Although the incidence of breast cancer in the United States is higher in Caucasian women compared with African American women, African-American patients have more aggressive disease as characterized by a higher percentage of triple-negative breast cancers (TNBCs), high-grade tumors, and a higher mortality rate. PKCα is a biomarker associated with endocrine resistance and poor prognosis and ERβ is emerging as a protective biomarker. Immunohistochemical analysis of ERβ and PKCα expression was performed on 198 formalin-fixed paraffin-embedded primary infiltrating ductal carcinomas from 105 African-American and 93 Caucasian patients. PKCα is positively correlated with TNBC in patients of both races and with high tumor grade in African-American patients. Patients with TNBC express less nuclear ERβ compared with all other subtypes. We find no difference in frequency or intensity of PKCα or ERβ expression between African-American and Caucasian patients. PKCα and ERβ are discussed as potential therapeutic targets for the treatment of patients with TNBC.

BackgroundTo reduce sampling error associated with cancer detection in prostate needle biopsies, we explored the possibility of using fluorescence in situ hybridisation (FISH) to detect chromosomal abnormalities in the histologically benign prostate tissue from patients with adenocarcinoma of prostate.MethodsTumour specimens from 33 radical prostatectomy (RP) cases, histologically benign tissue from 17 of the 33 RP cases, and 26 benign prostatic hyperplasia (BPH) control cases were evaluated with Locus Specific Identifier (LSI) probes MYC (8q24), LPL (8p21.22), and PTEN (10q23), as well as with centromere enumerator probes CEP8, CEP10, and CEP7. A distribution of FISH signals in the tumour and histologically benign adjacent tissue was compared to that in BPH specimens using receiver operating characteristic curve analysis.ResultsThe combination of MYC gain, CEP8 Abnormal, PTEN loss or chromosome 7 aneusomy was positive in the tumour area of all of the 33 specimens from patients with adenocarcinomas, and in 88% of adjacent histologically benign regions (15 out of 17) but in only 15% (4 out of 26) of the benign prostatic hyperplasia control specimens.ConclusionsA panel of FISH markers may allow detection of genomic abnormalities that associate with adenocarcinoma in the field adjacent to and surrounding the tumour, and thus could potentially indicate the presence of cancer in the specimen even if the cancer focus itself was missed by biopsy and histology review.

Introduction. The focal nature of prostate cancer (CA) contributes to needle biopsy sampling error with false negative rates of 15-30%. Here we used fluorescence in situ hybridization (FISH) analysis to assess molecular abnormalities in prostate specimens as an aid to CA diagnosis. We also evaluated the feasibility of combined immunofluorescence and FISH to facilitate assessment of chromosomal abnormalities. Experimental Procedure. 33 radical prostatectomy (RP) specimens from patients with adenocarcinoma of the prostate were evaluated by FISH with MYC, LPL, PTEN and centromere 8 probes. For each specimen, a tissue section was scribed by a pathologist to mark the tumor region(s). For 17 of the RP cases, a second section was available with only histologically benign tissue. FISH signals were enumerated in 50-100 cells per section. 26 hyperplasia (BPH) specimens, served as controls. Immunofluorescence (IF) with AMACR antibody was also used in the same assay with FISH. Results. Chromosomal copy number abnormalities were observed in most RP specimens, both within tumor regions and extending beyond histologically evident tumor, while few abnormalities were observed in the BPH specimens, using a cut-off value for FISH positivity based on the mean +/- 2 SD of cells with less than or greater than 2 signals in BPH specimens. A combination of MYC gain, LPL loss, PTEN loss or chromosome 8 aneusomy within the scribed tumor regions identified adenocarcinoma in 82% (27/33) of RP specimens, with a specificity of 81% relative to BPH (χ2 p<0.001). When detected in regions of normal histology, these abnormalities correlated with adenocarcinoma in 47% (8/17 RP specimens, χ2 p=0.05 relative to BPH). IF combined with FISH facilitated selection of the abnormal regions of interest for molecular assessment in the heterogeneous prostate specimens. The IF-staining closely correlated with morphological assessment of tumor by a trained pathologist. Conclusions. This study identified FISH probes for detection of chromosomal abnormalities associated with prostate CA that could potentially serve as a diagnostic aid in biopsy specimens. This study also indicates that chromosome abnormalities are present in RP specimens within regions of normal histology, indicating a substantial tumor field effect. Therefore, a molecular test based on FISH to measure abnormal MYC, LPL, PTEN and centromere 8 copy numbers may allow detection of cancer otherwise missed by histopathological examination and thus improve diagnosis of prostate cancer by reducing sampling error of needle biopsies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 823.

e18117 Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition (EMT). Previous work in a clinically enriched non-small cell lung cancer (NSCLC) population suggested low probability of an EGFR activating gene mutation in the absence of TTF-1 positivity (Somaiah ASCO 2011). This study's goal was to validate the relationship of TTF-1 and other immunohistochemical (IHC) markers of EMT to the presence of an EGFR activating gene mutation in a diverse group of NSCLC patients treated with erlotinib. Methods: Patients receiving erlotinib at two midwest institutions were retrospectively analyzed by IHC for TTF-1 (Greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining considered positive) and for PTEN, Ecadherin,vimentin, beta catinin, and snail (frequency(0-4) times intensity(0-4)). Exon 19 and L858R mutations were detectedusing single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR)).Fisher’s exact testand logistic regression wereused to correlate TTF-1(positive or negative) and the remaining EMT markers with the presence of EGFR mutation. Results: 216 patients were analyzed for EGFR activating gene mutations: 15% squamous, 80% smokers. EGFR mutation was found in 11.6% of cases. TTF-1 was present in 8% of squamous cell patients and 71% of adenocarcinoma patients. TTF-1 correlated with prolonged progression free survival (log rank p=.004). TTF-1 positivity was strongly correlated with the presence of mutation (p=.0006, negative predictive value=97.7%). Increasing Ecadherin and increasing PTEN expression by IHC correlated with the presence of EGFR gene mutation when measured on continuum (p=.006 and p=.04, respectively). Conclusions: Though retrospective, our work confirms the negative predictive value of TTF-1 for an EGFR activating gene mutation in a NSCLC cohort representative of a North American population.Though high PTEN and Ecadherin expression also correlated with EGFR mutation, TTF-1 positivity may be a more straight-forward marker that can select patients who should be screened for the mutation prior to initiation of first line therapy.

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