Jm. Bhatavdekar et al., Prognostic significance of immunohistochemically localized biomarkers in stage II and stage III breast cancer: A multivariate analysis, ANN SURG O, 7(4), 2000, pp. 305-311
Background: The aim was to investigate the expression of a panel of biomark
ers such as prolactin (PRL), p53, Bcl-2, c-erb B2, Ki-67, CD44, and factor
VIII-related antigen (FVIII-RA) in primary tumors of stage II and stage III
breast cancer and its correlation with disease prognostication.
Methods: The streptavidin-biotin peroxidase complex technique was used for
the detection of these antigens. Cytoplasmic staining pattern was observed
for PRL, Bcl-2, and Ki-67. Staining pattern for p53 was nuclear. Membranous
and/or cytoplasmic staining was noted for c-erb B2 and CD44. Microvessel s
taining was noted for FVIII-RA.
Results: Of the 93 primary breast tumors analyzed, positivity fur PRL was n
oted in 82%, for p53 in 56%, for Bcl-2 in 73%, fur c-erb B2 in 68%, and for
Ki-67 and CD44 in 78% each. The microvessel count (MVC) for FVIII-RA range
d from 0.0 to 29.0, with a median of 6.0, which was used as a cutoff. MVC g
reater than or equal to 6.0 was noted in 51% of breast tumors. With increas
ing tumor size, the higher frequency of positivity of MVC greater than or e
qual to 6.0 (P = .0001), CD44 (P = .001), PRL (P = .002), and c-erb B2 (P =
.008), and higher frequency of Bcl-2 negativity (P = .033), was noted. In
stage III patients, a higher positivity of the following biomarkers was not
ed, compared with stage II patients: MVC greater than or equal to 6.0 (P =
.0004), PRL (P = .0002), c-erb B2 (P = .001), and CD44 (P = .005). Further,
Bcl-2 positivity was significantly lower in patients with stage III diseas
e compared with those with stage II disease (P = .024). In patients with no
dal involvement, the frequency of c-erb B2 (P = .006), MVC greater than or
equal to 6.0 (P = .011), and PRL (P = .032) was higher than in those withou
t nodal involvement. Moreover, in these patients, with the increase in the
number of involved lymph nodes, there was a significant increase in frequen
cy of CD44(+) (P = .0004) and PRL+ (P = .013) tumors. Abnormal expression o
f one biomarker was seen in 7% of tumors, of two biomarkers in 4%, of three
in 15%, of four in 19%, of five in 28%, of six in 20%, and of all seven bi
omarkers in 7% of tumors. The frequency of an increasing number of biomarke
rs coexpressed was higher in stage III patients compared with stage II pati
ents (P = .00003). In the total number of patients (n = 93), tumors with Bc
l-2 negativity (P = .00001), MVC greater than or equal to 6.0 (P = .001), P
RL positivity (P = .02), and CD44 positivity (P = .034) had a significantly
poorer overall survival (OS) compared with their respective counterparts.
In stage II patients (n = 40), only p53 expression was significantly associ
ated with reduced relapse-free survival (P = .009) and OS (P = .040). In mu
ltivariate analysis, p53 expression was an independent prognostic factor th
at influenced relapse-free survival (P = .034) of stage II breast cancer pa
tients. However, it failed to attain statistical significance for OS. In st
age III patients (n = 53), tumors with Bcl-2 negativity (P = .0005) and MVC
greater than or equal to 6.0 (P = .039) had a significantly poorer OS comp
ared with their respective counterparts. In multivariate analysis of stage
III patients, Bcl-2 was the only independent prognostic factor (P = .001) f
or predicting OS. There was a significant association between coexpression
of the biomarkers and OS (P = .001). The OS rates decreased with the increa
se in number of abnormally expressed biomarkers,
Conclusions: p53 expression in primary tumors was an independent prognostic
factor that influenced relapse-free survival in patients with stage II dis
ease. In stage III patients, lack of Bcl-2 expression was independently ass
ociated with a poor prognosis and, thus, may be an indicator of aggressive
phenotype.