Breast cancer outcomes in a population with high prevalence of obesity.

BACKGROUND: Obesity has been associated with poor prognosis in breast cancer. However, most previous studies examined populations with relatively low proportions of obese patients. Given that forecasts predict obesity rates to exceed 50% by 2030, it is important to examine breast cancer outcomes in populations with higher rates of obesity. We hypothesized that obesity, as measured by body mass index (BMI), is associated with decreased overall survival and disease-free survival in patients with invasive breast cancer in a population with a high prevalence of obesity. METHODS: A retrospective review of a prospectively maintained database was conducted on patients treated for invasive breast cancer at an academic medical center between 1997 and 2013. BMI was calculated from each patient's height and weight at the time of diagnosis. Patients were categorized as normal (BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)), as per the definitions established by the World Health Organization. The end points of overall survival and disease-free survival were analyzed. RESULTS: A total of 523 patients with invasive breast cancer were included for analysis. Based on BMI, 87 (16%) were categorized as normal, 150 (29%) were overweight, and 286 (55%) were obese. The median follow-up was 49 mo. There were 16 deaths (18.4%) in normal patients, 25 (16.7 %) in overweight patients, and 45 (15.7%) in obese patients (P = 0.84). By Kaplan-Meier survival analysis, there were no differences in overall survival (P = 0.49) or in disease-free survival (P = 0.33) among the three groups. CONCLUSIONS: Obesity is not associated with decreased overall or disease-free survival in a patient population with a high prevalence of obesity. These findings suggest that there may be other factors that contribute to the poor prognosis of obese breast cancer patients observed in populations with lower rates of obesity.

Is chronic kidney disease an independent risk factor for mortality in breast cancer?

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for morbidity and mortality in multiple disease processes. However, not much is known about the relationship between breast cancer and CKD. CKD is associated with increased difficulty in breast cancer screening or surveillance due to increased calcifications on mammography. In addition, there is concern regarding the optimization of serum levels of chemotherapeutics in patients with CKD or on hemodialysis. We hypothesized that CKD is an independent risk factor for mortality in patients with breast cancer. METHODS: A case-matched, retrospective review of a prospectively maintained database was conducted on patients treated for breast cancer at an academic medical center between 1998 and 2011. Glomerular filtration rates (GFRs) were calculated for each patient at the time of diagnosis, and patients with CKD (GFR <60 mL/min) were matched in a 1:2 ratio with patients with GFR >60 mL/min, controlling for age, stage at diagnosis, and race. Primary end points measured were disease-free survival and overall survival. Statistical analysis was performed using Student t-test and Kaplan-Meier. RESULTS: Of the 1223 total patients, 54 (4%) had CKD. One hundred five patients without CKD were matched for age, stage at diagnosis, and race. Mean GFR among patients with and without CKD were 47.6 and 83.2 mL/min, respectively (P < 0.001). The 5-y overall survival was 77% for patients with CKD and 86% for patients without CKD (P = 0.47). Disease-free survival was 64% and 81%, respectively (P = 0.45). CONCLUSION: Based on our data, CKD does not appear to have a significant impact on outcomes in patients with breast cancer.

Does obesity have an effect on outcomes in triple-negative breast cancer?

BACKGROUND: Among patients with breast cancer, obesity has been associated with an increased likelihood of having triple-negative breast cancer (TNBC). This association has been thought to be due to the antiapoptotic effects of obesity-related proteins. However, the effect of obesity on the outcomes in patients with TNBC remains unclear. We hypothesized that obesity would be associated with decreased overall survival and disease-free survival in these patients. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database was conducted of patients treated for breast cancer at an academic medical center from March 1998 to September 2011. The body mass index (BMI) of patients with TNBC was calculated at diagnosis. The patients were categorized as normal (BMI < 25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI > 30 kg/m(2)). The endpoints of overall survival and disease-free survival were analyzed. RESULTS: A total of 183 patients with TNBC were included for analysis. Of the 183 patients, 24 (13.1%) were normal (BMI < 25 kg/m(2)), 42 (23.1%) were overweight (BMI 25-30 kg/m(2)), and 117 (63.7%) were obese (BMI > 30 kg/m(2)). The median follow-up period was 42.5 months. Of the 183 patients, 2 (9.1%) died in the normal group, 10 (23.1%) died in the overweight group, and 25 (21.4%) died in the obese group (P = 0.28). The patients who were overweight or obese had larger tumors (P = 0.02), a higher T stage (P = 0.001), and higher tumor grade (P = 0.01) than the normal BMI patients. By Kaplan-Meier analysis, normal patients had higher overall survival than the overweight or obese patients, but this difference was not statistically significant (P = 0.29). Disease-free survival was also not significantly different (P = 0.91). CONCLUSIONS: Despite an increased frequency of larger tumors, higher T stage, and higher tumor grade, obesity was not associated with decreased overall or disease-free survival in patients with TNBC.

The chemokine receptor CXCR4 as a novel independent prognostic marker for node-positive breast cancer patients.

BACKGROUND: Node-positive breast cancer patients are a high-risk group. However, not all such patients will succumb to the disease. The molecular basis for this biologic heterogeneity is poorly understood. The chemokine receptor CXCR4 is a marker of metastatic disease. Its prognostic role in node-positive patients is unknown. We postulate that high CXCR4 overexpression in node-positive breast cancer specimens predicts a poor outcome. METHODS: 185 node-positive breast cancer patients were evaluated. All had standardized treatment and surveillance protocols. CXCR4 levels were detected with Western blots. Results were quantified against 1 µg of HeLa cells. CXCR4 expression was defined as high (≥ 7.5-fold) or low (<7.5-fold). Primary endpoints were cancer recurrence and death. Statistical analyses were Kaplan-Meier curves, log-rank test, and Cox proportional hazard model, with a P-value of ≤ 0.05 as significant. RESULTS: The mean follow-up time was 54 months; 148 patients (80%) had low CXCR4 and 37 patients (20%) had high CXCR4 level. The 5-year overall survival (OS) for the low and high CXCR4 group was 69% and 57%, respectively (P=0.02). The 5-year disease-free survival (DFS) for the low and high CXCR4 group was 62% and 53%, respectively (P=0.08). On multivariate analysis, T stage (P=0.001) and grade (P=0.04) were independent predictors of DFS, while T stage (P=0.005), grade (P=0.024), and CXCR4 level (P=0.01) were independent predictors of OS. CONCLUSION: High CXCR4 level in cancer specimens independently predicts a poor outcome for patients with node-positive breast cancer.

CXCR4 as a predictive marker for locally advanced breast cancer post-neoadjuvant therapy.

BACKGROUND: CXCR4 is a G-protein coupled receptor that has been linked with metastasis in several cancers, including breast cancer. We recently demonstrated that high CXCR4 levels in primary tumors of patients with breast cancer had a prognostic significance. We hypothesize that patients whose tumors had a low CXCR4 overexpression level following neoadjuvant chemotherapy will have a lower recurrence rate than those whose tumors remained high. METHODS: Seventeen locally advanced breast cancer (LABC) patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. CXCR4 levels were quantified by Western blots against 1 µg of protein from HeLa cells. The primary end-point was cancer recurrence. Statistical tests utilized include Kaplan-Meier survival analysis and log-rank test. A P value ≤ 0.05 was considered significant. RESULTS: We previously defined low CXCR4 overexpression as ≤6-fold elevation and high overexpression as >6-fold elevation over HeLa cells. Of 17 LABC tumors evaluated, 10 (59%) remained in the low group, 5 (29%) reduced from high to low overexpression, and 2 (12%) maintained a high overexpression after neoadjuvant therapy. With a median follow-up of 28 mo, patients whose tumors maintained a high CXCR4 overexpression level after neoadjuvant therapy had a significantly higher rate of cancer recurrence (P = 0.0068). CONCLUSIONS: CXCR4 was a predictive molecular marker of response to neoadjuvant chemotherapy for patients with LABC. Patients whose tumors had a persistently high CXCR4 overexpression level after neoadjuvant therapy are at a significant risk for recurrence, and therefore, should be targeted for more intensive and/or novel therapy.

The role of chemokine receptor CXCR4 in the biologic behavior of human soft tissue sarcoma.

The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis.

High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome.

INTRODUCTION: Basal-like tumors or triple negative breast cancers are those that lack hormone-receptor and HER-2 expressions. They are considered to be aggressive tumors, and molecular mechanism to account for this is poorly understood. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that high CXCR4 overexpression level in cancer specimens predicts a poor outcome in patients with triple negative breast cancers. METHODS: One hundred fifty-one patients with triple negative breast cancers were prospectively accrued and analyzed. All had undergone standardized treatment and surveillance protocols. From each specimen, CXCR4 levels were detected using Western blots. Results were quantified against 1 microg of HeLa cells (positive controls). CXCR4 expression was defined as high (>or=6-fold) or low (<6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. RESULTS: At a median follow-up of 37 mo, patients whose tumors had high CXCR4 overexpression (>or=6-fold) had a significantly higher incidence of cancer recurrence (P=0.014) and cancer-related death (P=0.026) than those in the low CXCR4 group (<6-fold). After adjusting for tumor size and nodal status, the relative risk for cancer recurrence and death in the high CXCR4 group was 2.1-fold (P=0.007; 95% CI: 1.22 to 3.8) and 2-fold (P=0.047; 95% CI: 1.01 to 4.06) higher than those in the low CXCR4 group, respectively. CONCLUSION: High CXCR4 overexpression in cancer specimens predicts a worse outcome in patients who have triple negative breast cancer.

The utility of a tissue slice model system to determine breast cancer infectivity by oncolytic adenoviruses.

BACKGROUND: Due to advances in viral design, oncolytic adenoviruses have emerged as a promising approach for treatment of breast cancer. Tumor tissue slices offer a stringent model system for preclinical evaluation of adenovirus therapies, since the slices retain a morphology and phenotype that more closely resembles the in vivo setting than cell line cultures, and this system has been shown to have utility in the evaluation of viral infectivity and replication. In this study, we evaluated the efficacy of viral infection and replication using a tropism-modified oncolytic adenovirus. METHODS: Breast tumor tissue slices were infected with a tropism-modified oncolytic adenovirus, and a wild-type adenovirus for comparison. Efficiency of infection was evaluated using fluorescent microscopy, as the viruses used have been modified to express red fluorescent protein. Replication of the viruses was evaluated with quantitative real-time polymerase chain reaction (PCR) to assay viral E4 genome copy number, a surrogate indicator for the number of virions. The breast tumor tissue slices were evaluated for the expression of CD46 expression by immunohistochemistry. RESULTS: Infection and replication of our tropism modified oncolytic virus has been observed in the breast cancer tissue slice model system and is comparative to wild-type virus. A qualitative increase in the number of cells showing red fluorescent protein (RFP) expression was observed correlating with increasing multiplicity of infection. Higher relative infectivity of the virus was observed in tumor tissue compared with normal breast tissue. Replication of the virus was demonstrated through increases in E4 copy number at 48 and 72 h after infection in human breast tumor slices. CONCLUSIONS: We have shown that a tropism modified oncolytic adenovirus can infect and replicate in breast cancer tissue slices, which may be an important preclinical indicator for its therapeutic utility.

Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC).

Purpose Patients with locally advanced breast cancer (LABC) have a poor outcome. A molecular predictor to identify at-risk patients is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that in patients with LABC, CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome. Experimental design 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy and definitive surgical therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm(3) cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots, and results were quantified against 1 mug of protein from HeLa cells. CXCR4 expression was defined as low (<6.6-fold) or high (> or =6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included independent samples t-test, chi-square test, Spearman Rank analysis, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results With a median follow-up of 30 months, patients with high CXCR4 overexpression (> or =6.6-fold) had a significantly higher incidence of recurrence (P = 0.0006) and cancer death (P = 0.0128) than those with low CXCR4 overexpression (<6.6-fold). The relative risks for recurrence and death in the high CXCR4 group were 27.3-fold (95% CI: 6.2-120.8; P = 0.001) and 4.8-fold (95% CI: 1.5-15.0; P = 0.0076) higher, respectively than those in the low CXCR4 group. Conclusion High CXCR4 overexpression in specimens from LABC patients receiving neoadjuvant chemotherapy was predictive of cancer outcome.

Overexpression of CXCR4 in primary tumor of patients with HER-2 negative breast cancer was predictive of a poor disease-free survival: a validation study.

BACKGROUND: Although HER-2 negative tumors are thought to be less aggressive than their counterpart, there is a subset that behaves poorly. The molecular mechanism to account for this is unknown. The chemokine receptor CXCR4 is often upregulated in a wide array of cancers. Using a training dataset, we previously reported that high CXCR4 overexpression portends a poor outcome among patients with HER-2 negative breast tumors. This study aims to validate these findings, using our validation dataset. METHODS: There were 115 patients with stages I-III, HER-2 negative breast cancers who were prospectively accrued and analyzed. CXCR4 levels from primary tumors were detected using Western blots, and results were quantified against 1 microg of HeLa cells. CXCR4 expression was defined as low (<6.6 fold) or high (> or =6.6 fold). Primary endpoint was cancer recurrence. Statistical analysis performed included Spearman correlation, Fisher exact test, Kaplan-Meier survival analysis, Cox proportional hazard ratio model, and log-rank test. RESULTS: There were 13 patients in the high (> or =6.6 fold) and 102 patients in the low CXCR4 group (<6.6 fold). Overall survival (OS) and disease-free survival (DFS) for the cohort was 84 and 71%, respectively. The 5-year OS for the high CXCR4 group was 52% and for the low CXCR4 group was 86% (P = 0.08). The 5-year DFS for the high CXCR4 and low CXCR4 group was 38 and 74%, respectively (P = 0.01). CONCLUSION: We validated that high CXCR4 overexpression in primary tumors of patients with HER-2 negative tumors portend a poor outcome. These findings should be confirmed with either a prospective clinical trial and/or an external validation study.

Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats.

BACKGROUND: Breast cancer is a major problem in the United States leading to tens of thousands of deaths each year. Although citrus auraptene suppresses cancer in numerous rodent models, its role in breast cancer prevention previously has not been reported. Thus, our goal was to determine the anticarcinogenic effects of auraptene against breast cancer. METHODS: The effects of auraptene on cell proliferation of MCF-7 and MDA-MB-231 human breast carcinoma cells in culture was assessed by measuring metabolism of a substrate to a formazan dye. Dietary effects of auraptene on tumor incidence, multiplicity and latency were studied in the N-methyl nitrosourea (MNU) induced mammary carcinogenesis model in female Sprague Dawley rats. The concentration of auraptene in rat tissues was analyzed by reverse phase HPLC. Cyclin D1 expression in MCF-7 cells and rat tumors was measured by western blot. RESULTS: Auraptene (500 ppm) significantly delayed median time to tumor by 39 days compared to the MNU only group (p < 0.05, n = 24-26). Auraptene (10 microM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells. In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group. Analysis of rat mammary tissue extract by HPLC with fluorescence detection indicated an average concentration (means +/- S.E.) of 1.4 +/- 0.5 microM and 1.8 +/- 0.3 microM in the normal mammary glands of the auraptene 200 ppm and 500 ppm groups, respectively. The concentration (means +/- S.E.) of auraptene in the mammary tumors of the auraptene 200 ppm group was 0.31 +/- 0.98 microM. CONCLUSION: Overall, these observations suggest that the predominant effect of auraptene was to delay the development of tumors possibly through the suppression of cyclin D1 expression. These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

Predictive value of eIF4E reduction after neoadjuvant therapy in breast cancer.

INTRODUCTION: Initiation factor 4E (eIF4E) overexpression has prognostic significance in breast cancer. Up-regulation of downstream gene products associated with high eIF4E overexpression has been linked to chemoresistance. We hypothesize patients whose tumors had eIF4E reduction after neoadjuvant chemotherapy will have lower cancer recurrence compared with those who did not. METHODS: Seventeen locally advanced breast cancer patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. eIF4E was quantified by Western blots. Primary end-point was cancer recurrence. RESULTS: Low eIF4E was defined as < or =7.5-fold elevation and high eIF4E was >7.5-fold elevation. Of 17 patients, six tumors remained low after neoadjuvant therapy, six dropped from high to low eIF4E, and five remained high. With a median follow-up of 29 mo, four of five patients with tumors that remained high have recurred while only three of 12 patients in the low eIF4E post-therapy group have recurred (P=0.05, chi(2)). Survival analysis using the Kaplan-Meier method showed a higher rate of cancer recurrence in patients with post-treatment high eIF4E overexpression (P=0.026, log rank test). CONCLUSIONS: Breast cancer patients whose tumors had low eIF4E overexpression after neoadjuvant chemotherapy had lower cancer recurrence compared with those who did not.

Li-Fraumeni syndrome: the genetics and treatment considerations for the sarcoma and associated neoplasms.

Li-Fraumeni syndrome is an autosomal dominant disorder first reported by Drs Li and Fraumeni in 1969. Malkin was the first to describe a germline mutation as an underlying defect of Li-Fraumeni syndrome. Cancer risk in mutation carriers has been estimated to be 50% by age 40 and 90% by age 60. Children of affected parents have an approximate 50% risk of inheriting the familial mutation. Functional assays have been established that allow for easy genetic testing for TP53 mutation. Treatment goals center on early detection and surgical resection of affected organ. Targeted therapy for the TP53 gene may hold promise for the future.

A prospective trial on initiation factor 4E (eIF4E) overexpression and cancer recurrence in node-negative breast cancer.

BACKGROUND: Eukaryotic Initiation Factor 4E (eIF4E) plays a crucial role in translation control. High eIF4E increase in tumor specimens independently predicted recurrence by multivariate analysis. This prospective trial of node-negative only breast cancer patients was initiated to test the hypothesis that high eIF4E increase predicts cancer recurrence and death, independent of nodal status. METHODS: The trial was powered to detect a 2.4-fold increase in relative risk for cancer recurrence in 240 node-negative patients on the basis of high versus low eIF4E increase in tumor specimens (type I error = .05, statistical power = .08). eIF4E level was quantified by using Western blot test. Treatment and surveillance regimens were standardized. Primary endpoints were cancer recurrence and cancer-related death. RESULTS: Of the 242 patients accrued, 112 were in the low eIF4E group (<7.5-fold), 82 were in the intermediate eIF4E group (7.5- to 15-fold), and 48 were in the high eIF4E group (>15-fold). Patients in the high eIF4E group had a statistically significant higher rate of cancer recurrence and cancer-related death (P = .0001 and P < or = .0001, log rank test). The relative risk for cancer recurrence was 2.2-fold higher in the high eIF4E group (P = .001, Cox model), and 3.7-fold higher for cancer-related death (P = .0009). CONCLUSIONS: In node-negative breast cancer, high eIF4E increase predicted a higher rate of cancer recurrence and death. High eIF4E patients had a >2-fold increase in relative risk for cancer recurrence and nearly a 4-fold increase in relative risk for death. This supports our hypothesis that high eIF4E is an independent predictor for breast cancer outcome independent of nodal status.

A novel suicide gene therapy targeting the overexpression of eukaryotic initiation factor 4E improves survival in a rat peritoneal carcinomatosis model.

BACKGROUND: Eukaryotic Initiation Factor 4E (eIF4E) is pivotal in translating mRNAs with complex 5' un-translated regions (UTRs). A target-specific gene therapy was developed by splicing a complex 5'UTR upstream of the herpes simplex virus thymidine kinase (TK) gene in an adenovirus vector (Ad-HSV-UTK). Translation of the suicide TK gene is restricted to cells that overexpress eIF4E. We investigated the efficacy of this novel therapy in a rat peritoneal carcinomatosis (PC) model. METHODS: A PC model was developed by implanting a syngeneic 0.25 cm(3) tumor into Fisher 344 rats' omentum. Rats were grouped as follow: No surgery (Ø CS), cytoreductive surgery alone (CS), and CS + Ad-HSV-UTK + gancyclovir (GCV). 10(9) Ad-HSV-UTK was injected intraperitoneally (i.p.) and GCV (50 mg/kg) was administered i.p. every other day, beginning on postoperative day 2. The Kaplan-Meier survival method and log-rank test were statistical tests used. RESULTS: Treated rats had a significantly longer median and overall survival than the Ø CS and CS groups (P = .012). The median survivals for the treated rats, Ø CS, CS were 18 days, 9 days, and 11 days, respectively. CONCLUSIONS: Treatment with a novel suicide gene therapy following cytoreductive surgery prolonged survival in a rat peritoneal carcinomatosis model.

Correlation of TLK1B in elevation and recurrence in doxorubicin-treated breast cancer patients with high eIF4E overexpression.

BACKGROUND: Tousled-like kinase 1B (TLK1B), a mammalian threonine kinase, facilitates the repair of DNA breaks. Eukaryotic initiation factor 4E (eIF4E) overexpression leads to the upregulation of TLK1B. Doxorubicin, commonly used in the adjuvant setting for breast cancer, causes DNA breaks. We hypothesized that the degree of TLK1B elevation is correlated with eIF4E overexpression and translates clinically to an increased risk for recurrence in breast cancer patients treated with doxorubicin-based adjuvant chemotherapy. STUDY DESIGN: We prospectively accrued 152 patients with stage I to III breast cancer treated with a doxorubicin-based chemotherapy in an adjuvant setting. Standardized treatment and surveillance protocols were used. eIF4E and TLK1B protein levels were quantified using Western blots, and patients were divided into tertiles based on previously reported stratification of eIF4E and TLK1B levels. Primary end points were cancer recurrence and death. Statistical analysis included Spearman's correlation, Kaplan-Meier survival analysis, log rank test, and the Cox proportional hazard model. RESULTS: The degree of TLK1B overexpression was highly correlated with the degree of eIF4E elevation (r=0.25, p=0.0025, Spearman rank correlation). Patients whose tumors were in the highest tertile for eIF4E overexpression had a higher risk for cancer recurrence and cancer death (p=0.015 and 0.049, respectively, log rank test). After adjusting for T-stage, nodal status, age, and estrogen receptor and progesterone receptor status, patients with tumors in the highest tertile of TLK1B overexpression treated with doxorubicin were 1.7-fold more likely to suffer recurrence than those in the low TLK1B group treated similarly (p=0.0078, CI, 1.17 to 2.75, Cox model). CONCLUSIONS: TLK1B overexpression was highly correlated with the level of eIF4E elevation. High TLK1B in cancer specimens was associated with a higher risk for cancer recurrence in patients treated with doxorubicin-based adjuvant chemotherapy.

Positron emission tomography (PET) positive thyroid incidentaloma: the risk of malignancy observed in a tertiary referral center.

An incidental finding of focal thyroid uptake (thyroid incidentaloma) from an 18F-fluorodeoxyglucose positron emission tomography (PET) positron presents a diagnostic challenge. We evaluated the incidence of thyroid incidentaloma identified by PET scans and the likelihood of malignancy associated with this finding. Records from all patients from January 1, 2000 to November 30, 2003 who had focal thyroid uptake without any history of thyroid disease were culled. Of the 6241 PET scans performed, focal thyroid uptake was observed in 76 patients (1.2%). Only 14 patients (18%) underwent biopsy. Four of 14 patients (28.6%) had papillary thyroid carcinoma, 7 (50%) had hyperplasia, and 1 each had thyroiditis, nodular goiter, and follicular neoplasm. The incidence of PET thyroid incidentalomas was 1.2 per cent and the incidence of malignancy was 28.6 per cent. Given the high likelihood of malignancy, a further diagnostic workup for surgically fit patients is warranted.

Adjuvant therapy for patients who have node-positive breast cancer.

The treatment of node-positive breast cancer has improved dramatically in the last 3 decades. Adjuvant therapies have evolved from single-agent chemotherapy to anthracycline- and taxane-based polychemotherapeutics to target-specific trastuzumab, with or without endocrine manipulation and with or without PMRT. Almost 85% of patients who have node-positive disease can now enjoy a 5-year DFS. This progress has come from incremental improvements made over the years. In spite of these advances, lingering questions remain. Is it possible to reduce treatment-associated toxicity? Can patient selection be improved based on tumor genomic profiling? Given the high cost of many of these therapies (37,000 dollars with the newer agents versus $391 for the classic six cycles of intravenous CMF), is it possible to achieve equivalent efficacy and yet reduce the economic cost per patient? Only continued clinical trials and cooperative effort among researchers, clinicians, and patients can answer these questions and improve care for breast cancer.

Cystatin m: a novel candidate tumor suppressor gene for breast cancer.

The contribution of pericellular proteolysis to tumor progression is well documented. To better understand protease biology and facilitate clinical translation, specific proteolytic systems need to be better defined. In particular, the precise role of endogenous protease inhibitors still needs to be deciphered. We reported previously that cystatin M, a potent endogenous inhibitor of lysosomal cysteine proteases, significantly suppressed in vitro cell proliferation, migration, and Matrigel invasion. Here, we show that scid mice orthotopically implanted with breast cancer cells expressing cystatin M show significantly delayed primary tumor growth and lower metastatic burden in the lungs and liver when compared with mice implanted with mock controls. The incidence of metastasis, however, appeared to be unaltered between the cystatin M group and the control group. Experimental metastasis assays suggest that cystatin M suppressed tumor cell proliferation at the secondary site. By using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction, we found consistent expression of cystatin M in normal human breast epithelial cells, whereas expression was decreased by 86% in invasive ductal carcinoma (IDC) cells of stage I to IV patients. Complete loss of expression of cystatin M was observed in two of three IDCs from stage IV patients. Immunohistochemical studies confirmed that expression of cystatin M in IDCs was partially or completely lost. We propose cystatin M as a novel candidate tumor suppressor gene for breast cancer.