Current Cancer Therapy Reviews - Volume 8, Issue 3, 2012

Ductal carcinoma in situ (DCIS) is a heterogeneous entity, with a wide range of histological appearances including different architectural growth patterns, different nuclear morphology ranging from minimal to severe nuclear atypia, and the presence or absence of necrosis and calcification. Diagnostic criteria for DCIS depend on the degree of cytologic atypia, but in general include cytonuclear and architectural features, clonality of the cell population and extent of the lesion. Numerous classification systems have been proposed for DCIS in order to predict disease recurrence after surgical resection, and most systems are based primarily on nuclear grade and secondarily on cell polarization and the absence or presence of necrosis. Low grade DCIS needs to be distinguished from usual hyperplasia and atypical ductal hyperplasia (ADH). The main criteria for distinguishing usual hyperplasia from neoplasia (ADH and DCIS) are based on the identification of a clonal cell process, histologically recognized by the uniformity of cytonuclear features and immunophenotype. Distinction of low grade DCIS from ADH is mainly based on the extent of the lesion. Differentiation of DCIS from in situ lobular neoplasia may pose difficulties, however, it is important because of its therapeutic implications. Cancerization of lobules with associated sclerosis and distortion or involvement of complex sclerosing lesions and sclerosing adenosis by DCIS may mimic invasive carcinoma. DCIS may also involve a papilloma and these cases should be distinguished from DCIS with a papillary growth pattern (papillary DCIS), encapsulated papillary carcinoma and invasive papillary carcinoma. The goal of pathologic examination of breast specimens containing DCIS is to establish the diagnosis and determine relevant tumor features such as size, extent, grade and margin status.

Intraductal carcinoma (DCIS) was once an uncommon disease. Today, DCIS represents 20-30% of breast cancers that are diagnosed. Mammography has been the gold standard in detecting DCIS, however recent evidence demonstrates that magnetic resonance imaging (MRI) may be superior to mammography in detecting DCIS. In addition, MRI may be able to detect high grade, mammographically occult DCIS that are more likely to progress on to become invasive carcinoma.

Ductal carcinoma in situ (DCIS) represents the earliest stage of breast cancer and accounts for approximately 20% of new breast cancer diagnoses. Mastectomy was the surgical treatment of choice prior to seminal data from several randomized control trials which provided evidence supporting the efficacy of breast conservation surgery (BCS) in DCIS. Controversy, however, persists regarding all patients with DCIS require radiation treatment after lumpectomy. In this review, we summarize the findings from early clinical trials which attempted to identify risk factors associated with increased risk of local recurrence after BCS. We focus mainly on clinical features associated with women with “low risk DCIS”, i.e. those who may not need adjuvant radiation treatment after BCS. Clinical features that have been suggested as defining low risk DCIS include: older age at diagnosis, low or intermediate nuclear grade, smaller size of DCIS, absence of comedo necrosis and wide margins of resection (> 3 mm). We also review the results from several recent single arm studies examining the risk of local recurrence in women felt to have low risk DCIS treated by BCS without radiation. The mixed results of these studies indicate that the current risk stratification strategies for identifying low risk DCIS needs further refinement. Future directions will likely involve validated novel diagnostic and molecular methods to help guide the delivery of tailored treatment to women with DCIS.

The diagnosis of ductal carcinoma in situ (DCIS) has increased dramatically following the widespread adoption of screening mammography. DCIS has a favorable prognosis overall, but is associated with an increased risk of invasive breast cancer (IBC) and occasionally, with poor outcomes. The goal of the multidisciplinary treatment of DCIS is to prevent the development of invasive disease. The identification of patients at elevated risk for progression or recurrence who require more aggressive multimodality therapy and, conversely, those who can safely forgo elements of the current therapeutic armamentarium are important current challenges.

Introduction: Survivin, a member of the Inhibitor of Apoptosis Proteins (IAP), is involved in cell proliferation, apoptosis suppression, and angiogenesis. Survivin is highly expressed in many cancers and its expression is often correlated with more aggressive disease and worse outcomes. Our goal was to characterize survivin expression in ductal carcinoma in situ (DCIS) with a specific interest in correlation to histopathologic grade, hormone receptor (HR) and HER2 status, and the presence of invasion or microinvasion. Methods: Immunohistochemistry was performed on paraffin-embedded tissue containing clinical DCIS (n = 91). Survivin expression was evaluated for intensity (1-3+) as well the percentage of tumor staining (0-100%). A numerical score was calculated by multiplying the staining intensity by the percentage of tumor cells staining giving an overall score (0 -300). Immunoreactivity was scored separately for cytoplasm and nuclei. Results: Cytoplasmic survivin expression was found in 89/91 (97.8%) DCIS patients. There was a positive correlation between cytoplasmic survivin expression and histopathologic grade (p < 0.001). HR positive DCIS showed higher levels of nuclear survivin than HR negative DCIS (p = 0.02), while HER2 positive DCIS showed lower levels of nuclear expression than HER2 negative DCIS (p = 0.03). Survivin expression did not correlate with the presence of invasion. Conclusion: Increasing levels of cytoplasmic survivin expression appear to correlate with higher histopathologic grade. Survivin may be involved in the transition from a low to higher grade lesion. Since survivin is highly expressed in DCIS, survivin could serve as an excellent therapeutic target for the treatment and prevention of early breast cancer.

The incidence of ductal carcinoma in-situ (DCIS) is increasing significantly. DCIS has been demonstrated to arise from terminal duct-lobular units and it is generally accepted that DCIS is a precursor lesion to the majority of invasive ductal carcinoma. DCIS is a highly heterogeneous lesion with variable morphology, clinical presentation and behavior, however, the exact molecular biology of DCIS is not yet resolved. Commonly used markers include estrogen receptor (ER) and progesterone receptor (PR) and less commonly HER2, androgen receptor and TP53. Although significant advances have been made in our knowledge of the molecular pathology of invasive breast carcinoma over the past few decades, few studies focused on DCIS. Several gene expression signature studies suggest that DCIS is genetically advanced and heterogeneous and is a direct precursor of invasive cancer. It is now generally accepted that low grade DCIS is a precursor of low grade invasive carcinoma and high grade DCIS is a precursor of high grade invasive carcinoma. The role of microenvironment appears to be important in the transition of DCIS to invasive disease. Identification of molecular markers that predict the risk of disease progression is needed. Targeting markers that can riskstratify patients with pre-invasive breast cancer would be immensely beneficial in tailoring the treatment of this heterogeneous disease to each individual patient. Recent studies demonstrated the significantly greater rate of concurrent, occult invasive disease in HER2 positive DCIS, suggesting that effective targeting of HER2 in DCIS may be of particular benefit in risk stratification. In addition to ER, PR and HER2, other molecular markers are needed to better predict risk of developing invasive disease and to provide personalized management for patients with DCIS.

The RAF-MEK and PI3K-AKT pathways are both frequently deregulated in cancer, and often play a critical role in oncogenesis. In the previous years, major progress has been made in the development of targeted drugs against signaling kinases which are involved in carcinogenesis. Currently, targeted drugs against RAF, MEK, PI3K and AKT (among several others) have entered clinical investigation. Here we describe tumor causing mutations of these kinases, as well as the small molecule inhibitors that target these kinases, which contributes to improved ways of treating human cancer.

The most commonly encountered carcinoma of the sinonasal tract is the keratinizing/ non-keratinizing squamous cell carcinoma. However, this complex anatomic location may represent the site of other epithelial malignant neoplasms of varying histogenesis. These tumors are clinically aggressive and often fatal; historically, treatment outcomes have been poor. Differentiating these tumor types may have clinical impact as advances in therapeutic intervention could increase survival, quality of life and occasionally result in a cure. This review focuses on recent advances in the molecular and phenotypic characterization of sinonasal carcinomas and their impact on diagnosis and treatment.

Cyclin Dependent Kinase (CDKs) regulates cell cycle commitment and DNA synthesis. Cell division in mammalian cells is driven by protein kinase that regulates progression through the various phases of cell cycle. The activity of cyclins and their associated CDKs are frequently deranged in human cancers. For this reason, Cyclin-CDK complexes have been considered as very promising therapeutic targets in human malignancies. An obvious concern whether, blocking cyclin-CDK function would preferentially affects cancer cells but not normal and non-transformed cells. The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical part of the cell cycle machinery is the CDK, which, when activated, provide a means for the cell to move from one phase of the cell cycle to next. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest represents a survival mechanism that provides tumour cell, to repair its own damaged DNA Thus, abrogation of cell cycle checkpoints, before DNA repair is complete can activate the apoptotic cascade leading to cell death. Misregulation of CDK is one of the most frequent alterations in human cancer. CDK are critical regulators of cell cycle progression and RNA transcription. A series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In this review we are summarizing that why CDK is important target for cancer chemotherapy and why finding out the best and potent kinase inhibitor is essential.