Biomedical subjects
Samuel W Beenken
Publications and source records attributed to Samuel W Beenken.
Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.
PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.
9cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers.
Studies were performed in female Sprague-Dawley rats to determine the efficacy of a new RXR specific retinoid (9cUAB30) when combined with tamoxifen in the prevention of mammary cancers and to determine various pharmacokinetic parameters of the retinoid. When administered by gavage, 9cUAB30 was rapidly absorbed and had a serum t(1/2) of 13.5 h. Since the retinoid was administered in the diet for the chemoprevention study, a 28-day study in which 9cUAB30 was given at dose levels of 200, 400, and 600 mg/kg diet revealed fairly constant serum levels regardless of dose or length of treatment; possibly accounting for the observed low toxicity of this compound. When suboptimal doses of 9cUAB30 were given in the methylnitrosourea (MNU)-induced mammary cancer model, the following average number of mammary cancers were observed: 9cUAB30 (150 mg/kg diet), 4.3; tamoxifen (0.4 mg/kg diet), 4.6; 9cUAB30 (150 mg/kg diet)+tamoxifen (0.4 mg/kg diet), 2.6; and controls, 6.0. Thus, the combination of the agents resulted in an increased effect in preventing mammary cancers; suggesting that cancer cell proliferation was inhibited by the compounds blocking different pathways.
Therapy for calciphylaxis: an outcome analysis.
BACKGROUND: Violaceous skin lesions that progress to nonhealing ulcerations and gangrene characterize calciphylaxis. These lesions, which are associated with secondary hyperparathyroidism, are resistant to medical therapy and may lead to amputation, uncontrollable sepsis, and death. METHODS: In this retrospective analysis, patient, disease, and treatment variables were obtained from the patients' medical records. Paired t-tests, chi-square analysis, and two-tailed Fisher's exact tests compared variables. Survival curves were generated using the Kaplan-Meier method; the log-rank test determined survival differences. RESULTS: From 1993 to 2001, 35 patients were treated; 26 (74%) were female and 20 (57%) were African-American. The cause of the renal failure was hypertension in 37% and diabetes mellitus in 26%. Twenty-three patients (66%) underwent a parathyroid resection involving 4 glands and autotransplantation in 12, 3(1/2) glands in 7, and <3(1/2) glands in 4. Median follow-up was 26 months (range 2 to 90 months). Surgical patients showed improvement in serum calcium, phosphate, and parathyroid hormone values (P<.05) and had a longer median overall survival (80 months) than nonsurgical patients (35 months) (P<.001). CONCLUSIONS: Parathyroid resection for calciphylaxis reduces serum calcium, phosphate, and parathyroid hormone values and improves clinical response and overall survival.
Axillary lymph node status, but not tumor size, predicts locoregional recurrence and overall survival after mastectomy for breast cancer.
OBJECTIVE: To assess the significance of axillary lymph node status and tumor size for predicting locoregional recurrence (LRR) and overall survival after mastectomy for breast cancer and to discuss the utility of postmastectomy radiation therapy. SUMMARY BACKGROUND DATA: Patients with locally advanced breast cancer require multimodality treatment combining chemotherapy (and/or hormonal therapy), surgery, and radiation. Randomized trials have demonstrated that postmastectomy radiation reduces LRR, but no overall survival benefit has been established. METHODS: Criteria for accrual to the Alabama Breast Cancer Project (1975-1978) were female gender and T2-3 breast cancer with M0 status. Patients underwent a radical or a modified radical mastectomy. Node-positive patients received adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy or adjuvant melphalan. Patients were evaluated for LRR and overall survival based on the number of positive axillary lymph nodes and (in N0 patients) pathologic tumor size. Significance was determined using chi-square analysis. Survival curves were generated using the Kaplan-Meier method and were compared by log-rank analysis. RESULTS: After median follow-up of 15 years, neither type of surgery nor chemotherapy was shown to affect locoregional disease-free or overall survival. LRR rates were higher and overall survival rates were lower in patients with nodal involvement, while tumor size was not shown to significantly affect these rates. CONCLUSIONS: Patients with axillary lymph node metastases may benefit from postmastectomy radiation, but the use of postmastectomy radiation in N0 patients is not supported when it is based on tumor size alone.
Long-term complications of breast-conservation therapy: can the incidence be reduced?
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Transforming growth factor-alpha: a surrogate endpoint biomarker?
BACKGROUND: Dysplastic oral leukoplakia (DOL) has been the index lesion in prevention trials for upper aerodigestive tract squamous cell carcinoma (SCC). Vitamin A derivatives, including 13-cis retinoic acid (13-CRA), have been used to treat DOL and to reduce the risk of subsequent SCC. Results from a trial of 13-CRA in patients with DOL are presented here. Transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor messenger RNA (mRNA) expression were studied to validate their use as surrogate endpoint biomarkers in prevention trials for SCC. STUDY DESIGN: In a prospective, randomized, double-blind trial of 13-CRA in 28 patients with DOL, TGF-alpha and epidermal growth factor receptor mRNA expression were analyzed in sequential biopsy specimens of DOL and of adjacent normal-appearing mucosa, utilizing a quantitative, competitive, reverse transcriptase polymerase chain reaction and were compared using the Wilcoxon signed-rank test for paired comparisons. RESULTS: In biopsy specimens of DOL, TGF-alpha mRNA expression at baseline, but not baseline expression of epidermal growth factor receptor mRNA, was significantly elevated when compared with its expression in specimens from adjacent normal-appearing mucosa (p = 0.003). In patients randomized to 13-CRA who had > or = 50% clearance of DOL during treatment, significant modulation of TGF-alpha mRNA overexpression was seen after 6 months of treatment (p = 0.016). TGF-alpha mRNA overexpression at baseline predicted a subsequent response to 13-CRA (p 0.066). CONCLUSIONS: The full extent of the association between TGF-alpha overexpression and the development of SCC is unknown. Evidence is presented in this article that TGF-alpha overexpression mediates the relationship between 13-CRA and DOL, but there is no direct evidence that it mediates the relationship between 13-CRA and the prevention of SCC. Determination of the extent to which TGF-alpha overexpression mediates this relationship and complete validation of TGF-alpha's role as a surrogate endpoint biomarker await the results of animal and human trials that utilize reduction in the incidence of SCC as their endpoint.
Factors associated with local recurrence after skin-sparing mastectomy and immediate breast reconstruction for invasive breast cancer.
OBJECTIVE: To examine the incidence of local recurrence (LR) and factors associated with it in a population of patients who underwent skin-sparing mastectomy (SSM) and immediate reconstruction for invasive carcinoma. SUMMARY BACKGROUND DATA: The efficacy of SSM has been challenged by concerns about increased risks of LR. METHODS: A consecutive series of 173 patients (176 cancers) with invasive carcinoma underwent SSM and immediate breast reconstruction (June 1986 to December 1997). Data were analyzed by the Kaplan-Meier method, the log-rank statistic test, and the Cox proportional hazards model. RESULTS: Mean patient age was 47 +/- 9 years (27% were 40 or younger). The AJCC stages were 1 = 43%, 2 = 52%, and 3 = 5%. Thirty percent of tumors were poorly differentiated. With a median follow-up of 73 months, the LR rate was 4.5%. The mean local relapse-free interval was 26 months. Seventy-five percent of patients who presented with LR developed distant metastases and died of disease within a mean of 21 months. On univariate analysis, factors associated with higher LR rate were tumor stage 2 or 3, tumor size larger than 2 cm, node-positive disease, and poor tumor differentiation. Actuarial 1-, 3-, and 5-year overall survival rates were 98%, 94%, and 88%, respectively. On multivariate analysis, factors associated with decreased survival were advanced stage, presence of LR, and absence of hormone therapy. LR was a highly significant predictor of tumor-related death. CONCLUSIONS: There is a low incidence of LR after SSM, and it is associated with advanced disease at presentation. LR is an independent risk factor for tumor-related death.