EarlyR: A Robust Gene Expression Signature for Predicting Outcomes of Estrogen Receptor–Positive Breast Cancer

Introduction Early stage estrogen receptor (ER)-positive breast cancer may be treated with chemotherapy in addition to hormone therapy. Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. Methods The EarlyR prognostic score was developed using integrative analysis of microarray data sets and formalin-fixed, paraffin-embedded–based quantitative real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort using Cox proportional hazards models and Kaplan-Meier survival analysis. Concordance index was used to measure the probability of prognostic score agreement with outcome. Results The EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical P = 3.5 × 10−14; continuous P = 8.8 × 10−15) and METABRIC (categorical P < 2.2 × 10−16; continuous P < 10−16) data sets of ER+ breast cancer. Similar results were observed for the breast cancer–free interval end point. At most 13% of patients were intermediate risk and at least 66% patients were low risk in both ER+ cohorts. The EarlyR score was significantly prognostic (distant recurrence-free interval; P < .001) in both lymph node–negative and lymph node–positive patients and was independent from clinical factors. EarlyR and surrogates of current molecular signatures were comparable in prognostic significance by concordance index. Conclusion The 5-gene EarlyR score is a robust prognostic assay that identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Further validation of the assay in clinical trial–derived cohorts is ongoing

Upregulation of HSF1 in estrogen receptor positive breast cancer

Heat shock transcription factor 1 (HSF1), a key regulator of the heat-shock response, is deregulated in many cancers. HSF1 can mediate cancer cell survival and metastasis. High levels of HSF1 have been associated with poor prognosis in breast cancer. The nature of HSF1 upregulation needs to be validated in different cohorts to further validate its prognostic utility in breast cancer. We first evaluated its expression in a cohort of breast cancer tissue microarrays with Oncotype DX recurrence scores available using immunohistochemistry. To further confirm the clinical relevance and prognostic impact, mutational and methylation status of the gene were also assessed in The Cancer Genome Atlas and publically available microarray datasets. Immunohistochemical analysis showed that HSF1 expression is independent of Oncotype DX high recurrence score in ER-positive node-negative patients. Analysis of The Cancer Genome Atlas data revealed upregulation of HSF1 is not due to methylation or mutation. HSF1 copy number variations and amplifications (15%) were not associated with survival. In publicly available microarray datasets, a prognostic impact was observed in ER-positive tumors, but not in ER-negative tumors. Patients with ER-positive tumors with high HSF1 levels were associated with shorter overall survival (P = 0.00045) and relapse-free survival (P = 0.0057). In multivariable analysis, HSF1 remained a significant prognostic parameter. The mRNA expression levels of HSF1 in ER-positive breast cancer are associated with both shorter relapse-free and overall survival. This prognostic impact is specific to mRNA expression, but stayed insignificant by protein expression or by analyzing amplification events

Breast calcifications following electrical defibrillation: An unusual mammographic appearance

We present a case of a 57-year-old woman with a past medical history of end-stage renal disease and a recent history of electrical defibrillation who arrived for her annual mammogram with no breast-related complaints. The mammogram showed interval development of unusual clusters of heterogeneous calcifications. The patient underwent stereotactic core-needle biopsy for definitive diagnosis. The pathologic evaluation revealed fibrosis, abnormal adipocytes, and calcifications with no evidence of malignancy. The constellation of findings was consistent with fat necrosis and fibrosis related to tissue damage sustained during the recent defibrillation

NUT Midline Carcinoma Masquerading As a Thymic Carcinoma

Thymic carcinomas are rare tumors that arise from the epithelium of the thymus gland and characterized by cytologic atypia, invasiveness, and high risk of relapse and death.1–3 The current WHO schema recognizes at least 11 histologic subtypes.4–7 Undifferentiated thymic carcinoma is one of the subtypes that can be indistinguishable from other poorly differentiated carcinomas such as NUT midline carcinoma (NMC).8 Despite the aggressive nature of both diseases, a correct diagnosis is important because of the recent development of targeted therapies for NMCs. Herein we describe two cases of a particularly aggressive form of disease and discuss the differential diagnosis of these lesions

Spontaneous mammary intraepithelial lesions in dogs: a model for breast cancer

Noninvasive mammary intraepithelial lesions (IELs) in humans are detected with increasing frequency because of routine mammographic screening. The presence of IELs may herald increased risk of developing invasive breast carcinoma in women. An animal model is needed to study breast cancer and spontaneous IELS. This study describes the histologic and immunohistochemical similarity between human and canine IELs

Membranous Nephropathy

Membranous nephropathy (MN) is a glomerular disease that is the leading cause of nephrotic syndrome in non-diabetic Caucasian adults. MN is most often primary (idiopathic) and the remaining is secondary to systemic disease or exposure to infection or drugs. The majority of patients with MN have circulating antibodies to the podocyte antigens phospholipase A2 receptor (PLA2R) (70%) and thrombospondin type-1 domain-containing 7A (THSD7A) (3–5%). Immunologic remission (depletion of PLA2R antibodies) often precedes and may predict clinical remission. Untreated, about one-third of patients undergo spontaneous remission, one-third have persistent proteinuria but maintain kidney function and the remaining one-third will develop end stage kidney failure. All patients with idiopathic MN should be treated with conservative care from the time of diagnosis to minimise proteinuria. Immunosuppressive therapy is traditionally reserved for patients who have persistent nephrotic-range proteinuria despite conservative care. Immunosuppressive agents for primary MN include combination of corticosteroids/alkylating agent or calcineurin inhibitors and rituximab. This chapter will review the epidemiology, diagnosis and treatment of MN, particularly focusing on idiopathic MN

Prognostic Impact of HOTAIR Expression is Restricted to ER-Negative Breast Cancers

Expression of HOX transcript antisense intergenic RNA (HOTAIR), a large intergenic noncoding RNA (lincRNA), has been described as a metastases-associated lincRNA in various cancers including breast, liver and colon cancer cancers. We sought to determine if expression of HOTAIR could be used as a surrogate for assessing nodal metastases and evaluated RNA in situ hybridization (RNA-ISH) assay in a tissue microarray constructed from 133 breast cancer patients. The prognostic value of HOTAIR was further validated in large cohorts using The Cancer Genome Atlas (TCGA) breast cancer subjects. RNA-ISH analysis was successful in 94 cases (17% cases scored 0, 32.9% scored 1, 30.8% scored 2, and 19.1% scored 3). The expression of HOTAIR did not correlate with nodal metastasis regardless of the scoring intensity or with other study parameters (age, tumor size and grade, expression status). Further analysis of TCGA dataset showed that HOTAIR expression was lower in ductal carcinomas but higher in ER-negative tumors. Overexpression of HOTAIR was not associated with nodal metastases or prognosis in ER-positive patients. Its function as a poor prognostic indicator in ER-negative patients was restricted to node-positive patients. HOTAIR appears to be a marker for lymphatic metastases rather than hematogenous metastases in ER-negative patients