Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome.

BACKGROUND: CA 125 assays enable treatment response monitoring in ovarian cancer. PATIENTS AND METHODS: This multicentric study was carried out to assess the prognostic value of the CA 125 change after the first and the second courses of induction chemotherapy (CT). Of the 494 stage IIc-IV patients, 194 had a surgical second look, 397 (80.4%) relapsed and 382 (77.3%) died from cancer. Median (range) follow-up time was 34 months (3-215 months). RESULTS: In Cox models, CA 125 change after the first course (P < 0.0001), residual tumour (P = 0.003), CA 125 before the second course (P = 0.025) and patients' age (P = 0.048) were independent prognostic factors for overall survival (OS). A normal CA 125 before each of the two first CT courses or a CA 125 decrease >50% after the first course with a normal CA 125 before the second course identify patients with good prognosis. Both criteria retained a significant value in predicting second-look findings by univariate and multivariate analysis (P < 0.0001). CONCLUSION: Among well-established prognostic factors in ovarian cancers, the CA 125 change after first course of CT was independent prognostic factors for both achievement of pathological complete response and OS.

CA 125 half-life and CA 125 nadir during induction chemotherapy are independent predictors of epithelial ovarian cancer outcome: results of a French multicentric study.

BACKGROUND: CA 125 assays enable treatment-response monitoring in ovarian cancer. PATIENTS AND METHODS: A multicentric study of CA 125 kinetics under induction chemotherapy was performed in 631 patients. CA 125 half-life was calculated by mono-compartmental logarithmic regression. Nadir CA 125 concentration and time to nadir were also studied. Survival analyses for disease-free survival (DFS) and overall survival (OS) used univariate (Kaplan-Meier) and multivariate (Cox) models. RESULTS: For 553 stage IIC-IV patients, 459 (83.0%) relapsed and 444 (80.3%) died from cancer. Median (range) follow up time was 32 months (2-214 months). Median (range) for CA 125 kinetics were: 263 kU/l (5-52000 kU/l) before 1st course, 15.8 days (4.5-417.9 days) for CA 125 half-life, 16 kU/l (3-2610 kU/l) for nadir and 85 days (0-361 days) for time to nadir. Pre-chemotherapy CA 125, its half-life, nadir concentration and time to nadir all had a univariate prognostic value for DFS and OS (P<0.0001). In Cox models, CA 125 half-life, residual tumour (P<0.0001 for both), nadir concentration (P=0.0002) and stage (P=0.0118) were the most powerful prognostic factors for DFS. For OS, the significant variables were similar, with age ranking last (P=0.0319). CONCLUSION: Among well-established prognostic factors in ovarian cancers, CA 125 half-life and nadir concentration bear a strong and independent prognostic value.

Quantitative determination of c-erbB-2 in human breast tumours: potential prognostic significance of low values.

The purpose of this prospective multicentric study was to quantify the c-erbB-2 protein and investigate its relationship with DNA amplification and with various prognostic parameters of breast cancer. A total of 1062 primary operable human breast tumours were collected from six French anticancer centres. The c-erbB-2 protein was measured using an enzymoimmunoassay using two monoclonal antibodies directed against the extracellular domain of the protein. The results were expressed in arbitrary units/mg membrane protein (AU) after adjustment for the anticancer centre. A significant association was found between the dosage of the protein and DNA amplification (P = 0.0001). A value of 200 AU was found to maximise sensibility and specificity and was chosen as a cut-off for over-expression. Significant associations were found between c-erbB-2 values and oestrogen receptor (ER) (P = 0.01), progesterone receptor (PgR) (P = 0.0001) and histological grading (P = 0.01). The extreme high values (above the mean plus one standard deviation, S.D.) were significantly more numerous in ER- (P = 10(-16)), PgR- (P = 10(-14)) and grade III (P = 10(-8)) tumours. The extreme low values (below the mean minus one S.D.) were significantly more numerous in ER- (P = 10(-9)) and PgR- (P = 0.02) tumours. This prospective study confirms that high c-erbB-2 protein values are linked to poor prognostic factors and shows for the first time that low values are also linked to hormone receptor negative tumours, suggesting that these low values might also have a negative prognostic significance.

pS2 protein: a marker improving prediction of response to neoadjuvant tamoxifen in post-menopausal breast cancer patients.

Tamoxifen as sole initial therapy is gaining importance in the management of post-menopausal breast cancer patients. Age oestrogen (ER) and progesterone (PR) receptor status are accurately considered to select patients for hormonal treatment. However, additional markers are needed. By immunohistochemistry (IHC), we studied tumour expression of ER, PR, pS2, c-erbB-2 and glutathione S-transferase pi (GST pi) on initial core biopsies of 208 post-menopausal patients with a non-metastatic invasive ductal carcinoma, treated by neoadjuvant tamoxifen therapy. A good response to tamoxifen was defined as tumoral regression > or = 50% (110 patients). Relationship between response and age, tumour size, T, N, histological grade, ER and PR contents evaluated by radioimmunoassay, ER, PR, pS2, c-erbB-2 and GST pi expression evaluated by IHC were studied. Univariate and multivariate analysis showed that tumoral regression was linked only to pS2 (P = 0.004) and ER (P = 0.018) IHC expression. According to the immunohistochemical profile, three groups could be defined: pS2- and ER-positive tumours, pS2- or ER-positive tumours and pS2- and ER-negative tumours with response rates of 60%, 45% and 8% respectively. Although prospective studies are needed to confirm these results, we conclude that pS2 and ER immunohistochemical status are useful tools for predicting tumour regression with neoadjuvant tamoxifen in post-menopausal breast carcinoma patients.

The prognostic value of c-erbB2 in primary breast carcinomas: a study on 942 cases.

To assess the practical prognostic value of c-erbB2, we performed a study on 942 invasive ductal carcinomas treated with primary surgery between 1980 and 1986 in our center. We evaluated its expression by immunohistochemistry in paraffin-embedded tissue using a polyclonal antipeptide antibody. Of 942 tumors, 229 (24%) showed a positive membrane staining. We observed a significant association between c-erbB2 and Scarff-Bloom-Richardson grading (p < 0.0001) and a negative correlation between c-erbB2 and both estrogen and progesterone receptors (p < 0.0001). In our analysis, with respect to overall survival (OS), relapse-free survival (RFS), and metastasis-free survival (MFS), c-erbB2 was statistically significant (p < or = 0.0001) for the whole group and the node-positive subgroup. In multivariate analysis, c-erbB2 appeared to be an independent variable for RFS and MFS in the node-negative group. However, in our hands, c-erbB2 had a poor prognostic value in comparison with the classical prognostic variables such as histological grade, nodal status (N), hormonal receptor status (estrogen and progesterone receptors), and tumor size, and it did not supersede the classical parameters.

Immunohistochemical determination of pS2 in invasive breast carcinomas: a study on 942 cases.

To assess the practical prognostic value of pS2, we evaluated its expression by immunohistochemistry in paraffin-embedded tissue from 942 previously untreated invasive ductal carcinomas (IDC) resected in our center between 1980 and 1986. Positive staining of tumor cells was found in 684 cases (73%), but most of the tumors contained only a small amount of positive cells. There was a negative correlation between pS2 and tumor size (p = 0.01) and histological grade (p < 0.0001), and a positive correlation between pS2 and hormonal receptor status (p < 0.001). With respect to overall survival, pS2 positivity was associated with a better prognosis for the whole group and the node-positive sub-group. However, in terms of relapse and metastasis, pS2 was not significant. Furthermore, in multivariate analysis including tumor size, nodal status, histological grade, ER status, PR status, chemotherapy, hormonal treatment, and pS2, the latter appears to be of no prognostic value.

[PS2 as a prognostic factor in 1065 cases of human breast cancer. A multicenter study]. / Rôle pronostique de la protéine pS2 dans 1065 cas de cancer du sein. Etude multicentrique.

pS2 protein assay was performed with Elsa-pS2 kit (CIS-Biointernational) on a group of 1,065 patients with operable breast cancer who underwent breast surgery in the years 1982 through 1990. The median follow-up was 57 months. This group included exclusively infiltrating ductal carcinoma with primary surgery. Age mean was 58 yr; T0-T1, 33.6%; T2-T4, 66.4%; Differentiation grade I, 29%; node negative, 53%; estrogen receptor (ER) positive, 62.4%; progesterone receptor (PR) positive, 55.2%; mean tumor size, 2.4 cm; local recurrence, 5.2%; metastasis, 17.5%. pS2 values varied from 0.1 to 707 ng/mg of cytosol protein (median, 5.6; mean 24.5; 95th percentile 112 ng/mg p). There was no significant relationship between the mean level of pS2 and age, tumor size, nodal status, whereas pS2 was related to histological grade (P < 10(-3)), ER (P < 10(-5)), and PR (P < 10(-5)). By using 2 ng/mg p as pS2 cutoff, 77/391 (19.7%) of ER+PR+ tumors were pS2-, and 122/345 (35.4%) of ER-PR-tumors were pS2+; with this cutoff, a strong relationship existed between pS2 and overall survival, but not between pS2 and relapse-free survival. With Cox multivariate analysis, pS2 protein was classified after lymph node status, histological size, ER, differentiation grade, age, clinical stage, PR. In patients with axillary lymph node involvement (N+), pS2 status could discriminate between good and bad prognosis, specially for patients with small tumors (< 2 cm) and with less than seven invaded nodes. This study showed that pS2 protein was a poor prognostic factor in comparison with classical factors.

Production of monoclonal antibodies to human estrogen-receptor protein (ER) using recombinant ER (RER).

Two monoclonal antibodies (MAbs), IC5 and ID5, were produced using spleen cells from BALB/c mice immunized with recombinant estrogen-receptor protein (RER). On immunoblotting, both MAbs reacted with the 67-kDa polypeptide chain obtained by transformation of E. coli and transfection of COS cells with plasmid vectors expressing ER. The epitopes of both MAbs were in the N-terminal domain (A/B region) of the receptor. In normal human tissues, IC5 and ID5 reacted with cells known to contain large amount of ER, such as cells of the mammary gland and the uterus. Staining was localized predominantly in nuclei with little or no cytoplasmic reactivity. IC5 and ID5 were unreactive with tissues usually considered to be negative for ER. The reactions of these 2 MAbs were further tested on different tumor types, using immunohistochemical (IHC) method on frozen sections. In breast cancer, a good correlation was found between the results obtained on frozen sections and those using the conventional radioligand dextran-coated charcoal (DCC) assay. Immunostaining with IC5 and ID5 MAbs was also assessed on routinely processed paraffin sections using the antigen-retrieval method. Staining was comparable to that obtained on frozen sections in virtually all the breast carcinomas. Negative reactions were consistently obtained with both antibodies on human neoplasms derived from other non-estrogen-dependent organs. IC5 and ID5 MAbs may thus be of value in routine diagnostic histopathology for assessment of the estrogen-receptor content in human carcinomas.

[Value of thymidine kinase in the prediction of response to treatment by chemotherapy or hormone therapy in breast cancer]. / Intérêt de la thymidine kinase dans la prédiction de la réponse à un traitement par chimiothérapie ou hormonothérapie dans le cancer du sein.

Thymidine kinase (TK) was assayed in the cytosol of 210 primary breast cancers to assess its predictive value for response to first line chemotherapy and hormonotherapy. We performed correlations between TK and the other prognosis factors of breast cancer. TK activity is correlated with SBR grading and estrogen receptors. It has a low predictive value for response to chemotherapy and is not useful for hormonotherapy.

[Results of assays of estrogen, progesterone and androgen receptors in stage I and II adenocarcinoma of the endometrium]. / Résultats du dosage des récepteurs aux estrogènes, à la progestérone et aux androgènes dans les adénocarcinomes de l'endomètre aux stades cliniques I et II.

The prognosis for adenocarcinoma of the endometrium is dependent on the findings of the histopathological assessment of the tumor. In a retrospective study of patients treated in initially by surgery, the estrogen and progesterone receptors were assayed 89 times and the androgen receptors 64 times. No statistically significant correlation was found between any of these receptors and the degree of structural differentiation or degree of infiltration of the myometrium. The absence of any one of these receptors had no negative impact on the overall survival nor on recurrence-free survival. The same was true for the 9 tumors which were devoid of both estrogen and progesterone receptors. In the authors' experience, the results of these hormone assays did not provide any further information on which to base the prognosis of endometrial cancers.

Autoantibodies directed against lipid membrane components in sera of patients with malignant tumors.

Tumor-associated antigens (Ag) are expressed on neoplastic cells. Using an enzyme-linked immunosorbent assay (ELISA), an attempt was made to evaluate the autoimmune responses directed against lipid membrane components. A comparison was made of autoantibody (autoAb) levels in human sera of 684 patients with malignant tumors and those of 185 controls (healthy subjects and patients suffering from other diseases). A highly significant difference was found between the immunological binding of the groups for only one phospholipids (PL), i.e., phosphatidylinositol (PI). Using ELISA tests and PI-related compounds differing in fatty acid residue types and/or in phosphatidyl group, it was demonstrated that the hydrophilic residue is the immunodominant part recognized by the autoAb detected in sera of cancer patients.

[Autoantibodies directed against membrane phospholipid in serum in patients with malignant tumors]. / Autoanticorps dirigés contre un phospholipide membranaire dans les sérums de malades porteurs de tumeurs malignes.

Modifications of membrane lipids in the levels of fatty acids and phospholipids are associated with malignant tumors. In order to evaluate if these changes are recognized by the immune system, we have attempted to assay the possible presence of autoantibodies directed against the following lipids: phosphatidylinositol (PI), phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, gangliosides, galactocerebrosides, sphingomyelin, sphingosin, and cardiolipin, in the sera of patients with malignant tumors (n = 324) and from controls [healthy subjects (n = 20) and patients suffering of other diseases (n = 60)]. Using an adaptated immunoenzymatic assay (ELISA method), a highly significant difference (p less than 0.001) was found between the mean absorbances read on the cancer and control group for only one lipid, the PI. Whatsmore, these auto anti-PI were found in all sera (diluted 15,000 times) of patients with malignant tumors, whatever type, grade, or organ localization defined. These data indicated that the immune system recognized the PI antigenic modifications which appear to be linked to the cell transformation. This PI-immunological binding may have a predictive value as we have recently noticed in animals bearing chemically-induced malignant tumors.

[Cancers of the breast at metastatic high-risk: prediction of survival by steroidal receptors]. / Les cancers du sein à haut risque métastatique: prédiction de la survie par les récepteurs stéroïdiens.

From 1982 to 1985, 279 patients with locally advanced breast cancer have been treated with induction chemotherapy, adjusted loco-regional treatment (surgery and/or radiotherapy) and adjuvant chemotherapy with or without immunostimulation. Overall and relapse free survivals are better for tumors with estrogen and progesterone receptors (EPR). For these patients, we may hope that tumoral reduction with hormonotherapy would get the same overall and relapse-free survivals as induction chemotherapy.

Adjuvant trial for stage II receptor-positive breast cancer: CMF vs. CMF + tamoxifen in a single centre.

The purpose of a randomized trial achieved in a single centre (Fondation Bergonié, Bordeaux, France) was to compare chemotherapy alone (intravenous CMF) versus chemotherapy and hormonotherapy (CMF plus tamoxifen-30 mg per day during 2 years), for patients with stage II breast carcinoma and positive values of estrogen and/or progesterone receptor (EPR) (greater than 10 and greater than 15 fmoles mg protein-1 respectively). Three hundred and thirty four women treated by surgery +/- radiotherapy are included in this trial from 06.01.81 to 12.31.84. No patient is lost for follow-up. Eight are excluded. Three hundred and twenty six patients are evaluable with a 38 month median follow-up. For EPR assay, the dextran charcoal micromethod was used in the same centre. The two groups are identical as far as age, hormonal status, TNM, EPR values, and histological features are concerned. Analysis of results shows a significant improvement of relapse free survival (p = 0.018) and also overall survival (p = 0.04) for the CMF+ tamoxifen group.

[Inflammatory breast cancers: correlation between anatomopathology and steroid receptor assay]. / Les cancers du sein inflammatoires: corrélation entre anatomopathologie et dosage des récepteurs stéroïdiens.

From a series of 89 clinically inflammatory breast cancers, the authors settle a subgroup of tumors, the infiltrative ductal carcinomas with a pleomorphic structure. They have better histological and hormonal prognostic criteria than the other carcinomas, especially the infiltrative ductal carcinomas with an atypical structure: lower SBR grading (p = 6.10(-5)), estrogen and progesterone receptors positive rate more frequently (p = 10(-4)). A prospective study will allow to confirm the better response to treatment and especially the better survival rate of this metastatic high risk breast cancer subgroup.

[Contribution of drill-biopsies to pre-treatment investigation of breast adenocarcinomas (author's transl)]. / Apport de la drill-biopsie dans le bilan préthérapeutique des adénocarcinomes mammaires.

The sensitivity of drill-biopsies (Rousseau's technique) was studied before using them routinely in pre-treatment investigation of breast adenocarcinomas. Results of histological examination, and estrogen (ER) and progesterone (PR) receptors levels obtained preoperatively by this technique, were compared with those from the corresponding mastectomy or tumourectomy specimens in 85 cases. Cytological examination of the various specimens, performed on prints, was used to compare their cellular density. Measurement of receptors included the determination of cytosolic and nuclear sites, and was performed by the single point dextran charcoal method. The limits of positivity established for ER and PR were 10 and 15 fM/mg protein respectively. The results showed sensitivity of 91.8 p. cent for pathology examinations; furthermore, the Scarff-Bloom-Richardson histoprognosis grading could be performed satisfactorily on drill-biopsy specimens. No significant difference was observed between the percentage of positivity for ER and PR from surgical and drill-biopsy specimens. Good correlation existed between values obtained from drill-biopsy and from surgery both for ER (r = 0.86, p less than 10(-5)) and PR (r = 0.86, p less than 10(-5)).