Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry. This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

Purpose: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1protein expression correlated with genomic copy number changes. Experimental Design: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1staining. Results: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P = 0.006) or HER2 positive (P = 0.039) and <50 years old at diagnosis (P = 0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1protein expression and reduced disease-free survival when stratified by either loss of ER (P = 0.008) or PR (P = 0.029) or HER2 overexpression (P = 0.026). Overall, there was poor correlation between BRMS1protein staining and copy number status. Conclusions: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.The breast cancer metastasis suppressor 1 (BRMS1) is one of a growing number of genes that have the ability to suppress metastasis without affecting tumorigenicity in experimental in vivo models (1 -4). BRMS1 maps to chromosome 11q13, a region where nonrandom amplification and deletions have been associated with progression and metastasis in breast cancer patients (5). BRMS1 is a predominantly nuclear protein that contains an imperfect leucine zipper motif and coiledcoiled domains, implying that it may function as part of a transcriptional complex (1), and recent studies suggest that BRMS1 may inhibit metastasis, in part, through gene regulation via interaction with histone deacetylases (6, 7). The restoration of BRMS1 expression was recently shown to correlate with reduced phosphoinositide and nuclear factor nB signaling, suggesting specific mechanisms by which BRMS1 may regulate genes involved in the metastatic process (8,9).Despite the potential importance of BRMS1 as a determinant of metastasis in the clinical setting, the study of patient samples from human breast cancer has been hampered by the lack of antibodies to native BRMS1 (6). The recent development of suitable antibodies to BRMS1 now makes it possible to study primar...

Objectives To formally study the prevalence and histological classification of renal cell carcinoma (RCC) in a series of patients with PTEN Hamartoma Tumor syndrome (PHTS). Methods We evaluated prevalence of RCC within a prospectively-accrued series of 219 patients found to have pathogenic germline PTEN mutations. Clinical data including pathology reports were requested for all participants. Slides and tumor blocks were requested for central pathology re-review and immunohistochemistry (IHC) analysis. Results Nine patients were identified with RCC. Based on SEER data 0.28 RCC cases were expected for the group, giving an overall age-adjusted Standardized Incidence Ratio (SIR) of 31.7 (95% CI 15.4–58.1, p<0.001) with a higher sex-adjusted SIR for females (46.7 vs. 21.6 for males). Reported histology of each mutation positive patient’s RCC was variable. However, on central pathology re-review of 8 patients, six examined lesions were determined to be of papillary subhistology (pRCC), with the other two patients’ tumors consistent with the initial report of chromophobe RCC (chRCC). IHC demonstrated complete loss of PTEN protein in all PTEN mutation positive patients’ pRCCs and patchy positivity in one chRCC. Conclusions PHTS is a hereditary syndrome newly associated with pRCC, and PTEN IHC may be a helpful screening tool to identify pRCC patients with PHTS. Physicians caring for PHTS patients should note the >31-fold increased risk for RCC and have a low threshold for investigating possible RCC in patients with relevant complaints. Renal ultrasound is not sensitive for detecting pRCC and so PHTS patients should have alternate renal imaging (CT or MRI).

Background: Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC. Methods: A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of <10% and detect a true response rate of ≥30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins. Results: Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting >120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival. Conclusions: Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined. (Clin Cancer Res 2009;15(18):5895-901)