Insulin-like growth factor (IGF)-I is a potent mitogen for breast cancer cells and may play a role in the disease. Although the involvement of IGF-I phenotype in breast cancer has been studied extensively, little is known about IGF-I genotype in relation to the disease. The IGF-I gene contains a polymorphic region composed of multiple cytosine-adenine dinucleotides (CA repeats). Studies of other genes indicate that the CA-repeat region in the promoter of a gene may affect transcription activity and that the length of the repeat is inversely correlated with transactivation. To examine if the IGF-I polymorphism is associated with breast cancer, we compared the length of CA repeats in the IGF-I gene between 53 breast cancer patients and 53 controls. Genomic DNA extracted from peripheral blood was used to determine the number of CA repeats through PCR amplification and DNA sequencing. Associations between CA repeats and breast cancer were assessed using unconditional logistic regression analysis. The results showed that the median number of CA repeats was 19, ranging from 15 to 23, and that compared to women without 19 CA repeats, women with 19 CA repeats were more likely to be breast cancer patients (OR = 2.87, 95%CI: 1.16-7.06) after adjusting for age, race, menopausal status, age at menopause, and alcohol use. The study also suggested possible synergistic interplay between IGF-I genotype and phenotype as women with 19 CA repeats and high plasma IGF-I had a much higher odds ratio for breast cancer (OR = 5.12, 95%CI: 1.42-18.5) than those with only one of the conditions. If our observations can be confirmed in larger studies, the findings will provide further evidence to support the role of IGF-I in breast cancer and the link between genetic polymorphism and cancer susceptibility.

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ObjectiveThe objective of this study is to determine if high eukaryotic initiation factor 4E (elF4E) overexpression (sevenfold elevation or more over benign breast tissue) is associated with a worse clinical outcome. Summary Background DataDysregulation of cellular functions by selective overexpression of specific proteins can lead to malignant transformation. The overexpression of elF4E preferentially increases translation of mRNAs with long, G-C rich 5'-untranslated regions. Selective gene products, such as tumor neoangiogenic factors, ornithine decarboxylase, and cyclin Dl, are upregulated. MethodsOne hundred fourteen breast specimens were analyzed and elF4E overexpression was quantified by Western blot analysis. Quantification for elF4E protein level was accomplished using a rabbit anti-eIF4E antibody and colorimetric development of Western blots using nitro blue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate. The blots were scanned and analyzed by densitometry. Treatment, pathologic, and clinical outcome data variables were analyzed. Statistical analysis was performed to determine if elF4E overexpression is associated with breast cancer clinical outcome. ResultsIn the 55 benign specimens, the mean eIF4E expression was 1.1 ± 0.4 fold (mean ± standard deviation). All 59 malignant breast carcinoma specimens were noted to have eIF4E overexpression (range, 1.9-fold to 30.6-fold), with a mean overexpression of 10.8 ± 6.3-fold. The mean level of eIF4E expression in malignant specimens was higher than benign specimens (p < 0.05, unpaired t test). The degree of eIF4E overexpression appears to be independent of T and N stage.In the 21 patients with eIF4E overexpression of less than sevenfold, there was one cancer recurrence but no cancerrelated deaths. In the 38 patients with high eIF4E overexpression (sevenfold or more), 14 patients had breast cancer recurrences (p = 0.03, log rank test), of whom 11 have died from the disease (p = 0.04, log rank test). The average follow-up interval in this study was 40 months. ConclusionsPatients with stage I to Ill breast cancer and high eIF4E overexpression had a higher rate of cancer recurrence and a higher rate of cancer-related death when compared to similarstage breast cancer patients with low eIF4E overexpression. Therefore, elF4E protein overexpression may be of prognostic value in stage I to Ill breast carcinoma.Malignant transformation is a multistep process involving errors in molecules critical for normal cellular functions.

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ObjectiveTo determine the compliance with a standard breast-conservation therapy (BCT) program in a predominantly indigent, minority population of patients with early breast cancer (stage I and II) served by a rural state institution in the South; to compare the clinical outcomes of this group with those reported in clinical trials; and to examine the socioeconomic factors that may have contributed to the rate of compliance. Summary Background DataDisease-free survival and overall survival in early breast cancer treated by BCT versus modified radical mastectomy are reported to be equivalent in prospective randomized trials. However, patients enrolled in clinical trials may not be representative of patients living in the various diverse communities that make up the United States. The authors' hypothesis is that patients enrolled in clinical trials at the national level may not be representative of indigent patients in the rural South and that clinical trial results may not be directly applicable. MethodsA retrospective review of 55 women with early-stage breast cancer treated from 1990 to 1995 was performed. Clinical data, compliance with treatment and clinical follow-up, and recurrence rates were examined. Statistical analysis performed include the Fisher exact test, Kaplan-Meier survival analysis, and log-rank test. ResultsFull compliance (defined as completion of the entire course of radiation therapy and clinical follow-up) with the BCT program was observed in only 36% of patients. Fifteen of the 35 noncompliant patients did not complete radiation therapy. A significantly higher local failure rate was observed: 8 of these 15 patients (53%) have had local failure. In contrast, patients who were either in full compliance with the BCT program or were deficient only in that they missed part of their clinical follow-up had local failure rates of 5% (1/20) and 10% (2/20), respectively. Age, race, stage of cancer, economic status (measured by availability of medical insurance), distance of patient's residence from the hospital, and education level were evaluated as potential predictors of compliance. None predicted patient compliance, although a trend toward higher compliance was noted in patients with a higher education level, as determined by literacy testing. ConclusionsCompliance with the BCT protocol at the authors' institution was worse than reported in clinical trials, and noncompliance translated into a significant increase in the local failure rate. Factors examined suggest that literacy may play a role in predicting compliance. Although BCT should be discussed with all breast cancer patients, the judicious application of clinical trial data to an institution's local population is warranted.

ObjectiveTo validate the authors' initial hypothesis-generating observation that eukaryotic initiation factor 4E (eIF4E) protein elevation predicts a higher cancer recurrence rate in patients with stage 1 to 3 breast cancer. Summary Background DataTumor size and nodal status continue to be the two most important independent prognostic markers in breast cancer, despite well-documented limitations. In a previous smaller retrospective study, eIF4E, important in the regulation of protein synthesis of mRNAs with long or complex 5' untranslated regions, appeared promising as an independent predictor of breast cancer recurrence. MethodsSpecimens and clinical data from 191 patients with stage 1 to 3 breast cancer were accrued prospectively. Data collected include stage of disease, tumor grade, age at diagnosis, and menopausal status. Endpoints measured were disease recurrence and cancer-related death. eIF4E protein level was quantified using Western blot analysis. Immunohistochemical staining was used to determine estrogen receptor, progesterone receptor, and HER-2/neu receptor status. Statistical analysis include Cox proportional hazards model, log-rank test, Kaplan-Meier survival curve, Fisher exact test, and t test. ResultsPatients were divided into three groups based on tertile distribution of eIF4E: low, defined as less than 7.5-fold elevation (n ϭ 64); intermediate, defined as 7.5-to 14-fold elevation (n ϭ 61); and high, defined as more than 14-fold elevation (n ϭ 66). The relative risk for cancer recurrence with intermediate elevation was 4.1 times that of patients with low elevation. For patients with high elevation, the relative risk for recurrence was higher, at 7.2 times that of the low group. The relative risk for cancer-related death for high elevation was 7.3 times that of patients with low eIF4E. Using multivariate analysis, high eIF4E remained an independent predictor of cancer recurrence after adjusting for tumor size, tumor grade, nodal disease, estrogen receptor status, progesterone receptor status, and menopausal status. ConclusionsHigh eIF4E is an independent predictor of cancer recurrence in patients with stage 1 to 3 breast cancer. The relative risk for cancer recurrence increases with eIF4E protein elevation. High eIF4E elevation is also associated with an increased relative risk for cancer-related death.To date, the two most important independent prognostic markers in breast cancer continue to be tumor size and nodal status.1,2 However, systemic failure can and does occur in patients with small, node-negative tumors.3 Approximately two thirds of invasive breast carcinomas present without evidence of axillary lymph node involvement, but at least 25% of these carcinomas eventually recur.1,3 Conversely, more than 30% of node-positive breast carcinomas do not develop recurrent disease.1 These inherent deficiencies in the TNM staging system have necessitated the search for a prognostic marker in breast carcinoma, independent of tumor size and nodal status.Malignant transformation is a multistep proce...