Biomedical subjects

Gary M Clark

Publications and source records attributed to Gary M Clark.

25 records · Page 2Linked to original sources

PubMed2003

Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor.

BACKGROUND: Women with metastatic breast carcinoma have a highly variable clinical course and outcome. Intrinsic genetic heterogeneity of the primary breast tumor may play a role in this variability and may explain it in part. Therefore, the authors tested the hypothesis that the characteristics of primary breast tumors are important determinants of prognosis and survival in patients with metastatic breast carcinoma. METHODS: The prognostic significance of the biology of the primary tumor for outcome in patients with metastatic breast disease was assessed in 346 patients with lymph node positive breast carcinoma who developed distant, recurrent disease. Traditional prognostic indicators (age, tumor size, number of involved lymph nodes, sites of recurrence, disease free interval [DFI], adjuvant treatments, estrogen receptor [ER] expression, progesterone receptor [PgR] expression, S-phase fraction [SPF], and DNA ploidy), together with three newer biologic markers (c-erbB-2, p53, and bcl-2) were assessed. Sites of recurrence were defined as nonvisceral (bone and locoregional lymph nodes) or visceral (lung, liver, brain, and other organs). RESULTS: The median duration of survival was 17.8 months (95% confidence interval, 15.2-21.5 months). Univariate analysis showed that age > 50 years, visceral disease, and shorter DFI were associated significantly with poor outcome (P < 0.05). In addition, the molecular phenotype of the primary breast tumor was significant, with primary tumors that showed ER negativity and PgR negativity, high SPF, aneuploidy, accumulation of p53 protein, and lower bcl-2 expression, together with c-erbB-2 overexpression, all associated with a poorer clinical outcome (P < 0.05). In a multivariate analysis, older age, visceral disease, shorter DFI, PgR negativity, high SPF, and lower bcl-2 expression were significant predictors of worse survival (P < 0.05). CONCLUSIONS: In addition to traditional risk factors, bcl-2 negativity was associated significantly with a worse clinical outcome. Biologic features of primary tumors were correlated independently with outcome after first recurrence in patients with metastatic breast carcinoma and may be used as indicators of prognosis in the metastatic setting.

Adult↗

PubMed2003

Maspin expression in invasive breast cancer: association with other prognostic factors.

Maspin is a unique serine protease inhibitor with a molecular weight of 42 kDa. It has been shown to inhibit tumour cell motility and invasion in cell culture, and tumour growth and metastasis in animal models. There is very limited data on the prognostic utility of maspin in human breast cancer. We performed a preliminary study to assess the associations of maspin with other established prognostic factors in invasive breast cancer (IBC). 1068 paraffin-embedded IBCs were immunohistochemically stained with a monoclonal antibody to maspin. A nuclear signal was present in 96% and a cytoplasmic signal in 35% of the cases. Nuclear staining was related to oestrogen (ER) and progesterone receptor (PR) positivity (p < 0.0001), but not to S-phase fraction (SPF) or ploidy. Cytoplasmic staining was related to ER and PR negativity (p < 0.0001), high SPF (p < 0.0001), and aneuploidy (p = 0.003). Thus, maspin nuclear staining was significantly associated with good prognostic factors, while cytoplasmic staining was associated with poor prognostic markers. These findings suggest that the presence of maspin in two different compartments of the cell may have different biological and clinical implications. Additional studies are needed to evaluate further this expression profile of maspin in breast cancer.

Antibodies, Monoclonal↗

PubMed2003

Staging system for breast cancer: revisions for the 6th edition of the AJCC Cancer Staging Manual.

Since its inception, the AJCC staging system for breast cancer has been in an almost constant state of evolution, striving with each revision to reflect the most up-to-date clinical research as well as the widespread consensus among physicians about appropriate diagnostic and treatment standards. To date, these revisions have essentially represented a "fine-tuning" of the initial judgment that tumor size, lymph node status, and presence of distant metastases are the most significant prognostic factors for breast cancer. With the problems of standardization and reproducibility being resolved, it is likely that histologic grade will join this group of independent markers and be incorporated into the AJCC staging system in the near future. Over the last 15 years. considerable attention has been focused on the discovery of new markers visualized with immunohistochemistry and RT-PCR that may be validated as independent prognostic indicators (reviewed by Mirza et al). To date, the usefulness of many of these markers has been limited by lack of standardization in measurement techniques, but several show great promise for the future. By increasing the number of prognostic markers that can give independent information about patient outcome, physicians will be better able to determine optimal treatment approaches for individual patients.

Advisory Committees↗

PubMed2002

Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer.

The importance of estrogen-related receptors (ERRs) in human breast cancer was assessed by comparing their mRNA profiles with established clinicopathological indicators and mRNA profiles of estrogen receptors (ERs) and ErbB family members. Using real-time quantitative PCR assays, mRNA levels of ERalpha, ERbeta, epidermal growth factor receptor, ErbB2, ErbB3, ErbB4, ERRalpha, ERRbeta, and ERRgamma were determined in unselected primary breast tumors (n = 38) and normal mammary epithelial cells enriched from reduction mammoplasties (n = 9). ERRalpha showed potential as a biomarker of unfavorable clinical outcome and, possibly, hormonal insensitivity. ERRalpha mRNA was expressed at levels greater than or similar to ERalpha mRNA in 24% of unselected breast tumors, and generally at higher levels than ERalpha in the progesterone receptor (PgR)-negative tumor subgroup (1-way ANOVA with repeated measures, P = 0.030). Increased ERRalpha levels associated with ER-negative (Fisher's exact, P = 0.003) and PgR-negative tumor status (Fisher's exact, P = 0.006; Kruskal-Wallis ANOVA, P = 0.021). ERRalpha levels also correlated with expression of ErbB2 (Spearman's rho, P = 0.005), an indicator of aggressive tumor behavior. Thus, ERRalpha was the most abundant nuclear receptor in a subset of tumors that tended to lack functional ERalpha and expressed ErbB2 at high levels. Consequently, ERRalpha may potentiate constitutive transcription of estrogen response element-containing genes independently of ERalpha and antiestrogens in ErbB2-positive tumors. ERRbeta's potential as a biomarker remains unclear; it showed a direct relationship with ERbeta (Spearman's rho, P = 0.0002) and an inverse correlation with S-phase fraction (Spearman's rho, P = 0.026). Unlike ERRalpha, ERRgamma showed potential as a biomarker of favorable clinical course and, possibly, hormonal sensitivity. ERRgamma was overexpressed in 75% of the tumors, resulting in the median ERRgamma level being elevated in breast tumors compared with normal mammary epithelial cells (Kruskal-Wallis ANOVA, P = 0.001). ERRgamma overexpression associated with hormonally responsive ER- and PgR-positive status (Fisher's exact, P = 0.054 and P = 0.045, respectively). Additionally, ERRgamma expression correlated with levels of ErbB4 (Spearman's rho, P = 0.052), a likely indicator of preferred clinical course, and associated with diploid-typed tumors (Fisher's exact, P = 0.042). Hence, ERRalpha and ERRgamma status may be predictive of sensitivity to hormonal blockade therapy, and ERRalpha status may also be predictive of ErbB2-based therapy such as Herceptin. Moreover, ERRalpha and ERRgamma are candidate targets for therapeutic development.

Biomarkers, Tumor↗

PubMed2002

Adenoid cystic carcinoma of the breast: molecular markers, treatment, and clinical outcome.

BACKGROUND: The objective of this study was to comprehensively characterize the clinical and biologic features of adenoid cystic carcinoma (ACC) and to assess the implications for management in a large cohort of patients. METHODS: From a database of 50,000 patients, 28 were identified with ACC for which clinical follow-up and biologic information was available. The biologic features examined included estrogen receptor and progesterone receptor status, DNA ploidy, and S-phase fraction. Median follow-up was 83 months with a range of 29 to 144 months. Overall survival and disease free survival curves were drawn using Kaplan and Meier estimates and were compared by the log-rank test. RESULTS: All but one patient were postmenopausal with a median age at diagnosis of 66 years (range, 40-96 years). One patient had macroscopic metastatic disease at diagnosis. Median tumor size was 1.9 cm (range, 0.5-7.0 cm). Axillary lymph node dissection was performed in 23 patients. Only 1 patient (4%) had histologic positive lymph nodes (2 of 10), and no recurrence was detected for this patient. Forty-six percent were ER positive (median, 16 fmol/mg protein; range, 5-1017 fmol/mg), and 35% were PgR positive (median, 61 fmol/mg protein; range, 6-854 fmol/mg). S-phase fraction and DNA ploidy were assessable in 24 cases. Ninety percent of tumors had low S-phase (median, 3.3%; range, 0.1-34.2%), and 92% were diploid. Simple or modified radical mastectomy was performed in 22 patients, and 6 patients were treated by lumpectomy. Five of these six patients also received radiation therapy after lumpectomy. Despite the different surgical approaches, there were no local recurrences. The 5-year disease free survival rate was 100%, and the 5-year overall survival rate was 85% (95% confidence interval, 71.7-98.6%). CONCLUSIONS: Adenoid cystic carcinomas of the breast have very favorable biologic characteristics and, consistent with this, an excellent prognosis. Good local control can be achieved by lumpectomy with radiation or by simple mastectomy. Axillary lymph node dissection is not helpful in clinical management.

Adult↗

PubMed2002

Real-time quantitative analysis of telomerase activity in breast tumor specimens using a highly specific and sensitive fluorescent-based assay.

Telomerase activity has been associated with almost 90% of malignant human cancers from a variety of tissue sources, making it one of the most prominent molecular cancer markers known to date. As such, telomerase has become a very attractive diagnostic and therapeutic target. The advent of the telomeric repeat amplification protocol (TRAP) has allowed for the semiquantitative detection of telomerase from limiting sample amounts. Both the standard TRAP assay and a real-time assay using Amplifluor technology with primers designed specifically for telomerase activity amplification were used to quantitatively assess telomerase activity in primary tumors and tumor-derived cell lines. We have adapted the recently developed TRAPeze XL telomerase detection kit (Intergen, Gaithersburg, MD) for use with real-time polymerase chain reaction for more accurate quantification and high-throughput capabilities. In doing so, the reliability, assay time, and accuracy of quantitation have all been dramatically improved. A comparison of the quantitative analysis for the standard TRAP assay versus the real-time assay using 19 breast tumors revealed telomerase quantitation and standardization using the real-time assay was superior to the standard assay. Our data suggest that this assay will be useful for clinical and research studies involving detection of telomerase activity as it relates to cancer diagnosis.

Breast Neoplasms↗

PubMed2002

A phase I and pharmacokinetic study of SAM486A, a novel polyamine biosynthesis inhibitor, administered on a daily-times-five every-three-week schedule in patients with Advanced solid malignancies.

PURPOSE: SAM486A is a novel inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC). This study was performed to characterize the toxicity profile and the pharmacological behavior and to determine the maximum tolerated dose (MTD) of SAM486A administered by a 1-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced cancer. EXPERIMENTAL DESIGN: Twenty-three patients received 46 cycles of SAM486A at dose levels ranging from 3.6 to 202.8 mg/m(2)/day. SAM486A plasma concentrations were measured during the first cycle for pharmacokinetic and pharmacodynamic evaluations. Paired tumor biopsy specimens pre- and posttreatment were obtained in 1 patient to assess the impact of SAM486A on intratumoral enzymes and metabolites involved in the polyamine biosynthetic pathway. RESULTS: The dose-limiting toxicity of SAM486A on this schedule was myelosuppression. Nonhematological toxicities, including nausea, vomiting, anorexia, and fatigue, were mild to moderate in severity. The MTD of SAM486A was 102.4 mg/m(2)/day. Pharmacokinetic analyses demonstrated a rapid initial decrease in plasma drug concentrations at the end of infusion, followed by a long terminal elimination phase with a mean (+/- SD) terminal elimination half-life of 65.4 +/- 55.6 h. Dose and area under the concentration-time curve correlated with the appearance of grade 4 neutropenia with correlation coefficients of 0.70 and 0.69, respectively. Analysis of paired tumor biopsy specimens taken before and after SAM486A treatment in 1 patient with metastatic melanoma revealed decreased SAMDC activity, increased ornithine decarboxylase activity, increased levels of putrescine, and depleted levels of decarboxylated S-adenosylmethionine and spermine, all of which are consistent with the proposed mode of action of SAM486A. CONCLUSIONS: SAM486A was well tolerated on this schedule of administration with the MTD established at 102.4 mg/m(2)/day. Neutropenia was dose-limiting and correlated with dose and area under the concentration-time curve. Pharmacodynamic assessment of tumoral tissues in 1 study patient demonstrated changes in the levels of polyamines and their biosynthetic enzymes consistent with SAMDC inhibition.

Adenosylmethionine Decarboxylase↗