Testing for HER2 in Breast Cancer: A Continuing Evolution

Human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive factor in breast cancer. HER2 is overexpressed in approximately 15%–20% of invasive breast carcinomas and is associated with earlier recurrence, shortened disease free survival, and poor prognosis. Trastuzumab (Herceptin) a “humanized” monoclonal antibody targets the extracellular domain of HER2 and is widely used in the management of HER2 positive breast cancers. Accurate assessment of HER2 is thus critical in the management of breast cancer. The aim of this paper is to present a comprehensive review of HER2 with reference to its discovery and biology, clinical significance, prognostic value, targeted therapy, current and new testing modalities, and the interpretation guidelines and pitfalls

Diabetic Mastopathy as a Radiographically Occult Palpable Breast Mass

Diabetic mastopathy is an uncommon, benign disease of the breast that can occur in women with diabetes and clinically mimic breast cancer. We describe a patient with long-standing type 1 diabetes who presented with a palpable breast mass with negative imaging findings on mammography, ultrasonography, and breast MRI. Surgical biopsy and histopathology confirmed diabetic mastopathy. We use this case to highlight the recognition, radiographic features, pathology, and management of this benign breast condition and emphasize that, in diabetic patients, the differential diagnosis of a new breast mass should include diabetic mastopathy

Expression profiling of formalin-fixed paraffin-embedded primary breast tumors using cancer-specific and whole genome gene panels on the DASL® platform

<p>Abstract</p> <p>Background</p> <p>The cDNA-mediated Annealing, extension, Selection and Ligation (DASL) assay has become a suitable gene expression profiling system for degraded RNA from paraffin-embedded tissue. We examined assay characteristics and the performance of the DASL 502-gene Cancer Panel^v1(1.5K) and 24,526-gene panel (24K) platforms at differentiating nine human epidermal growth factor receptor 2- positive (HER2+) and 11 HER2-negative (HER2-) paraffin-embedded breast tumors.</p> <p>Methods</p> <p>Bland-Altman plots and Spearman correlations evaluated intra/inter-panel agreement of normalized expression values. Unequal-variance <it>t</it>-statistics tested for differences in expression levels between HER2 + and HER2 - tumors. Regulatory network analysis was performed using Metacore (GeneGo Inc., St. Joseph, MI).</p> <p>Results</p> <p>Technical replicate correlations ranged between 0.815-0.956 and 0.986-0.997 for the 1.5K and 24K panels, respectively. Inter-panel correlations of expression values for the common 498 genes across the two panels ranged between 0.485-0.573. Inter-panel correlations of expression values of 17 probes with base-pair sequence matches between the 1.5K and 24K panels ranged between 0.652-0.899. In both panels, <it>erythroblastic leukemia viral oncogene homolog 2 </it>(<it>ERBB2</it>) was the most differentially expressed gene between the HER2 + and HER2 - tumors and seven additional genes had p-values < 0.05 and log2 -fold changes > |0.5| in expression between HER2 + and HER2 - tumors: <it>topoisomerase II alpha </it>(<it>TOP2A</it>), <it>cyclin a2 </it>(<it>CCNA2</it>), <it>v-fos fbj murine osteosarcoma viral oncogene homolog </it>(<it>FOS</it>), <it>wingless-type mmtv integration site family, member 5a </it>(<it>WNT5A</it>), <it>growth factor receptor-bound protein </it><it>7 </it>(<it>GRB7</it>), <it>cell division cycle 2 </it>(<it>CDC2</it>), <it>and baculoviral iap repeat-containing protein 5 </it>(<it>BIRC5</it>). The top 52 discriminating probes from the 24K panel are enriched with genes belonging to the regulatory networks centered around <it>v-myc avian myelocytomatosis viral oncogene homolog </it>(<it>MYC</it>), <it>tumor protein p53 </it>(<it>TP53</it>), and <it>estrogen receptor α </it>(<it>ESR1</it>). Network analysis with a two-step extension also showed that the eight discriminating genes common to the 1.5K and 24K panels are functionally linked together through <it>MYC</it>, <it>TP53</it>, and <it>ESR1</it>.</p> <p>Conclusions</p> <p>The relative RNA abundance obtained from two highly differing density gene panels are correlated with eight common genes differentiating HER2 + and HER2 - breast tumors. Network analyses demonstrated biological consistency between the 1.5K and 24K gene panels.</p

Association between epithelial-cadherin and rat embryo malformations during organogenesis in vitro

This thesis has examined the association between the expression of a cell adhesion molecule, epithelial-cadherin (E-cadherin), and rat embryo malformations induced by three model teratogens and an E-cadherin antisense oligonucleotide during organogenesis in vitro. The embryo malformations induced by phosphoramide mustard (PAM), an active metabolite of an anticancer drug, cyclophosphamide, were not associated with any change in the expression of E-cadherin. The embryo malformations induced by exposure to the phorbol ester, 12-0-tetradecanoyl-phorbol-13-acetate (TPA), were associated with an increased steady state concentration of E-cadherin mRNA in the embryo, but not in the yolk sac. This increase in E-cadherin mRNA did not seem to be the cause of the embryo malformations. Exposure of embryos to the heavy metal, cadmium chloride, resulted in an increase in the steady state concentration of E-cadherin protein in the yolk sac, but not in the embryo. The timing of this increase would suggest that it may be one of the factors leading to the embryo malformations. An 18-base E-cadherin antisense oligodeoxynucleotide, injected into the amniotic cavity of 5-7 somite stage rat embryo, down regulated the expression of E-cadherin in the yolk sac, and caused specific open anterior neuropore malformations. Together, these data would suggest that E-cadherin expression is regulated in a tissue-specific manner, and that altering the expression of E-cadherin in the yolk sac is associated with embryo malformations