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We examined the relation between ERBB2 gene expression (as determined by a real-time quantitative RT-PCR assay) and the response to adjuvant tamoxifen therapy in a well-defined cohort of 125 ER α-positive postmenopausal patients with breast cancer. Although ERBB2 overexpression was associated with shorter relapse-free survival in univariate analysis ( P =0.00029), ERBB2 did not persist as an independent prognostic factor in multivariate analysis. Nevertheless, when we analyzed the ERBB2 mRNA level as a continuous variable, the higher the ERBB2 RNA level, the poorer the outcome ( P =0.00036). The results point to the need for a quantitative ERBB2 expression assay for use in future studies of ERBB2 -based clinical management of breast cancer.

A multitude of clinical, pathological and biological parameters have been reliably associated with prognosis in breast cancer patients. Recently much interest has been engendered by multifactorial computing methods attempting to produce higher prognostic accuracy as well as being of clinical utility for treatment selection. Clinical, pathological and a number of more recent biological parameters were evaluated retrospectively in a population of 196 breast cancer patients who had been treated with first line surgery and followed for a median of 7.3 years. Clinical tumour size, menopausal status, type of treatment as well as tumour grade, pathological tumour size, node invasion, the presence of vascular emboli and steroid hormone receptor status were evaluated together with gene amplification (by Southern blot) of c-erbB2/neu, c-myc and int-2/FGF3 as well as overexpression (by immunohistochemistry, IHC) of c-erbB2/neu, EGF receptor, CSF-1 and CSF-1 receptor. The presence and abundance of inflammatory cell infiltrates (T, B cells and monocytes) were also evaluated by IHC. The risk of cancer related death as tested in univariate and multivariate analyses was consistently higher in patients with positive axillary nodes and in those whose tumours showed evidence of int-2/FGF3 gene amplification, of overexpression of c-erbB2/neu at the cellular membrane, of vascular invasion by tumour cells and of abundant CD45RO+ T cells infiltrates. A prognostic score was calculated for each patient by computing the prognostic index associated with each of these five parameters and risk profiles were established by order of increasing risk. Survival curves drawn for three groups of high, intermediate or lowest risk showed a highly significant poorer survival for the highest risk group. The model we present, although far from the complexity of a ‘neural network’ analysis, does discriminate effectively between low, moderate and high risk groups. Future prospective studies should test these independent prognostic markers together with more recently established markers in an attempt to determine not only the most predictive but also the most cost-effective ‘prognostikit’ for breast cancer patients. Such a molecular prognostic index will allow the evaluation of current therapies in the light of specific molecular alterations and may aid the design of new therapeutic approaches geared to the genetic profile of a given tumour.

Usually, the SBR histoprognostic grading is not considered appropriate for lobular invasive carcinoma. We previously demonstrated improved prognostic value of a modified SBR grading (MSBR) for invasive ductal carcinoma (IDC), specially when node negative. We did a multivariate analysis of 291 patients with operable, invasive, lobular breast carcinoma, to assess the prognostic value of the SBR/MSBR grading. We applied this MSBR to the studied population. The Cox multivariate analysis showed that the nodal status, clinical tumor size and MSBR were the three most important prognostic factors for DFS, and nodal metastasis, MSBR and progesterone receptor (PR) status for MFS. Indeed, we concluded that SBR grading is relevant for lobular invasive carcinoma, MSBR being more accurate, mainly because it discriminates grade II SBR patients. This result was not surprising as the pattern of ILC implicated a higher proportion of grade II SBR patients (78%), than IDC (55%).

The prognostic significance of the three genes most frequently amplified in breast tumors was investigated by multivariate analysis in a retrospective study of 112 primary human breast cancers. These three genes, c-myc, int-2/FGF3 (a marker for the 11q13 amplicon) and c-erbB-2/neu, were amplified in 37, 14 and 10% of breast tumors studied respectively. Amplification of the c-myc gene was not related to metastasis-free survival (MFS) in the total population, but was a discriminant prognostic indicator in premenopausal patients. Int-2/FGF3 gene ampli-cations were good indicators of prognosis, especially in premenopausal patients, and also in lymph-node-positive and steroid receptor-negative patients. Int-2/FGF3 amplification and progesterone receptor (PgR) status together proved to be the only independent variable predictive of MFS. The risk of relapse in the sub-group of PgR-negative patients was five times greater for those with int-2/FGF3 amplification than patients without this alteration. These results suggest that the combined use of classical prognostic factors and molecular markers may improve prognostic value and be applicable to patients with specific tumor phenotypes.

A specific protein from the liquid of a mammary cyst with a molecular weight of 15,000 (GCDFP 15) was studied in normal and pathological mammary tissue using an immunohistochemical method (peroxidase-anti-peroxidase complex). An immunoreactivity of the GCDFP type was found in normal idrosadenoid glands having an apocrine secretion. Histologically normal mammary tissue was not immunoreactive. In benign breast tissue the GCDFP was found particularly in epithelium undergoing apocrine metaplasia (55/55) and in atypical lobular epithelial hyperplasia (8/10). Of the adenocarcinomas of the breast 136/161 (84%) were immunoreactive, especially lobular carcinoma (13/13). The proportion of tumors with a high percentage of immunoreactive cells (76-100%) was greater for Bloom's grade I (1/29: 34%) than for grade III (10/66: 15%). A significant correlation was found between the percentage of immunoreactive cells and the cytosolic concentration of progesterone receptors. The morphological intracellular identification of GCDFP (due to its greater sensitivity) and its correlation with progesterone receptors allowed a more precise evaluation of the functional state and the hormonal dependency of the breast cells by underlining the heterogeneity of the tumoral cell population.

Nine prognostic variables were evaluated for their significance in predicting the overall survival (OS), the length of disease-free survival (DFS) and the length of metastasis-free survival (MFS) of 1262 patients with primary breast cancer. The variables studied were: UICC clinical stage; menopausal status; histologic grade; number of involved nodes; anatomic tumor size; estrogen and progesterone receptors; local and adjuvant therapies. Three sequential multivariate analyses, at 2, 5 and 10 years, using the Cox proportional hazard regression model, were carried out to identify those variables most highly related to the criteria studied (overall, disease-free, metastasis-free survivals) and especially to fully evaluate the effects of hormonal receptors on prognosis and their stability over time. Our results showed that number of involved nodes and histologic grade were the most significant prognostic factors for all periods of time and whatever the criterion studied; ER had no predictive value while PR was an independent prognostic factor for metastasis-free survival at 2 years (P = 0.01) and 5 years (P = 0.02) but lost its significance at 10 years (P = 0.06). In the subgroup of 261 patients who received prolonged post-operative adjuvant chemotherapies, PR was the main prognostic factor for MFS at 2 years (P = 0.03) and the second at 5 years (P = 0.05) just after number of involved nodes. In the 1001 patients who did not receive prolonged post-operative adjuvant chemotherapies ER was significant for MFS at 5 and 10 years. The present data urge the need for a periodic redefinition of prognostic factors in primary breast cancer.

Alphalactalbumin was investigated in breast cells using the immunoperoxidase technique with a specific anti-alphalactalbumin serum. In 50 benign tumors alphalactalbumin immunoreactivity was demonstrated in the epithelium of fibroadenomas and in fibrocystic disease showing apocrine metaplasia. Alphalactalbumin immunoreactivity, investigated in 124 breast cancers, was present in all cells of lobular tumors but in only 76% of other cancers where the pattern was heterogeneous. Perineoplastic mammary tissue of normal appearance was not labeled with the anti-alphalactalbumin antiserum except where lobular hyperplasia was present. The presence of alphalactalbumin-type immunoreactivity was not correlated with the histopathological staging of Bloom and Richardson, nor with menopausal status. The incidence of positivity was 90% when estrogen and progesterone receptors were present in the tumor. The demonstration of alphalactalbumin using immunoperoxidase could be used to complement the histological classification of breast cancers.