Sequencing of hormonal therapy in breast cancer

Hormonal therapy plays an integral role in the management of the majority of women with breast cancer who can be considered to have hormone-dependent breast cancer because of the presence of the molecular predictive markers, estrogen receptor and progesterone receptor. Numerous hormonal agents are available from multiple classes of drugs, including selective estrogen receptor modulators, aromatase inhibitors, progestins, androgens, and luteinizing hormone-releasing hormone analogues. Multiple clinical trials involving these agents have been conducted which permit an evidence-based approach to the development of a sequencing strategy for treatment of women with breast cancer.     

Current status of hormone therapy in patients with hormone receptor positive (HR+) advanced breast cancer

The natural history of HR+ breast cancer tends to be different from hormone receptor-negative disease in terms of time to recurrence, site of recurrence and overall aggressiveness of the disease.The developmental strategies of hormone therapy for the treatment of breast cancer have led to the classes of selective estrogen receptor modulators, selective estrogen receptor downregulators, and aromatase inhibitors. These therapeutic options have improved breast cancer outcomes in the metastatic setting, thereby delaying the need for chemotherapy.However, a subset of hormone receptor-positive breast cancers do not benefit from endocrine therapy (intrinsic resistance), and all HR+ metastatic breast cancers ultimately develop resistance to hormonal therapies (acquired resistance). Considering the multiple pathways involved in the HR network, targeting other components of pathologically activated intracellular signaling in breast cancer may prove to be a new direction in clinical research.This review focuses on current and emerging treatments for HR+ metastatic breast cancer.     

Breast cancer risk reduction: Notable achievements and remaining challenges

Millions of women in the United States are at increased risk of breast cancer. Multiple prospective, randomized clinical trials have demonstrated both the efficacy and safety of selective estrogen receptor modulators and aromatase inhibitors in reducing substantially the risk of invasive breast cancer in women at increased risk. Published tables are available to aid clinicians in shared decision‐making regarding drug interventions with their patients who are at increased risk of breast cancer. Both professional and governmental agencies have advised that these interventions should be offered to women at increased risk of breast cancer. Doing so would reduce breast cancer morbidity substantially.     

Ductal lavage: clinical utility and future promise

This article discusses the use of ductal lavage to enhance the tolerability, efficiency, and reproducibility of collecting breast duct epithelial cells for analysis for breast cancer risk assessment. Aspects discussed include the rationale for use of ductal lavage, identification of appropriate candidates for the procedure, clinical implications, ongoing evaluation of the procedure, and its future utility.     

Do estrogen or selective estrogen receptor modulators improve quality of life for women with postmenopausal osteoporosis?

Osteoporotic fractures result in significant deficits in health-related quality of life (HRQOL). The accumulation of deficits resulting from osteoporosis and fractures is now recognized as a major cause of reduced HRQOL in women after the menopause and in later life. Some of these same postmenopausal women may also have deficits in HRQOL related to vasomotor symptoms during the menopausal transition. Although estrogen therapy has not been shown to improve overall HRQOL in late postmenopausal women in randomized, controlled trials, it may improve menopausal symptoms. In contrast, selective estrogen receptor modulators (SERMs) such as raloxifene may increase vasomotor symptoms. Although estrogen is not indicated for the primary prevention of osteoporosis, estrogen therapy may be considered for the postmenopausal woman at risk of osteoporotic fracture who is symptomatic and who is not at high risk of breast cancer or cardiovascular events. Raloxifene decreases risk of invasive breast cancer and may be considered in women at high risk of breast cancer. Decision making about osteoporosis treatment should also consider the impact of the treatment on HRQOL.     

Breast cancer chemoprevention

Chemoprevention of breast cancer is a rapidly growing field. Chemoprevention was initiated with the development of the antiestrogen tamoxifen. A major clinical trial in the United States found that tamoxifen reduced the incidence of breast cancer by almost 50% in women at an increased risk for the disease. Although two European trials did not confirm these findings, the Food and Drug Administration found the American studies significant enough to approve tamoxifen for the delaying of breast cancer in women at high risk for the disease. However, adverse effects associated with tamoxifen include a minimally increased rate of endometrial cancer, cataracts, and strokes. Newer classes of antiestrogens, called selective estrogen receptor modulators (SERMs), are being investigated as potential chemopreventive agents. These SERMS, such as raloxifene, will hopefully provide some of the benefits of estrogen without its inherent risks. In addition, naturally occurring compounds and their analogues are also under investigation.     

Prevention of Breast Cancer Using SERMs and Aromatase Inhibitors

Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of aromatase inhibitors in this setting are outlined.     

Ductal lavage in the high-risk patient

BACKGROUND: [corrected] This analysis was conducted in a single-surgeon clinical practice to evaluate the utility and practicality of performing ductal lavage in a population determined to be at high risk for breast cancer. METHODS: One hundred twenty patients with negative mammograms and/or negative breast examinations had nipple aspiration and ductal lavage performed by a single surgeon. All were at high risk either according to Gail risk score, a previous breast carcinoma, or nipple discharge. RESULTS: One hundred twenty patients underwent nipple aspiration. Thirty-two did not undergo lavage: 29 had no fluid, and 3 had unsuccessful cannulation. Eighty-eight underwent lavage: 15 had insufficient epithelial content, 51 had benign cytology, and 22 had abnormal cells. Of the 22, 20 had mild atypia, 1 had marked atypia, and 1 had malignant cells. CONCLUSIONS: Ductal lavage can be done in a surgical practice and can stratify risk for the individual patient. This is important to both patient and surgeon in formulating a treatment plan based on objective cytologic criteria.     

A review of mammary ductoscopy in breast cancer

Breast carcinoma and hyperplasia are thought to start in the lining of the breast duct. Mammary ductoscopy is an emerging technique allowing direct visual access of the ductal system of the breast through the nipple. This article reviews and discusses the utility of mammary ductoscopy. Abnormalities can be identified successfully by mammary ductoscopy, and intraductal biopsy can be used when the tumor is a polypoid type. Ductal lavage using microcatheters is effective in identifying malignant cells in high-risk women and this has stimulated interest in exploring the role of mammary ductoscopy in breast cancer screening. Mammary ductoscopy combined with ductal lavage may have a role in the management of patients with nipple discharge, the guiding of breast-conserving surgery for cancer, and in screening for high-risk women. The addition of molecular and genetic analysis of cells obtained by mammary ductoscopy are likely to enhance the use of this technique. Mammary ductoscopy techniques are safe and appear useful for detecting abnormalities in the breast. The additional molecular biologic study or ductal lavage may enhance the ability to direct and limit subsequent surgery when removing the offending lesions.     

Impact of Oncotype DX on Treatment Decisions in ER‐Positive,Node‐Negative Breast Cancer with Histologic Correlation

Oncotype DX, a gene‐expression profiling assay, provides stratification of patients with estrogen‐receptor positive, lymph‐node‐negative early breast cancer into risk groups based on recurrence score, which are associated with distant recurrence and response to chemotherapy. This study aims to determine whether Oncotype DX influences clinicians' treatment decisions, and whether assay results correlate with histologic assessment. Fifty patients with estrogen‐receptor positive, node‐negative early breast cancer analyzed by Oncotype DX and operated on by two breast surgeons were included. To assess effect on treatment decisions, clinical vignettes were created by retrospective chart review. Physicians were then presented with the clinical vignettes and instructed to make a treatment decisions (i.e., hormone therapy alone versus hormone therapy combined with chemotherapy) both before and after knowledge of the recurrence score. To assess correlation with histologic assessment, a prospective, blinded review of tumor slides was performed by two pathologists. Based on this review, tumors were placed into low, intermediate and high risk groups for comparison with Oncotype DX assay results. Treatment decisions were changed based on Oncotype DX results in 36 and 18% of cases by breast surgeons and medical oncologists, respectively. All tumors categorized as high risk by Oncotype DX were categorized as high risk based on histologic assessment, and 96% of cases categorized as low risk by recurrence score were categorized as low or intermediate risk by histologic assessment. Oncotype DX significantly influences management of estrogen‐receptor positive, lymph‐node‐negative early breast cancer. Further studies are needed to assess association of histologic categorization to assay results.     

Clinical results of selective estrogen receptor modulators (SERM)

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.     

Résultats cliniques des modulateurs sélectifs du récepteur des estrogènes (SERM)

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.     

Development of a Novel Approach for Breast Cancer Prediction and Early Detection Using Minimally Invasive Procedures and Molecular Analysis: How Cytomorphology Became a Breast Cancer Risk Predictor

With enhanced public awareness, advances in breast imaging, and emphasis on early breast cancer detection and prevention, more women are seeking consultation to assess the status of their breast health. Risk assessment has become an integral part of established multi‐disciplinary breast care, and breast cancer risk reduction interventions have received a great deal of attention. Similarly, interest in identification of high‐risk individuals has increased significantly. Atypical proliferative changes in breast epithelial cells are ranked high among various known breast cancer risk factors and, in recent years, have been the subject of several investigations. Breast tissue and fluid in the ductal system provide a rich source of cells and biomarkers that have the potential to aid in the assessment of short‐term risk of breast cancer development, and assess responses to interventional prevention efforts. There are three minimally invasive procedures currently being utilized to sample breast tissue in asymptomatic high‐risk individuals. These procedures are: fine‐needle aspiration biopsy, nipple aspiration fluid, and ductal lavage. In this review article, the merits and limitations of each procedure are presented, and the contribution of cytomorphology and molecular analysis in breast cancer prediction is highlighted. In addition, the role of Masood Cytology Index as a surrogate endpoint biomarker in chemopreventative trials is discussed.     

Personalized prevention in high risk individuals: Managing hormones and beyond

Increasing numbers of women are being identified at ‘high-risk’ of breast cancer, defined by The National Institute of Health and Care Excellence (NICE) as a 10-year risk of ≥8%. Classically women have been so identified through family history based risk algorithms or genetic testing of high-risk genes. Recent research has shown that assessment of mammographic density and single nucleotide polymorphisms (SNPs), when combined with established risk factors, trebles the number of women reaching the high risk threshold. The options for risk reduction in such women include endocrine chemoprevention with the selective estrogen receptor modulators tamoxifen and raloxifene or the aromatase inhibitors anastrozole or exemestane. NICE recommends offering anastrozole to postmenopausal women at high-risk of breast cancer as cost effectiveness analysis showed this to be cost saving to the National Health Service. Overall uptake to chemoprevention has been disappointingly low but this may improve with the improved efficacy of aromatase inhibitors, particularly the lack of toxicity to the endometrium and thrombogenic risks. Novel approaches to chemoprevention under investigation include lower dose and topical tamoxifen, denosumab, anti-progestins and metformin.Although oophorectomy is usually only recommended to women at increased risk of ovarian cancer it has been shown in numerous studies to reduce breast cancer risks in the general population and in those with mutations in BRCA1/2. However, recent evidence from studies that have confined analysis to true prospective follow up have cast doubt on the efficacy of oophorectomy to reduce breast cancer risk in BRCA1 mutation carriers, at least in the short-term.     

Aromatase Inhibitor Adjuvant Chemotherapy of Breast Cancer Results in Cancer Therapy Induced Bone Loss

Aromatase Inhibitors are anti-estrogen agents that have proven efficacy for adjuvant therapy of estrogen receptor positive breast cancer primarily in post menopausal women with estrogen receptor positive breast cancer but increase the risk of cancer therapy induced bone loss (CTIBL). Recent studies have shown the potential benefit of bisphosphonate therapy to play a dual role in the management of breast cancer. These studies provide evidence that bisphosphonate therapy in conjunction with aromatase inhibitors (AI), not only decreases the risk of osteoporosis but, in addition, may improve survival from breast cancer.     

The apoptotic action of estrogen following exhaustive antihormonal therapy: a new clinical treatment strategy

Long-term antihormonal therapy is effective at controlling the recurrence of estrogen receptor (ER)-positive breast cancer, but there may be unanticipated consequences for the development of new forms of drug resistance. Laboratory studies of exhaustive antihormonal therapy demonstrate there are at least two phases of resistance to selective ER modulators (SERMs; tamoxifen and raloxifene) and to estrogen withdrawal (aromatase inhibitors). In Phase I drug resistance, estrogen or a SERM promote tumor growth, but in Phase II drug resistance estrogen induces apoptosis. Understanding of the new biology of estrogen action has clinical relevance. There are paradoxical interactions between fulvestrant and postmenopausal levels of estrogen that cause robust growth of Phase II tamoxifen resistance or autonomous aromatase-resistant tumors. These new data suggest a rational approach for the treatment of patients with ER-positive breast cancer that have failed exhaustive antihormonal treatment. Low-dose estrogen could be used to debulk patients followed by fulvestrant in a low estrogen environment (aromatase treatment) to maintain tumor control.     

Bone and hormones. Estrogens and antiestrogens: action on osteoporosis

ESTROGEN INSUFFICIENCY: Estrogens play a cardinal role in bone tissue in women. Estrogen insufficiency leads to accelerated bone loss within 5 to 8 years after menopause. HORMONE SUBSTITUTION THERAPY: Substitution therapy prevents postmenopausic bone loss (lumbar vertebrae, hip, radius) and reduces the risk of osteoporotic fracture. Cohort studies have demonstrated that women given hormone substitution therapy for at least 7 years have a significantly higher bone density than untreated women. Although still controversial, it would appear that the risk of breast cancer increases with prolonged use of hormone substitution therapy. SERM: Observations in patients given tamoxifen, an antiestrogen used in the treatment of breast cancer, have led to the concept of selective estrogen receptor modulators (SERM), a new class of compounds with estrogen agonistic or antagonistic activity, depending on the tissue. Among these molecules, raloxifen has reached advanced clinical testing phases. Phase III trials have demonstrated that raloxifen can prevent bone loss and reduce the risk of vertebral fractures while reducing total cholesterol and LDL-cholesterol in menopaused women without stimulating the endometrium. SERMs are a promising alternative to hormone substitution therapy for the treatment of menopaused women.     

The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer

Although selective estrogen receptor modulators (SERMs), such as tamoxifen, or aromatase inhibitors (AIs), such as anastrozole, are the preferred endocrine treatment approach for most patients with hormone receptor-positive breast cancer, many patients progress despite this therapy or become resistant. Fulvestrant is a selective estrogen receptor down-regulator (SERD) that has demonstrated activity and efficacy in patients with hormone receptor-positive breast cancer previously untreated or treated with hormonal therapy. The efficacy of fulvestrant has been demonstrated in the neoadjuvant and metastatic settings, either alone or in combination with other therapies such as anastrozole or targeted drugs. Additionally, 500 mg of fulvestrant have been shown to be more effective than 250 mg, without significant differences in the toxicity profile. In this review, the unique mode of action of fulvestrant and the clinical data for different dosing regimens both alone or in combination with other drugs is critically assessed.     

The use of ductal lavage as a screening tool in women at high risk for developing breast carcinoma

BACKGROUND: The purpose of the study was to determine if ductal lavage could predict the occurrence of breast cancer as well as further stratify patients at high-risk for developing breast cancer. METHODS: Ductal lavage was performed in 116 high-risk patients (Gail Risk score > or = 1.7%, previous breast cancer, strong family history, previous suspicious biopsy specimen). If atypia or papillary cells were identified, a standard protocol of evaluation was initiated. RESULTS: Two hundred twenty-three lavages were performed on 116 patients. Twenty-seven lavages in 25 patients yielded atypical or papillary-like cells. The 15 patients who underwent further evaluation for atypia had no evidence of cancerous or precancerous lesions. All patients were followed-up: 2 developed breast cancer, both of whom had had normal previous lavage. No patient with abnormal lavage developed cancer during follow-up. CONCLUSIONS: We find ductal lavage to be of limited value in the screening of high-risk patients and have removed it from our treatment algorithm.     

Bone quality: Implications in geriatricorthopaedic patients

Bone quality is an important component of orthopaedic care in geriatric patients because it relates to fracture risk andprevention, fracture treatment and fixation techniques, and implant/bone interface stability. Quality includes static parameters such as bone strength (density) and dynamic parameters (physiologic functions) including bone formation, resorption, and repair. All of these change with normal bone aging. Techniques are available to assess the parameters of quality including bone mineral density measurement, biochemical markers of bone turnover, and histomorphometry. Treatment regimes are available to alter the rates of bone resorption and formation. These include estrogen, bisphosphonates, calcitonin, selective estrogen receptor modulators, and parathyroid hormone. Using these tools, progress is being made in fracture risk assessment and prevention strategies, enhancement of fracture fixation in aging bone, and control of periprosthetic bone resorption after total joint arthroplasty. More information and additional studies are needed as these modalities continue to evolve but significant potential now exists for improving orthopaedic care in the geriatric patient if we are willing to put these tools to work.