Characterization of breast cancer subtypes by quantitative assessment of biological parameters: relationship with clinicopathological characteristics, biological features and prognosis.

OBJECTIVES: Gene expression analysis has identified several breast cancer subtypes, including luminal, epidermal growth factor receptor-2 positive (HER2+), and basal-like. To determine if our proposed molecular taxonomy correlates with biological and clinical behavior. This is based on four biological markers: estrogen and progesterone receptors (ER and PR, respectively), HER2 and the epidermal growth factor receptor-1 (HER1), all of them being determined by quantitative assays. STUDY DESIGN: The biological parameters were examined by enzyme immunoassay, radioligand-binding assay or ELISA, in tumors from 787 patients with invasive breast cancer. Patients were prospectively evaluated over a median follow-up period of 50 months. Subtype definitions were as follows: luminal (ER+), HER2+ (HER2+, ER-, PgR-) and basal-like (HER2-, ER-, PgR-). In addition, we divided basal tumors into two groups based on their HER1 status. RESULTS: A 55.8% of tumors were of luminal type, 11.9% basal-like HER1+, 10.7 basal-like HER1-, and the remainder 21.6% HER2+. Both HER2+ and basal-like subtypes were more frequent in younger and premenopausal women, showing a higher percentage of cases of poorly differentiated tumors and higher S-phase fraction, when compared with those of luminal subtype. Multivariate analysis demonstrated that the subtype of tumor was related to both relapse and overall survival, being those of luminal subtype associated with the best prognosis. CONCLUSIONS: Through the classification of breast tumors in four groups, according to their ER, PgR, HER2 and HER1 status, it is possible to obtain a major division of breast tumors associated with significant differences in biological features and clinical behavior.

Expression and prognostic value of EGFR in invasive breast cancer.

Epidermal growth factor receptor (EGFR) is a membrane receptor expressed in a variety of solid human cancers and directly related with poor prognosis. The objective of this work was to evaluate the EGFR content in breast carcinomas, its possible relationship with different clinical-pathological parameters, and its potential prognostic significance and predictive value. EGFR levels were examined by radioligand binding assays in 846 patients with invasive breast cancer. The median follow-up period was 50 months. There was a wide variability of EGFR levels among the studied tumors (0.01-403 fmol/mg protein). Statistical analysis showed that EGFR levels were significantly higher in younger patients (p=0.0001). EGFR were also notably higher in ER-negative or PgR-negative tumors than in ER-positive (p=0.0001) or PgR-positive tumors (p=0.001). In addition, the presence of high intratumoral EGFR levels (cut-off: 6 fmol/mg protein) was associated with both shorter relapse-free survival (p=0.04) and overall survival (p=0.01) in the group of patients as a whole, as well as with overall survival in the subgroup of patients without any type of systemic adjuvant treatment (p=0.02). However, EGFR levels did not achieve significance as independent prognostic factor in the multivariate analysis. There is a wide variability of intratumoral EGFR levels in breast carcinomas, and these protein levels correlated positively with a poor prognosis in the t univariate analysis. However, further studies are necessary in order to assess the possible clinical value of EGFR in combination with other essential components of the EGFR family network.

Membranous levels of c-erbB-2 oncoprotein in gastric cancer: their relationship with clinicopathological parameters and their prognostic significance.

BACKGROUND: The protein encoded by the c-erbB-2 gene is a membrane receptor expressed in a variety of solid human cancers and directly related to poor prognosis. The objective of this work was to evaluate the clinical value of the quantification of membranous oncoprotein levels in gastric cancer. MATERIALS AND METHODS: Membranous c-erbB-2 levels were examined by means of a sandwich immunoenzymatic assay in 82 patients with gastric cancer. The median follow-up period for these patients was 16 months. In addition, c-erbB-2 expression was analyzed by immunohistochemistry in 57 gastric carcinomas. RESULTS: Membranous c-erbB-2 levels ranged widely in the studied tumors (44-112,000 NHU/mg protein). Median c-erbB2 content was significantly higher in intestinal-type tumors than in diffuse-type tumors (p = 0.01). In addition, high levels of c-erbB-2 were significantly associated with shorter relapse-free survival and overall survival in patients with resectable gastric carcinomas (p = 0.01 and p = 0.04, respectively). However, the correlation between immunohistochemistry and ELISA determinations did not reach statistical significance. CONCLUSION: Our results suggest a potential prognostic value of membranous c-erbB-2 quantification by immunoenzymatic assay in gastric cancer. However, its possible role in the selection of patients with a view to the possible introduction of Herceptin as a novel drug against gastric cancer is at present uncertain.

[Clinical significance of tumor content of epidermal growth factor receptor in breast cancer]. / Significación clínica del contenido tumoral del receptor del factor de crecimiento epidérmico en el cáncer de mama.

OBJECTIVE: To determine the content of epidermal growth factor receptor (EGFR) using a radioligand method in breast cancer and to analyze the relationship between the EGFR levels and the characteristics of patients and tumors. Prognostic significance was also analyzed. MATERIAL AND METHODS: EGFR was measured by a single point radioligand assay in 265 invasive breast carcinomas tissues. In addition, estrogen and progesterone receptors (ER and PR) were measured by enzymatic immunoassays. We analyze the relationship of EGFR levels with the different clinico-pathologic parameters. RESULTS: EGFR levels in breast carcinomas varied widely (0.1 to 403) with a median at 4 fmol/mg prot. The significantly higher concentrations of EGFR were detected in patients under 60 years old (p = 0.042), undifferentiated tumors (p = 0.04), and carcinomas with negative ER and PR (p < 0.019 y p < 0018, respectively). In addition, there was a negative correlation between EGFR and the ER and PR levels (p < 0.05). EGFR levels did not show any relationship with the patient's prognosis. CONCLUSIONS: In addition, intratumoral levels of EGFR in breast carcinomas vary widely and the highest concentrations are associated with the most aggresive characteristics of the tumor.

Significación clínica del contenido tumoral del receptor del factor de crecimiento epidérmico en el cáncer de mama / Clinical significance of tumor content of epidermal growth factor receptor in breast cancer

Objetivo: Cuantificar el contenido del receptor del factor de crecimiento epidérmico (EGFR) mediante técnica de radioligando en el cáncer de mama, y analizar su relación con las características de las pacientes y de sus tumores así como su significado pronóstico. Material y método: Se cuantificó la concentración de EGFR mediante técnica de radioligando de un sólo punto en 265 carcinomas invasivos de mama. Igualmente se determinaron los receptores de estrógenos (RE) y progesterona (RP) mediante inmunoensayo enzimático. Analizamos el contenido de EGFR y su relación con los diferentes parámetros clínico-patológicos. Resultados: Los niveles de EGFR en carcinomas de mama oscilaron ampliamente (de 0,1 a 403) con una mediana de 4 fmol/mg prot. Los niveles significativamente más altos de EGFR se detectaron en las pacientes menores de 60 años (p < 0,042), en los tumores indiferenciados (p < 0,004) y en los que eran negativos para RE y RP (p < 0,019 y p < 0,018, respectivamente). Además, hubo correlación negativa entre los niveles de EGFR y los de RE y RP (p < 0,05). No observamos relación entre los niveles de EGFR y el pronóstico de las pacientes. Conclusión: Los niveles intratumorales de EGFR en los carcinomas mamarios presentan una amplia variabilidad, y las concentraciones más elevadas se relacionan con las características más agresivas del tumor (AU)

Epidermal growth factor receptor and c-erbB-2 contents in unresectable (UICC R1 or R2) gastric cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) and c-erbB-2 are membrane receptors expressed in a variety of solid human cancers and directly correlated with poor prognosis. The objective of this work was to evaluate the EGFR and c-erbB-2 levels in non-resectable gastric carcinomas, their possible relationship with a variety of clinicopathological tumor parameters, and their prognostic significance. METHODS: This was a prospective analysis of 65 patients with unresectable gastric carcinomas (UICC R1 or R2), who underwent palliative surgery and were followed up for a median period of 13 months. Membranous EGFR levels were examined by radioligand binding assays and cytosolic c-erbB-2 levels by means of an immunoenzymatic assay. RESULTS: There was a wide variability in EGFR (80.3-2910 fmol/mg of protein) and c-erbB-2 (0.4-10071 NHU/mg of protein) levels in neoplastic tissues from patients with unresectable gastric carcinomas. Median c-erbB2 was significantly higher in tumors of the intestinal type than in tumors of the diffuse type (p = 0.035) and in R2 than in R1 tumors (p = 0.016). Statistical analysis showed that there was no relationship between tumor c-erbB-2 or EGFR content and any other patient or tumor characteristics. However, high levels of EGFR were significantly associated with a shorter overall survival (p = 0.01). CONCLUSION: Our data suggest a role of both transmembrane proteins in the progression of gastric cancer. EGFR and c-erbB-2 contents in unresectable gastric cancer could be utilized as appropriate biological markers for selecting candidates for treatment based on EGFR and/or c-erbB-2 inhibition.

Cytosolic levels of an estrogen-induced breast cancer-associated peptide (TFF1/pS2) in colorectal cancer: clinical significance and relationship with steroid receptors.

BACKGROUND: The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA in MCF-7 breast cancer cells and is also expressed by colorectal carcinomas. The objective of this work was to evaluate the cytosolic TFF1 content in colorectal carcinomas, its possible relationship with estrogen and progesterone receptors as well as with clinicopathological tumor parameters, and its potential prognostic significance. METHODS: Cytosolic TFF1 levels were examined by immunoradiometric assay in 178 patients with resectable colorectal cancer. The mean follow-up period was 32 months. RESULTS: There was a wide variability of cytosolic TFF1 levels in tumor-surrounding mucosa samples (0.09-42.5 ng/mg protein) as well as in tumors (0.01-270 ng/mg protein). Comparison of paired mucosa and carcinoma samples showed significantly higher TFF1 levels in tumors (mean: 17.1 ng/mg protein) than in mucosa samples (10 ng/mg protein) (p = 0.027). TFF1 levels were significantly higher in mucosa samples surrounding distal colon and rectal tumors (p = 0.0001) and in tumor samples obtained from older patients (p = 0.007). However, there were no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, tumor location, stage, histological grade, ploidy, S-phase, or tumor estrogen and progesterone receptors. In addition, there was no significant relationship between tumor TFF1 levels and disease outcome. CONCLUSIONS: TFF1 may play an as yet undetermined role in the tumorigenesis of colorectal carcinomas. However, cytosolic levels of TFF1 do not seem to have any prognostic significance in colorectal carcinomas.

Prognostic significance of tissue-type plasminogen activator (tPA) content in gastric cancer and surrounding mucosa.

AIMS: We analyzed the tPA content in primary gastric carcinomas and surrounding mucosa in order to assess the relationship between tPA content, clinicopathological tumor characteristics, and estrogen and progesterone receptor content. We evaluated the prognostic value of this serine protease in gastric cancer patients. PATIENTS AND METHODS: 122 resected gastric neoplasms and 95 adjacent mucosa samples were studied. The tPA content was measured in cytosol by an ELISA method. Cytosolic ER and PgR were measured with a solid phase enzyme immunoassay. RESULTS: Cytosolic tPA levels in neoplastic tissues (median 1.0 ng/mg prot) were significantly lower (p=0.002) than those found in paired mucosa samples (median 2.3 ng/mg prot). There was no significant association between tPA levels and clinicopathological parameters or PgR content, but tPA levels were significantly correlated with ER content. The intermediate-tPA-content group, corresponding to samples with between 0.3 and 1.70 ng/mg protein, proved to have a significantly high risk of relapse. CONCLUSIONS: We found a wide variability in tPA levels in gastric carcinoma and adjacent mucosa samples, with significantly decreased levels in tumors and a significantly positive relationship between tPA levels and ER status. There was a non-monotonic relationship between tPA levels and prognosis in patients with gastric cancer.

[Analysis of the cytosolic content of the pS2 protein in breast cancer]. / Análisis del contenido citosólico de la proteína pS2 en el cáncer de mama.

OBJECTIVE: To analyze pS2 cytosolic levels in breast carcinomas and their correlation with different clinical characteristics of the patients and their tumours. MATERIAL AND METHODS: Cytosolic pS2 levels were measured by radioimmunometric assay in tumours from 168 breast cancer patients. RESULTS: The pS2 values ranged from 0 to 251 ng/mg protein (mean SD: 21.8 38.1; median: 7.9 ng/mg protein). These protein levels were significantly (p < 0.05) higher in premenopausal patients (27.6 45.2) than in postmenopausal patients (19.5 33.8). Intratumour pS2 levels were also significantly (p < 0.05) correlated with histologic grade of the tumours, and were higher in well diferentiated tumours (grade I: 28.8 42.8) than in moderately differentiated tumours (grade II: 19.7 35.6) and than in poorly differentiated tumours (grade III: 18.9 37.3). Similarly, significant differences in pS2 content were found between positive estrogen receptor (ER) tumours and ER-negative tumours (29.1 46.5 vs 11.3 15.9, respectively; p<0.0001), as well as between positive progesterone receptor (PR) tumours and PR-negative tumours (29.1 49.8 vs 15.3 21.5, respectively; p < 0.05). CONCLUSIONS: The results suggest that pS2 may be a useful prognostic marker in breast cancer, and may also be useful to identify patients who are likely to benefit from hormone therapy.

Análisis del contenido citosólico de la proteína ps2 en el cáncer de mama / Analysis of the cytosolic content of the ps2 protein in breast cancer

Objetivo: Analizar los niveles citosólicos de pS2 en carcinomas de mama y su correlación con las diferentes características clínicas de las pacientes y de sus tumores.Material y métodos: Se determinaron por método inmunorradiométrico los niveles citosólicos de pS2 en 168 tumores de pacientes con cáncer de mama. Resultados: Los valores de pS2 variaron de 0 a 251 ng/mg proteína (media ñ DE: 21,8 ñ 38,1; mediana: 7,9 ng/mg proteína). Esos niveles de la proteína fueron significativamente (p < 0,05) más elevados en las pacientes premenopáusicas (27,6 ñ 45,2) que en las pacientes postmenopáusicas (19,5 ñ 33,8). Los niveles intratumorales de pS2 también estuvieron significativamente (p < 0,05) correlacionados con el grado histológico de los tumores, siendo más elevados en los tumores bien diferenciados (grado I: 28,8 ñ 42,8) que en los tumores moderadamente diferenciados (grado II: 19,7 ñ 35,6) y que en los tumores pobremente diferenciados (grado III: 18,9 ñ 937,3). Similarmente, se encontraron diferencias significativas en el contenido de pS2 entre los tumores receptor de estrógeno (RE)-positivos y los tumores RE-negativos (29,1 ñ 46,5 vs 11,3 ñ 15,9, respectivamente; p < 0,0001), así como también entre los tumores receptor de progesterona (RP)-positivos y los tumores RP-negativos (29,1 ñ 49,8 vs 15,3 ñ 21,5, respectivamente; p < 0,05). Conclusión: Estos resultados sugieren que la pS2 puede ser un útil marcador pronóstico en el cáncer de mama, así como también para identificar pacientes que pueden beneficiarse de terapia hormonal (AU)

Clinical significance of epidermal growth factor receptor content in gastric cancer.

The objective of this work was to evaluate the epidermal growth factor receptor (EGFR) content in gastric cancer, its possible relationship with clinicopathological parameters of tumors and its prognostic significance. Membranous EGFR levels were examined by radioligand binding assays in 110 patients with gastric cancer. The mean follow-up period was 30.7 months. EGFR levels of tumors ranged widely, from 0.3 to 510 fmol/mg protein. EGFR levels were significantly higher (p<0.0005) in neoplastic tissue than in paired adjacent mucosa samples (median) (n= 84; 8.7 vs. 3.9 fmol/mg protein). Intratumoral EGFR levels were significantly correlated with tumor stage (p<0.05), and were higher in patients with stage III tumors (median) (7.6, 6.4, 12.3 and 7.5 fmol/mg protein for stages I, II, III and IV, respectively). In addition, the tumor/mucosa ratios of the EGFR content were significantly higher (p<0.05) in patients with stage III tumors (1, 1.8, 3.9, and 0.92, respectively). Although there was no significant relationship between EGFR levels of tumors and overall survival, the results suggest a role for EGFR in tumor progression of gastric cancer.

Prognostic significance of cytosolic pS2 protein content in gastric cancer.

pS2, a 60-amino-acid chain peptide which is the most widespread estrogen-induced RNA messenger in MCF-7 breast cancer cells, is normally detected in the epithelium of gastric mucosa. The aims of this work were to evaluate the cytosolic pS2 content and its clinical significance in gastric carcinomas. Cytosolic pS2 levels were examined by immunoradiometric methods in 108 patients with primary gastric adenocarcinomas. The mean follow-up period was 23.3 months. The cytosolic pS2 levels of the tumors ranged widely, i.e., from 0.1 to 3217 ng/mg protein. There were no significant differences in pS2 content between tumors (mean +/- standard error: 137.2+/-31.4 ng/mg protein) and paired adjacent mucosa samples (n=84; mean +/- standard error: 249.6+/-32.6 ng/mg protein), nor were there any significant differences in tumoral pS2 levels with respect to clinicopathologic parameters such as patient age and sex or tumor location, stage, histologic type or grade. However, the results indicated that high intratumoral pS2 levels were significantly and independently associated with an unfavorable outcome in the overall group of patients (p=0.0266) and in patients with resectable gastric cancer (p=0.003). In conclusion, pS2 may represent a useful biological marker in gastric cancer.

Hyaluronic acid as prognostic marker in resectable colorectal cancer.

BACKGROUND: Hyaluronic acid (HA), an extracellular high molecular mass polysaccharide, is thought to be involved in the growth and progression of malignant tumours. The objective of this work was to evaluate the cytosolic HA content in resectable colorectal cancer, its possible relationship with clinicopathological parameters of tumours and its prognostic significance. METHODS: Cytosolic HA levels were examined by radiometric assay in 120 patients with resectable colorectal cancer. The mean follow-up period was 33.4 months. RESULTS: Cytosolic HA levels of tumours ranged widely, from 30 to 29 412 ng per mg protein. Intratumour HA levels were significantly correlated with Dukes stage (P < 0.005), and were higher in patients with advanced tumours (mean(s.e.m.) 2695(446), 2858(293) and 5274(967) ng per mg protein for stages A, B and C respectively). In addition, Cox multivariate analysis demonstrated that tumour HA levels higher than 2000 ng per mg protein predicted shorter relapse-free survival and overall survival periods (both P < 0.05). CONCLUSION: There is a wide variability in cytosolic HA levels in colorectal carcinomas, which seems to be related to the biological heterogeneity of these tumours. In addition, high tumour cytosolic HA levels were associated with an unfavourable outcome in patients with resectable colorectal cancer. HA may provide additional information to that given by other biochemical markers currently used in colorectal cancer.

C-erbB-2 oncoprotein content in gastric cancer and in adjacent mucosa.

The aim of this study was to evaluate, by means of an immunoenzymatic assay, the membranous and cytosolic c-erbB-2 oncoprotein contents in primary tumors and in adjacent mucosa from gastric cancer patients. Fifty-two patients with primary gastric adenocarcinomas were enrolled in this prospective study. c-erbB-2 protein levels were significantly higher in membranous than in cytosolic samples, both in neoplastic tissues (median: 3602 vs 525 NHU/mg protein; p<0.0001) and in adjacent mucosa samples (median: 3174 vs 509 NHU/mg protein; p<0.0001). Nevertheless, there was a significant positive relation between membranous and cytosolic c-erbB-2 protein contents in both neoplastic tissue (p<0.001) and adjacent mucosa (p<0.001) samples. There was no significant difference in the membranous c-erbB-2 protein content between neoplastic tissues and adjacent mucosa samples. However, the cytosolic c-erbB-2 content was significantly higher in neoplastic tissues than in adjacent mucosa (p<0.05). Finally, the results did not show any significant correlations of these oncoprotein contents with patient characteristics, clinicopathologic parameters and overall survival of the study population.

Tissue-type plasminogen activator (tPA) content in colorectal cancer and in surrounding mucosa: relationship with clinicopathologic parameters and prognostic significance.

The aim of this study was to evaluate the cytosolic tissue-type plasminogen activator (tPA) content in colorectal cancer, its possible relationship with the clinicopathologic parameters of tumors, and its prognostic significance. We have therefore examined by immunoenzymatic assay the cytosolic tPA content in tumors and paired surrounding normal mucosa samples from 162 colorectal cancer patients. Cytosolic tPA levels were significantly higher in surrounding normal mucosa samples than in neoplastic tissues (4.01 +/- 5.07 vs 2.63 +/- 5.82 ng/mg protein; p < 0.0001). By contrast, no significant correlation was found between tPA content and clinicopathologic tumor parameters such as location, Dukes' stage, histologic grade, and DNA content or S-phase fraction. However, the results indicated that a high cytosolic tPA content (> 0.75 ng/mg protein) in tumors predicted for a shorter relapse-free and overall survival (both p < 0.05) in 123 resectable colorectal cancer patients who were prospectively evaluated during a mean follow-up period of 32.2 months. This suggests that tPA may give additional information to that provided by other biochemical markers currently used in colorectal cancer.

[Quantification of bladder tumor antigen (BTA trak) and its correlation with bladder cancer grade and stage]. / Cuantificación del antígeno tumoral vesical (BTA trak) y su correlación con el grado y estadio del cáncer vesical.

OBJECTIVE: To analyze the efficacy of the BTA Trak test as a diagnostic marker for bladder cancer, determine its correlation with tumor grade and stage, compare its sensitivity with urinary cytology and its utility in urological conditions other than bladder cancer. METHODS: 77 patients comprised the study; 33 with bladder cancer and 44 without. A urine sample was obtained from all patients for the BTA Trak test and another three samples for urinary cytology from each of the 33 patients with bladder cancer. Of the 44 patients without bladder cancer, 36 had conditions involving the urinary tract and 8 presented conditions without urothelial involvement. The BTA Trak test was repeated three months after treatment in 11 of the patients with bladder cancer and three months after the first test in 13 patients without bladder cancer. RESULTS: Using BTA Trak threshold values of 14 U/ml as first reference and 50 U/ml as the value indicating clinical warning, these were found to be higher in 24 of 33 patients with bladder tumor (sensitivity 72.7%). By tumor stage, BTA Trak was positive in 12 of 21 pT1 (sensitivity 57%) and in 11 of 11 pT2 (sensitivity 100%). Concerning tumor grade, values were higher than threshold in 13 of 22 GI-II (sensitivity 59.9%) and 10 of 10 GIII (sensitivity 100%). Urinary cytology was positive in only 8 cases (sensitivity 24.4%). In the patients without bladder cancer, values are higher than threshold in 3 of 8 patients with urological conditions without urinary tract involvement and 14 of 36 with a probable urothelial involvement without tumor, accounting for an overall sensitivity of BTA Trak of 61.4%. The BTA Trak test three months after treatment showed lower value in 7 of 8 patients with bladder tumor and pretreatment values higher than threshold. CONCLUSIONS: The BTA Trak test is a simple quantitative method with a high sensitivity for the diagnosis of bladder tumors, especially those in the advanced stages and grades. It is superior to cytology, although it has a lower specificity, particularly in conditions with urinary tract involvement.

C-erbB-2 oncoprotein content in colorectal cancer and in surrounding mucosa: relationship with clinicopathologic parameters and prognostic significance.

BACKGROUND: c-erbB-2 is a transmembrane signaling molecule closely related in structure to the epidermal-growth-factor receptor (EGFR) but biologically distinct from it. c-erbB-2 has been implicated in cell transformation and tumor pathogenesis, but very little is known about its content and clinical significance in colorectal cancer. AIMS: To evaluate the c-erbB-2 content in colorectal cancer and its possible relationship with clinicopathologic parameters from tumors and prognostic significance. METHODS: Membranous and cytologic c-erbB-2 oncoprotein contents were examined by an immunoenzymatic assay in tumors and paired normal surrounding mucosa samples from 131 colorectal cancer patients. In addition, survival analysis were prospectively performed in a subgroup of 69 consecutive patients with resectable colorectal carcinomas, who underwent a mean follow-up period of 28 months. RESULTS: In the overall group of patients, c-erbB-2 levels were significantly higher in membranous than in cytosolic samples, in neoplastic tissues (5,830.4 +/- 1085.3 vs. 934.2 +/- 107.5 NHU/mg protein; p < 0.0001) and in surrounding normal mucosa samples (5,257.8 +/- 646.3 vs. 837.4 +/- 187.4 NHU/mg protein; p < 0.0001). Nevertheless, a significant positive relation was found between membranous and cytosolic oncoprotein levels in these two paired sets (p < 0.0001, for both). There were no significant differences in membranous or cytosolic c-erbB-2 protein levels between neoplastic tissues and surrounding mucosa samples in this overall group of patients. In addition, the results did not show significant correlations of these oncoprotein contents with clinicopathologic parameters from tumors such as location, stage, histologic grade, and DNA content or S-phase fraction. However, the results indicated that low membranous c-erbB-2 content (< 4,500 NHU/mg protein) in tumors predict shorter relapse-free survival and overall survival (p < 0.05, for both) in resectable colorectal cancer patients. CONCLUSIONS: There are a wide variability of both membranous and cytologic c-erbB-2 contents in colorectal carcinomas, which seems to correspond to the biological heterogeneity of these tumors. In addition, our results also demonstrate that high membranous c-erbB-2 levels are associated with lesions of favorable evolution in resectable colorectal cancer patients.