: 149 pts with EC

mTOR, p53 and COX-2 assessed by IHC mTOR overexpression: 10 (7.1%) cases

mTOR expression highly correlated with old age, menopausal status and COX-2 expression (P<0.05).

Multivariate analysis revealed that COX-2 was the only independent factor related to expression of mTOR.

No correlation of mTOR expression with usual prognostic factors (histologic type, grade, myometrial invasion, lymph-node status) and OS

Expression of mTOR protein and its clinical significance in EC

No, 2009

 Loss of DNA mismatch repair: genomic instability through the accumulation of mutations in a wide range of sequences including key regulatory genes related to cell growth and/or apoptosis

MSI is the hallmark of tumours with defects in DNA mismatch repair and occurs in approximately 20-30% EC

MSI is determined using 5 NCI consensus panel markers (BAT-25, BAT- 26, NR21, NR24, and NR27)

MSI is seen in EEC associated with Lynch syndrome, as well as sporadic EEC

PTEN loss and DNA mismatch repair frequent molecular

alterations in EEC

 Conflicting results about the prognostic impact of MSI in EEC (small sample sizes, nonstandard definitions of the MSI phenotype, inclusion or exclusion of histologic types associated with aggressive disease (Basil 2000,MacDonald 2000, Maxwell 2001, Muresu 2002, Pijnenborg 2004, Black 2006)

In a recent study including 446 pts, MSI was found in 147 (33%) and was related to higher grade (p < 0.0001).

 MSI not associated with OS [HR= 1.011; 95% CI, 0.688-1.484) or DFS (HR= 0.951; 95% CI, 0.554 -1.635).

MSI and epigenetic inactivation of MLH1 and outcome of pts with EEC

Zighelboi, 2007

Study population: 93 pts with EEC treated with surgery and adjuvant RT 25 (22%) pts were classified as MSI.

Whole series: MSI was significantly related to poorer DFS and

cancer-specific OS at univariate but not at multivariate analysis

Early stages (I-II): MSI was an independent prognostic factor for DFS (HR= 3.25, 95% CI, 1.01-10.49; p= 0.04) and cancer-specific OS (HR= 4.20, 95% CI, 1.23-14.35; p= 0.022).

MSI and clinical outcome in RT-treated EEC

Bilbao, 2010

Study population: 120 EC (93 type I, 27 type II) HER2, p53, and 4E-BP1 assessed by IHC

The nuclear expression of phospho-4E-BP1 and HER2 overexpression had prognostic significance

Cell signaling in EC: phosphorylated 4E-BP1 expression correlates with aggressive tumors and prognosis

Castellvi, 2009

Study population: 315 EEC pts FIGO stage I: 59.0%, II: 17.1%, III:

19.4%, IV: 4.1% (IHC)

65 pts (20.6%) had a recurrence and 38 (12.1%) DOD

Multivariate analysis in early stage disease (IHC)

absence of ER-α related to risk of death (OR 7.28, 95% CI 1.42-37.25, p= 0.017)

absence of PR-A related to risk of relapse (OR 4.2, 95% CI 1.32- 13.33, p= 0.015).

Yongen 2009

Expression of ER-α and -β and PR -A and -Bin a large cohort

of pts with EEC

Study population: 103 EEC pts (IHC)

PR-A and PR-B isoforms expression significantly lower in pts with higher G (p= 0.0001 and p= 0.002, respectively).

Absence of either one or both of PR isoforms in 100% of the pts who died vs 45.7% of those who had lived during the same period.

Multivariate analysis: absence of PRA immunoreactivity independent risk factor for DFS (p= 0.0258)

Saito 2009

PR isoforms as a prognostic marker in human EC

Author pts Aneuploidy rate poorer OS

univariate multivariate

Susini ²⁰⁰⁷ 174 28% yes yes

Suehiro ²⁰⁰⁸ 106 NA yes yes

Mangili ²⁰⁰⁸ 222 NA yes yes

Wik ²⁰⁰⁰ 262 25% yes yes

DNA aneuploidy in endometrial cancer

DNA aneuploidy is related to

Higher age at diagnosis Non-endometrioid subtype High grade

DNA aneuploidy in endometrial cancer

Wik 2009

Study population: 174 EC

10 –year OS All series G2 tumor

Aneuploid tumor 53.2% 45.0%

Diploid tumor 91.1% 91.9%

p<0. 0001 p<0.0001

DNA aneuploidy identifies high-risk cases among the so-called 'low-risk' pts with well and moderately differentiated tumours.

10-year results of a prospective study on the prognostic role of ploidy in EC

Susini 2007

Study population: 222 pts with stage I EC( median follow-up 4.6 years) i) group A (1990-1998, n= 141), receiving AT in Ic stage

ii) group B (1999-2003 n= 81), receiving AT in case of DNA index >1.2 or stage Ic G3 with unknown N

Since ploidy was introduced as a decision-making factor, only 30.6% of pts with stage IC received AT

No tumour-related deaths occurred in pts with diploid IC stage who did not receive AT

Only DNA ploidy and age at diagnosis were independent predictors of OS

DNA ploidy in postoperative management of stage I EC

Mangili 2008

Aim: to determine the prognostic value of intratumoral CD8(+) cytotoxic T-lymphocytes (CTL), FoxP3(+) regulatory T-lymphocytes (Treg) and CD45R0(+) memory T-lymphocytes in EC .

Study population : 368 FIGO stage I-IV EC pts.

High numbers CD8(+) CTL, a high CD8(+)/Treg ratio and the presence of CD45R0(+) T-lymphocytes: strongly associated with well-known favourable

prognostic factors

High numbers of CD8(+) CTL and high CD8(+)/T egratio: better DFS at univariate analysis

High numbers of CD8(+) CTL and presence of CD45R0(+) T-lymphocytes:

better OS at univariate analysis .

Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II EC

Dejong 2009

HR for OS 95% CI High numbers of CD8(+) CTL

entire series 0.48 0.26-0.89, p=0.019

type 2- EC 0.17 0.08-0.36, p<0.001 A high CD8(+)/T reg

type 1 EC 0.44 0.23-0.84, p=0.013 CD45R0(+) lymphocytes

entire series 0.42 0.19-0.93, p=0.033

Dejong 2009

Presence of tumor-infiltrating lymphocytes is an independent

prognostic factor in type I and II EC

Chung 2005

Use of preoperative serum CA-125 and prognosis of EC

Study population : 141 women with EC

Stage pts CA 125 > 35 U/ml II 106 13 (12.3%)

III-IV 11 10 (91%) p< 0.001)

Similar trends in correlation of CA-125 levels seen with the highest grade and the deepest myometrial invasion

CA-125 should be included as part of the preoperative workup

Powell 2005

Preoperative serum CA-125 levels in treating EC

Study population 214 EC pts

Independent risk factors for pelvic N+ OR (95% CI) p

Histology (not serous vs serous) 11.4 (1.6-83.3) <0.05

CA 125 (high vs low) 4.3 (11.6-11.6) 0.005

Volume index (>25 vs < 25) 4.3 (1.4-13.3) <0.05

Grade (3 vs 1-2) 3.7 (1.0-13.7) <0.05

Independent risk factors for aortic N+ OR (95% CI) p

Volume index (>25 vs < 25) 8.2 (2.0-32.6) <0.005 CA 125 (high vs low) 5.0 (1.5-16.2) <0.01

Combined use of MRI, CA 125 assay, histologic type, and histologic grade in the prediction of N+ in EC

Todo 2003

P53 + --

PTEN- PI3K-AKT–mTOR investigational

Microsatellite instability (MSI) investigational

Progesterone receptor (PR) ++-

DNA ploidy ++-

tumor-infiltrating lymphocytes investigational

Serum CA 125 levels +++

Biological prognostic variables

in endometrial cancer (EC)