Premalignant Breast Neoplasia: A Paradigm of Interlesional and Intralesional Molecular Heterogeneity and Its Biological and Clinical Ramifications

Abstract

As is well established in invasive breast disease, it is becoming increasingly clear that molecular heterogeneity, both between and within lesions, is a prevalent, distinct phenotype of premalignant lesions of the breast. Key pathways of tumorigenesis modulate critical features of premalignant lesions such as proliferation, differentiation, stress response, and even the generation of diversity. Current studies show that evaluation of these lesions may provide clinically useful information on future tumor formation as well as biological insights into the origin and functional significance of this distinct phenotype. Cancer Prev Res; 3(5); 579-87. ©2010 AACR.

Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma

“…The striking p16 homogeneous expression pattern, frequently used as a marker of RB1 loss, seen in approximately 66% of high-grade serous carcinoma and uncommon in other epithelial ovarian cancer histotypes, 7,[25][26][27][28] predicts for a decreased progressionfree survival and overall survival. The heterogeneous p16 pattern, present in about 33% of high-grade serous carcinoma cases and frequently seen in other epithelial ovarian cancer, predicts a better clinical outcome for high-grade serous carcinoma patients.…”

“…Mechanisms of retinoblastoma pathway deregulation in other tumor types have previously been associated with clinical parameter differences including type, recurrence, and outcome, 7,8,25,26,32,33 and can be exploited for targeted therapy approaches to identify the most responsive patient subgroups. [33][34][35] However, our study is unique because we have identified differential clinical behavior in a specific cancer histotype.…”

Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions

“…For instance, many studies have suggested that the tumor size is a strong predictor of local recurrence [7,11]. Nuclear grade and margin status are other factors that appear to influence recurrence in DCIS, though certainly there are studies that refute these findings [12]. Two major clinical tools that aid in risk stratification and treatment planning--the University of Southern California/Van Nuys Prognostic Index and the DCIS nomogram introduced by Rudloff et al--utilize both clinical and pathologic factors such as tumor size, necrosis, and margin status [10,13,14].…”

“…The ideal classification scheme would be clinically useful and easy to adapt with the ability to stratify patients into prognostic groups. While not consistently identified in all studies, certain histopathological parameters such as lesion size, margin status, architectural pattern, nuclear grade, presence of comedo necrosis, and expression of various immunohistochemical markers have been variably shown to affect the risk of recurrence in premalignant breast lesions [12]. Improved molecular characterization of DCIS will offer additional, perhaps more definitive, prognostic information and may provide the opportunity for personalized therapeutic options for patients with DCIS.…”

“…COX-2 has also been shown to be significantly up-regulated in DCIS with higher cell proliferation rates, nuclear grade, ER negativity, and HER-2/neu positivity [18]. Berman et al showed that DCIS showing overexpression of Ki67 and p16 by immunohistochemistry are more likely to recur compared to tumors with low levels of expression [12].…”