Esther Rhei

High-sensitivity array analysis of gene expression for the early detection of disseminated breast tumor cells in peripheral blood

Early detection is an effective means of reducing cancer mortality. Here, we describe a highly sensitive high-throughput screen that can identify panels of markers for the early detection of solid tumor cells disseminated in peripheral blood. The method is a two-step combination of differential display and high-sensitivity cDNA arrays. In a primary screen, differential display identified 170 candidate marker genes differentially expressed between breast tumor cells and normal breast epithelial cells. In a secondary screen, high-sensitivity arrays assessed expression levels of these genes in 48 blood samples, 22 from healthy volunteers and 26 from breast cancer patients. Cluster analysis identified a group of 12 genes that were elevated in the blood of cancer patients. Permutation analysis of individual genes defined five core genes (P ≤ 0.05, permax test). As a group, the 12 genes generally distinguished accurately between healthy volunteers and patients with breast cancer. Mean expression levels of the 12 genes were elevated in 77% (10 of 13) untreated invasive cancer patients, whereas cluster analysis correctly classified volunteers and patients (P = 0.0022, Fishers exact test). Quantitative real-time PCR confirmed array results and indicated that the sensitivity of the assay (1:2 × 108 transcripts) was sufficient to detect disseminated solid tumor cells in blood. Expression-based blood assays developed with the screening approach described here have the potential to detect and classify solid tumor cells originating from virtually any primary site in the body.

HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells

To identify molecular alterations implicated in the initiating steps of breast tumorogenesis, we compared the gene expression profiles of normal and ductal carcinoma in situ (DCIS) mammary epithelial cells by using serial analysis of gene expression (SAGE). Through the pair-wise comparison of normal and DCIS SAGE libraries, we identified several differentially expressed genes. Here, we report the characterization of one of these genes, HIN-1 (high in normal-1). HIN-1 expression is significantly down regulated in 94% of human breast carcinomas and in 95% of preinvasive lesions, such as ductal and lobular carcinoma in situ. This decrease in HIN-1 expression is accompanied by hypermethylation of its promoter in the majority of breast cancer cell lines (>90%) and primary tumors (74%). HIN-1 is a putative cytokine with no significant homology to known proteins. Reintroduction of HIN-1 into breast cancer cells inhibits cell growth. These results indicate that HIN-1 is a candidate tumor suppressor gene that is inactivated at high frequency in the earliest stages of breast tumorogenesis.

The Utility of Ultrasonographically Guided Large-Core Needle Biopsy Results From 500 Consecutive Breast Biopsies

Five hundred ultrasonographically guided large‐core needle breast biopsies of solid masses were performed in 446 women. Histopathologic results were correlated with imaging findings. Ultrasonographically guided large‐core needle biopsy resulted in diagnosis of malignancy (n = 124) or severe atypical ductal hyperplasia (n = 4) in 128 lesions (26%). In the remaining 372 lesions (74%), ultrasonographically guided large‐core needle biopsy yielded benign pathologic results. Follow‐up of more than 1 year (n = 225), results of surgical excision (n = 50), or both were obtainable in 275 (74%) of the benign lesions. No malignancies were discovered at surgical excision or during follow‐up of this group of benign lesions. There were no complications related to large‐core needle biopsy that required additional treatment. Ultrasonographically guided large‐core needle biopsy is a safe and accurate method for evaluating breast lesions that require tissue sampling.

Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome

A male member of a large HNPCC kindred, affected by primary malignancies of the breast and colon, was identified. This individual was found to harbor a germline mutation of the MLH1 mismatch repair gene previously shown to segregate with disease in this kindred. The breast tumor exhibited somatic reduction to homozygosity for the MLH1 mutation, and microsatellite instability was evident in the breast tumor. We conclude that hereditary male breast cancer can occur as an integral tumor in the HNPCC syndrome.

Lactating Adenoma: Sonographic Features

Abstract: The lactating adenoma is a benign breast lesion occurring as a palpable mass in pregnant or lactating patients. The ultrasound characteristics of 15 lactating adenomas in 15 patients were reviewed retrospectively. Most of the lactating adenomas in this series (10 of 15) had one or more typically benign features such as circumscribed borders, smooth lobulations, or an echogenic pseudocapsule. The remaining five, however, had features typically associated with malignancy, including irregular, angulated, or ill‐defined margins, or posterior acoustic shadowing.

The APC I1307K Allele and BRCA-Associated Ovarian Cancer Risk

This work was supported by National Institutes of Health grant R01-CA71840. The authors are also grateful to Drs. William J. Hoskins and Patrick I. Borgen for their support of this laboratory.

Predictive value of sentinel lymph node biopsy prior to neoadjuvant chemotherapy in clinically node negative breast cancer

606 Background: Applicability and optimal timing of sentinel node biopsy (SNB) in breast cancer patients treated with neoadjuvant therapy is not yet known. SNB prior to neoadjuvant therapy is relatively untested, while SNB after neoadjuvant therapy is associated with lower mapping success and higher false negative rates. SNB prior to neoadjuvant therapy may give data useful in guiding systemic, radiation and surgical treatment decisions. METHODS 52 T2-T4, N0 breast cancer patients who had SNB prior to neoadjuvant therapy from 7/2000 to 10/2003 were reviewed. Initial 1° tumor size, SNB pathology, clinical response to therapy and findings at definitive surgery were examined. RESULTS 22 patients (42%) were SNB(-) and 21 had no further axillary treatment. None have recurred locally. 1 SNB(-) patient had tumor progression during chemo and a positive axillary node dissection (ALND). 30 patients (58%) were SNB(+); to date 26 have had ALND after neoadjuvant therapy; 1 with a micromet had no further surgery. At ALND for initially SNB(+), 17 (65%) were node negative, 4(15%) had micromets <0.2cm, and only 5(19%) had residual axillary macromets. Residual tumor sizes ranged from 0-9.0cm (median 2.0cm, 5 tumors >4cm) in 21 SNB(+) with (-) or micromet-only ALNDs. In 5 SNB(+) with macromets on ALND, residual tumor sizes ranged from 0.3- 5.2cm. CONCLUSIONS There were no early axillary relapses in patients with (-)SNBs prior to neoadjuvant therapy. The majority of clinically N0 breast cancer patients with (+) SNBs prior to neoadjuvant therapy will have minimal residual axillary disease at ALND. Among SNB(+)s, residual 1° tumor size did not predict ALND status. These data suggest it may be possible to explore less morbid alternatives to axillary dissection in clinically N0 patients undergoing neoadjuvant therapy. [Figure: see text] No significant financial relationships to disclose.

Immediate breast reconstruction following mastectomy in pregnant women with breast cancer

Surgical management of breast cancer in pregnancy (BCP) requires balancing benefits of therapy with potential risks to the developing fetus. Minimal data describe outcomes after mastectomy with immediate breast reconstruction (IR) in pregnant patients.

Abstract P5-11-02: Impact of pre-operative exercise and mind-body interventions on patient-reported outcomes in women with newly diagnosed breast cancer

Background: Breast cancer diagnosis has a number of adverse psychological effects. The Pre-Operative Health and Body (PreHAB) Study tested the impact of exercise and mind-body interventions upon on mood, quality of life, and patient-reported outcomes in women with newly diagnosed breast cancer. Methods: Women with newly diagnosed Stage I-III breast cancer were enrolled through Dana-Farber Cancer Institute and Yale University breast cancer clinics prior to surgery. Participants were randomized 1:1 to an aerobic and strength-training exercise intervention, comprised of twice-weekly meetings with an exercise trainer and home based aerobic exercise, or to a self-directed mind-body relaxation intervention, comprised of a book and CD focused on relaxation and visualization. Participants engaged in the interventions between enrollment and surgery. The EORTC QLQ C-30, Hospital Anxiety and Depression Scale, and Perceived Stress Scale were collected at enrollment and prior to surgery. Results: 49 women were randomized (27 exercise and 22 control). Mean time between enrollment and surgery was 4.2 weeks. At baseline, patients reported moderate levels of anxiety, stress, insomnia, and lack of appetite, as well as diminished emotional and cognitive functioning (Table). Exercise participants significantly increased minutes of weekly exercise vs. mind-body participants (increase of 203 vs. 23 min/wk, p Conclusions: Women with newly diagnosed breast cancer reported a number of physical and psychological symptoms in the pre-operative period. Exercise and mind-body interventions demonstrated promising benefits in improving functioning and reducing symptoms. More work is needed to develop pre-operative programs to help reduce the distress imparted by a cancer diagnosis in the critical time between diagnosis and surgery. Table* *Results reported as means (SD). Positive scores on functional and QOL measures indicate improvements; negative scores on symptom measures indicate a decrease in symptoms. Citation Format: Ligibel JA, Giobbie-Hurder A, Dillion D, Shockro L, Campbell N, Rhei E, Troyan S, Dominici L, Golshan M, Chagpar A, Yung R, Freedman R, Tolaney S, Winer E, Frank E, McTiernan A, Irwin M. Impact of pre-operative exercise and mind-body interventions on patient-reported outcomes in women with newly diagnosed breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-02.

Surgical Management of High-Risk Patients

Within the past decade, scientists have reported the discovery of potent genes that predispose to major cancers, including breast, ovarian, and colorectal cancer. The discovery of human cancer susceptibility genes is important for fundamental research into the cause of cancer. In addition, these discoveries will certainly have profound implications for the prevention and diagnosis of breast cancer. However, it is not yet clear whether and to what extent cancer susceptibility genes will alter the treatment of cancer. While breast cancer is an important malignant disease in women, it is hoped that knowledge gained from the management of this common disease will provide a template for the approach to other malignancies, caused by hereditary factors. In this paper, we will review the state of knowledge about genes that predispose to breast cancer. Our focus will be to summarize the available information, addressing how genetic factors may alter the initial approach to cancer in the breast. We will concentrate on the surgical management of early breast cancer. Issues include the use of limited surgery with radiation (breast conservation), the approach to the opposite breast, and prophylactic mastectomy in patients at high risk.