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D C Allred

Publications and source records attributed to D C Allred.

At least 37 records · Page 2Linked to original sources
PubMed1999

Loss of heterozygosity at D14S62 and metastatic potential of breast cancer.

BACKGROUND: In breast cancer progression, the prevalence of damage at specific genetic loci often increases with the stage of the lesion (i.e., from noninvasive to invasive to metastatic). By use of genetic markers and analysis of allelic imbalances (loss of heterozygosity [LOH]) to compare DNA samples from paired normal and breast tumor tissues, we examined whether specific genetic changes in primary breast cancers can serve as biomarkers of metastatic potential. METHODS: DNA samples from 76 patients with primary breast cancer (42 with axillary lymph node-negative disease and 34 with axillary lymph node-positive disease) were genotyped with four genetic markers spanning chromosome 14q31-q32. The intensity ratios of the two genetic alleles in normal-tumor DNA pairs were examined in genetically informative individuals. LOH was scored when the tumor allele intensity ratio (tumor allele 1/tumor allele 2) divided by the normal allele intensity ratio (normal allele 1/normal allele 2) was either less than 0.71 (tumor allele 1 LOH) or greater than 1. 4 (tumor allele 2 LOH). RESULTS/CONCLUSIONS: Contrary to our expectations, we found statistically significantly more LOH events at markers D14S62 (two-sided P =.001) and D14S51 (two-sided P =.02) in primary breast cancers from patients with lymph node-negative disease versus lymph node-positive disease, suggesting the presence of a gene in this region that affects metastatic potential. Analysis of small interstitial or terminal deletions in the tumors of six especially informative patients with lymph node-negative disease places the putative metastasis-related gene in a 1490-kilobase region near D14S62. IMPLICATIONS: LOH in the D14S62 region may impede the process of metastasis. Therefore, the D14S62 region LOH profile may have prognostic implications, and the isolation of the metastasis-related gene(s) in this region may lead to better diagnosis and treatment of breast cancer.

Biomarkers, Tumor↗
PubMed1999

Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: a pilot study.

AIM: To quantify the changes in biological molecular markers during primary medical treatment in patients with operable breast cancer and to assess their possible relationship with response to treatment. METHODS: The treatment group consisted of 31 patients with operable breast carcinomas, median age 57 years (range 41-67), treated with four 3-weekly cycles of chemotherapy with Mitoxantrone, methotrexate (+/- mitomycin C), and tamoxifen before surgery. Fine needle aspiration (FNA) was used to obtain samples from patients prior to and at 10 or 21 days post-treatment. The following molecular markers were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Bcl-2, and Ki67 measured by immunocytochemistry, and ploidy and S-phase fraction (SPF) by flow cytometry. To evaluate the reproducibility of the technique, repeat FNA was performed in a separate non-treatment control group of 20 patients and the same molecular markers assessed, two weeks after the first sample with no intervening treatment. RESULTS: The non-treatment control group showed a high reproducibility for the measurement of molecular markers from repeat FNA. In the treatment group there was a non-significant reduction in SPF and a significant reduction (p = 0.005) in Ki67. Patients who responded to neoadjuvant therapy were more likely to have a reduction in these two markers than those who failed to respond. Similarly, a reduction in ER scores was observed between the first and second samples (p = 0.04). For PgR, the change between the first and second samples was not significant although there was a significant difference between responders and non-responders (p = 0.03). All nine patients with an increase in PgR were responders. No significant changes in p53 or Bcl-2 were observed during treatment. CONCLUSION: Molecular markers can be adequately measured from FNA samples prior to and during neoadjuvant therapy. Changes in cellular proliferation and hormone receptors have been shown that may be related to tumour response. These relationships should be assessed in a larger cohort of patients.

Adult↗
PubMed1999

Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer.

PURPOSE: To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy. PATIENTS AND METHODS: Mitoxantrone, methotrexate (with or without mitomycin), and tamoxifen chemoendocrine therapy was administered to 158 patients before surgery. Clinical response was assessed after four cycles of treatment. Fine-needle aspiration cytology for estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53, bcl-2, Ki67, S-phase fraction (SPF), and ploidy were performed pretreatment and repeated on day 10 or day 21 after the first cycle of treatment. RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158). Tumor size, nodal disease, response, ER, PgR, c-erbB-2, p53, bcl-2, Ki67, SPF, and ploidy were analyzed as predictors of survival. By univariate analysis, node-positive disease (P =.05), lack of ER (P <.05) and PgR (P <.05), and failure to attain GCR (P =.008) were associated with a significantly increased risk of relapse. A significantly increased risk of death was associated with node-positive disease (P =.02), lack of ER expression (P =.04), and failure to attain GCR. By multivariate analysis, GCR was an independent predictor for survival (P =.05). ER expression (P =.03), absence of c-erbB-2 (P =.03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P <.05) significantly predicted for subsequent GCR. CONCLUSION: Molecular markers may be used to predict the likelihood of achieving GCR, which seems to be a valid surrogate marker for survival.

Adult↗
PubMed1999

Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas.

PURPOSE: To comprehensively characterize the clinical and biologic features of tubular and mucinous carcinomas in a large cohort of patients and to relate this to clinical outcome and management. PATIENTS AND METHODS: The clinical and biologic features of 444 patients with tubular and 1,221 patients with mucinous carcinomas were compared with those of 43,587 patients with infiltrating ductal carcinoma, not otherwise specified (NOS). Disease-free survival (DFS) and overall survival (OS) for patients with tubular and mucinous carcinomas were compared with those of patients with NOS carcinomas and with age-matched sets from the general population. RESULTS: Tubular and mucinous carcinomas were more likely to occur in older patients, be smaller in size (tubular only), have substantially less nodal involvement, be estrogen receptor- and progesterone receptor-positive, have a lower S-phase fraction, be diploid, and be c-erbB-2- and epidermal growth factor receptor-negative compared with NOS carcinomas. Axillary node involvement was a poor prognostic feature in mucinous but not tubular carcinomas. Mucinous carcinomas < or = 1 cm had a < or = 5% incidence of node involvement. The 5-year DFS and OS were 94% and 88% for tubular, 90% and 80% for mucinous, and 80% and 77% for NOS carcinoma, respectively (P < .001 for differences among all three types for both DFS and OS). The 5-year OS of females from the general population age-matched to the patients with tubular and mucinous carcinomas was 89% and 82%, respectively, which is not different from the OS of patients with tubular or mucinous carcinomas. CONCLUSION: The biologic phenotype of tubular and mucinous carcinomas is quite favorable. Consistent with this observation, the survival of patients with tubular and mucinous carcinomas is similar to that of the general population. Systemic adjuvant therapy and node dissection may be avoided in many patients with these special types of carcinoma.

Adenocarcinoma↗
PubMed1999

Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

Adult↗
PubMed1998

Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci.

BACKGROUND: Usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) are risk factors for invasive breast cancer (IBC), suggesting that these lesions may be direct precursors of IBC. To identify genetic changes that may be important in the early development of precursor lesions and their progression to malignant or invasive disease, we examined 399 putative precursors (211 UDH, 51 ADH, 81 non-comedo DCIS, and 56 comedo DCIS) for loss of heterozygosity (LOH) at 15 polymorphic genetic loci known to exhibit high rates of loss in IBC. We also assessed the sharing of LOH by putative precursors and synchronous cancers. METHODS: The polymerase chain reaction was used to analyze DNA from microdissected archival specimens. RESULTS AND CONCLUSIONS: In hyperplasias from noncancerous breasts (i.e., without DCIS and/or IBC in analyses of hyperplasias), LOH at any given locus was rare (range, 0%-15%), although 37% of UDH and 42% of ADH lesions showed loss for at least one locus, suggesting that the development of hyperplasias can involve many different tumor suppressor genes. In DCIS from noncancerous breasts (i.e., without IBC in analyses of DCIS), LOH was common, with 70% of noncomedo lesions and 79% of comedo lesions showing at least one loss. In DCIS, substantial rates of loss (up to 37%) were observed at loci on chromosomes 16q, 17p, and 17q, suggesting that inactivated tumor suppressor genes in these regions may be important in the development of noninvasive breast cancer. When DCIS lesions from cancerous and noncancerous breasts were compared, substantially more LOH was observed in the cancerous breasts at a few loci (on chromosomes 2p, 11p, and 17q), suggesting that genetic alterations in these regions may be important in the progression to invasive disease. Among specimens harvested from cancerous breasts, 37% of UDH, 45% of ADH, 77% of noncomedo DCIS, and 80% of comedo DCIS lesions shared LOH with synchronous cancers at one locus or more, supporting the idea that the putative precursors and the cancers are genetically related.

Breast Diseases↗
PubMed1998

bcl-2 and apoptosis in lymph node positive breast carcinoma.

BACKGROUND: Because bcl-2 can block apoptosis in vitro, and because lower levels of apoptosis might lead to malignant cell accumulation and therefore to a more aggressive clinical course, the authors tested the hypothesis that high bcl-2 and low apoptosis would result in a worse prognosis for breast carcinoma patients. METHODS: Primary breast tumor specimens from 979 patients with positive axillary lymph nodes were evaluated for bcl-2 protein expression by immunohistochemistry (IHC). Apoptosis was evaluated by using IHC to detect 3' DNA fragments end-labeled with biotinylated uridine. Results were analyzed with respect to patient characteristics, prognostic factors, and clinical outcome. Median follow-up was 61 months. RESULTS: High bcl-2 expression was significantly associated with a number of favorable prognostic factors, including a lower number of positive lymph nodes, absence of p53 protein accumulation, estrogen receptor (ER) and progesterone receptor (PR) positivity, diploidy, and a lower proliferative rate. However, although bcl-2 is generally considered a negative regulator of apoptosis, in these tumors there was no significant association between bcl-2 and apoptosis. Patients with high bcl-2 expression had significantly improved disease free survival (DFS) (P < 0.0001) and overall survival (OS) (P < 0.0001). In a multivariate analysis, bcl-2 expression was independently associated with better DFS (P = 0.004). Regarding apoptosis, the presence of > or = 1% apoptotic cells was significantly associated with a greater number of positive lymph nodes, p53 protein expression, ER and PR negativity, aneuploidy, and a higher proliferation rate, although there was no significant association with a worse clinical outcome when this dichotomized cutoff was used. CONCLUSIONS: For lymph node positive breast carcinoma patients, high bcl-2 expression is associated with a number of good prognostic factors and is independently associated with better clinical outcome. Apoptosis is associated with a number of poor prognostic factors but not with a significantly worse outcome.

Apoptosis↗
PubMed1998

Epstein-Barr virus infection is associated with p53 accumulation in nasopharyngeal carcinoma.

Eighty-three cases of nasopharyngeal carcinoma were evaluated for the presence of Epstein-Barr virus (EBV) infection in tumor cells by in situ hybridization to EBER1 transcripts, and for p53 expression by immunostains using the D07 antibody which detects native and mutant forms of the p53 protein. A highly significant association was found between EBV infection and p53 overexpression (P = .0004), with 77% of cases coexpressing both markers. This newly discovered association suggests that EBV is not an innocent bystander with respect to p53 accumulation. One possible mediator of the interaction between EBV and p53, viral BZLF1, was not colocalized with p53 in these tumors, suggesting that BZLF1 is not the factor responsible for p53 accumulation. From an epidemiological standpoint, this series of cancers represents an international cohort in which cases from an endemic part of the world (Hong Kong) were examined alongside cases from the United States, where the disease is 50-fold less prevalent. The cancers from Hong Kong tended to be less differentiated and more frequently associated with EBV, suggesting that biological differences might underlie epidemiological variations in tumor prevalence. Finally, we examined 18 potential premalignant lesions of the surface epithelium of the nasopharynx. Although our numbers are small, our data suggest that p53 accumulation might precede EBV infection in the transition from metaplasia to carcinoma in situ. Further studies are needed to dissect the stepwise progression of nasopharyngeal carcinogenesis.

Carcinoma in Situ↗
PubMed1998

Changes in hormone receptors and proliferation markers in tamoxifen treated breast cancer patients and the relationship with response.

AIM: To determine the effects of tamoxifen on the levels of hormone receptors and proliferation markers in the early phase of treatment and the relationship of the changes with tumor response in patients with primary breast cancer. METHODS: Twenty-one women with primary, operable breast carcinomas were treated with tamoxifen 20 mg daily. Fine needle aspiration (FNA) was used to obtain samples prior to the start and at 14 days and 8-weeks post-treatment. From these samples estrogen receptor (ER), progesterone receptor (PgR), and Ki67 levels were determined using immunocytochemistry and ploidy and S-phase fraction (SPF) using flow cytometry. Tumor response was measured clinically according to UICC criteria. RESULTS: There were 12 responders (2 CR, 10 PR) and 9 non-responders (2 NC, 7 PD). Responders were more likely to be ER+ (p = 0.002), PgR+ (p = 0.006), and low SPF (p = 0.06). At 14 days post-tamoxifen, the median decrease in Ki67 (% cells staining) for responders was -4.8 and for non-responders -0.15 (p = 0.005). This decrease was seen predominantly in ER+ tumours. The difference in SPF was not significant. A decrease in ER was seen in 3/15 patients all of whom were responders. A rise in PgR was seen in 7/17 patients and all but one were responders. Similar changes for ER and PgR were seen at 8-weeks post-tamoxifen, although the reductions in Ki67 and SPF at that time point were not related to response. CONCLUSION: We have observed a decrease in Ki67 and ER and a rise in PgR after 14 days of treatment with tamoxifen that was related to subsequent response. This is the first study in which an early decrease in a proliferation marker has been shown to relate to subsequent clinical response.

Aged↗
PubMed1998

Prognostic and predictive value of p53 and p21 in breast cancer.

The prognostic and predictive value of p53 has been extensively studied in breast cancer. p53 serves a multifunctional role as a transcriptional regulator, genomic stabilizer, inhibitor of cell cycle progression, facilitator of apoptosis, and also perhaps an inhibitor of angiogenesis. Abrogation of its function should therefore lead to a more aggressive breast cancer phenotype and a worse clinical outcome, and indeed the preponderance of studies confirm this, with the risk of recurrence and death increasing by 50% or more if p53 is abnormal. Lack of unanimity of results may be due to differences in technique, study design, or population, as well as the subjectivity inherent in some approaches; however, the complexity and random nature of genomic change present in cancer cells may well also contribute to the lack of unanimity. Because many anticancer agents may exert a therapeutic effect through genomic damage and subsequent triggering of apoptosis, and because p53 can respond to genomic damage and facilitate apoptosis, it can be hypothesized that an intact p53 would predict sensitivity to therapy. Present data in breast cancer, however, does not clearly indicate that this is the case. There are several potential explanations. Study designs to accurately test the predictive value of a molecular marker are more exacting and difficult to achieve than prognostic studies. There may also be multiple alternative pathways, not involving p53, that play a part in determining the therapeutic effect of a treatment. The prognostic value of a downstream effector of p53 has also been assessed, though less extensively. p21 is transcriptionally upregulated by p53 and is an inhibitor of cyclin-dependent kinases and thus of cell cycle progression. Higher levels of p21 might indicate a more indolent type of breast cancer. However, data from a number of clinical studies is very conflicting, and at present p21 is not a promising prognostic factor in breast cancer.

Breast Neoplasms↗
PubMed1998

Prognostic and predictive factors in breast cancer by immunohistochemical analysis.

Most recent decisions for breast cancer patients are made on the basis of prognostic and predictive factors. In addition to the traditional tumor/nodal/metastasis staging variables, estrogen and progesterone receptor status as assessed by biochemical ligand-binding assays are the only other factors that have been adequately validated and recommended for routine clinical use. Pathologists today, however, are evaluating estrogen and progesterone receptors almost exclusively by immunohistochemical means. Although many studies suggest that these tests might have equivalent or even superior abilities to predict patient outcome, there are important methodologic shortcomings to resolve before this technology achieves the clinical and technical validation necessary to justify its routine use. Many laboratories are also evaluating other factors for clinical use by immunohistochemical techniques, including, in particular, c-erbB-2, p53, and Ki-67 proliferation indices. Although available studies suggest that these factors might indeed be helpful in making treatment decisions, their clinical usefulness is still controversial, and, like the assessment of hormone receptors, there are important unresolved technical issues, such as how to prepare the tissue, which reagents to use and, most importantly, how to interpret the results. A few laboratories have gone to considerable effort to develop reproducible methods for evaluating these factors, and they have performed comprehensive studies demonstrating the prognostic and predictive significance of their results. Nonetheless, most laboratories offering these tests have not adequately validated them and might not even be aware of the issues needing attention. Unless laboratories validate their tests or follow the procedures of others who have, they run the risk of reporting meaningless and potentially harmful results. In the future, these and other factors will be incorporated into a prognostic index that will better reflect the biologic diversity of breast cancer and that will more accurately predict clinical outcome.

Biomarkers, Tumor↗
PubMed1998

HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study.

HER-2/neu is a growth factor receptor, the expression of which has been associated with a more aggressive breast tumor biology and resistance to some types of chemotherapy. Preliminary laboratory and clinical data have led to claims that HER-2/neu expression is also associated with resistance to tamoxifen. Therefore, to test the hypothesis that HER-2/neu expression is associated with a poorer response to tamoxifen, a shorter time to treatment failure (TTF), and worse survival in estrogen receptor (ER)-positive metastatic breast cancer, we examined 205 paraffin-embedded blocks of tumors from patients enrolled on Southwest Oncology Group 8228 for HER-2/neu expression. Tumors were ER positive (ER level > 3 fmol/mg cytosolic protein in either primary tumors or metastases), and patients had not received any prior therapy for metastatic disease. All patients were treated with daily tamoxifen. The study began in 1982, and median follow-up of patients who are still alive is now 9 years. Membrane staining for HER-2/neu was evaluated by immunohistochemistry using antibody TAB 250 and was scored according to the proportion of cells staining positive; tumors were deemed positive if > 1% of the cells stained for HER-2/neu. HER-2/neu positivity was associated with lower ER values (P = 0.04) and low bcl-2 (P = 0.01). HER-2/neu positivity was not significantly associated with response rate (negative versus positive, 57 versus 54%; P = 0.67), TTF (median, 8 versus 6 months; P = 0.15), or survival (median, 31 versus 29 months; P = 0.36). There was also no significant evidence of a progressive relationship between an increasing proportion of cells expressing HER-2/neu and a shorter TTF or survival. HER-2/neu expression in ER-positive metastatic breast cancer is not significantly associated with a poorer response to tamoxifen or a more aggressive clinical course. Earlier suggestions to the contrary may have been due to failure to rigorously exclude ER-negative tumors, which are much less likely to respond to tamoxifen and more likely to have high HER-2/neu levels.

Adult↗
PubMed1997

Mitosin (a new proliferation marker) correlates with clinical outcome in node-negative breast cancer.

Tumor proliferation rate is an important prognostic factor in breast cancer, and S-phase fraction (SPF), as measured by flow cytometry, is the most clinically validated of several methods for measuring it. However, flow cytometry is not well suited to evaluating the formalin-fixed, paraffin-embedded tumors that are routinely available or to the increasing number of small breast cancers. These and other limitations have motivated research into alternative methods for measuring proliferation, including immunohistochemistry (IHC) against cell cycle-related antigens, which are better suited for the evaluation of small archival tissue samples. Mitosin is a recently described 350 kD nuclear phosphoprotein that is expressed in the late G1, S, G2, and M phases of the cell cycle but not in G0. Using a new monoclonal antibody (14C10), this pilot study evaluated mitosin expression by IHC in a series of 386 node-negative, formalin-fixed, archival breast cancers and correlated the results with several prognostic factors and clinical outcome (median follow-up, 78 months; range 3-214 months). The median and range of mitosin positive cells were 7% and 1-47%, respectively. There was a strong positive correlation between mitosin and SPF (r = 0.57; P = 0.0001), and there were significant negative correlations with estrogen receptor, progesterone receptor, and patient age. Mitosin was not related to overall survival in this pilot study. However, in a univariate cutpoint analysis of disease-free survival (DFS), patients with high levels of mitosin (>9% positive cells) had significantly worse DFS than did patients with lower levels (68% versus 84% at 5 years, respectively). In a multivariate analysis of DFS, large tumor size (>2 cm) and high mitosin were the only independently significant predictors of recurrence (relative risks = 2.47 and 1.72, respectively) in a model containing the additional factors estrogen receptor, progesterone receptor, patient age, and SPF. These preliminary results suggest that mitosin as assessed by IHC may be superior to SPF as a prognostic factor in node-negative breast cancer, but additional studies are necessary to validate these promising findings.

Animals↗
PubMed1997

Cytological evaluation of biological prognostic markers from primary breast carcinomas.

This study was undertaken to evaluate our ability to detect multiple molecular markers of prognosis and response to treatment in fine needle aspirates (FNA) from patients with primary breast carcinomas. 147 patients with operable primary breast carcinomas who had been recruited to a randomized trial of primary medical therapy (PMT) versus adjuvant chemoendocrine therapy were analysed. FNAs were taken prior to therapy and from this multiple slides were produced using cytospin cytocentrifugation and stored at -80 degrees C for subsequent immunocytochemical analysis (ICA). ICA was performed for oestrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, and Bcl-2. Part of the aspirate was snap frozen and used for flow cytometric analysis of ploidy and S-phase fraction (SPF). In a subgroup of 50 patients who had surgery prior to systemic therapy, as well as FNAs, sections were also taken from paraffin-embedded blocks and stained by ICA for ER, PgR and p53 for validation. In these patients ER was additionally measured by enzyme immunoassay (EIA) from frozen tissue taken at surgery. ER, PgR, p53, Bcl-2, and Ki67 were successfully detected by ICA while ploidy and SPF were successfully measured by flow cytometry from FNA material. The percentage positive values obtained were reasonable and as follows: 74% for ER, 70% for PgR, 36% for p53, 80% for Bcl-2,68% of tumours were aneuploid and 32% diploid. Significant relationships between these measurements were observed in accordance with expectations. The concordance for ER, PgR, and p53 from FNA when compared to ICA of matching histological sections was 91.5%, 75.5%, and 75% respectively. For ER the concordance between measurement by ICA of cytological and histological samples and by EIA of frozen tissue was 82.5% and 84% respectively. These results indicate that multiple molecular markers can be adequately tested on cytological preparations from primary breast tumours. These markers can be used to determine prognosis and predict response to PMT.

Adult↗
PubMed1997

WAF1/CIP1 protein expression in human breast tumors.

UNLABELLED: WAF1/CIP1 is a cyclin-dependent kinase inhibitor which is directly induced by p53 and negatively controls cell proliferation. To test the hypothesis that increased levels of WAF1 would be associated with a lower S-phase fraction and better prognosis, WAF1 protein was assessed by immunohistochemistry (IHC) in 115 node-negative human breast tumors, and results were correlated with established prognostic factors and clinical outcome. Nuclear staining was observed in malignant cells in 43% of tumors. In most (90%) of the positive tumors, the proportion of cells staining for WAF1 was low (< 10%). WAF1 was not detected in the cytoplasm, or in non-malignant epithelium. Contrary to expectations, the accumulation of p53 protein, a surrogate marker of p53 inactivation, was weakly but positively associated with WAF1 expression (p = 0.05). Surprisingly, there was no significant correlation with S-phase fraction, ER or PgR status, tumor size, age, ploidy, nuclear grade, or survival. CONCLUSION: WAF1 expression is found in the nuclei of a small fraction of cells in human breast tumors. WAF1 status is not significantly associated with cell proliferation, other established prognostic factors, or clinical outcome.

Breast Neoplasms↗
PubMed1997

bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study.

PURPOSE: To test the hypothesis that high bcl-2 expression and accumulation of p53 protein, both of which should inhibit apoptosis, are associated with a poorer tamoxifen response and a more aggressive clinical course in estrogen receptor (ER)-positive metastatic breast cancer. METHODS: A total of 205 paraffin-embedded tumor blocks were evaluated for nuclear p53 (a marker of p53 inactivation) and cytoplasmic bcl-2 by immunohistochemistry (IHC). All patients received tamoxifen as initial therapy for metastatic disease. The study began in 1982 and follow-up duration of the 24 patients last known alive is 8 years. RESULTS: Response to tamoxifen and time to treatment failure (TTF) were not significantly associated with p53 status, although patients with higher p53 had a worse survival (P = .008; median, 36 v 20 months). Higher bcl-2 expression was associated with higher levels of ER (P = .02), better response to tamoxifen (62% v 49%; P = .07), longer TTF (median, 9 v 5 months; P = .002), and better survival (median, 40 months v 25 months; P = .009). In multivariate analyses, including ER, progesterone receptor (PgR), and p53, high bcl-2 remained significantly associated with a longer TTF (P = .007) and survival (P = .07). p53 status was a significant factor for shorter survival (P = .05), but not for TTF (P = .61). CONCLUSION: p53 status, as determined by IHC is not significantly associated with response to tamoxifen, although tumors with altered p53 protein are inherently more aggressive. Contrary to expectation, high bcl-2 identifies a relatively indolent phenotype of ER-positive metastatic breast cancer, in which patients experience a better clinical response to tamoxifen and a longer survival.

Adult↗
PubMed1997

Insulin receptor expression and clinical outcome in node-negative breast cancer.

The insulin receptor (IR), a ligand-activated tyrosine kinase, is present in breast cancers, but its relationship to patient survival is unknown. The IR was measured in 584 tumor specimens from patients with node-negative breast carcinoma by frozen-section immunohistochemistry and light microscopy. The immunostaining signal was quantitated in relation to both the staining intensity and the proportion of positive malignant epithelial cells. Analyses indicated that patients with tumors with undetectable IR content in malignant epithelial cells (260 cases) had a relatively lower predicted 5-year disease-free survival (DFS) (69% +/- 3%) than did patients with tumors with detectable IR content (324 cases; DFS 76% +/- 3%, p = .032). The significance of IR content in these breast malignant epithelial cells was then analyzed along with patient age, tumor size, progesterone and estrogen receptor status, p53 accumulation, and S-phase. Multivariate analysis of these data revealed that after adjustment for these other variables, IR content was the strongest independent predictive factor for DFS (relative risk = 1.73, p = .005). Interestingly, in a small subset of patients with very high IR content (n = 62), DFS was decreased. These data indicate that IR content in node-negative breast cancers is a significant major predictor of reduced DFS. Moreover, they raise the possibility that the measurement of IR content might provide important information concerning breast cancer biology.

Adult↗