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Background: The RESORT trial showed no longer relapse free survival (RFS) with sorafenib following radical metastasectomy in metastatic renal cell carcinoma. We present the updated 42-month follow-up data. Methods: The phase II RESORT trial randomized patients to sorafenib or observation within 12 weeks from surgery. RFS was the primary endpoint. Results: We analyzed 68 patients (32 in sorafenib and 36 in the observation arm), randomized between November 2012 and November 2017. Eighty-one percent in the sorafenib arm and 80% in the observation arm had one metastasis. At a median follow-up of 42 months (interquartile range 31–58), in the observation arm the median RFS was 35 months, RFS probability was 57% (95% CI 42–76%) at 24 and 44% (95% CI 30–65%) at 48 months. In the sorafenib arm, median RFS was 21 months, RFS probability was 50% (95% CI 34–71%) at 24 and 32% (95% CI 18–57%) at 48 months (p = 0.342;HR 1.35;95% CI 0.72–2.54). Forty-seven percent and 37.5% of the patients in the two arms, respectively, are disease free. The site of relapses was independent of the previous metastasectomy site. Expert commentary: Sorafenib after metastasectomy did not improve RFS, but surgery in selected patients should be considered in order to potentially improve survival. Clinical trial registration: www.clinicaltrials.gov identifier is NCT0144480 [ABSTRACT FROM AUTHOR]

Background:Breast cancer clinical outcome is affected by tumor molecular features, and the identification of subtype-specific prognostic biomarkers is relevant for breast cancer translational research. Gene expression signatures proved to be able to complement prognostic information provided by classical clinico-pathological features. Recently, microRNAs (miRNAs) have been causally linked to tumorigenesis and cancer progression and have been associated with patient outcome, also in breast cancer.Methods:MicroRNAs associated with the development of distant metastasis were identified in a cohort of 92 ESR1+/ERBB2− lymph node-negative breast cancers from patients not receiving adjuvant treatment. Results were confirmed and further investigated in a total of 1246 miRNA and gene expression profiles of the Molecular Taxonomy of Breast Cancer International Consortium data set. Moderated t-test, univariable and multivariable Cox regression models were used for statistical analyses.Results:miR-30e* was identified as independent protective prognostic factor in lymph node-negative untreated patients with ESR1+/ERBB2− tumours and retained a significant association with a good prognosis in treated patients with the same tumor subtype as well as in the ERBB2+ subtype, but not in ESR1−/ERBB2− tumours.Conclusions:We highlighted a relevant and subtype-specific role in breast cancer for miR-30e* and demonstrated that adding miRNA markers to gene signatures and clinico-pathological features can help for a better prognostication. [ABSTRACT FROM AUTHOR]

We compared the oestrogenic and anti-oestrogenic properties of the two well-known phyto-oestrogens, genistein and quercetin, on the oestrogen-sensitive breast cancer cell line MCF-7. Genistein exerted a biphasic effect on growth of MCF-7 cells, stimulating at low and inhibiting at high concentrations, whereas quercetin was only growth inhibitory. At doses which did not inhibit cell growth, respectively 5 and 1 μM, genistein and quercetin counteracted oestrogen- and transforming growth factor-α-promoted cell growth stimulation. Furthermore, genistein promoted transcription of the oestrogen-regulated genes pS2 and cathepsin-D, whereas quercetin interfered with the oestrogen-induced expression of the proteins. In in vitro binding experiments, genistein competed with oestradiol for binding to the oestrogen receptor (ER), but quercetin did not. Quercetin and genistein down-regulated cytoplasmic ER levels and promoted a tighter nuclear association of the ER, but only genistein was able to up-regulate progesterone receptor protein levels. In gel mobility assays, ER preincubation with oestradiol or with the two phyto-oestrogens led to the appearance of the same retarded band, excluding differences between the various complexes in binding to the consensus sequence. The data allowed us to conclude that quercetin acts like a pure anti-oestrogen, whereas genistein displays mixed agonist/antagonist properties, and to formulate a hypothesis on the possible mechanism of action of such phyto-oestrogens. © 1999 Cancer Research Campaign [ABSTRACT FROM AUTHOR]

Cathepsin-D and pS2 are two estrogen-regulated proteins in human breast cancer cell lines. They have been considered possible prognostic factors in breast cancer, but results have been contradictory. To better understand the regulation of these proteins, we investigated the role of estradiol (E2), serum, and growth factors in hormone-dependent (MCF-7, ZR75.1) and hormone-independent (MDAMB-231, BT20) breast cancer cell lines. E2 treatment in serum-free conditions increased intracellular and secreted levels of pS2 in ZR75.1 and in MCF-7, secreted levels only of cathepsin-D in MCF-7, and both levels of cathepsin-D in ZR75.1. Insulin-like growth factor I (IGF-I) and progesterone receptors were also stimulated by E2, whereas the estrogen receptor was down-regulated. Following treatment with epidermal growth factor (EGF), secreted pS2 levels doubled only in MCF-7 cells. IGF-I did not modify cathepsin-D or pS2 levels in either cell line, but caused an increase in its own receptor. Cathepsin-D and pS2 doubled in MCF-7 cells grown in medium supplemented with denatu-rated serum, but estrogen regulation of these proteins was still maintained. Cathepsin-D was expressed in MDAMB-231 and BT20, but its levels were modified by neither E2 nor growth factor treatment. Conversely, neither cell line expressed detectable levels of pS2 before or after treatment. In conclusion, our results show that in different types of breast cancer cells, some estrogen-regulated proteins (e.g. pS2) are also regulated by growth factors such as EGF and other unknown serum factors. This may account for the contradictory results obtained regarding the prognostic relevance of cathepsin-D and pS2. Copyright © 1996 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To better understand the mechanism of action of antiestrogens, the growth-inhibitory effect of tamoxifen and its main metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, was studied in 6 breast cancer cell lines characterized by different steroid receptor contents. On the basis of the results, our cell lines could be classified into three groups: a first group, including 734B and ZR-75.1 cell lines, characterized by a clear endocrine-dependent behavior, in which cells were sensitive to antiestrogens although to different degrees; a second group, including MDA-MB 231 and BT20 cell lines, characterized by a clear endocrine-insensitive behavior, in which cells were affected only by the highest (10-6M) antiestrogen concentration; a third group, including MCF7 and T47D cell lines, characterized by a peculiar behavior. The T47D cell line displayed an increased growth rate after treatment with all three antiestrogens considered. Despite the positive receptor content in the MCF7 cell line, only 4-hydroxytamoxifen showed a clear antiestrogen dose-dependent effect, whereas tamoxifen decreased the cell growth rate only at lower concentrations (10-8 and 10-7M). These results and the well-known heterogeneity of human breast tumors explain the failure of antiestrogen treatment in a certain percentage of patients with breast cancer with a positive estrogen receptor status. Copyright © 1991 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Human breast cancer cell lines, as well as human breast cancer biopsies, possess specific high-affinity epidermal growth factor receptors (EGF-r). However, reports on the presence of EGF-r in human breast cancer biopsies are still controversial, especially concerning the relationship between EGF-r and other biological variables whose prognostic relevance is well known, such as the estrogen (ER) and progesterone (PgR) receptors. In the present study, the EGF-r content was estimated in a series of 136 unselected breast cancer primaries along with cytoplasmic (ERc) and nuclear (ERn) ER and cytoplasmic PgR. EGF-binding activity consisted of a single class of high-affinity binding sites (Kd = 0.55 nM) and ranged from 0 to 275 fmol/mg protein. We observed a strong inverse association between EGF-r and ERc (p < 0.001); in fact, about two thirds of the tumors were ERc-positive/EGF-r-negative or ERc-negative/EGF-r-positive. The same type of association was found between EGF-r and either ERn or PgR.Kendall's rank correlation test confirmed that the EGF-r concentrations were correlated with the levels of ERc (τ = -0.291, p < 0.0001), ERn (τ = -0.27, p < 0.0005) and PgR (τ = -0.162, p < 0.01). The EGF-r content was significantly higher (p < 0.0001) in the ERc-negative tumors (72.6 ± 54.4 fmol/mg protein) as compared to the ERc-positive ones (33.0 ± 37.4 fmol/mg protein). Similarly, the subset of PgR-positive tumors was characterized by lower EGF-r mean concentrations when compared to PgR-negative cases (35.4 ± 54.4 vs. 63.8 ± 54.4 fmol/mg protein). These results confirm the previously described inverse relationship between EGF-r and steroid receptors. Moreover, they suggest the existence of an interaction between steroid hormones and EGF and support the need for further studies to better understand their respective roles in modulating breast cancer growth. Copyright © 1988 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: At present, most decisions concerning the use of adjuvant therapy in lymph node-negative breast cancer patients are made on the basis of traditional factors such as tumor size, nodal status, and histopathologic features. However, prognostic factors are being investigated that could identify high-risk groups and that could better address treatment efforts for those patients. Identification of more accurate prognostic markers, such as the expression of the mutant p53 protein encoded by the p53 (also known as TP53) tumor suppressor gene, that are reproducible, easily assessable, and independent in predicting clinical outcome would have a beneficial impact on cancer treatment decisions.Purpose: Our purpose was to analyze the predictive relevance of mutant p53 protein expression on 6-year relapse-free and overall survival in node-negative breast cancer patients in relation to menopausal status, tumor size, cell kinetics, and estrogen receptor status.Methods: Expression of mutant p53 protein was detected by an immunohistochemical technique using a 1:50 dilution of PAb1801 monoclonal antibody on paraffin-embedded tumor specimens obtained from 256 axillary lymph node-negative breast cancer patients, with long-term follow-up (median, 72 months). The [3H]thymidine labeling index, a measure of cell kinetics, was evaluated on histologic sections after fresh tumor tissue was labeled with [3H]thymidine. Estrogen receptor status was determined by the dextran-coated charcoal absorption technique. Statistical comparisons were made for levels of p53 protein expression, [3H]thymidine labeling index, estrogen receptor status, tumor size, and menopausal status with respect to 6-year relapse-free survival and overall survival.Results: Overexpression of the p53 protein, defined as the presence of more than 5% positive cells, was detected in 113 (44%) of 256 tumors. Odds ratios (ORs) for multiple regression analysis of 6-year relapse-free survival were significantly higher for p53 (OR = 3.24; 95% confidence limits [CL] = 2.01-5.23) and [3H]thymidine labeling index (OR = 1.92; 95% CL = 1.19-3.12), both of which appeared to be the most relevant indicators of relapse, than for tumor size (OR = 1.49; 95% CL = 0.94-2.38) and estrogen receptor status (OR = 0.91; 95% CL = 0.55-1.51). Overexpression was found to be unrelated to menopausal status.Conclusions: Immunohistochemically detected p53 overexpression is an independent marker for shortened 6-year relapse-free and overall survival in node-negative patients with resectable breast cancers. Based on these findings, p53 overexpression should be used with other established prognostic factors, such as [3H]thymidine labeling index and estrogen receptor status, to further refine the prognostic assessment of node-negative breast cancer. [ABSTRACT FROM AUTHOR]