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A majority of breast cancers (BC) are age-related and we seek to determine what cellular and molecular changes occur in breast tissue with age that make women more susceptible to cancer initiation. Immune-epithelial cell interactions are important during mammary gland development and the immune system plays an important role in BC progression. The composition of human immune cell populations is known to change in peripheral blood with age and in breast tissue during BC progression. Less is known about changes in immune populations in normal breast tissue and how their interactions with mammary epithelia change with age. We quantified densities of T cells, B cells, and macrophage subsets in pathologically normal breast tissue from 122 different women who ranged in age from 24 to 74 years old. Donor-matched peripheral blood from a subset of 20 donors was analyzed by flow cytometry. Tissue immune cell densities and localizations relative to the epithelium were quantified in situ with machine learning-based image analyses of multiplex immunohistochemistry-stained tissue sections. In situ results were corroborated with flow cytometry analyses of peri-epithelial immune cells from primary breast tissue preparations and transcriptome analyses of public data from bulk tissue reduction mammoplasties. Proportions of immune cell subsets in breast tissue and donor-matched peripheral blood were not correlated. Density (cells/mm2) of T and B lymphocytes in situ decreased with age. T cells and macrophages preferentially localized near or within epithelial bilayers, rather than the intralobular stroma. M2 macrophage density was higher than M1 macrophage density and this difference was due to higher density of M2 in the intralobular stroma. Transcriptional signature analyses suggested age-dependent decline in adaptive immune cell populations and functions and increased innate immune cell activity. T cells and macrophages are so intimately associated with the epithelia that they are embedded within the bilayer, suggesting an important role for immune-epithelial cell interactions. Age-associated decreased T cell density in peri-epithelial regions, and increased M2 macrophage density in intralobular stroma suggests the emergence of a tissue microenvironment that is simultaneously immune-senescent and immunosuppressive with age. Supplementary Information The online version contains supplementary material available at 10.1007/s10911-021-09495-2.

Estrogens have pleiotropic effects on many reproductive and non-reproductive tissues and organs including the mammary gland, uterus, ovaries, vagina, and endothelium. Estrogen receptor α functions as the principal mediator of estrogenic action in most of these tissues. Estetrol (E4) is a native fetal estrogen with selective tissue actions that is currently approved for use as the estrogen component in a combined oral contraceptive and is being developed as a menopause hormone therapy (MHT, also known as hormone replacement therapy). However, exogenous hormonal treatments, in particular MHTs, have been shown to promote the growth of preexisting breast cancers and are associated with a variable risk of breast cancer depending on the treatment modality. Therefore, evaluating the safety of E4-based formulations on the breast forms a crucial part of the clinical development process. This review highlights preclinical and clinical studies that have assessed the effects of E4 and E4-progestogen combinations on the mammary gland and breast cancer, focusing in particular on the estrogenic and anti-estrogenic properties of E4. We discuss the potential advantages of E4 over current available estrogen-formulations as a contraceptive and for the treatment of symptoms due to menopause. We also consider the potential of E4 for the treatment of endocrine-resistant breast cancer.

Regions of high mammographic density (MD) in the breast are characterised by a proteoglycan (PG)-rich fibrous stroma, where PGs mediate aligned collagen fibrils to control tissue stiffness and hence the response to mechanical forces. Literature is accumulating to support the notion that mechanical stiffness may drive PG synthesis in the breast contributing to MD. We review emerging patterns in MD and other biological settings, of a positive feedback cycle of force promoting PG synthesis, such as in articular cartilage, due to increased pressure on weight bearing joints. Furthermore, we present evidence to suggest a pro-tumorigenic effect of increased mechanical force on epithelial cells in contexts where PG-mediated, aligned collagen fibrous tissue abounds, with implications for breast cancer development attributable to high MD. Finally, we summarise means through which this positive feedback mechanism of PG synthesis may be intercepted to reduce mechanical force within tissues and thus reduce disease burden.

Lipofilling may constitute a technique to assist reconstruction of breasts following prophylactic mastectomy for patients with mutated BRCA1 or BRCA2 genes. However, to date it is not clear whether adipose-derived stromal cells (ADSCs) increase the risk of tumor initiation and progression in this situation. Therefore, the interactions of BRCA1 mutated breast cancer cell lines with normal ADSCs were investigated in the present study. Characteristics of MDA-MB-436 (BRCA1 c.5277 + 1G > A) and HCC1937 (BRCA1 p.Gln1756.Profs*74) were compared to MDA-MB-231 and T47D BRCA1/2 wild-type breast cancer cell lines. ADSCs were cultivated from lipoaspirates of a panel of BRCA1/2- wildtype patients. Interactions of conditioned medium (CM) of these cells with the breast cancer lines were studied using proliferation and migration assays as well as adipokine expression western blot arrays. CM of ADSCs exhibit a dose-dependent stimulation of the proliferation of the breast cancer cell lines. However, of the ADSC preparations tested, only 1 out of 18 samples showed a significant higher stimulation of BRCA1-mutated MDA-MB-436 versus wildtype MDA-MB-231 cells, and all CM revealed lower stimulatory activity for BRCA1-mutated HCC1937 versus wildtype T47D cells. Additionally, migration of breast cancer cells in response to CM of ADSCs proved to be equivalent or slower for BRCA1/2 mutated versus nonmutated cancer cells and, with exception of angiopoietin-like 2, induced expression of adipokines showed no major difference. Effects of media conditioned by normal ADSCs showed largely comparable effects on BRCA1-mutated and wildtype breast cancer cell lines thus advocating lipofilling, preferentially employing allogeneic non-mutated ADSCs.

Purpose Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. Methods Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. Results The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; P P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms. Conclusions Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.

Salivary duct carcinomas (SDC) and Her2/Neu3-overexpressing invasive breast carcinomas (HNPIBC/IBC) are histologically indistinguishable. We investigated whether common histopathologic and immunophenotypic features of SDC and IBC are mirrored by a similar microRNA (miRNA) profile. MiRNA profiling of 5 SDCs, 6 IBCs Her2/Neu3+, and 5 high-grade ductal breast carcinoma in situ (DCIS) was performed by NanoString platform. Selected miRNAs and HOXA1 gene were validated by RT-PCR. We observed similar miRNA expression profiles between IBC and SDC with the exception of 2 miRNAs, miR-10a and miR-142-3p, which were higher in IBC tumors. DCIS tumors displayed increased expression of miR-10a, miR-99a, miR-331-3p and miR-335, and decreased expression of miR-15a, miR-16 and miR-19b compared to SDC. The normal salivary gland and breast tissues also showed similar expression profiles. Interestingly, miR-10a was selectively increased in both IBC and normal breast tissue compared to SDC and normal salivary gland tissue. Moreover, our NanoString and RT-PCR data confirmed that miR-10a was upregulated in IBC and DCIS compared to SDC. Finally, we show downregulation of HOXA1, a miR-10 target, in IBC tumors compared to normal breast tissue. Taken together, our data demonstrates that, based on miRNA profiling, SDC is closely related to HNPIBC. Our results also suggest that miR-10a is differentially expressed in IBC compared to SDC and may have potential utility as a diagnostic biomarker in synchronous or metachronous malignant epithelial malignancies involving both organs. In addition, miR-10a could be playing an important role as a mammary-specific oncogene, involved in breast cancer initiation (DCIS) and progression (IBC), through mechanisms that include modulation of HOXA1 gene expression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-018-0971-x) contains supplementary material, which is available to authorized users.

Breast cancer screening combined with follow-up and treatment reduces breast cancer mortality. However, in the study clinic, only 12 % of eligible women ≥40 years received a mammogram in the previous year. The objective of this project was to implement patient navigation, in our partner health clinic to (1) identify women overdue for a mammogram; and (2) increase mammography utilization in this population over a 2-year period. Women overdue for a mammogram were identified. One patient navigator made navigation attempts over a 2-year period (2009–2011). Navigation included working around systems- and individual-level barriers to receive a mammogram as well as the appropriate follow-up post screening. Women were contacted up to three times to initiate navigation. The proportion of women navigated and who received a mammogram during the study period were compared to women who did not receive a mammogram using Chi square tests for categorical variables and t tests for continuous variables with an α = 0.05. Barriers to previous mammography were also assessed. With 94.8 % of eligible women navigated and 94 % of these women completing mammography, the implementation project reached 89 % of the target population. This project was a successful implementation of an evidence-based patient navigation program that continues to provide significant impact in a high-need area. Cost was the most commonly cite barrier to mammography. Increasing awareness of resources in the community for mammography and follow-up care remains a necessary adjunct to removing structural and financial barriers to accessing preventive services.

Distant metastases are relatively common in breast cancer, but spread to the head and neck region is uncommon and can be diagnostically challenging. Pathology databases of two academic hospitals were searched for patients. The diagnoses were by morphologic comparison with the primary breast specimen (when available) or through the use of immunohistochemical stains characteristic of breast carcinoma (cytokeratin 7, mammaglobin, GCDFP15, and/or GATA3 positive—excluding new primary tumors at the respective head and neck sites). Of the 25 patients identified, only 22 (88.0 %) had a known history of breast carcinoma. Time from primary diagnosis to head and neck metastasis was highly variable, ranging from 1 to 33 years (mean = 10.9 years). The most common locations were neck lymph nodes (8 cases), orbital soft tissue (5), oral cavity (3), skull base (3), mastoid sinus (2), nasal cavity (1), palatine tonsil (1), and facial skin (1). Clinical presentations were highly variable, ranging from cranial nerve palsies without a mass lesion to oral cavity erythema and swelling to bone pain. Histologically, two cases showed mucosal (or skin)-based mass lesions with associated pagetoid spread in the adjacent epithelium, a feature normally associated with primary carcinomas. Three tumors were misdiagnosed pathologically as new head and neck primary tumors. This series demonstrates the extreme variability in clinical and pathologic features of breast cancer metastatic to the head and neck, including long time intervals to metastasis.

Anterior gradient 2 (AGR2) is a promising anti-tumor target associated with estrogen receptor expression and metastatic progression of breast cancer. Insulin-like growth factor-1 (IGF-1) is another potent factor that stimulates breast cancer progression and mediates anti-estrogen drug resistance. However, the precise mechanism and connections between these two factors in breast cancer drug resistance have not been fully elucidated. Here, for the first time, we decipher that IGF-1 remarkably induces AGR2 in the MCF7 cell line, through an estrogen response element (ERE) between −802 and −808 bp and a leucine zipper transcription factor-binding site located between −972 and −982 bp on the AGR2 promoter. We also found that the ERK1/2 and AKT pathways mediate estrogen receptor-α at the upstream of ERE and that the JNK pathway activates the leucine zipper site through the c-Jun/c-Fos complex. Additionally, our data suggest that knockdown of AGR2 reduces IGF-1-induced cell proliferation, migration and cell cycle progression. Therefore, we report that AGR2 is a key modulator involved in IGF-1-induced breast cancer development. We propose that the identification of the mechanism linking the IGF-1/insulin signal and AGR2 promoter activation is important, because it provides insights into the development of anti-breast cancer drugs.

e11553 Background: The aim of the study was to assess the rate, pattern and time of recurrence in patients with triple-negative breast cancer (TNBC) treated in one institution. The second goal was to evaluate factors influencing recurrence and overall survival in this group of patients. Methods: 2534 consecutive breast cancer patients were diagnosed at the Cancer Center and Institute of Oncology in Warsaw, Poland, between January 2005 and December 2006. Out of 2534 patients, 228 (9%) were TNBC (ER/PR/HER2-negative). The clinicopathological characteristics were determined using descriptive statistics. The overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. The univariate and multivariate analyses were developed to identify factors influencing recurrence and survival in TNBC patients. Results: Most of the patients were diagnosed with stage II or III breast cancer (47% and 34%, respectively), the median age at diagnosis was 54.5 years. The most common histological type was ductal cancer (81%). 31% of patients were treated with neoadjuvant chemotherapy and 49% with adjuvant chemotherapy – almost all consisted of anthracyclines. 6 years of observation revealed that the metastatic disease occurred in 35% of all TNBC patients: 15% in the brain, 14% in the lungs, 11% in the bones, 8% in the liver and 14% had locoregional relapse. The highest risk of recurrence was during the first 3 years after primary treatment and then during the next two years of observation it did not change. Median DFS and OS were not reached at the time of analysis, 6-year DFS and OS were 68% and 62%, respectively.Factors influencing recurrence were: tumor size and systemic adjuvant chemotherapy while factors influencing overall survival were: tumor size, nodal status, adjuvant/neoadjuvant treatment and metastases in the brain, liver and bones. Conclusions: Characteristic pattern of recurrence in time was revealed. The tumor size was responsible for recurrence despite lack of involvement of lymph nodes. Aggressive adjuvant/neoadjuvant treatment ordered in all clinical stages of TNBC (including N0) was factor responsible for avoiding local and distant relapse and prolonging overall survival.

The aim of the study was to define biological subtypes of breast cancer that have the propensity to metastasize to the leptomeninges and to assess factors influencing survival from detection of leptomeningeal metastatis (LM). One hundred and eighteen consecutive breast cancer patients with LM were treated in one institution, between the years 1999 and 2009; 40.5 % of patients had triple-negative subtype, 37.5 % had luminal A subtype and 22 % had HER2-positive subtypes (luminal B and HER2). Of patients with LM, 35 % had lobular cancer. Median survival from the detection of LM was 18 weeks, and 1-year survival was 16 %. Cox multivariate analysis revealed that performance status and systemic treatment statistically significantly influenced survival of patients with LM. Triple-negative biological subtype and lobular histological type of breast cancer had the propensity to metastasize to the leptomeninges. Performance status and systemic treatment ordered after detection of LM statistically significantly influenced survival.

This paper describes a methodology for redesigning the clinical processes to manage diagnosis, follow-up, and response to treatment episodes of breast cancer. This methodology includes three fundamental elements: (1) identification of similar and contrasting cases that may be of clinical relevance based upon a target study, (2) codification of reports with standard medical terminologies, and (3) linking and indexing the structured reports obtained with different techniques in a common system. The combination of these elements should lead to improvements in the clinical management of breast cancer patients. The motivation for this work is the adaptation of the clinical processes for breast cancer created by the Valencian Community health authorities to the new techniques available for data processing. To achieve this adaptation, it was necessary to design nine Digital Imaging and Communications in Medicine (DICOM) structured report templates: six diagnosis templates and three summary templates that combine reports from clinical episodes. A prototype system is also described that links the lesion to the reports. Preliminary tests of the prototype have shown that the interoperability among the report templates allows correlating parameters from different reports. Further work is in progress to improve the methodology in order that it can be applied to clinical practice., We thank the subject matter experts for sharing their insights through this study. We are especially appreciative of the efforts of the Radiology Unit and Medical Oncology Unit teams at the University Hospital Dr. Peset. This work was partially supported by the Vicerectorat d'Investigacio de la Universitat Politecnica de Valencia (UPVLC) to develop the project "Mejora del proceso diagnostico del cancer de mama" with reference UPV-FE-2013-8.

In recent years, computational diagnostic tools and artificial intelligence techniques provide automated procedures for objective judgments by making use of quantitative measures and machine learning. The paper presents a Support Vector Machine (SVM) approach for the prognosis and diagnosis of breast cancer implemented on the Wisconsin Diagnostic Breast Cancer (WDBC) and the Wisconsin Prognostic Breast Cancer (WPBC) datasets found in literature. The SVM algorithm performs excellently in both problems for the case study datasets, exhibiting high accuracy, sensitivity and specificity indices.

The role of adjuvant chemotherapy in the treatment of breast cancer has been the subject of intense research activity in recent years. It is now generally accepted that some types of adjuvant therapy have a positive effect on disease-free and overall survival, but the effect size appears to be modest and the optimal type of adjuvant therapy for different groups of patients remains unclear. One major study of adjuvant therapy in breast cancer patients that generated considerable interest and controversy was an intergroup trial of the value of increasing the dose of doxorubicin or adding paclitaxel (Taxol®) to standard chemotherapy. The design was a 3 x 2 factorial design (three different doses of doxorubicin with and without paclitaxel). Based on the results of the first planned interim analysis suggesting improved disease-free and overall survival in patients receiving paclitaxel, the DSMB released the results to the study team. The events and considerations leading to the decision to release the results and some of the subsequent controversies that arose in the medical community because of this decision are discussed in this paper.

Cancer is a complicated disease with each individual tumor exhibiting to a variable degree a set of overlapping phenotypes that include abnormal proliferation and cell survival, genetic instability, tissue invasion, metastasis and angiogenesis. Each of these pathophysiological functions requires abnormal signaling that fails to respect the normal restraints imposed on healthy cells through homeostatic regulation. Understanding of deregulated gene expression is therefore an essential goal for cancer research because unraveling this problem will provide insights into the fundamental nature of cancer as well as provide opportunities for therapeutic intervention. Gene expression profiling is a remarkable technique that addresses this complexity by documenting the expression of thousands of genes at the level of mRNA abundance. From the standpoint of clinical investigation, the initial focus of gene profiling experiments has been on screening primary tumors for markers of poor prognosis. However this is only a first step in demonstrating the utility of this technique. Future advances will focus on understanding the evolution of an organ confined primary cancer to a treatment resistant lethal systemic disease through repeated tumor sampling and analysis, an approach termed in this paper “dynamic profiling”. Using breast cancer endocrine therapy as an example our initial approaches to dynamic profiling will be described.

It is estimated1 that 179,000 women in the United States will be diagnosed with breast cancer in 1998 and that 44,000 will die from it. About one in eight women will develop breast cancer sometime in her life.2 Many women are therefore concerned about the risk of developing breast cancer, especially women with known risk factors such as a history of breast cancer in close relatives. The purpose of this paper is to review and compare two models for projecting the individualized risk of developing breast cancer over defined age ranges. One model,3 based on data from the Breast Cancer Detection Demonstration Project (BCDDP), uses information on family history, age at menarche, age at first live birth, number of biopsies, and the presence of atypical hyperplasia. A second model by Claus, Risch, and Thompson,4 which we refer to as the “Claus model”, relies on detailed family history information, including age at breast cancer onset in affected relatives. Published tables5 based on that model cover individuals with at least one affected relative.

First of all I should like to thank Dr. Avshalom Mizrahi, and THE DEAD SEA CONFERENCES organizing committee for the opportunity of participating in this forum of specialists on health, medicine and alternative medicine. The paper I am going to present is not the result of theoretical knowledge in any of these fields; my need to participate stems from personal experience in the struggle against cancer.

In the United States, high dose chemotherapy with stem cell support (bone marrow or peripheral blood) is rapidly becoming accepted therapy for many patients with Hodgkin’s disease, non-Hodgkin’s lymphoma, and breast cancer, despite concerns by insurers and patients over high costs and the potential of significant economic burden on the health care system. Issues such as comparative costs and efficacy of supportive care modalities, hematopoietic growth factors, and adjunctive measures such as purging of stem cells are important. Most often these studies have not evaluated the costs and cost-effectiveness of these pharmaceuticals and technologies. Physicians are now under increasing pressures to accept capitated payments for high dose chemotherapy patients. These capitated rates are often significantly lower than the amount that had been charged for the procedure in the previous year. Furthermore, hospital pharmacies are facing cost-containment pressures and need cost-effectiveness data on pharmaceuticals that are used in high-dose chemotherapy programs. In this paper, we address the economic implications of high dose chemotherapy programs.

Anecdotal evidence for familial clustering of ovarian cancer dates back many years, ovarian tumours occurring in more than one member of the same family being reported as early as 1877 [1]. Since then a number of families containing multiple cases of ovarian cancer have been reported [2,3]. Many of these families also segregate early onset breast cancer [4] or other cancers [5] and the families have generally been suggestive of an autosomal dominant gene conferring a high lifetime risk of disease. Over the past few years more rapid progress has been made in understanding the possible inherited basis of ovarian cancer, firstly through population based epidemiological studies of familial risks and secondly through genetic linkage studies which have demonstrated that many breast-ovarian cancer families are the result of a predisposing gene on chromosome 17q known as BRCAl [6,7]. In this paper we review some of the epidemiological evidence on genetic susceptibility to ovarian cancer and the 17q linkage studies. We also consider the risks of ovarian cancer conferred by mutations in the BRCAl gene and examine the likely contribution of BRCAl to familial ovarian cancer and to ovarian cancer in general.

Presents papers and abstracts from a poster session from the September 1993 conference, on the role of dietary fat in breast cancer incidence and prognosis in human and animals. Topics include mechanisms potentially mediating dietary fat effects on breast cancer, hormone studies and the diet/breast

The 1992 session of the biennial workshop concerned with the immunology of breast cancer focused on the recent advances in understanding the molecular biology both of antigens associated with breast cancer and of their corresponding antibodies. Among the topics of the 19 papers are peptide epitopes

Antibody-drug conjugates utilize the targetting potential of antibodies to improve the potential of cytostatic or cytocidal drugs. One such murine monoclonal antibody, CTM01 (mCTM0l), which recognizes an epitope on breast epithelial mucin, has potential for the treatment of breast and ovarian cancers. We examine in this paper the comparative properties of mCTM01 against a number of other anti-mucin antibodies. We then describe the humanization and high level re-expression of humanized CTM01 (hCTM0l), a process designed to avoid the immune response to administered murine antibodies in human patients and to produce sufficient material for clinical studies. We show that the humanized form has properties superior to mCTM01 in terms of binding affinity to antigen presented on tumour cells.

The human milk fat globule (HMFG) membrane has been the source of antigens for the production of polyclonal and monoclonal antibodies against normal and malignant breast epithelial cells that have found important applications in diagnosis and therapy of breast cancer (Ceriani et al., 1977). Monoclonal antibodies (MoAbs) prepared against the HMFG membrane, for the first time, identified a highly glycosylated, large molecular weight glycoprotein (breast mucin) as a major component of the surface membrane of breast epithelial cells (Ceriani et al, 1983). In addition, MoAbs against smaller glycoproteins of the HMFG have identified new and potentially important components of breast epithelial cell membranes, namely two glycoproteins of 70 kDa and a 46 kDa, respectively (Ceriani et al., 1983; Peterson et al, 1990). The 70 kDa glycoprotein (BA70) has been shown to be associated with the breast mucin by disulfide linkages, suggesting it to be a putative linker protein (Duwe et al., 1989) for the breast mucin. The 46 kDa glycoprotein (BA46) appears to be a member of a family of proteins having a domain with homology with the C1C2 domain of human coagulation factors V and VIII (Larocca et al, 1991). In this paper we will summarize the characteristics of the breast mucin and the 46 kDa antigen, present evidence on their epitopic heterogeneity, and suggest possible molecular strategy for selecting the most appropriate MoAbs for use in breast cancer diagnosis and therapy.

The elucidation of the molecular mechanisms responsible for the hormonal control of cell proliferation in breast cancer has been the object of intense research. Because most breast cancers are initially dependent upon estrogens for continued growth, much of this research has focused on the role of estrogen receptor (ER) in the control of gene expression and mitosis (1), and on its use as a marker for hormone responsiveness and prognosis (2). In addition, progesterone receptor (PR), as both a mediator of hormonal responses and as a product of estrogen action on breast cancer cells, has been studied extensively as a tumor marker (3) and in terms of its regulation by estrogen agonists and antagonists (4). Although its function in breast cancer is unknown, the presence as well as the induction of PR has been coupled to estrogen-induced proliferative responses in breast cancer cells. An improved understanding of the function and regulation of expression of these transcription factors is emerging from studies of the structure, composition and dynamics of the receptor proteins and the genes that encode them. The cloning and molecular analysis of all of the known steroid receptors has led to the definition of common functional domains and a proposed mechanism by which they interact with responsive genes, via cis-acting DNA enhancer elements, in normal and neoplastic tissues (5, 6) (7). For ER and PR, these studies have been aided by the availability of a number of monoclonal antibody probes directed against specific regions of each receptor (8, 9). In addition, the same antibodies have been used to develop validated quantitative and histochemical immunoassays for ER and PR in a variety of hormone-responsive tissues and related cancers. Such assays have proved particularly useful in the evaluation of ER and PR in breast tumor extracts (10), in frozen and paraffin-embedded tissues and tumor sections (11, 12, 13) (14) (15) and in needle biopsies (16) (17). This paper summarizes the results of recent studies on ER and PR structure, composition and activity in breast cancer cells as a function of agonist and antagonist binding.

Present research in the field of clinical breast cancer is focussed on new diagnostic methods and on the development of new treatment modalities. A number of modern cell biological parameters such as oncogenes, growth factors and secretory proteins, appear to be important prognostic factors because they strongly influence the behaviour of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and the development of therapy resistance. These factors are also relevant for the development of new treatment strategies. In this paper we will deal first with these new diagnostic methods and then we will summarize new developments in the treatment of breast cancer.

The elucidation of the molecular mechanisms responsible for the hormonal control of cell proliferation in breast cancer has been the object of intense research. Because most breast cancers are initially dependent upon estrogens for continued growth, much of this research has focused on the role of estrogen receptor (ER) in the control of gene expression and mitosis [1], and on its use as a marker for hormone responsiveness and prognosis [2]. In addition, progesterone receptor (PR), as both a mediator of hormonal responses and as a product of estrogen action on breast cancer cells, has been studied extensively as a tumor marker [3] and in terms of its regulation by estrogen agonists and antagonists [4]. Although its function in breast cancer is unknown, the presence as well as the induction of PR has been coupled to estrogen-induced proliferative responses in breast cancer cells. An improved understanding of the function and regulation of expression of these transcription factors is emerging from studies of the structure, composition, and dynamic of the receptor proteins and the genes that encode them. The cloning and molecular analysis of all of the known steroid receptors has led to the definition of common functional domains and a proposed mechanism by which they interact with responsive genes, via cis-acting DNA enhancer elements, in normal and neoplastic tissues [5, 6, 7]. For ER and PR, these studies have been aided by the availability of a number of monoclonal antibody probes directed against specific regions of each receptor [8, 9]. In addition, the same antibodies have been used to develop validated quantitative and histochemical immunoassays for ER and PR in a variety of hormone-responsive tissues and related cancers. Such assays have proved particularly useful in the evaluation of ER and PR in breast tumor extracts [10], in frozen and paraffin-embedded tissues and tumor sections [11, 12, 13, 14, 15], and in needle biopsies [16, 17]. This paper summarizes the results of recent studies on ER and PR structure, composition, and activity in breast cancer cells as a function of agonist and antagonist binding.

The present paper will cover research related to breast epithelial antigens, which have been chosen to be defined as those antigens specific or at least characteristic to breast epithelia, for which antibodies had been generated as a result of the use of breast cells and their products for immunization. However, excluded from this paper will be studies dealing with non-breast-characteristic components such as receptors for hormones and other factors, cytokeratins, and oncogenes. An effort has been made to identify leading research efforts in a field that has increased prodigiously in size and scope in the last ten years, provide some current and pertinent experimental examples and identify areas requiring further research involvement.

The workshop entitled “Markers for Differentiation and Malignancy” comprised sixteen short papers that on hindsight could be divided into three groups: Cell nuclear parameters and breast cancer prognosis; use of breast differentiation and other antigens identified by monoclonal antibodies in histopathoiogy; and the use of anti-breast monoclonal antibodies for sero-diagnostic and therapeutic purposes.

There are few studies reporting the combined use of hormones and non-hormonal agents. In addition, in vitro methods are now available to predict the effectiveness of oestrogens, fluorouracil, methotrexate and adriamycin. We wished to undertake a trial of methotrexate, adriamycin, fluorouracil, and oestrogen in patients with breast cancer following determination of their cellular predictive indices. However, it was first necessary to determine the tolerability of the drug regimen. This paper reports the results of our preliminary phase I trial.

The advent of monoclonal antibodies has opened a new area of breast cancer therapy, and because of unique aspects compared to conventional therapy new approaches have to be defined, and new problems addressed. Monoclonal antibodies have to be selected specifically for therapy, ideal characteristics have to be defined, conjugates must be selected, conjugation methods must be evaluated, and appropriate target antigens have to be identified. One aspect of the latter that must be taken into consideration is the complexity and cell heterogeneity in expression of most antigens that have an appropriate tissue or tumor cell specificity for therapy. This paper will address the question of antigenic heterogeneity in approaching the use of monoclonal antibodies for therapy of breast cancer.

Although there has been a great deal of study of the epidemiology of breast cancer, it is only fairly recently that people have begun to think seriously about the possibilities for prevention.(1,2) Although there are some clues, it is not yet possible to provide an unequivocal answer to the question. Rather, this paper is intended to be a contribution to a debate with particular consideration of two potential approaches to primary prevention of breast cancer: hormonal manipulation and dietary change.

Although single cell heterogeneity in breast and other tumors has become a well-established observation, neither the underlying reasons for it nor its biological significance are yet clearly understood. However, it exemplifies the dynamic nature of a tumor cell population; it may play an important role in the effectiveness of breast cancer therapy, especially with the new possibilities for monoclonal antibody (MoAb) therapy; and it also could be used in improving diagnosis and prognostic evaluation. The type of single cell heterogeneity addressed in this paper is quantitative heterogeneity, especially that which has been revealed with monoclonal antibodies to surface antigens, but it must be emphasized that quantitative single cell heterogeneity has also been observed for other cell components, such as enzymes (1), secretory products (2), and hormone receptors (3).

This paper will briefly review the current situation in the treatment of advanced breast cancer. Historically hormonotherapy was the first modality, which was used in the therapy of this disease. In an unselected population the results of endocrine treatment have remained stable in the last three decades: about 30$ of the patients will achieve a partial remission, which will last between 10–20 months. In the last 10 years combination chemotherapy became the most widely applied treatment modality for advanced breast cancer. However nowadays it has been realised, that combination chemotherapy can only be palliative, whereas a few years ago it was hoped that with this treament at least some patients could be cured. With an optimal combination chemotherapy 50–70$ of the patients will achieve a partial remission, which generally last 10–15 months. Because it is at present widely felt, that combination chemotherapy has reached a plateau in its effectiveness and because of the discovery of hormone receptors, hormonotherapy is presently experiencing an unexpected revival.

The word ‘cure’was used in the title of Hal stead’s paper in 1894 in which he described his technique of radical mastectomy (1) and this had so powerful an effect that the treatment remained standard for the next 50 years. There appeared to be little practical point in investigating factors which might be related to prognosis since patients received identical treatment whether their outlook was good or bad. Clinical or pathological staging was used mainly to compare results between centres but was not used to determine treatment. Histological grading was used as an academic excercise.

The effect of steroid hormones is mediated by the interaction with specific hormone receptors of the target cell. It was obvious, that this concept should be applied to the management of so-called hormone responsive tumours. Steroid-hormone receptors - mostly oestrogen receptors - have been detected in the following neoplasias of the female reproductive system: cervical cancer, endometrial cancer, ovarian cancer, breast cancer. Our information on the implication and function of receptor protein in these tumours is still incomplete and their presence does not necessarily indicate responsiveness to endocrine manipulation. Although there is a reasonable chance of successful hormonal treatment of carcinomas of the endometrium and the breast, the same does not hold true for cervical and ovarian cancers. The present paper deals with the practical value of receptor measurements in patients with endometrial, ovarian or breast cancer.