Download Prognostic Importance of Low c-erbB2 Expression in Breast Tumors

Table 1. Prognostic value of c-erbB2 oncoprotein expression in 117 patients with operable breast
cancer after a mean follow-up of 38 months*
CORRESPONDENCE
c-erbB2 expression level†
Prognostic Importance of Low
c-erbB2 Expression in Breast
Tumors
In a recent multicenter, prospective
study (1) conducted in France from September 1993 through October 1994, we
measured the levels of c-erbB2 oncoprotein in tumor specimens of 1062 patients
with breast cancer, and we used a quantitative enzymatic-based immunoassay
(Triton Diagnostics, Alameda, CA) to
measure the correlation of c-erbB2 with
prognostic indicators. Surprisingly, low
values (defined below as the mean value
minus one standard deviation) were observed to be significantly more numerous in estrogen receptor (ER)-negative
(P 4 10−9) and progesterone receptornegative tumors (P 4 .02) (chi-squared
test, two-sided), suggesting that these
low levels might have a negative prognostic value. This study suggested a possible interaction between several oncogenes (e.g., the one encoding the
epidermal growth factor receptor), for
which the absence of expression of one
of them might be counterbalanced by
the overexpression (i.e., expression at a
higher than normal level) of another. In
such a context, overexpression is not the
important factor, rather, it is the deviation from normality that might be considered a yardstick of the imbalance.
Unfortunately, a direct estimation of the
prognostic significance of these values
was not possible because the follow-up
time of the patients in the cohort was too
short.
Inasmuch as the follow-up time has
now attained 40 months, we now report
in this letter the direct prognostic significance of low c-erbB2 protein expression in breast tumor tissue specimens
from the 117 patients from the Institut
Gustav-Roussy (Villejuif, France) who
were included in the above-mentioned
study (1). The results, detailed in Table
1, confirm our previously formulated
hypothesis that low expression of cerbB2 oncoprotein is an unfavorable
712 CORRESPONDENCE
(a) Low expression
(below the mean minus)
1 standard deviation (SD)
(b) Normal expression (mean ± 1 SD)
(c) High expression (above the mean
plus 1 SD)
No. of
patients
Overall
No. with
metastasis
38-month
metastasis-free
survival proportion,
actuarial method
95%
confidence
interval
10
4
56%
23%–89%
90
17
8
4
90%
80%
83%–97%
59%–100%
Overall statistical significance (heterogeneity): P‡ 4 .006
a versus b + c P 4 .01
c versus a + b P 4 .09
*Standard deviation (SD) 4 8 months.
†c-erbB2 oncoprotein was measured by using a quantitative enzymatic-based immunoassay (Triton
Diagnostic, Alameda, CA).
‡Logrank test two-sided P value.
prognostic factor for disease-free survival of patients with breast cancer (P 4
.01), and is worse than overexpression
(P 4 .09) (logrank test, two-sided). Dittadi et al. (2) recently reported similar
findings. As mentioned above, the important factor is the deviation from normality, which assumes that c-erbB2 is
expressed in normal breast tissue. In this
regard, c-erbB2 was measured in specimens of healthy and tumor breast tissue
from nine patients. Surprisingly, the median c-erbB2 level in healthy breast tissue (112 arbitrary units/mg membrane
protein) (interquartile range: 96–124)
was not significantly different (P 4 .65;
two-sided t test performed on the logarithms of the values) from that in tumor
tissue (171 arbitrary units/mg) (interquartile range: 86–240). Furthermore,
the absence of very low or very high
expression in specimens of healthy tissue suggests that c-erbB2 levels are
more homogeneous in this tissue than in
tumor tissue (two-sided F test, P 4 .01).
Such a result is consistent with the recent observations of Robertson et al. (3)
concerning expression of c-erbB2 oncoprotein in breast cancer and of Zhang et
al. (4) for expression of the products of
other oncogenes in colorectal cancer.
In conclusion, the median levels of
c-erbB2 protein expression were comparable in normal and tumor breast tissues;
however, c-erbB2 expression was found
to be significantly more heterogeneous
in tumor tissues than in healthy tissues
(smaller variations from the median
value are observed in the former than in
the latter tissues). Given these varia-
tions, very low c-erbB2 expression appears to be a strong negative prognostic
factor for women with breast cancer.
SERGE KOSCIELNY
PHILIPPE TERRIER
MARC SPIELMANN
JEAN-CLAUDE DELARUE
References
(1) Koscielny S, Terrier P, Daver A, Wafflart J,
Goussard J, Ricolleau G, et al. Quantitative
determination of c.erbB.2 in human breast tumors: potential prognostic significance of low
values. Eur J Cancer. In press.
(2) Dittadi R, Brazzale A, Pappagallo G, Salbe C,
Nascimben O, Rosabian A, et al. ErbB2 assay
in breast cancer: possibly improved clinical
information using a quantitative method. Anticancer Res 1997;17:1245–7.
(3) Robertson KW, Reeves JR, Smith G, Keith
WN, Ozanne BW, Cooke TG, et al. Quantitative estimation of epidermal growth factor receptor and c-erbB-2 in human breast cancer.
Cancer Res 1996;56:3823–30.
(4) Zhang L, Zhou W, Velculescu VE, Kern SE,
Hruban RH, Hamilton SR, et al. Gene expression profiles in normal and cancer cells. Science 1997;276:1268–72.
Notes
Affiliations of authors: S. Koscielny (Department of Biostatistics and Epidemiology), P. Terrier (Department of Pathology), M. Spielmann
(Department of Medicine), J.C. Delarue (Department of Clinical Biochemistry), Institut GustaveRoussy, Villejuif, France.
Correspondence to: J. C. Delarue, Ph.D., Institut Gustave-Roussy, Department of Clinical Biochemistry, 94805 Villejuif, France. E-mail:
[email protected]
Journal of the National Cancer Institute, Vol. 90, No. 9, May 6, 1998