prognostic value of p53 and urokinase-type plasminogen ......vol. 4, 189-196, january 1998 clinical...

Vol. 4, 189-196, January 1998 Clinical Cancer Research 189

Prognostic Value of p53 and Urokinase-type Plasminogen Activator

in Node-negative Human Breast Cancers’

Jean-Philippe Peyrat,2 Laurence Vanlemmens,

Jo#{235}lleFournier, Guillemette Huet,

Fran#{231}oise R#{233}villion, and Jacques BonneterreLaboratoire d’Oncologie Moldculaire Humaine [J-P. P., J. F., F. R.]

and D#{233}partementd’Oncologie M#{233}dicale[L. V., J. B.], Centre OscarLambret, 59020 Lille, and Laboratoire de Biochimie, H#{244}pitalClaudeHuriez, Centre Hospitalier Universitaire de Lille, 59037 Lille [G. H.],France

ABSTRACTWe measured the levels of p53 and urokinase-type plas-

minogen activator (uPA) in 634 tumor tissues from 634different node-negative primary breast cancer patients who

underwent locoregional surgery in the Center Oscar Lam-bret between July 1989 and September 1994. p53 and uPAwere assayed using commercially available kits in cytosols

prepared for estradiob receptor (ER) and progesterone re-ceptor (PgR) assays. The optimum clinical thresholds werechosen for prognostic studies: 4 nglml for p53 and 0.5 nglml

for uPA. p53 was elevated in 13.7% of the tumors, and uPAwas elevated in 27.5% of the tumors; they were negativelyrelated (x2 test) to ER and PgR and positively related tohistoprognostic grading (HPG) and tumor diameter. uPA

was negatively correlated to ER and PgR, and p53 and uPA

were positively correlated to each other (P 0.0001; Spear-man test). In the prognostic studies, the 316 patients who didnot receive adjuvant chemotherapy were included to avoidtreatment interference; this number corresponds to all of

the patients operated on between 1989 and 1992. The meanduration of follow-up of living patients was 4 years. In

overall survival studies, Cox univariate analyses demon-strated a prognostic value of p53 (P = 0.011; risk ratio,1.59), uPA (P = 0.038; risk ratio, 2.32), PgR, HPG, and

tumor diameter. In Cox multivariate analyses, only HPGhad a statistically significant prognostic value. In relapse-free survival studies, univariate analyses demonstrated

prognostic values of uPA (P 0.0011) and of age, and bothparameters retained their prognostic value in multivariate

Received 3/26/97; revised 10/8/97; accepted 10/17/97.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby marked

advertisement in accordance with 1 8 U.S.C. Section 1734 solely to

indicate this fact.

I This work was supported by grants from the Ligue Nationale contre le

Cancer (Paris, France), the Comit#{233}sD#{233}partementaux du Nord (Lille,France) et du Pas-de-Calais (Arras, France) de Ia Ligue Nationale contrebe Cancer, and the Commission Mixte de Recherche do Centre Hospi-talier Universitaire de Lille (Grant 9714).

2 To whom requests for reprints should be addressed. at Laboratoired’Oncobogie Mob#{233}culaire, Centre Oscar Lambret, BP 307, 59020 Lille

C#{233}dex,France. Phone and Fax: 33 3 20 29 55 35.

analyses (uPA: P = 0.0004). This study demonstrates not

only that p53 and uPA have prognostic value but also that

these two parameters are linked to other classical clinical,

histological, or biological prognostic parameters, as well asto each other. Moreover, because uPA is of prognostic value

in multivariate relapse-free survival studies, uPA is an im-

portant prognostic factor in node-negative breast cancerpatients.

INTRODUCTIONThe results of prospective randomized clinical trials and of

overview analyses suggest that systematic adjuvant therapy can

benefit node-negative breast cancer patients ( 1). Node-negativebreast cancers are heterogenous; 75% of the patients were alive

and without recurrence after 10 years. The finding of selective

prognostic factors to identify patients in this group at high risk

of recurrence would avoid excessive treatment morbidity and

costs (2).

Among the plethora of potentially useful markers that have

been identified, two appear to be of particular interest: p53 and

uPA.3

Of the genetic changes found in human cancer, the alter-

ation of the tumor suppressor gene p.53 is the most common (3).

In the majority of cases, these alterations correspond to point

mutations localized in one allele of the gene, whereas the second

wild-type allele is lost. In tumors, p53 mutations change the

conformation of the protein and lead to stabilization of p53 and

its accumulation in the nuclei of cancerous cells (4). Using

molecular analyses of the p53 gene (sequencing), immunohis-

tochemistry, or measurement of circulating p53 antibodies, it

has been demonstrated in a number of studies that alterations to

p53 are related to shorter RFS and poorer OS (Table 1). All of

these technical approaches have pitfalls and/or are difficult to

use for routine detection.

uPA is a serine protease that catalyzes the conversion of the

inactive proenzyme plasminogen to plasmin. It was initially

identified in urine and is produced by many normal and malig-

nant cells. This protease has a role in tissue remodelling, in the

degradation of extracellular matrices, and in the destruction of

the basement membrane in malignant cell proliferation and

metastasis (5). Overexpression of uPA is strongly related to

shorter RFS and poorer OS (Ref. 6; Table 2).

Consequently, p53 and uPA, which are differently impli-

cated in the development of breast cancer, are prognostic pa-

rameters. However, no study has simultaneously evaluated, in

the same patient population, the relative prognostic weight of

3 The abbreviations used are: uPA, urokinase-type plasminogen activa-

tor; HPG, histoprognostic grading; ER, estradiol receptor; PgR, proges-

terone receptor; LIA, luminometric immunoassay; OS, overall survival;

RFS. relapse-free survival; RR, risk ratio.

Research. on May 31, 2021. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

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190 p53, uPA, and Breast Cancer

Table 1 p53 prognostic value in primary brea St cancer

Follow-up RFS UV RFS MV OS UV OS MVReference Methoda Pop. p53+/n (%) (months)” (P) (P) (P) (P)

Ostrowski et al. (21) IHC 32/90 (36) 28 NS NS

Thor et a!. (18, 19)

Isoba et al. (16)

IHC

IHCN-

N-

68/295 (23)

31/127(24.4)

41/289 (14)

72

96

0.0030.018

0.0391 0.0080.057

0.0001

0.0524

NSSilvestrini et al. (17) IHC N- 1 13/256 (44) 72

80

0).0

E 70� 10�

0E

I-

0

Fig. I Distribution of breast cancer samples as a function of their

cytosolic p53 concentration.

n = 634

0 10 20 30 40 >50

p53 concentration (ng/mg protein)

Clinical Cancer Research 191

Table 2 UPA prognostic value in primary brea st cancer

Reference Method Pop.” uPA+/n (%)

Follow-up(months)”

RFS UV(P)

RFS MV(P)

OS UV

(P)OS MV

(P)

Duffy et al. (36) ELISA 84/166 (51) 35 0.0005 0.0336 0.0004 0.031Foekens et al. (37)

Grondahb et a!. (41)

ELISA

ELISA

N-

Prc-menopausal

Post-menopausal

215/671 (32)

88/272 (32)

59/1 18 (50)

36/72 (50)

48

102

a � positivity threshold, 4 ng/mg protein.

b uPA positivity threshold, 0.5 ng/mg protein.C ER and PgR positivity threshold, 10 fmollmg protein.

20

15

I 1� n 6000!

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 16.0 16.5 17.0

uPA concentration (ng/mg protein)

Fig. 2 Distribution of breast cancer samples as a function of theircytosolic uPA concentration.


Table 3 Description of the studied popul ation considering biological

parameters

Parameter Total no. of tumors No. of positive tumors

PS3” 634 78

uPA” 600 165ERC 633 448PgR’ 633 397

tions between ER and PgR (P < 0.0001; r = 0.37), ER and age

(P < 0.0001; r 0.35), and PgR and age (0.0142; r 0.10)

were observed. The presence of p53 or uPA was inversely

related using the x2 test, with the presence of ER and PgR,whereas it was positively related with HPG and tumor diameter

(Table 4). uPA concentrations were inversely correlated (Spear-

man test) with ER (P < 0.0001; r = -0.245) and PgR (P <

0.0002; r = -0.149). Finally, there was a positive relationship

between p53 and uPA (x2 = 21.58; P < 0.0001), and there wasalso a positive correlation between these two parameters (Spear-

man test; P < 0.0001; r = 0.295). The distributions of p53 and

uPA were log (in) normal, confirming what we had found for

other biological parameters in breast cancers (12). A statistically

significant linear positive correlation was found between in p53

and in uPA (Fig. 3).

Prognosis Studies

OS. A total of 313 patients were included in this study

because we lost contact with 3 patients. In actuarial survival

studies, the best p53 threshold for prognosis was 4 ng/mg

protein; however thresholds of 3, 5, or 10 ng/mg protein also

allowed us to distinguish two populations of different prognosis.

For uPA, the best threshold was 0.5 ng/mg protein; thresholds of

0.2, 0.3, 0.4, 0.6, 0.7, and 0.8 ng/mg protein also allowed us to

distinguish two populations of different prognosis. Shorter OS

was found in patients with elevated p53 (Fig. 4) and elevated

uPA (Fig. 5). HPG, PgR (threshold, 10 fmoLlmg protein), and

tumor size were also prognostic factors (Table 5). In multivari-

ate analyses, when combining the parameters that have a prog-

nostic value in univariate studies, only HPG had a statistically

significant prognostic value (RR confidence interval, 1.13-3.39;

Table 5).

RFS. A total of 301 patients were included in this study.

For uPA, the best threshold was 0.5 ng/mg protein; a threshold

of 0.6 ng/mg protein also allowed us to distinguish two popu-

bations of different prognoses. In actuarial survival studies,

shorter RFS was found in patients with high levels of uPA (Fig.

6). Age was also a prognostic factor. Neither p53 (whatever the

positive threshold was), ER, HPG, PgR, nor tumor size was a

prognostic factor (Table 5). In multivariate analyses with the

parameters that have a prognostic value in univariate studies,

uPA (RR confidence interval, 1.2-3.44) preserved its statisti-

cally significant prognostic value (Table 6).

DISCUSSION

In this study, p53 and uPA were detected with a reliable

LIA. An analogous p53 assay was used by Borg et a!. (7), who

chose a positive clinical threshold at 0.15 ng/mg protein, with

about 30% of the tumors being positive. In the present study, 40

of 281 (14.2%) cases were p53 positive, with a threshold at 0.15

ng/mg protein, whereas 30% of the tumors were positive when

the threshold was 0.9 ng/mg protein; 13.7% of the tumors were

p53 positive when the optimum cutoff point (4 ng/mg protein)

was used. A major source of discrepancies between the two

studies was that the populations studied were different: in the

study of Borg et a!. (7), all of the primary breast cancers were

included, whereas the present study was concerned only with

node-negative primary breast cancers. There was no difference

in tissue preservation and cytosol preparation between the two

studies. Another source of discrepancies was the difference

between an in-house methodology and the standard commer-

cialby available methodology used by ourselves. In fact, we

observed that the standard curve in our experiments was shifted

to the left compared to the standard curve published by Borg et

a!. (7).

In the literature, the percentage of p53-positive tumors

ranged from 12% (14) to 52% (Ref. 15; Table 1). In most of the

studies published (15 of 21 cases; shown in Table 1 ), the method

used was immunohistochemistry. This method is not standard-

ized: comparison of the published studies is hampered by the

diversity of procedures and reagents used by different investi-

gators. There are differences in the antibodies used and the

preservation of tissues. Another important difference among

reported studies is the lack of standardized criteria to classify a

carcinoma as p53 positive. In most cases, staining was evaluated

by a semi-quantitative method estimating the percentage of

positive cells. The percentage of positive tumors varies from

14% ( 16) to 52% ( 15). Even in studies that used the samemonoclonal antibody, Pabl8Ol, Silvestrini et a!. (17) required

that more than 5% of nuclei be immunoreactive and found 44%

of the tumors to be positive; Thor et a!. (18, 19) and Allred et al.

(15) classified carcinomas as p53 positive if any of the cells



2

C

a)00.

a,E 0-a)C

-1

-2

100-

90#{149}

80

70#{149}

�n�mgprot.

p53>4 ng/mg prot.

p�0.011

,.:....-

(a

>

U)

-3 -2 -1 0 1 2 3

P53 (ng/mg protein)

Fig. 3 Distribution of ln uPA as a function of ln p53. The zero values

were excluded. A statistically significant positive correlation was found(Pearson test; r = 0.310; P < 0.0001; n = 584).


Table 4 Relation (x2 test) beposi

tween the presence of cytosolic p53 (n = 634; positivity threshold, 4 ng/mg protein) or cytosolictivity threshold, 0.5 ng!mg protein) and clinical, histological, or biological parameters

uPA (n 600;

PS3- pS3+ x2 P uPA- uPA+ x2 PTumor diameter

5cm 11 2 8 5

Histoprognostic gradingI 63 1 55.2

70 � uPA>0.5 ng/mg prot.

� 60

CO

.� 50 p0.038U) 40-

30 -

20 -

10 -

0--- J!� j ! � ! J � � � I

0 360 720 1080 1440 1800 2160

Time (days)

Fig. 5 05 according to the presence of uPA (clinical positive thresh-old, 0.5 ng!mg protein).

100

90

80

70

60

50

40

30

20

10

0

uPA>0.5 ng/mg prot.

p = 0.0008

0 360 720 1080 1440 1800 2160

Time (days)

Fig. 6 RFS according to the presence of uPA.

194 p53. uPA, and Breast Cancer

Table 5 Prognostic factors in Cox univariate analyses

The optimal threshold used in this analysis was 4 ng/mg protein forp53 and 0.5 ng/mg protein for uPA. The threshold was 10 ng/mg protein

for PgR.

OS

P RR

RFS

P RR

p53 (


prognostic parameters together, HPG was the strongest prog-

nostic parameter, and neither p53 nor uPA had a significant

prognostic value. In RFS analyses, two parameters (uPA and

age) were of significant value, but the RR for uPA was 2.21,

whereas for age, it was 0.97.

In conclusion, these results show that uPA and p53 are

prognostic parameters. Considering its value in multivariate

RFS studies, uPA is clearly an important prognostic parameter

in node-negative breast cancer patients that may be of use in the

clinic.

ACKNOWLEDGMENTSWe thank Dr. David Femig (Liverpool University, Liverpool,

United Kingdom) and Dr. Kent Willman (Sangtec Medical, Bromma,Sweden) for their helpful discussion and Susan Leclcrcq for correctingthe English.

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1998;4:189-196. Clin Cancer Res J P Peyrat, L Vanlemmens, J Fournier, et al. activator in node-negative human breast cancers.Prognostic value of p53 and urokinase-type plasminogen

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prognostic value of p53 and urokinase-type plasminogen ......vol. 4, 189-196, january 1998 clinical...

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