Retinoids,retinoic acid receptors,and breast cancer

Retinoids comprise both naturally and synthetically occurring compounds that have been proven to be differentiation agents for a variety of neoplasias, including breast cancer and promyelocytic leukemia in animal models and humans. They offer a unique panoply of therapeutics for the prevention or treatment of breast cancer. Nonetheless, considerable controversy remains as to the efficacy and potential toxic side-effects and as to which group of patients may most benefit. In this article, we review evidence of retinoid efficacy in breast cancer in humans and in animal models and provide possible mechanisms of retinoid action in breast cancer treatment, focusing on the roles of the different retinoic acid receptors and the metabolic pathways necessary for gene activation and cellular homeostasis.     

Prevention and treatment of experimental breast cancer with the combination of a new selective estrogen receptor modulator, arzoxifene, and a new rexinoid, LG 100268.

The selective estrogen receptor modulator arzoxifene and the rexinoid LG 100268 were active not only as single agents for prevention and treatment of breast cancer in the rat model that uses nitrosomethylurea as the carcinogen but also showed striking synergy, both preventively and therapeutically, in a series of six experiments with a total of 465 rats. Mechanistic studies in cell culture reported here suggest that enhancement of stromal-epithelial interactions may contribute to this synergy. The possible clinical use of the combination of arzoxifene and LG 100268 for prevention of breast cancer in women at high risk, for treatment of women in the adjuvant setting, or for treatment of end-stage disease should now be considered.     

Tumor suppression and sensitization to tumor necrosis factor alpha-induced apoptosis by an interferon-inducible protein, p202, in breast cancer cells

p202, an IFN-inducible protein, interacts with several important regulatory proteins, leading to growth arrest or differentiation. In this report, we demonstrate that, in addition to inhibiting in vitro cell growth, p202 can also suppress the tumorigenicity of breast cancer cells in vivo. Furthermore, we found that p202 expression could sensitize breast cancer cells to apoptosis induced by tumor necrosis factor alpha treatment. One possible mechanism contributing to this sensitization is the inactivation of nuclear factor-kappaB by its interaction with p202. These results provide a scientific basis for a novel therapeutic strategy that combines p202 and tumor necrosis factor alpha treatment against breast cancer.     

即刻乳房再造在乳腺癌治疗中的应用

随着乳腺癌治疗水平与整形外科技术的提高,即刻乳房再造越来越广泛地应用于乳腺癌的治疗中,成为乳腺癌综合治疗的一部分,因而即刻再造与乳腺癌辅助治疗的关系及其可能对乳腺癌预后带来的影响成为研究的热点.本文对近年来这一方面的研究进展做一综述.     

Comparison of shoulder flexibility, strength, and function between breast cancer survivors and healthy participants

Introduction  

Deficits after breast cancer treatment have been examined by comparing the surgically affected upper extremity to the unaffected extremity. It is not possible to know precisely if anti-cancer treatment such as radiation and chemotherapy had any effect on the unaffected arm. The purpose of this study was to compare ROM, strength, and shoulder function between breast cancer survivors and healthy, matched controls.     

A male patient with metachronous triple cancers of small cell lung,prostate and breast

We present a very rare case of metachronous triple cancers, including small cell carcinoma of the lung, as well as prostate and male breast cancer. To our knowledge, this is the first documented case of its kind. A 64-year-old man was referred to our hospital with left nipple retraction. He had previously undergone lobectomy of the right lung as treatment for small cell lung cancer at 57 years of age, and at 61 years of age, he had undergone prostatectomy and bilateral orchiectomy for prostate cancer, histologically determined to be moderately or poorly differentiated adenocarcinoma. Physical examination identified a painless irregular hard tumor in the left breast. Ultrasonography and magnetic resonance imaging (MRI) showed a nodular mass, and fine needle aspiration cytology of the mass revealed adenocarcinoma. Modified radical mastectomy was performed. Histological examination revealed that the breast tumor was scirrhous carcinoma, t1, n0, m0, stage T. Immunohistochemistry demonstrated that the prostate tumor was positive for prostatic specific antigen (PSA) and negative for estrogen receptor (ER), while the breast tumor was positive for ER and negative for PSA. Primary breast cancer was diagnosed. At present, 1 year and 8 months after surgical removal of the breast cancer, the patient has had no recurrence of breast cancer, small cell lung cancer, or prostate cancer. We discuss the possible causes of the triple cancers in this case with reference to the literature.     

长链非编码RNA NEAT1在乳腺癌中的研究进展

长链非编码RNA NEAT1（lncRNA NEAT1）已经证实在多种恶性肿瘤中有调控作用,其中包括乳腺癌。多个研究表明NEAT1在乳腺癌中过度表达可以促进乳腺癌细胞的增殖、侵袭和转移。一些研究表明在乳腺癌中NEAT1通过调控microRNA发挥其功能,另一些研究表明NEAT1通过诱导上皮间充质转化促进乳腺癌的进展。本文将综述lncRNA NEAT1在乳腺癌进展及耐药中的作用及可能的机制,为进一步研究NEAT1在乳腺癌中的诊断、治疗及预后提供见解。     

Breast Radiotherapy: An Overview of Available Radiation Treatment Options and Treatment Induced Sequelae

The past two decades have seen dramatic changes in the treatment of breast cancer, the most important being the shift towards breast conservation. With recent advances in diagnostic and treatment of breast cancer, the number of long-term survivors is increasing. The ongoing improvements and developments in radiotherapy techniques are leading to treatments, which offer both volume coverage and are minimizing the risk of treatment related side effects. In this article we review the role of radiation therapy in management of breast cancer, treatment techniques, as well as possible radiation induced sequelae.     

Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients.

PURPOSE: Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment. HER2, epidermal growth factor receptor (EGFR), and p53 have all been suggested as possible markers of tamoxifen resistance. The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR, HER2, and p53 in steroid receptor-positive patients. PATIENTS AND METHODS: A total of 1,716 high-risk postmenopausal breast cancer patients were randomly assigned to treatment with tamoxifen (868 women) or to observation (848 women) in a prospective trial (Danish Breast Cancer Cooperative Group's 77c protocol). The content of the steroid receptors and expression of p53, EGFR, and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue. The length of follow-up was 10 years. The end point for this analysis was disease-free survival. RESULTS: Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2-, EGFR-, and p53-positive, high-risk, steroid receptor-positive patients. Patients with steroid receptor-positive tumors and positive immunohistochemical staining for HER2, EGFR or p53 benefited from treatment with tamoxifen for 1 year, although the latter variable contained independent prognostic information by itself. CONCLUSION: With the statistical power of the present randomized study, we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor-positive patients with early-stage breast cancer. Thus, neither HER2, EGFR, nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen.     

Carcinoma of the breast during pregnancy: a review and update on treatment options.

Gestational breast cancer is occurring with increasing incidence because more women are delaying childbirth into their thirties and forties. Although breast cancer during pregnancy or within the first year postpartum is occurring more often, there is still some confusion regarding its treatment. Although breast conservation therapy has evolved as the major treatment in breast cancer, it has been thought that pregnancy was a contraindication for this type of breast cancer therapy due to risks imposed on the fetus by chemotherapy and radiation. However, recent studies have shown that the use of chemotherapeutics during the second and third trimesters is possible. Also, if chemotherapy is initiated after a lumpectomy, radiation can be withheld until after the birth of the baby when the cancer is detected in the second or third trimester.     

Early adult body weight,body mass index,and premenopausal bilateral breast cancer: data from a case-control study

Previous studies using current or recent adult body weight and body mass index are inconclusive as to a possible effect of increased body mass on premenopausal breast cancer incidence. Only five studies have presented data onearly adult body mass, and no study has reported these data for premenopausalbilateral breast cancer. Because premenopausal bilateral breast cancer is assumed to be partly genetic and partly environmental in origin, it is crucial to identify possible modifiable risk factors for this cancer. We present data on early adult body weight and body mass (Quetelet Index, QI) from a case-control study of 142 premenopausal bilateral breast cancer cases from Los Angeles County, California, Connecticut, and Quebec, Canada, and 229 sister controls. The odds ratio (and 95% confidence interval) of premenopausal breast cancer adjusted for age, education, alcohol consumption, and oral contraceptive use was 0.7 (0.3-1.4) for women in the highest tertile of QI at age 18. The results do not suggest thatelevated body mass index at a young age increases the risk of premenopausal bilateral breast cancer, but lend only weak support to the hypothesis of aninverse association between body mass index and premenopausal breast cancer.     

Oestrogens,Oestrogen Receptors and Breast Cancer

Tamoxifen has been the endocrine treatment of choice for all stages of oestrogen receptor positive breast cancer for 20 years and the first chemical therapeutic to be tested to reduce the incidence of breast cancer in high-risk women. It is now clear that the oestrogen receptor is proving to be an invaluable target for the treatment and chemoprevention of breast cancer. The success of tamoxifen clinically can be quantitated: 400 000 women are alive today because of the application of 5 years of adjuvant tamoxifen therapy in node-positive and node-negative breast cancer. This advance has resulted in vigorous efforts to reduce side-effects and to improve objective response rates by the rapid application of laboratory principles. Tamoxifen is known to have a mixture of oestrogen-like and anti-oestrogen actions so it is reasoned that completely anti-oestrogenic agents would enhance treatment response rates while lowering the incidence of oestrogen-like side-effects such as endometrial cancer and blood clots. A new pure anti-oestrogen, fulvestrant, that destroys the oestrogen receptor, is available after drug resistance to tamoxifen develops. The group of drugs known as aromatase inhibitors block the production of oestrogens from androstenedione and testosterone in the body fat of postmenopausal women. New agents such as anastrozole, exemestane, and letrozole have shown promise as new treatment modalities for advanced breast cancer. Most importantly, the successful testing of anastrozole as an adjuvant treatment for breast cancer has enhanced enthusiasm for the evaluation of aromatase inhibitors and selective oestrogen receptor modulators (SERMs) to be tested as chemopreventives. SERMs express anti-oestrogenic actions in the breast but oestrogen-like actions in bone and lower circulating cholesterol. This insight not only allowed the safe application of tamoxifen to well high-risk women to test the worth of an ‘anti-oestrogen’ to prevent breast cancer, but also caused a paradigm shift in the strategy of chemoprevention. The question was posed that if, tamoxifen prevents breast cancer but an added benefit is the maintenance of bone density, why not develop a drug to prevent osteoporosis or atherosclerosis that prevents breast cancer in the general population as a beneficial side-effect? Raloxifene is the result of this new strategy to seek multifunctional medicines for women's health. Raloxifene is currently available for the treatment and prevention of osteoporosis but is being tested in high-risk postmenopausal women for the prevention of breast cancer against tamoxifen in the study of tamoxifen and raloxifene (STAR trial) and for the prevention of coronary heart disease (CHD) in a placebo-controlled trial in women at high risk for CHD called raloxifene use for the heart (RUTH).     

Aromatase inhibitors for treatment of postmenopausal patients with breast cancer

The third generation of aromatase inhibitors and inactivators, such as anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin), have become available for treatment of postmenopausal breast cancer patients. Several clinical trials have demonstrated that these new drugs can achieve better treatment results than megestrol acetate (Megace) and may replace tamoxifen for the first-line hormonal therapy for metastatic breast cancer patients. In fact, these drugs are now used in many hospitals and clinics for patients with metastatic breast cancer who were previously given tamoxifen as adjuvant treatment. However, the primary concern is whether they can be used as first-line agents for adjuvant treatment of primary breast cancer or are suitable for breast cancer prevention in view of possible adverse side effects. Recently, the Arimidex and Tamoxifen Alone or in Combination trial demonstrated the superiority in terms of disease-free survival of anastrozole over tamoxifen in adjuvant use for postmenopausal patients with Stage I and II primary breast cancer. The results of this report indicate the potential of anastrozole as an alternative drug in the adjuvant setting, although the mean follow-up time is so far only 47 months. Additional data regarding survival resulting from comparative trials of letrozole and tamoxifen and of exemestane and tamoxifen are expected to be available in a few years. However, limited information is available regarding adverse events caused by long-term administration of aromatase inhibitors. Longer follow-up is needed to determine the efficacy and safety of these new aromatase inhibitors when used for adjuvant treatment of postmenopausal patients with breast cancer.     

Pregnancy-associated breast cancer.

The incidence of pregnancy-associated (PA) breast cancer is rising, as childbirth is being delayed to the women's 30s and early 40s, when breast cancer is more frequent. Most reports consider "PA breast cancer" as that being diagnosed during pregnancy, or within one year after. The delay of diagnosis often seen in PA breast cancer may be due to physician oversight or reluctance to perform a biopsy during pregnancy. Two-stage procedures are favored in this setting, with biopsy under local anesthesia, then extent-of-disease work-up and definitive treatment, usually mastectomy. The use of scans for staging, and irradiation for treatment, is avoided, where possible, due to fetal risk. Likewise, chemotherapy is carefully gauged to avoid fetal damage. With these precautions, the prognosis for women with PA breast cancer, stage for stage, is similar to that of women of the same age treated at the same time period at MSKCC.     

Radiation exposure from diagnostic and therapeutic treatments and risk of breast cancer.

An association between low-dose diagnostic X-ray exposure or therapeutic radiation treatment and breast cancer risk has not been established. To further investigate the issue, we analysed data from a case-control study of breast cancer in Connecticut in 1994-1997. A total of 1217 subjects (608 breast cancer cases and 609 controls), 30-80 years old, participated in the study. A standardized, structured questionnaire was used to collect information through in-person interviews on diagnostic or therapeutic radiation and other breast cancer risk factors. An odds ratio (OR) of 1.7 (95% confidence interval (CI) 0.8-3.6) was observed for postmenopausal women with therapeutic radiation treatment for skin problems such as ringworm and acne, and an OR of 2.5 (95% CI 1.0-6.8) for those who reported having been treated six or more times. Radiation treatment received at younger ages seems to carry a higher risk. In earlier studies therapeutic radiation for skin problems has been associated with an increased risk of breast cancer. Therefore, it is possible that scattered radiation from these treatments could increase the risk of breast cancer. Radiation exposure from diagnostic X-rays was not associated with a significantly increased risk of breast cancer in this study.     

Breast cancer measurements with magnetic resonance imaging,ultrasonography, and mammography

Summary In 1986, the National Cancer Institute published its cancer control objectives for the nation, which included projected reductions in breast cancer mortality. The reductions were estimated to be 25.0% from reducing fat, 16.0% from expanding use of breast cancer screening services, and 14.3% from expanding access to state-of-the-art breast cancer treatment. During the same decade, the U.S. population aged and became significantly more ethnically diverse, and accompanying this increase in ethnic diversity was endemic poverty, disproportionately experienced by black and Hispanic minorities. These populations may be seen as medically underserved. With respect to breast cancer, as well as many other cancers, the medically underserved are understudied, not well understood by many in the medical and academic research community, and attended by health care institutions that are under-funded and often do not have the resources necessary to ensure access to state-of-the-art cancer screening, clinical follow-up, diagnosis, and treatment. At the same time, medically underserved women are more likely to be diagnosed with late-stage breast cancer, and some groups (e.g. black women) bear the greatest breast cancer mortality burden in the nation. In this special issue of Breast Cancer Research and Treatment, eight papers describe what we know and what we don't about breast cancer prevention and control in medically underserved populations.     

乳腺癌抗肿瘤血管治疗的临床进展

血管生成是肿瘤发生发展的关键条件之一,抗血管生成药物可阻断血管生成,被认为是治疗各种癌症,特别是晚期癌症的一个重要的突破。抗血管生成药物在晚期胃癌、结直肠癌、前列腺癌及肝癌患者联合化疗中显示出较好的疗效。然而,在乳腺癌中,研究却显示了矛盾的结果,引起了关于这种药物价值的争论。本文回顾了乳腺癌抗血管生成治疗选择的证据,并讨论了限制抗血管生成药物有效性的可能因素,并提出了关于乳腺癌未来治疗方法研究的建议。     

Pharmacological profiles of exemestane and formestane,steroidal aromatase inhibitors used for treatment of postmenopausal breast cancer

Steroidal aromatase inhibitors like formestane and exemestane are useful drugs for endocrine treatment of postmenopausal breast cancer. In addition, these drugs should be considered valuable probes to explore the biology of breast cancer with particular emphasis on possible relations between the degree of estrogen suppression and clinical efficacy and the possible role of intratumor estrogen synthesis. The fact that steroidal and non-steroidal aromatase inhibitors bind to different parts of the aromatase enzyme suggests these drugs may act in concert aggravating plasma estrogen suppression. Thus, use of a steroidal and a non-steroidal aromatase inhibitors in concert may be one way to improve breast cancer treatment and may also provide important information to a better understanding of the dose-response relationship between estrogen suppression and clinical effects. Further, the finding that patients progressing on non-steroidal aromatase inhibitors may respond to formestane as well as exemestane suggests these drugs may have differential effects, probably on the aromatization in the tumor tissue. Further studies are warranted to explore the influence of steroidal and non-steroidal aromatase inhibitors on intratumor aromatase activity and intratumor estrogen concentrations and to correlate these findings to intratumor drug concentrations. The findings that steroidal aromatase inhibitors may have clinical effects in patients progressing on treatment with the non-steroidal aromatase inhibitor aminoglutethimide is challenging, and suggest further studies to evaluate possible benefits of using different novel aromatase inhibitors in concert or sequence.     

The role of BRCA mutation testing in determining breast cancer therapy

Landmark discoveries in the field of breast cancer research include the identification of germline BRCA mutations as a cause of hereditary disease, and the use of gene-expression profiling to identify distinct subtypes of breast cancer. These findings, coupled with the availability of rapid germline testing, make it possible to identify a BRCA mutation carrier contemporaneous with a diagnosis of breast cancer. For the first time, testing for a germline mutation that predisposes to cancer has the potential to influence the immediate surgical, radiotherapeutic, and drug treatment choices of an individual with a new diagnosis of breast cancer. In this Review, we examine the implications of moving germline BRCA mutation testing from highly specialized family cancer clinics to mainstream settings.