乳腺癌预防性治疗研究进展

一系列化学干预试验显示,雌激素受体调节剂（三苯氧胺、雷诺昔芬）等药物能够显著降低高危人群乳腺癌的发病率。针对BRCA基因突变携带者开展的预防性双侧乳腺切除术和预防性双侧卵巢切除也取得了明显的疗效,特别是预防性双侧乳腺切除术被充分汪明是一个有效的治疗手段,既能显著降低高危妇女乳腺癌风险也显著降低乳腺癌相关死亡。     

乳腺癌高危妇女的评估与预防策略

乳腺癌是女性最常见的恶性肿瘤之一。流行病学研究发现乳腺癌有许多高危因素,其中最主要的因素包括年龄、乳腺癌家庭史和既往某些乳腺疾病史。对于乳腺癌的高危人群开展预防工作是目前的一项重要课题,常用的方法包括预防性乳腺切除术、严密监测和化学预防。多项研究表明预防性乳腺切除术不能百分之百起到预防效果;乳房切除容易给妇女带来严重的精神创伤,因而必须严格掌握手术指证,术后也宜首选即刻乳房重建。严密监测应包括定期     

乳腺癌的风险评估与预防

乳腺癌的风险评估模型是建立在不同国家和学术组织的研究基础上的,所以适用的人群不同,侧重基因检测及流行病学资料也各有不同。随着对乳腺癌患病危险因素研究的深入,纳入更多相关因素如乳腺密度、单核苷酸多态性、激素水平、肿瘤标志物等,有可能提高现有模型的预测能力。现有的风险评估与预防方面的指南如美国预防服务工作组(USPSTF)、美国癌症学会(ACS)、美国国家综合癌症网络(NCCN)和国家健康和保健研究所(NICE),都是根据风险评估结果划分出高危人群和一般风险人群,所有人群都应该进行生活方式方面的预防,高危人群可以进行药物预防,非常高危者还可以考虑预防性乳房切除。     

乳腺癌化学预防临床研究进展

介绍乳腺癌高危妇女药物预防性治疗前瞻性临床试验的现状和最新进展,并综述高危妇女的危险估计、乳腺癌化学预防的风险和效益.     

乳腺癌化学预防临床研究进展

介绍乳腺癌高危妇女药物预防性治疗前瞻性临床试验的现状和最新进展，并综述高危妇女的危险估计、乳腺癌化学预防的风险和效益。     

乳腺癌化学预防研究进展

雌激素与乳腺癌发生发展之间存在联系,使用药物干预这个过程可以达到抑制癌变的作用.目前允许用于临床的化学预防药物仅有三苯氧胺一种,其他药物的应用尚待进一步的临床试验提供依据.在进行化学预防之前应该对人群进行风险预测,选择合适人群进行用药.现介绍几种乳腺癌化学预防药物与相关临床试验以及对高危易患人群进行筛选的手段.     

乳腺癌化学预防研究进展

雌激素与乳腺癌发生发展之间存在联系，使用药物干预这个过程可以达到抑制癌变的作用。目前允许用于临床的化学预防药物仅有三苯氧胺一种，其他药物的应用尚待进一步的临床试验提供依据。在进行化学预防之前应该对人群进行风险预测，选择合适人群进行用药。现介绍几种乳腺癌化学预防药物与相关临床试验以及对高危易患人群进行筛选的手段。     

乳腺癌长期三苯氧胺治疗国际会议概述

三苯氧胺(TMX)为非甾体类抗雌激素药物,20年前,首先作为绝经后晚期乳腺癌患者的姑息性治疗,而今,TMX可为各期乳腺癌选择病例提供有益的内分泌治疗.同时已有计划的应用于乳腺癌高危人群,以评价其对乳腺癌预防性治疗的价值.1977年,在英国剑桥会议,实验室研究结果就支持对高危女性乳腺癌辅以长期TMX治疗,可能获得最有益的结果.当时,几组为期1年的TMX辅助治疗研究是基于:①TMX使     

1484 例腋淋巴结阴性乳腺癌患者预后的多因素 Cox 模型分析

目的对腋淋巴结阴性乳腺癌患者进行预后分析。方法选择２２个可能对腋淋巴结阴性乳腺癌患者预后产生影响的非重复特征性临床因素，通过计算机Ｃｏｘ多因素分析模型，利用累积生存率，对１４８４例手术切除的腋淋巴结阴性乳腺癌患者进行预后分析。结果在选取的２２个因素中，月经状况、妊娠次数、病期、合并妊娠或哺乳、肿瘤大小、内乳淋巴结、术后放疗、术后三苯氧胺辅助治疗是影响腋淋巴结阴性乳腺癌患者预后的独立预后因素（Ｐ＜０．０５）。结论用临床资料对腋淋巴结阴性乳腺癌患者进行预后分析，可发现部分高危人群。腋淋巴结阴性的乳腺癌患者术后不宜放疗或行卵巢切除，术后三苯氧胺辅助治疗不应仅局限于绝经后或雌激素受体阳性的患者。如何选择高危人群进行术后化疗，有待进一步研究。     

预防对侧乳腺癌发生的治疗方式的研究进展

对侧乳腺癌(CBC)的发生概率因首发乳腺癌患者的生存时间延长而呈上升趋势，与一般女性群体中罹患乳腺癌的风险相比，首发乳腺癌患者CBC发生的终生风险增加2～4倍，且预后更差。分析导致CBC发生的危险因素，积极进行首发乳腺癌的治疗，通过内分泌治疗、放化疗、其他药物和预防性切除手术等个性化预防治疗，进而降低CBC发生率。本文将简述CBC发病的危险因素、风险控制措施和预防性治疗的临床管理方案。     

Advances in Preventive Therapy for Estrogen-Receptor-Negative Breast Cancer

Preventing breast cancer is an effective strategy for reducing breast cancer deaths. The purpose of chemoprevention (also termed preventive therapy) is to reduce cancer incidence by use of natural, synthetic, or biological agents. The efficacy of tamoxifen, raloxifene, and exemestane as preventive therapy against estrogen-receptor (ER)-positive breast cancer is well established for women at increased risk for breast cancer. However, because breast cancer is a heterogeneous disease, distinct preventive approaches may be required for effective prevention of each subtype. Current research is, therefore, focused on identifying alternative mechanisms by which biologically active compounds can reduce the risk of all breast cancer subtypes including ER-negative breast cancer. Promising agents are currently being developed for prevention of HER2-positive and triple-negative breast cancer (TNBC) and include inhibitors of the ErbB family receptors, COX-2 inhibitors, metformin, retinoids, statins, poly(ADP-ribose) polymerase inhibitors, and natural compounds. This review focuses on recent progress in research to develop more effective preventive agents, in particular for prevention of ER-negative breast cancer.     

The quality of life associated with prophylactic treatments for women with BRCA1/2 mutations.

PURPOSE: This study was conducted to obtain and compare the preferences assigned to cancer states and prevention measures by women who had breast cancer, were at high risk for breast cancer, or had neither condition. PATIENTS AND METHODS: We administered a time trade-off questionnaire to 21 breast cancer patients, 28 women with a personal history of multiple breast biopsies or a family history of breast cancer, and 135 women without these conditions (the reference group). We stratified the reference group into two groups aged 20 to 32 years and 33 to 50 years, respectively. RESULTS: All four groups assigned higher preference to breast cancer than to ovarian cancer. Both reference groups preferred using a tamoxifen-like drug to having mastectomy or oophorectomy for cancer prevention; the high-risk and breast cancer groups did not. None of the four groups had a preference between prophylactic mastectomy and breast cancer. All the groups were willing to subtract more years from their life expectancy to protect offspring from genetic risk than to protect themselves. Reference group members in the 33- to 50-year age range had lower mean ratings than the breast cancer group for almost all the health states, and breast cancer patients were less willing than other respondents to trade time for health. Most of these differences were not statistically significant. The high-risk group was similar to the older reference group in time trade-off ratings. DISCUSSION: The time trade-off-based preferences of healthy women may be used to predict the treatment preferences of women with BRCA1/2 mutations. Obtaining healthy women's ratings of treatment outcomes may help health care policy makers envision the consequences of the difficult choices that high-risk women face.     

Future possibilities in the prevention of breast cancer: Role of genetic variation in breast cancer prevention

Risk factors for breast cancer are related to endogenous hormonesand reproductive events. As such, traditional cancer prevention strategies arenot easily applicable. Tamoxifen and other selective estrogen receptormodulators (SERMs) offer a new preventive strategy for some high-risk women,but have not yet been shown to be efficacious for all women. New tools toidentify high-risk women are needed. One such tool is the development of amultigenic model of breast cancer susceptibility that can be used to screenwomen in order to identify those who carry a combination of alleles that putsthem at significantly increased risk.     

The molecular etiology of breast cancer: evidence from biomarkers of risk

Estrogens can become endogenous carcinogens via formation of catechol estrogen quinones, which react with DNA to form specific depurinating estrogen-DNA adducts. The mutations resulting from these adducts can lead to cell transformation and the initiation of breast cancer. Estrogen metabolites, conjugates and depurinating DNA adducts in urine samples from 46 healthy control women, 12 high-risk women and 17 women with breast cancer were analyzed. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of the ratios of depurinating DNA adducts to their respective estrogen metabolites and conjugates were significantly higher in high-risk women (p < 0.001) and women with breast cancer (p < 0.001) than in control subjects. The high-risk and breast cancer groups were not significantly different (p = 0.62). After adjusting for patient characteristics, these ratios were still significantly associated with health status. Thus, the depurinating estrogen-DNA adducts are possible biomarkers for early detection of breast cancer risk and response to preventive treatment.     

Breast cancer prevention based on gene-environment interaction

Breast cancer, the most common cancer in women, results from combined effects of genetic and environmental factors. Although a number of preventive measures have been suggested to reduce the risk of breast cancer, only a few (e.g., regular mammogram, etc.) proved to be efficient preventive modalities. Among many potential reasons, differences in individual susceptibility factors may complicate the efficacy of the intervention. A growing body of evidence shows that the strength of association between various dietary, behavioral (exercise and obesity), and environmental exposures, and breast cancer risk may be modified by individual genetic factors. Preventive strategies against breast cancer will be discussed considering the findings of the gene-environment interaction of breast cancer. These include behavior modification for high-risk subjects (primary prevention), early detection and extensive monitoring of genetically susceptible subjects and noninvasive treatment of early stage cancer cases (secondary prevention), and finally prophylactic and therapeutic intervention to slow the progression of diseases (tertiary prevention). The accumulating evidences of the gene-environment interactions provide a better understanding of the breast cancer development and enable us to adopt individualized preventive strategies for personalized health care.     

Screening of high-risk groups for breast and ovarian cancer in Europe: a focus on the Jewish population

Low breast cancer screening rates are often found among ethnic minority groups and those born outside the host country. This is of particular concern for high-risk groups, who should benefit from ongoing trials aimed at optimizing screening strategies for breast, as well as ovarian cancer. Both of these issues are germane for Jewish women in Europe. We systematically review the literature concerning breast cancer early detection practices (BCEDP) among Jewish women, and examine European surveillance studies of high-risk for breast and/or ovarian cancer that had imaging in the surveillance protocol, in order to assess the likelihood of adequately including women from minority ethnic groups. No studies were found about BCEDP among Jewish women in Europe. Twenty-one research groups from Israel or the US addressed BCEDP among Jewish women. Some Jewish women in the US and Israel, including recent immigrants, are under-screened. Twenty-four research groups reported imaging surveillance of women at increased risk for breast and/or ovarian cancer in Europe. There was a clear benefit to magnetic resonance imaging and/or more intensive screening for women with increased breast cancer risk. Some of these surveillance studies considered ethnic minority groups at high risk, including Jewish women, but none provided adequate outreach to ensure that these groups were included in their programs. The specific screening needs of Jewish and other high-risk ethnic minority groups in Europe have not been met regarding breast and ovarian cancer. A European-wide, population-based approach is suggested, with cultural sensitivity being vital for these efforts.     

Women's Expectations for Breast Cancer Prevention and Early Detection: High Expectations Can Be Achieved

Additional research is needed to improve the ability to detect life-threatening cancer at an early curable stage and to prevent the development of such cancer. Many research groups are working to discover more effective and safer methods to detect and prevent life-threatening breast cancer. The results from such research studies will ultimately allow women’s expectations for breast cancer prevention and early detection to be met.In his commentary titled “Breast Cancer Prevention: Can Women’s Expectations Be Met?” [1], Dr. Ponzone raises an important and timely question. Dr. Ponzone asks whether breast “cancer prevention” and “early detection” are attainable goals and whether these phrases have the same meaning to women at risk of breast cancer as to health professionals. This is a critically important issue, because researchers and health care providers strive to reduce the incidence and mortality from breast cancer by working to develop safe and effective methods to prevent breast cancer.As Dr. Ponzone points out, mammography “is not without its drawbacks” [1]. Mammography, although associated with reduced breast cancer-specific mortality in some studies [2, 3], has not been found to reduce breast cancer-specific mortality in others [4]. In addition, mammograms can detect noninvasive cancers, some of which might not evolve to invasive breast cancer (the problem of overdiagnosis) [5]. However, I believe it is misguided to conclude that “preventive measures for a given individual might have only modest impact” and that “efforts of cancer specialists should focus more on improving the length and quality of life of patients through therapeutic advances.” Although cancer specialists should work to develop more effective therapies for women with all stages of breast cancer, the greatest impact on breast cancer incidence and mortality will come from appropriately applying risk-based cancer preventive and early detection strategies.The word “prevention” is often interpreted differently by the general population and health care providers. For health care experts, interventions that reduce the incidence of disease (in this case, cancer), even if incompletely, are considered to have prevented the disease in some individuals. However, for most of the general population, interventions that “prevent” disease are considered to be 100% effective (i.e., to reduce the incidence to zero) and to have minimal toxicity. The common perception is that an individual receiving preventive treatment will have no side effects and will never develop the disease to be prevented (cancer, in this case). The common example of such a “preventive intervention” is that of the polio vaccine given in childhood with minimal toxicity and almost 100% efficacy [6]. Other acceptable “preventive interventions” include treatment with statins to reduce cholesterol levels to prevent heart disease [7], antihypertensive drugs to prevent strokes [8], and bisphosphonate drugs to prevent bone fractures [9]. However, in each of these cases, the intervention is neither 100% effective nor risk-free. It is remarkable that the general population accepts medical intervention to prevent heart disease, strokes, and bone fractures but often does not accept “preventive interventions” to prevent cancer.There are currently available interventions that clearly prevent many breast cancers in high-risk women. These include bilateral prophylactic mastectomy, which prevents up to 90% of breast cancers in very high-risk women [10, 11]; antiestrogen preventive therapy (with anti-estrogen selective estrogen receptor modulators, such as tamoxifen or raloxifene), which prevents approximately 50% of breast cancers [12]; and aromatase inhibitors, which prevent up to 70% of breast cancers in moderately high-risk women [13]). These interventions prevent breast cancer in many women but are often not accepted because of the possible side effects. The behavioral interventions that Dr. Ponzone mentions (avoidance of environmental carcinogens and lifestyle factors such as diet and exercise) likely also prevent some cancers; however, these highly tolerable interventions are less effective than the surgical or medical interventions mentioned. In clinical practice, these various preventive interventions are being used in a tiered fashion according to risk. Thus, for women at extremely high risk of breast cancer (such as those carrying BRCA1 or BRCA2 mutations), bilateral prophylactic mastectomies are considered and frequently performed. For women at moderately high risk (e.g., those with precancerous lesions such as atypical ductal hyperplasia), preventive therapy with tamoxifen, raloxifene, or an aromatase inhibitor is being prescribed and accepted by many women. The remaining women (those at low to moderate risk of breast cancer) might benefit from behavioral interventions such as exercise, diet, and alcohol avoidance alone. The current interest in healthy lifestyles has led Dr. Graham Colditz to suggest that by avoiding exposure to carcinogens, receiving vaccination for oncogenic viruses, and implementing lifestyle measures to minimize tobacco use and obesity, it is possible to reduce cancer incidence by 50% or more [14]. Although it is currently difficult to determine whether an individual woman will benefit from these behavioral interventions, such measures are generally healthful and thus should be recommended.Dr. Ponzone also cites the recent report by Tomasetti and Vogelstein as evidence that cancer prevention interventions are unlikely to be generally useful. Drs. Tomasetti and Vogelstein investigated the relationship between the lifetime risk of specific cancer types and the total number of divisions of “normal self-renewing cells” [15]. These investigators reached the provocative conclusion that only one third of cancer risk can be attributed to inherited predispositions or environmental factors, with the remaining two thirds of cancer risk attributable to random DNA mutations occurring in normal, noncancerous cells. These investigators attributed this random DNA mutation rate as “bad luck” and concluded that such findings suggest that cancer preventive interventions such as avoiding environmental or endogenous carcinogens will do little to reduce the risk of these cancers. The conclusion that much of cancer risk can be attributed to DNA mutations is certainly correct; however, the conclusion that the rate of DNA mutation has little to do with endogenous and exogenous exposure to carcinogens and mutagens is unlikely to be true.The report by Drs. Tomasetti and Vogelstein has been criticized by others [16–18]. However, it is important to point out several major issues with their analysis here. Central to the study by Tomasetti and Vogelstein is the hypothesis that cancer risk can be directly related to the number of stem cell divisions in normal tissue [15]. In their report, they showed a positive linear relationship between the lifetime risk of cancer (abstracted from incidence data from the Surveillance, Epidemiology, and End Results Program database) and the number of stem cell divisions in normal tissues over an average lifetime (estimated from immunostaining for stem cell markers or from biologic studies). However, they carefully selected the tumor types to include in their study. Tomasetti and Vogelstein left out important common cancers that might not fit their linear relationship (e.g., breast, prostate, and ovary) [15]. Equally problematic is the “expansion” of some tumors into nontraditional subsets that are treated as separate tumors (e.g., splitting osteosarcomas into five different subtypes, each equally weighted as esophageal, testicular, and head and neck cancer). This process of selecting specific tumors that fit their hypothesis, and leaving out those that do not, greatly weakens the validity of their conclusion and does not allow their analysis to be generally applicable to many cancer types.Dr. Ponzone also cites problems with the “early detection” of breast cancer. Mammograms are certainly able to detect breast cancer at an early stage. However, the current debate has been focused on whether mammograms detect too many cancers that are not life-threatening [2–5]. This problem of “overdiagnosis” of nonlethal cancers is a major focus of current early detection research. Similar to “prevention,” the phrase “early detection” often implies to the general population a test that is 100% effective in detecting cancer (i.e., is 100% sensitive), with no false-positive results (i.e., 100% specific). However, no screening test will be 100% sensitive and 100% specific. Although mammograms will not detect all breast cancers, currently, with computer-aided detection, mammograms are 85% sensitive and 92% specific [19]. Thus, mammography remains the reference standard breast screening test. However, a need certainly exists to develop breast screening tests that more effectively detect lethal cancers without identifying nonlethal cancers.The concept of breast cancer “early detection” is also evolving. Clinicians now use a risk-based approach to detect breast cancer. For low- to average-risk women, the generally accepted screening guidelines for the general population are being used. Although debate is ongoing concerning at what age mammographic screening should start (40 or 50 years old or older) and whether mammograms should be obtained yearly or every other year [20–23], such screening approaches should only be applied to those women with the population or average risk. For high-risk women, more aggressive screening approaches are generally used (and are authorized for payment by Medicare and insurance companies). For women with a lifetime risk of 20%–25% or higher, including women with BRCA1 or BRCA2 mutations, annual mammograms and annual breast magnetic resonance imaging scans have been recommended. Bilateral breast ultrasonography is also often added to mammography for breast cancer screening in women with lobular premalignant lesions (e.g., atypical lobular hyperplasia and lobular carcinoma in situ). Thus, a risk-based approach is also now being used for breast cancer screening.So, are women’s expectations for breast cancer prevention and early detection being met? For the highest risk women, the answer appears to be yes. However, for most women (in particular, those at low to moderate risk), the answer is clearly no. For such women, it is clear that additional research is needed to improve the ability to detect life-threatening cancer at an early curable stage and to prevent the development of these cancers. Many research groups are working to discover more effective and safer methods to detect and prevent life-threatening breast cancers. Promising prevention strategies include using novel medical therapies such as drugs targeting precancerous cells [24], natural products [25], cancer vaccines [26], and combinations of exercise, diet, and antidiabetic drugs such as metformin [27, 28]. Novel early detection strategies are also being developed that use blood-based DNA, RNA, or protein markers to detect life-threatening cancer [29]. The results from such research studies will ultimately allow women’s expectations for breast cancer prevention and early detection to be met.     

Metronomic chemotherapy for patients with metastatic breast cancer: Review of effectiveness and potential use during pandemics

Metronomic chemotherapy (M-CT) is defined as dose dense administration of chemotherapy at lower doses than maximum tolerated dose but at shorter free intervals, to obtain a near continuous exposure of cancer cells to those potentially effective drugs. M-CT is a useful strategy to obtain response, overcome resistance and reduce side effects, with low costs. This review will focus on the use of M-CT in advanced breast cancer (ABC). Cytostatic and cytotoxic effect on cancer cells, the anti-angiogenic and the immunomodulatory effects are its main mechanisms of actions. Many clinical trials proved the efficacy and tolerability of different monotherapies and combinations of chemotherapeutic agents administered in metronomic doses and frequencies in ABC. M-CT is a reasonable option for second and later lines of chemotherapy in metastatic breast cancer including those with prior anthracycline or taxane exposure, older patients and patients with comorbidities, and even as first-line in certain groups of patients. The acceptable efficacy and low toxicity of oral metronomic chemotherapy makes it a reasonable option during COVID-19 pandemic as well as in the post-COVID era which is projected to last for some time.     

The Prevention of Hereditary Breast and Ovarian Cancer: A Personal View

Options for the prevention of hereditary breast and ovarian cancer include screening, preventive surgery and chemoprevention. Screening studies with magnetic resonance imaging of the breast are promising but the technology is not widespread and MRI is unlikely to be available as a screening tool in the near future. Prophylactic oophorectomy and mastectomy are effective preventive measures and are gaining in acceptance by patients and physicians. Preventive mastectomy is effective against both primary and contralateral breast cancer. Oophorectomy prevents ovarian cancer, and if done prior to menopause, will prevent breast cancer as well. Tamoxifen has been shown to prevent contralateral breast cancers in BRCA1 and BRCA2 carriers but is not widely accepted as a means of primary prevention. Oral contraceptives and tubal ligation will reduce the risk of hereditary ovarian cancer and should be considered in women who wish to retain ovarian function.