A four-gene predictive model of clinical response to AIs by 2 weeks has been generated and validated. Deregulated immune and apoptotic responses before treatment and cell proliferation that is not reduced 2 weeks after initiation of treatment are functional characteristics of breast tumors that do not respond to AIs.

Invasive lobular carcinoma (ILC) accounts for approximately 10% to 15% of breast carcinomas, and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre-and ontreatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 postmenopausal women with estrogen receptor-positive (ER þ ) histologically confirmed ILC who responded to 3 months of neoadjuvant letrozole and were compared with a cohort of 14 responding invasive ductal carcinomas (IDC) matched on clinicopathologic features. RNA was extracted and processed for whole human genome expression microarray. Dynamic clinical response was assessed using periodic three-dimensional ultrasound measurements performed during treatment and defined as a reduction of >70% in tumor volume by 3 months. Pretreatment profiles of ILC and IDC tumors showed distinctive expression of genes associated with E-cadherin signaling, epithelial adhesion, and stromal rearrangement. The changes in gene expression in response to letrozole were highly similar between responding ILC and IDC tumors; genes involved in proliferation were downregulated and those involved with immune function and extracellular matrix remodeling were upregulated. However, molecular differences between the histologic subtypes were maintained upon treatment. This is the first study of molecular changes in ILC in response to endocrine therapy to date. The genes that change on letrozole are highly consistent between ILC and IDC. Differences in gene expression between ILC and IDC at diagnosis are maintained at each time point on treatment. Cancer Res; 74(19);

Ductal carcinoma in situ (DCIS) of the breast represents a group of heterogeneous non-invasive lesions the incidence of which has risen dramatically since the advent of mammography screening. In this review we summarise current treatment trends and up-to-date results from clinical trials studying surgery and adjuvant therapy alternatives, including the recent consensus on excision margin width and its role in decision-making for post-excision radiotherapy. The main challenge in the clinical management of DCIS continues to be the tailoring of treatment to individual risk, in order to avoid the over-treatment of low-risk lesions or under-treatment of DCIS with higher risk of recurring or progressing into invasion. While studies estimate that only about 40% of DCIS would become invasive if untreated, heterogeneity and complex natural history have prevented adequate identification of these higher-risk lesions. Here we discuss attempts to develop prognostic tools for the risk stratification of DCIS lesions and their limitations. Early results of a UK-wide audit of DCIS management (the Sloane Project) have also demonstrated a lack of consistency in treatment. In this review we offer up-to-date perspectives on current treatment and prediction of DCIS, highlighting the pressing clinical need for better prognostic indices. Tools integrating both clinical and histopathological factors together with molecular biomarkers may hold potential for adequate stratification of DCIS according to risk. This could help develop standardised practices for optimal management of patients with DCIS, improving clinical outcomes while providing only the amount of therapy required for each individual patient.