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Biomedical subjects

J F Robertson

Publications and source records attributed to J F Robertson.

At least 37 records · Page 2Linked to original sources
PubMed2001

ICI 182,780 (Fulvestrant)--the first oestrogen receptor down-regulator--current clinical data.

ICI 182,780 (Fulvestrant) is the first in a new class of novel, steroidal, 'pure' antioestrogens--the oestrogen receptor (ER) down-regulators. Its unique mode of action and the absence of partial agonist activity make it a candidate for the treatment of advanced breast cancer in both pre- and postmenopausal women. Tamoxifen has been available for use over the past 25 years. However, its partial agonist activity has been associated with detrimental effects, particularly on the endometrium, and may be associated with the development of tamoxifen resistance. Other antioestrogen agents have previously been unable to demonstrate clinically relevant activity following the development of resistance to tamoxifen. In contrast, the unique mechanism of action of ICI 182,780 results in significant clinical activity in patients failing on tamoxifen therapy. Indeed, phase III clinical trials have demonstrated that ICI 182,780 is at least as effective as the aromatase inhibitor anastrozole in the treatment of postmenopausal patients with advanced disease who have progressed during threatment with prior enocrine therapy. As such, ICI 182,780 will provide a valuable addition to the armamentarium for the treatment of advanced breast cancer.

Antineoplastic Agents↗
PubMed2001

Preoperative hormone therapy trials for breast cancer.

Preoperative hormone therapy for breast cancer has the potential to downstage a primary tumour hence increasing operability as well as making breast conservation feasible. Whether it will achieve any clinically significant survival benefit remains to be elucidated. Preoperative hormone therapy, in contrast to neoadjuvant chemotherapy, produces less severe side effects and can be continued throughout the perioperative period. Presurgical studies have demonstrated anti-tumour effects of hormone therapy, e.g. down-regulation of ER. Current clinical trials have shown that, in patients with ER positive tumours, a response approaching 70% is reached in approximately three months using the traditional hormonal agent tamoxifen. The tumour seldom progresses during this period. New agents (such as third generation aromatase inhibitors and pure anti-oestrogens) may produce more profound and rapid responses. Future trials are required to identify factors other than ER to precisely predict response so that appropriate patients can be selected. The best agents, the ideal methods of monitoring response and the optimum duration of therapy also need to be identified. Clinical trials also need to test if pre- and perioperative hormone therapy is superior to conventional adjuvant hormone therapy in patients with early breast cancer.

Journal Article↗
PubMed2000

Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study.

PURPOSE: To compare the efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) with that of tamoxifen as first-line therapy for advanced breast cancer (ABC) in postmenopausal women. PATIENTS AND METHODS: This randomized, double-blind, multicenter study evaluated the efficacy of anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with tumors that were hormone receptor-positive or of unknown receptor status who were eligible for endocrine therapy. The primary end points were time to progression (TTP), objective response (OR), and tolerability. RESULTS: A total of 668 patients (340 in the anastrozole arm and 328 in the tamoxifen arm) were randomized to treatment and followed-up for a median of 19 months. Median TTP was similar for both treatments (8.2 months in patients who received anastrozole and 8.3 months in patients who received tamoxifen). The tamoxifen:anastrozole hazards ratio was 0.99 (lower one-sided 95% confidence limit, 0.86), demonstrating that anastrozole was at least equivalent to tamoxifen. Anastrozole was also as effective as tamoxifen in terms of OR (32.9% of anastrozole and 32.6% of tamoxifen patients achieved a complete response [CR] or partial response [PR]). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 56.2% and 55.5% for patients receiving anastrozole and tamoxifen, respectively. Both treatments were well tolerated. However, incidences of thromboembolic events and vaginal bleeding were reported in fewer patients treated with anastrozole than with tamoxifen (4.8% v 7.3% [thromboembolic events] and 1.2% v 2.4% [vaginal bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Together with the lower observed incidence of thromboembolic events and vaginal bleeding, these findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with ABC.

Adult↗
PubMed2000

Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression.

The protein tyrosine phosphatase SHP-1 is predominantly expressed in hemopoietic cell lineages, where its function is relatively well defined. However, its expression profile also extends to certain epithelial cell types. Furthermore, the negative regulatory role of this enzyme in hemopoietic cell signaling may not apply to other systems, where positive effects on particular tyrosine kinase signaling pathways have been described. Expression of SHP-1 was therefore investigated in human breast cancer cell lines and primary breast cancers. Differential expression of SHP-1 mRNA was observed among the 19 breast cancer cell lines examined, and in an analysis of 72 primary breast cancers, SHP-1 mRNA expression was increased 2- to 12-fold relative to normal breast epithelial cells in 58% of the samples. Interestingly, a subset of the cancers also over-expressed GRB2 mRNA by 2- to 7-fold, and a significant (p < 0.01) positive correlation was observed between SHP-1 and GRB2 mRNA expression. Since these proteins can bind to each other and regulate MEK/MAP kinase activation, their co-ordinate up-regulation may amplify tyrosine kinase signaling in breast cancer cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Biological and clinical associations of c-jun activation in human breast cancer.

Sub-units and regulators of the activating protein-1(AP-1) complex have been implicated in breast-cancer biology, therapeutic response and prognosis. This study has immunocytochemically examined the impact of c-jun-protein activation on biological and clinical parameters in human primary breast cancers, employing an antibody specific for the serine 63-phosphorylated c-jun protein. Substantial nuclear immunostaining was commonly apparent, indicative of an activated c-jun pool, with associations with MAP-kinase-signalling elements, e.g., transforming growth factor-alpha (p = 0.04), epidermal growth factor receptor (p = 0.08), phosphorylated erk 1/2 MAP kinase (p = 0.001) and phosphorylated jun kinase (p = 0.05) Little association was noted with c-fos protein, perhaps indicating alternative AP-1 partners for c-jun with a diversity of cellular end-points. This may explain the lack of relationship with proliferation and grade, the imperfect association between increased c-jun activation and poorer survival (p = 0.061), and the apparent relationship with distant metastasis (p = 0.05). While increased c-jun activation related to poorer quality (p = 0.09) and shortened duration of endocrine response in oestrogen-receptor-positive patients (p = 0.018), no generalized effects on oestrogen-regulated gene products were noted, indicating that AP-1 influences on oestrogen-receptor/oestrogen-response element transactivation are unlikely to explain endocrine insensitivity. These data reinforce our belief that elevated AP-1 signalling influences aspects of the breast-cancer phenotype.

Breast Neoplasms↗
PubMed2000

A possible divergent role for the oestrogen receptor alpha and beta subtypes in clinical breast cancer.

We have examined the relative levels of oestrogen receptor beta (ERbeta) mRNA in 94 breast cancer specimens using a semi-quantitative RT-PCR procedure. We correlated its expression with ERalpha and various clinical, pathological and biochemical features of the disease. The level of ERbeta mRNA expression in these samples was found to be much lower than ERalpha. Although ERalpha mRNA species were found to be most frequently associated with histological grade I and II tumours, displaying tubular differentiation, low grades of nuclear pleomorphism and low mitotic activity, such features were not characteristic of ERbeta positive samples. Indeed, application of the Spearman rank correlation test revealed that there was an inverse association between ERbeta normalised levels and ERalpha protein HScore. Also ERbeta mRNA positive cancers were more frequently EGFR protein positive than their negative counterparts (p = 0.016), a feature normally associated with endocrine-insensitive disease. Our data suggest that although ERbeta levels are most likely lower than ERalpha, they may influence the biological behaviour of breast cancers containing low levels of ERalpha.

Breast Neoplasms↗
PubMed2000

Gamma linolenic acid with tamoxifen as primary therapy in breast cancer.

Gamma linolenic acid (GLA) has been proposed as a valuable new cancer therapy having selective anti-tumour properties with negligible systemic toxicity. Proposed mechanisms of action include modulation of steroid hormone receptors. We have investigated the effects of GLA with primary hormone therapy in an endocrine-sensitive cancer. Thirty-eight breast cancer patients (20 elderly Stage I-II, 14 locally advanced, 4 metastatic) took 8 capsules of oral GLA/day (total = 2.8 g) in addition to tamoxifen 20 mg od (T+GLA). Quality and duration of response were compared with matched controls receiving tamoxifen 20 mg od alone (n = 47). Serial tumour biopsies were taken to assess changes in oestrogen receptor (ER) and bcl-2 expression during treatment. GLA was well tolerated with no major side effects. T+GLA cases achieved a significantly faster clinical response (objective response vs. static disease) than tamoxifen controls, evident by 6 weeks on treatment (p = 0.010). There was significant reduction in ER expression in both treatment arms with T+GLA objective responders sustaining greater ER fall than tamoxifen counterparts (6-week biopsy p = 0.026; 6-month biopsy p = 0.019). We propose GLA as a useful adjunct to primary tamoxifen in endocrine-sensitive breast cancer. The effects of GLA on ER function and the apparent enhancement of tamoxifen-induced ER down-regulation by GLA require further investigation.

Administration, Oral↗
PubMed2000

Letter 2

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Biopsy, Needle↗
PubMed2000

Tumour marker measurements in the diagnosis and monitoring of breast cancer.

Elevation of established blood tumour markers correlates with the stage of breast cancer. The major role of current blood markers is therefore in the diagnosis and monitoring of metastatic disease. A combination of markers is better than a single marker with the most widely adopted combination being CEA and one MUC1 mucin, commonly detected as either CA15.3 or CA27.29. Tumour marker measurement is now used as a complementary test in the diagnosis of symptomatic metastases. In the monitoring of therapeutic response to both endocrine and cytotoxic therapies in advanced disease, biochemical assessment using blood markers not only correlates with conventional UICC criteria but has a lot of advantages which make it a potentially superior way of assessment. In this regard, CA15.3, CEA and ESR are the best validated combination. Studies are ongoing to evaluate the use of sequential blood tumour marker measurements in the follow-up of patients after treatment for their primary breast cancer, in terms of both early detection and early therapeutic intervention. Further randomized studies are also required to ascertain that marker-directed therapy is superior to the current practice for metastatic disease. In line with clinical studies, intensive laboratory work is being carried out to optimize the use of blood markers in advanced disease as well as to exploit their use in screening and diagnosis of early primary breast cancer.

Biomarkers, Tumor↗
PubMed2000

Effect of evening primrose oil on clinically diagnosed fibroadenomas.

The effects of oil of evening primrose oil on fibroadenomas was assessed over a 6-month period. Eleven out of 21 (52%) of fibroadenomas receiving evening primrose oil and 8 out of 19 (42%) controls reduced in size. This study demonstrates that evening primrose oil does not significantly effect the natural history of breast fibroadenomas.

Journal Article↗
PubMed2000

New calmodulin antagonists inhibit in vitro growth of human breast cancer cell lines independent of their estrogen receptor status.

Calmodulin plays a key role in the regulation of cell proliferation and calmodulin antagonists may offer a new therapeutic approach in the treatment of breast cancer. Three new specific calmodulin antagonists with improved potency were synthesized and screened on human breast cancer cell lines known to be estrogen receptor (ER)-positive or -negative. These calmodulin antagonists significantly inhibited cell growth as measured by the MTT proliferation assay (p<0.001). Their IC50 values were in the low micromolar range against both ER-positive and -negative variants of the MCF-7 cell line. Two other breast cancer cell lines (ER-positive T-47D and ER-negative MDA-MB-231) were also inhibited by these calmodulin antagonists with IC50 values in a similar range. The level of inhibition was independent of any stimulation of cell growth by estradiol. Calmodulin antagonists effectively reduced cell growth of both ER-positive and -negative human breast cancer cell lines in vitro. Calmodulin antagonists represent a novel therapeutic approach requiring further investigation.

Breast Neoplasms↗
PubMed2000

The effectiveness of a rural nursing center in improving health care access in a three-county area.

The purpose of this article is to describe an innovative nurse-managed health center that has been effective in improving access to primary health care for residents of a Midwestern three-county rural area. Penchansky and Thomas's (1981) framework for evaluating health care access was used to analyze client satisfaction and utilization data. Findings clearly indicate success in improving access. Client satisfaction surveys consistently show a high level of satisfaction across all framework dimensions, including overall satisfaction with the health care received. Utilization data indicate a steady increase in the number of clients served, especially those who are uninsured or underinsured. This article demonstrates that key dimensions of access can be effectively measured using the Penchansky and Thomas framework and concludes with recommendations for enhancing the model.

Community Health Centers↗
PubMed2000

Preoperative endocrine therapy for breast cancer.

The preoperative use of systemic therapy for primary breast cancer has the potential to downstage tumours. This would render suitable for breast conservation some tumours that were unsuitable at initial presentation, or would convert some inoperable locally advanced breast cancers into tumours that are operable. No survival benefit has been demonstrated for neoadjuvant chemotherapy compared with the same therapy given in an adjuvant setting. Preoperative endocrine therapy, in contrast to neoadjuvant chemotherapy, has fewer side effects and has the potential additional advantage that it can be continued throughout the perioperative period. Current data have shown that, in patients with an oestrogen receptor (ER)-positive tumour, a response approaching 70% could be reached in approximately 3 months using traditional endocrine manipulation such as tamoxifen. Randomised clinical trials are warranted to demonstrate the superiority of preoperative endocrine therapy over conventional adjuvant endocrine therapy, to define the optimum duration of therapy, and to identify the best endocrine agents. Both clinical and laboratory studies are also required to identify factors (in addition to ER) that would precisely predict the response and hence to select appropriate patients and to improve existing methods of monitoring response.

Antineoplastic Agents, Hormonal↗
PubMed2000

INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis.

Frequent deletions or mutations of the INK4 gene, which encodes the cyclin-dependent kinase 4 inhibitor p16INK4a, have been documented in various human cancers, but little is known about the role of this tumor suppressor gene in primary breast cancer. We examined p16INK4a mRNA expression and its relationship with cyclin D1 and estrogen receptor (ER) expression in 314 primary breast cancers using Northern blots probed with a p16 exon 1alpha-specific cDNA. Tumor samples overexpressing p16INK4a were predominantly ER negative with low levels of cyclin D1. Cyclin D1 and ER mRNA levels in the high p16INK4a expressers were significantly lower than those in the remainder of the population (P = 0.0001). Furthermore, the mean p16INK4a mRNA level in the ER-negative tumors was significantly higher than that in the ER-positive group (P = 0.0001). Because the INK4 gene is frequently inactivated by de novo methylation, we investigated the frequency of INK4a exon 1alpha methylation in a subset of 120 primary breast cancers using methylation-specific PCR; 24 of these were methylated. These findings indicate that high expression of p16INK4a and reduced expression due to de novo INK4a methylation are frequent events in primary breast cancer. In a subset of 217 patients for whom detailed clinical data were available, high p16INK4a mRNA expression was associated with high tumor grade (P = 0.006), > or = 4 axillary lymph node involvement (P = 0.004), ER negativity (P = 0.0001), and increased risk of relapse (P = 0.006). The significant negative correlation between p16INK4a and ER gene expression raises issues regarding their functional interrelationships and whether high p16INK4a expression may be associated with a lack of hormone responsiveness in breast cancer.

Breast Neoplasms↗
PubMed2000

Nursing students' evaluation of clinical experiences in a rural differentiated-practice setting.

This article describes nursing students' evaluations of clinical experiences in a rural nursing center that uses a differentiated practice model. The center provides clinical experiences for associate degree, baccalaureate degree, and master's degree nursing students. Learning objectives and student roles are differentiated according to educational level and reflect the practice model used by the nursing center. Student evaluations showed high levels of satisfaction for all three groups and indicated that experience at the center increased students' knowledge of rural health. Findings also showed that autonomy, independence, and a supportive staff are valued characteristics of this practice setting.

Attitude of Health Personnel↗
PubMed1999

BRCA1 expression levels predict distant metastasis of sporadic breast cancers.

The role of BRCA1 in progression of sporadic breast cancers has to date been equivocal, although preliminary studies on small numbers of samples have suggested an association between expression levels of this gene and acquisition of an invasive phenotype. We have further reasoned that loss of oestrogen receptor positivity may have a detrimental effect on BRCA1 expression. In order to test this hypothesis and extend earlier investigations we have applied a sensitive RT-PCR procedure to determine the associations between BRCA1 expression and a variety of clinical parameters in a sample cohort derived from sporadic breast tumour specimens. We have established that BRCA1 and ER mRNA expression are closely associated (p=0.013), indicating a possible functional relationship between these 2 genes. We have further identified an association between low levels of BRCA1 expression and acquisition of distant metastasis in sporadic disease (p=0.019). In light of our findings, we suggest that suppression of BRCA1 has a role to play in progression of a significant fraction of sporadic breast cancers and may additionally prove to be a useful, novel, prognostic marker for this disease type.

BRCA1 Protein↗
PubMed1999

Endocrine response and resistance in breast cancer: a role for the transcription factor Fos.

We have previously demonstrated that elevated Fos expression may be important in de novo endocrine resistance in breast cancer. However, changes in Fos expression during endocrine response and subsequently on acquisition of resistance are unknown. This study immunocytochemically monitors Fos protein within sequential biopsies from primary human breast cancer patients obtained pre-treatment (T1), during tamoxifen therapy (T2, T3) and on disease progression (T5), examining in parallel proliferation [i.e., MIBI (Ki67) immunostaining, mitotic activity], cellularity and endocrine response. Significantly diminished Fos, proliferation and cellularity were observed after 6 weeks of therapy in patients exhibiting a better quality and/or duration of response, while modest Fos increases and a maintained proliferation and cellularity were seen in poorer responders. Decreases in Fos, proliferation and cellularity at 6 months similarly hallmarked better responders. We confirmed a significant association between de novo resistance and elevated Fos and proliferation. Additionally, however, these parameters increased at the time of disease relapse over pre-treatment and "on therapy" values. Our data indicate that tamoxifen response involves a reduction in both tumor cell proliferation and cell survival, potentially entailing diminished Fos protein expression in better-responding patients. Our data are also supportive of elevated Fos expression being involved in the departure from endocrine control inherent in both primary and acquired resistance.

Aged↗