Breast Cancer in Men—Should Aromatase Inhibitors Become First‐Line Hormonal Treatment?

Abstract: Breast cancer is an uncommon malignancy in men; therefore, the approach to treatment is mostly modeled on that used in females. First‐line use of aromatase inhibitors (AIs) is now standard practice in hormone‐sensitive metastatic breast cancer in postmenopausal females. However, tamoxifen continues to be regarded as first‐line treatment in hormone‐sensitive male breast cancer. This article reviews the role of second and third generation AIs as first‐ or second‐line hormonal treatment in male patients with metastatic breast cancer. It also explores the potential use of AIs in combination with gonadotropin‐releasing hormone analogs or trastuzumab suggesting that in the future this may prove a useful alternative to tamoxifen.     

Ocular Surface Disease in Breast Cancer Patients Using Aromatase Inhibitors

Aromatase inhibitors (AIs) are widely used as adjuvant hormonal therapy in postmenopausal women with hormone receptor‐positive breast cancer. The purpose of this study was to investigate the potential impact of AIs on the anterior segment of the eye and especially the ocular surface. Participants in our study were 41 hormone receptor‐positive early stage breast cancer patients (80 eyes), treated with AIs, while 80 eyes of 40 age‐ and gender‐matched healthy controls, not previously used AIs for any purpose, were also evaluated. All participants underwent a complete ophthalmological examination, including best corrected visual acuity (BCVA) assessment, slit‐lamp biomicroscopy, and dilated fundus examination. Ocular surface disease‐related symptoms and signs were also recorded. The most common symptom was found to be blurred vision, while other symptoms included foreign body sensation, tearing, redness, and photophobia. Slit‐lamp examination revealed blepharitis and meibomian gland dysfunction in 75% and 42.5% of patients, respectively. Superficial punctate keratitis and conjunctival injection were also present. Our results demonstrated a high prevalence of ocular surface disease‐related symptoms and signs in patients receiving AIs compared to healthy controls. This study may raise a flag regarding the use of AIs. However, further and larger prospective longitudinal studies are needed to examine the possible effect of AIs alone or in combination with chemotherapy in the eyes of breast cancer patients.     

Prevention and Management of Lymphedema after Breast Cancer Treatment

Lymphedema of the arm after breast cancer treatment continues to challenge clinicians worldwide. In this review, we examine the main modalities, both nonsurgical and surgical, to prevent and treat this as yet incurable condition.     

COX-2 Inhibitors for the Prevention of Breast Cancer

The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is normally expressed predominantly in kidney and brain, and also has important roles in reproduction and inflammation. COX-2 misexpression has been observed in numerous human cancers, including the majority of colorectal cancers. Recently, COX-2 overexpression has been described in human breast cancer. COX-2 is present in about 40% of invasive breast carcinomas, particularly those that overexpress HER2/neu, and COX-2 expression correlates with poor patient prognosis. Manipulation of Cox-2 gene dosage by using transgenic overexpression and knockout approaches has revealed an important role for Cox-2 in tumorigenesis. Furthermore, translational experiments using rodent breast cancer models suggest COX-2 inhibition to be an effective strategy for both prevention and treatment of experimental breast cancers. Since COX-2 can contribute to multiple facets of tumorigenesis, including angiogenesis, several mechanisms are likely to underlie the anticancer action of COX inhibitors. Thus, selective COX-2 inhibitors offer considerable promise for the prevention and treatment of human breast cancer.     

芳香化酶与乳腺癌的相关研究

雌激素在乳腺癌的发生发展中起着重要作用。绝经后妇女的雌激素主要由肾上腺分泌的雄激素前体转化而来,芳香化酶是这一转变过程的关键酶、限速酶。因此,深入研究芳香化酶和乳腺癌的关系具有重要的临床意义。现就芳香化酶在乳腺癌组织中的表达、调控及芳香化酶抑制剂在乳腺癌内分泌治疗中的临床进展作一综述。     

Breast Cancer Prevention Trials Using Retinoids

Retinoids have been studied as chemopreventive agents in clinical trials. Given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide has extensively been investigated because of its favorable toxicological profile in humans. In a phase III secondary prevention trial, fenretinide showed a trend to a reduction of second breast malignancies in premenopausal women but not in postmenopausal women. This pattern was associated with a similar modulation of circulating IGF-I. A trend towards a reduction of ovarian cancer was also noted. Biomarker studies of fenretinide or novel selective retinoids alone and in combination with different nuclear receptor ligands are being conducted. These studies provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women, and offer clues as to both the pathophysiology of carcinogenesis and the drug mechanisms of action, and help select new compounds and doses for testing in large randomized studies.     

Vertebral Fractures After Denosumab Discontinuation in Breast Cancer Survivors: A Single Institution Experience

Background: Denosumab is approved to prevent fragility fractures in patients with osteoporosis at high risk for fracture and to prevent bone loss in patients with breast and prostate cancer who receive endocrine therapy. The antiresorptive effect of denosumab rapidly dissipates when it is delayed or discontinued, but the risk for, and incidence of, multiple clinical vertebral fractures in patients with breast cancer after stopping denosumab is currently unclear. Question/Purposes: We sought to identify the incidence of clinical vertebral fractures in patients with breast cancer who received at least 2 doses of denosumab (60 mg) and then discontinued the medication. Methods: We conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010, and July 18, 2018, at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal women and 1 man with nonmetastatic breast cancer who received their final denosumab injection at least 6.5 months earlier. Data recorded included baseline bone density and the incidence of vertebral fractures after denosumab discontinuation. Results: The median age of patients was 62 years. Patients received between 2 and 13 denosumab doses before drug discontinuation. Most of the patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months. We identified 1 case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. Most of the patients (88%) had a gap in denosumab dosing. Conclusions: Clinicians treating patients with breast cancer—especially those continuing to take aromatase inhibitors—should be aware of the possible risks of delaying doses of or discontinuing denosumab and should educate their patients accordingly. Prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab.     

Cardiovascular Health among Black and White Breast Cancer Patients Initiating Aromatase Inhibitor Therapy

The purpose of this study was to compare the cardiovascular health of Black and White breast cancer patients undergoing adjuvant treatment. Baseline data from a cohort study of Black (n = 45) and White (n = 101) breast cancer patients initiating aromatase inhibitor treatment were analyzed. Participants had a cardiovascular health assessment, including carotid intimal medial thickness measurement, donated a blood sample, and completed a questionnaire. Atherosclerotic cardiovascular disease (ASCVD) event risk scores were calculated. Compared to their White counterparts, the Black patients had a significantly higher median ASCVD risk score (p = 0.009) and had a higher number of CVD risk factors (p < 0.05). Black patients were also more likely to have hypertension, diabetes, or to be obese than the White participants. The prevalence of cardiovascular disease and cardiovascular disease risk factors among Black and White breast cancer patients is high, and racial disparities exist which may have treatment implications.     

Fulvestrant in Advanced Breast Cancer Following Tamoxifen and Aromatase Inhibition: A Single Center Experience

Abstract:  Fulvestrant is a pure estrogen receptor (ER) antagonist with no agonist effects. We describe the experience of a single center involving 45 postmenopausal women with advanced breast cancer where fulvestrant was utilized following progression on tamoxifen and a third generation aromatase inhibitor. Patients received fulvestrant as first line one (2%), second line 18 (40%), third line 13 (29%), fourth line 10 (22%), and fifth line three (7%) treatment. Median duration of treatment with Fulvestrant was 4 months (range 1–20 months). One patient had a partial response, 14 other (31%) experienced clinical benefit (CB) (defined as response or stable disease for at least 6 months). The median time to progression (TTP) from initiation of fulvestrant was 4 months (range 1–20 months) and the median survival was 10 months (range 1–55 months). In those patients who experienced CB the median TTP was 10 months (range 6–20) and median survival was 21 months (range 7–55). Fulvestrant was well tolerated; two patients experienced side effects severe enough to stop therapy. Despite the fact that fulvestrant was used in the majority of cases, later in the treatment sequence CB was seen in a number of patients. This data suggest fulvestrant is well tolerated and is a useful treatment option in patients with advanced breast cancer who progress on prior endocrine treatment.     

Breast Cancer Prevention

Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women.     

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.     

Biology of Aromatase in the Mammary Gland

While the ovaries are the principal source of systemic estrogen in the premenopausal nonpregnant woman, other sites of estrogen biosynthesis are present throughout the body and these become the major sources of estrogen beyond menopause. These sites include the mesenchymal cells of the adipose tissue and skin, osteoblasts, and perhaps chondrocytes in bone, vascular endothelial and aortic smooth muscle cells, as well as a number of sites in the brain including the medial preoptic/anterior hypothalamus, the medial basal hypothalamus and the amygdala. These extragonadal sites of estrogen biosynthesis possess several fundamental features which differ from those of the ovaries. Principally, the estrogen synthesized within these compartments is probably only biologically active at a local tissue level in a paracrine or `intracrine' fashion. Thus the total amount of estrogen synthesized by these extragonadal sites may be small, but the local tissue concentrations achieved are probably quite high, and exert significant biological influence locally. Thus these sources of estrogen play an important but hitherto largely unrecognized, physiological and pathophysiological role.     

Klinefelter's Syndrome and Breast Cancer

Klinefelter Syndrome und Brustkrebs
Es wird über einen Patienten mit Mammacarcinom bei Klinefelter-Syndrom berichtet. Eine Beziehung zwischen den Serumkonzentrationen von Testosteron und Östradiol nach Substitution mit Testosteronenanthat, den nachgewiesenen Östrogenreceptoren im Tumorgewebe und der klinischen Symptomatik wird vermutet. Die verschiedenen Vorstellungen über die Ätiologie des Mammacarcinoms beim Klinefelter-Syndrom sowie die therapeutischen Möglichkeiten werden besprochen. Es wird darauf hingewiesen, daß durch die Behandlung mit Testosteron und die gesteigerte Konversion von Testosteron zu Östradiol die Entwicklung eines Mammacarcinoms beim Klinefelter-Syndrom begünstigt werden könnte.     

Enhancing the Adjuvant Treatment of Hormone Receptor Positive Breast Cancer

Abstract:  Aromatase inhibitors (AIs) are now regarded as the optimum hormonal therapy for postmenopausal women with hormone receptor positive breast cancer. However, it is unclear which of the currently available AIs offers patients the most effective and the best-tolerated treatment strategy. We performed a systematic review and meta-analysis of randomized-controlled trials that compared AIs (as first-line agents) with standard hormonal treatment in patients with breast cancer. The results suggest that letrozole offers a more favorable side-effect profile particularly in terms of musculoskeletal adverse events. However, the available data suggests a small survival benefit from the use of anastrozole although patients treated with anastrozole appear to have a more favorable disease profile at study entry. Examination of survival data on adjuvant tamoxifen therapy from these trials supports this observation.     

Potential Use of Vaccines in the Primary Prevention of Breast Cancer in High-Risk Patients

Cancer vaccines are an emerging therapeutic and prophylactic modality that may play a more important role in cancer prevention and treatment in the future. Therapeutic cancer vaccines are designed to generate a targeted, immune-mediated antitumor response. Successful prophylactic vaccines are those against oncogenic viral infections, such as the human papillomavirus and cervical cancer. However, a tough challenge for the majority of tumor vaccines is the self-nature of tumor antigens. Ongoing studies are investigating methods to enhance vaccine strategies including immune-modulating agents. The present review analyzes the potential use of vaccines in the primary prevention of breast cancer, focusing on the recent extension of vaccine target selection to self-proteins that are overexpressed during the early stages of tumor development but whose expression no longer occurs as we age, a feature that may avoid clinically significant autoimmune sequelae.