Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy

This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given×5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T×5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first×2–3 years followed by AIs×2–3 years, or the other way round; and third, T×5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or ‘pure’ antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.     

前列腺癌内分泌治疗现状

前列腺癌（prostatecancerPC）是欧美国家男性发病率最高的恶性肿瘤,近年来其在我国的发病率也逐年升高。雄激素在PC的发生、发展过程中扮演着重要的角色,所以内分泌治疗一直是前列腺癌研究领域的重点,但是其可能诱发激素非依赖型PC这也是临床医学面临的一大问题。本文就前列腺癌内分泌治疗的分类、作用机制、用药策略及临床效果等作一综述。     

老年乳腺癌患者的临床病理特点及其辅助治疗模式的研究

目的:探讨老年乳腺癌患者的临床病理特点及其辅助治疗模式,为老年乳腺癌患者的临床治疗提供参考。方法:选取2008年1月-2012年1月期间我院收治的50例老年乳腺癌患者作为研究对象,同时选取同期收治的50例中青年乳腺癌患者,比较两组患者的临床病理特征,并采用新辅助内分泌疗法治疗本组50例老年乳腺癌患者,治疗4个月后观察治疗效果。结果:老年乳腺癌患者的病灶5cm比例以及ER和PR阳性率均明显高于中青年患者,两组患者数据比较差异有统计学意义(P0.05);老年乳腺癌患者的淋巴结转移率、Ki67阳性率以及HER-2阳性率均低于中青年患者,两组患者数据比较差异均有统计学意义(P0.05);本组50例老年乳腺癌患者治疗总有疗效为82.0%,ER、PR均为阳性患者的治疗有效率为90.0%,明显高于ER和PR非双阳性患者(76.9%,57.1%),数据比较差异均有统计学意义(P0.05);TNM I期患者的治疗有效率为93.8%,明显高于TNM II期(76.9%)或TNM III期患者(20.0%),数据比较差异均有统计学意义(P0.05)。患者在治疗期间均未出现严重不良反应。结论:老年乳腺癌患者的生物学行为较好,病灶大、淋巴转移率低以及ER和PR阳性率高;新辅助内分泌治疗老年乳腺癌患者,尤其对ER、PR均为阳性以及TNM分期低的患者临床效果安全有效,不良反应发生率低,值得临床推广应用。     

Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy

Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10 mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers.     

Differential responses of cellular immunity in patients undergoing neoadjuvant therapy followed by surgery for carcinoma of the oesophagus

Background  To compare immune responses following neoadjuvant chemoradiation therapy in combination with hyperthermia plus surgery to those induced by surgery alone in patients with oesophageal cancer. Methods  Thirty-two patients with histopathologically proven oesophageal cancer, scheduled for potentially curative transhiatal or transthoracic oesophagectomy with (neo, n = 20) or without (control, n = 12) neoadjuvant thermochemoradiation therapy (ThCR) were included. Peripheral blood samples were obtained before ThCR, after 2 weeks of ThCR, 1 day before surgery, on postoperative days 1, 3, 7, and 6 weeks after surgery, for white blood cell counts, lymphocyte subsets and T helper type 1 (Th1) and type 2 (Th2) lymphocyte responses. Results  Neo patients showed a significant decrease in granulocytes and lymphocyte subsets, and T cell cytokines after 2 weeks of ThCR. Only CD8+ (cytotoxic) T cells recovered after ThCR to reach normal levels prior to surgery. In contrast, CD4+ T (helper) cells, and NK- and B cells in neo patients did not recover prior to surgery (all P < 0.05). Oesophagectomy induced a significant increase in granulocytes and a decrease in lymphocytes (and subsets). Only those subsets that had not recovered after ThCR (CD4+ T cells, NK and B cells but not CD8+ T cells), were significantly lower (all P < 0.05) during the entire postoperative study period. Postoperatively, the stimulated cytokine production capacity of Th1 and Th2 cells, corrected for number of T cells, was not significantly different between the groups. Conclusion  Neoadjuvant thermochemoradiation for oesophageal cancer caused significant disturbances of host cellular immunity with reduced T, NK and B cell counts, and differential recovery of cytotoxic and helper T cells leading to prolonged T cell imbalance that extends beyond the time of surgery. The functional and anti-tumour consequences of this immunodisturbance need further investigation, as recovery of T helper cytokine production towards surgery was less impaired than T helper cell counts.     

乳腺癌对新辅助肌注睾酮-阿那曲唑治疗的快速反应的超声评估研究

摘要 目的：探究使用超声对接受肌注睾酮-阿那曲唑新辅助治疗（NAC）乳腺癌患者临床疗效评估的可行性,以期找出能够用于评估乳腺癌NAC疗效的可靠指标。方法：选择2018年1月至2021年1月于我院接受治疗的100例乳腺癌患者（100个病灶）为研究对象,分别于其接受化疗前和化疗后实施超声检测,记录入组患者二维超声指标（包括肿瘤形态、边界、内部回声、后方回声）、彩色多普勒超声指标（包括血流分级、血流阻力指数（RI）、收缩期最高血流速度（PSV））、超声弹性成像指标（包括弹性评分、弹性应变率（SR））,将入组患者按照化疗后病理结果区分为有效组（MHR组）和无效组（NMHR组）,对比两组患者化疗前后上述参数的差异,分别对上述参数实施单因素和多因素Logistic回归分析,并通过绘制受试者工作特征曲线（ROC）的方式计算上述参数的诊断效能。结果：（1）定性参数方面,NAC治疗后MHR和NMHR组患者在病灶内部回声变化、血流分级变化、弹性评分变化方面具有差异（P<0.05）;定量参数方面,化疗结束后MHR组患者的RI、SR以及PSV均明显低于NMHR组（P<0.05）;（2）RI、SR以及PSV对乳腺癌患者接受肌注睾酮-阿那曲唑NAC治疗有效性的ROC曲线,其AUC分别为0.811（95% CI=0.666-0.957,P=0.002）、0.697（95% CI=0.524-0.869,P=0.038）、0.734（95% CI=0.570-0.897,P=0.011）;（3）单因素分析内部回声、血流分级、弹性评分、RI、SR以及PSV是乳腺癌患者NAC疗效影响因素,多因素Logistic回归分析RI、SR以及PSV会影响乳腺癌患者NAC疗效（P<0.05）。结论：超声在评估乳腺癌患者接受肌注睾酮-阿那曲唑NAC治疗有效性具有较好的应用价值,其中RI、SR及PSV可对乳腺癌NAC早期疗效做出可靠评估,可考虑将其应用于临床中。     

Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy

Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P = 0.0001), objective response (30% versus 20%, P = 0.0006), and clinical benefit (49% versus 38%, P = 0.0001). Superiority of letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after letrozole, compared with 197 crossed over to letrozole after tamoxifen. Median overall survival was 34 months for letrozole versus 30 months for tamoxifen (not significant).

In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2–T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for letrozole versus 36% for tamoxifen (P < 0.001). Conservative surgery was possible in 45% of patients treated with letrozole versus 35% with tamoxifen (P = 0.022).

In both trials, both treatments were well tolerated with no significant differences in side effects.

These results indicate that letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments.     

Expanding the protein catalogue in the proteome reference map of human breast cancer cells

In this report we present a catalogue of 162 proteins (including isoforms and variants) identified in a prototype of proteomic map of breast cancer cells. This work represents the prosecution of previous studies describing the protein complement of breast cancer cells of the line 8701-BC, which has been well characterized for several parameters, providing to be a useful model for the study of breast cancer-associated candidate biomarkers. In particular, 110 spots were identified ex novo by PMF, or validated following previous gel matching identification method; 30 were identified by N-terminal microsequencing and the remaining by gel matching with maps available from our former work. As a consequence of the expanded number of proteins, we have updated our previous classification extending the number of protein groups from 4 to 13. In order to facilitate comparative proteome studies of different kinds of breast cancers, in this report we provide the whole complement of proteins so far identified and grouped into the new classification. A consistent number of them were not described before in other proteomic maps of breast cancer cells or tissues, and therefore they represent a valuable contribution for breast cancer protein databases and for future application in basic and clinical researches.     

Clinical management of secondary angiosarcoma after breast conservation therapy

Aim

The aim of this paper is to summarize the treatment outputs of secondary angiosarcoma after breast conservation therapy at St. Eizabeth Cancer Centre, Slovakia.

Background

Angiosarcoma of the breast is a rare but very aggressive malignant tumor of the vascular endothelium, characterized by rapidly proliferating and extensively infiltrating growth. Breast angiosarcoma may occur de novo, or as a complication of radiation therapy, or chronic lymphedema secondary to axillary lymph node dissection for mammary carcinoma. Radiotherapy in the treatment of breast cancer is associated with an increased risk of subsequent sarcoma.

Materials and methods

Retrospective study of medical records from the cancer databases was done in order to analyze the secondary breast angiosarcoma. This disease is an iatrogenic condition that warrants close follow-up and judicial use of radiotherapy in breast conserving therapy. Therefore, it is more prevalent in cases treated with radiotherapy, occurring especially in or adjacent to the radiation field. Clinical histories and follow-up data of identified patients after breast conservation therapy of invasive breast cancer were reviewed. In addition, a comprehensive literature review on diagnosis and treatment procedures was done in order to summarize state-of-the-art clinical approach.

Results and discussions

Three cases of secondary angiosarcoma after breast conservation therapy (BCT) were identified among 4600 patients treated at St. Elizabeth Cancer Institute during previous 16 years (1995–2011). Secondary breast angiosarcoma was diagnosed in a median period of 11 years following primary radiotherapy, median age at the time of diagnosis was 75 years. Surgical treatment consisted of radical mastectomy. The first patient, a 56-year-old woman received neoadjuvant chemotherapy (docetaxel + gemcitabin), second one (75 year) was treated by radiotherapy (TD 26 Gy, 2 Gy per fraction), since chemotherapy was not indicated. The last patient (80 year) got adjuvant chemotherapy (paclitaxel). Average follow up of the patients was 31 months. As of 31 July 2012, our patients were doing well without evidence of recurrent disease after treatment.

Conclusions

Angiosarcoma remains a difficult management problem with poor loco-regional and distal control. In our study, an overall incidence rate of secondary breast angiosarcoma is 0.065%. Although the prognosis for this disease is poor (typical survival period is 14.5–34 months with a 5-year survival rate of approximately 15%), all the three patients treated at our institute are alive and disease-free at the end of reported period. Finally, it is assumed that the use of breast conserving therapy will increase the incidence of post-irradiation angiosarcoma but the small difference in risk of subsequent sarcoma of the breast cancer patients receiving radiotherapy does not suppress its benefit.     

The menopause,hormone replacement therapy and breast cancer

Concern exists that the reduction in breast cancer risk associated with the onset of the menopause will be negated with exposure to hormone replacement therapy (HRT). Evidence from large-scale randomised HRT trials support observational data that have shown a modest increase in breast cancer risk with long-term use (i.e. >15 years) of combined therapy, although this falls following HRT cessation suggesting a growth-promoting effect. Randomised evidence demonstrates that the efficacy of anti-estrogens, aromatase inhibitors and raloxifene in the treatment and chemoprevention of breast cancer are restricted to women with oestrogen receptor positive (ER +ve) disease; however, HRT has not been associated conclusively with a predominance of hormone sensitive breast cancer. Despite stimulating the breast cancer cell growth, HRT has not been shown to increase breast cancer recurrence or mortality when prescribed to breast cancer survivors experiencing oestrogen deficiency symptoms and randomised trials have been recommended and commenced. In conjunction with controlled breast cancer trials demonstrating a therapeutic benefit of high dose estrogens and interest in the use of additive oestrogen therapy in patients developing resistance to oestrogen deprivation, the dogma that HRT is an absolute contra-indication following diagnosis is challenged.     

Tissue and plasma globotriaosylsphingosine could be a biomarker for assessing enzyme replacement therapy for Fabry disease

Fabry disease is a genetic disease caused by a deficiency of α-galactosidase A (GLA), which leads to systemic accumulation of glycolipids, predominantly globotriaosylceramide (Gb3). With the introduction and spread of enzyme replacement therapy (ERT) with recombinant GLAs for this disease, a useful biomarker for assessing the response to ERT is strongly required. We measured the tissue level of lyso-globotriaosylsphingosine (lyso-Gb3) in Fabry mice by means of high performance liquid chromatography, and compared it with the Gb3 level. The results revealed a marked increase in the lyso-Gb3 level in most tissues of Fabry mice, and which decreased after the administration of a recombinant GLA as in the case of Gb3, which is usually used as a biomarker of Fabry disease. The response was more impressive for lyso-Gb3 compared with for Gb3, especially in kidney tissues, in which a defect significantly influences the morbidity and mortality in patients with this disease. The plasma level of lyso-Gb3 also decreased after the injection of the enzyme, and it was well related to the degradation of tissue lyso-Gb3. Thus, lyso-Gb3 is expected to be a useful new biomarker for assessing the response to ERT for Fabry disease.     

The effects of hormone therapy on cognition in breast cancer

The use of hormonal therapies for the treatment of breast cancer is common, yet few studies have examined the possible cognitive effects. Several regions of the brain, important in memory and cognition, are rich in oestrogen receptors. As a result, the long-term use of anti-oestrogens may have potential consequences for cognition. This project aims to establish whether significant cognitive deficit exists in women receiving hormone therapy for breast cancer and to develop a cognitive package that is sensitive to the potential effects of oestrogen deficiency on cognition. Cognitive assessments measured a range of memory and attention functions in patient and control groups to identify whether cognitive impairment, if apparent, occurs at a widespread or function specific level. Ninety-four patients from the anastrozole, tamoxifen and combined (ATAC) trial and 35 non-cancer controls were assessed. Groups did not differ significantly in age or estimated full-scale intelligence. The patient group did not differ from controls on measures of working memory, attention and visual memory but was significantly impaired compared to the control group on measures of verbal memory (P=0.026) and processing speed (P=0.032). Cognitive performance in the patient group was not significantly related to length of time on trial or measures of psychological morbidity. As more and more hormonal agents are used in clinical trials of both adjuvant and preventive settings it is of vital importance that any potentially deleterious effects on cognitive function are measured adequately. Preliminary results from this study suggest that anti-oestrogen therapy may cause a specific deficit in verbal memory that corroborates the links between oestrogen levels and verbal memory often reported in studies of the cognitive benefits of hormone replacement therapy.     

Proteomic analysis of estrogen response of premalignant human breast cells using a 2-D liquid separation/mass mapping technique

A 2-D liquid-phase separation method based on chromatofocusing and nonporous silica RP-HPLC followed by ESI-TOF-MS was used to analyze proteins in whole cell lysates from estrogen-treated and untreated premalignant, estrogen-responsive cell line MCF10AT1 cells. 2-D mass maps in the pH range 4.6-6.0 were generated with good correlation to theoretical M(r) values for intact proteins. Proteins were identified based on intact M(r), pI and PMF, or MS/MS sequencing. About 300 unique proteins were identified and 120 proteins in mass range 5-75 kDa were quantified upon treatment of estrogen. Around 40 proteins were found to be more highly expressed (>four-fold) and 17 were down-regulated (>four-fold) in treated cells. In our study, we found that many altered proteins have characteristics consistent with the development of a malignant phenotype. Some of them have a role in the ras pathway or play an important role in signal pathways. These changed proteins might be essential in the estrogen regulation mechanism. Our study highlights the use of the MCF10AT1 cell line to examine estrogen-induced changes in premalignant breast cells and the ability of the 2-D mass mapping technique to quantitatively study protein expression changes on a proteomic scale.     

Imaging mass spectrometry in biomarker discovery and validation

Biomarker discovery and validation involves the consideration of many issues and challenges in order to be effectively used for translation from bench to bedside. Imaging mass spectrometry (IMS) is a new technology to assess spatial molecular arrangements in tissue sections, going far beyond microscopy in providing hundreds of different molecular images from a single scan without the need of target-specific reagents. The possibility to correlate distribution maps of multiple analytes with histological and clinical features makes it an ideal tool to discover diagnostic and prognostic markers of diseases. Some recently published studies that show the usefulness and advantages of this technology in the field of cancer research are highlighted.     

Clinical considerations in study designs that use cotinine as a biomarker

Subjects enrolled in studies are not always screened for routine habits such as smoking. Personal history is not always reliable and therefore an objective biomarker is necessary to screen for smokers. The objectives of this article were to review the metabolism of nicotine and other metabolic considerations associated with smoking; to review some of the routine methods used to assess exposure to nicotine-containing products; to revisit cotinine breakpoints utilized to distinguish smokers from non-smokers during screening for clinical trials; to assess the utility of screening questions regarding smoking practices; and to recommend standards for clinical pharmacology studies. The results indicated that cotinine levels serve as a useful biomarker of tobacco exposure; racial issues may be clinically relevant in determining smoking status; cessation of smoking should occur at least 14 days prior to the start of the study; adverse effects from nicotine withdrawal such as craving, hunger and weight gain may persist for more than 6 months; potential metabolic interactions via cytochrome P2A6 and P1A2 need to be considered when designing a study; and the use of a single calibrator as a breakpoint is acceptable if a categorical outcome such as 'smoker' versus 'non-smoker' is desired. Nicotine from food products is not expected to impact assay sensitivity or to be clinically relevant; a serum cotinine concentration of 10 ng ml^-1 be employed as a breakpoint for non-smokers versus smokers; other non-invasive alternatives are collection of urine, saliva, or hair (with suggested breakpoints of 200 ng ml^-1, 5 ng ml^-1 and 0.3 ng mg^-1, respectively; screening questions be accompanied by testing for cotinine; and the inclusion of smokers in studies should be considered once the impact of smoking on the targeted population is understood.     

Clinical considerations in study designs that use cotinine as a biomarker

Subjects enrolled in studies are not always screened for routine habits such as smoking. Personal history is not always reliable and therefore an objective biomarker is necessary to screen for smokers. The objectives of this article were to review the metabolism of nicotine and other metabolic considerations associated with smoking; to review some of the routine methods used to assess exposure to nicotine-containing products; to revisit cotinine breakpoints utilized to distinguish smokers from non-smokers during screening for clinical trials; to assess the utility of screening questions regarding smoking practices; and to recommend standards for clinical pharmacology studies. The results indicated that cotinine levels serve as a useful biomarker of tobacco exposure; racial issues may be clinically relevant in determining smoking status; cessation of smoking should occur at least 14 days prior to the start of the study; adverse effects from nicotine withdrawal such as craving, hunger and weight gain may persist for more than 6 months; potential metabolic interactions via cytochrome P2A6 and P1A2 need to be considered when designing a study; and the use of a single calibrator as a breakpoint is acceptable if a categorical outcome such as 'smoker' versus 'non-smoker' is desired. Nicotine from food products is not expected to impact assay sensitivity or to be clinically relevant; a serum cotinine concentration of 10 ng ml^?1 be employed as a breakpoint for non-smokers versus smokers; other non-invasive alternatives are collection of urine, saliva, or hair (with suggested breakpoints of 200 ng ml^?1, 5 ng ml^?1 and 0.3 ng mg^?1, respectively; screening questions be accompanied by testing for cotinine; and the inclusion of smokers in studies should be considered once the impact of smoking on the targeted population is understood.     

Patterns of treatment effects in subsets of patients in clinical trials

We discuss the practice of examining patterns of treatment effects across overlapping patient subpopulations. In particular, we focus on the case in which patient subgroups are defined to contain patients having increasingly larger (or smaller) values of one particular covariate of interest, with the intent of exploring the possible interaction between treatment effect and that covariate. We formalize these subgroup approaches (STEPP: subpopulation treatment effect pattern plots) and implement them when treatment effect is defined as the difference in survival at a fixed time point between two treatment arms. The joint asymptotic distribution of the treatment effect estimates is derived, and used to construct simultaneous confidence bands around the estimates and to test the null hypothesis of no interaction. These methods are illustrated using data from a clinical trial conducted by the International Breast Cancer Study Group, which demonstrates the critical role of estrogen receptor content of the primary breast cancer for selecting appropriate adjuvant therapy. The considerations are also relevant for general subset analysis, since information from the same patients is typically used in the estimation of treatment effects within two or more subgroups of patients defined with respect to different covariates.