Mammographic screening: evidence from randomised controlled trials.

BACKGROUND: All randomised breast cancer screening trials have shown a reduction in breast cancer mortality in the 'invited for mammography' screening arm compared with the 'control arm' for women aged 50 years and older at randomisation (overall 25%). However, individually published point estimates differ and concern has been raised about methodological quality and outcome measures. Materials and Methods Review of the evidence on breast cancer mortality reduction and discussion of the causes of difference in point estimates in the five Swedish and Canadian trials. A summary of the prerequisites for methodological quality and its available evidence from the trials is given. Data to support breast cancer mortality as a correct outcome measure are presented. RESULTS: There is no reason not to use breast cancer mortality as an outcome measure for trials intended to reduce breast cancer mortality, both from a clinical and a methodological point of view. Everything possible was performed in these trials in order to determine this outcome measure as accurately as possible. The fact that a few of the trials showed a relatively large breast cancer mortality reduction and others far lower reduction rates is irrelevant, if one does not consider the background situation in the region before the trial started, the design of the trial or quality of screening. CONCLUSIONS: There seems no reason to change or halt the current nation-wide population-based screening programmes. Nor is there any justifiable reason for negative reports towards women or professionals.     

The role of the multidisciplinary team in recruiting to cancer clinical trials

This research analyses factors affecting the accrual of women to two breast cancer trials, the British Association of Surgical Oncology (BASO) II trial (a treatment trial) and the International Breast cancer Intervention Study (IBIS) (a prevention trial). The research sought to identify the factors affecting the recruitment of women to breast cancer clinical trials from the multidisciplinary teams' and women's perspectives using multiple methods. This paper reports on the findings from research undertaken with multidisciplinary teams across the United Kingdom and highlights their role in recruiting people to cancer clinical trials. The findings contribute to the debate and knowledge on recruitment in a number of ways by including the views of key stakeholders concerned with these trials, by highlighting the factors affecting recruitment to these two trials, and finally, by making recommendations on methods to enhance recruitment.     

Biologic basis and evolving role of aromatase inhibitors in the management of invasive carcinoma of the breast

BACKGROUND AND OBJECTIVES: The most powerful predictor of the response of breast cancers to hormonal therapy is the presence of estrogen receptors in the tumor cells. Estrogen receptors are expressed in approximately 35-55% of all breast tumors but up to 80-90% of tumors from women older than 55 years. METHODS: At this time, tamoxifen remains the first-line hormonal therapy for breast cancer of all stages. However, the aromatase inhibitors are evolving into an important treatment option. Aromatase inhibitors prevent the conversion of precursors (androgens) to estrogens. RESULTS: On the basis of several randomized clinical trials, aromatase inhibitors have become established as the second-line therapy for postmenopausal women with advanced breast cancer progressing during tamoxifen therapy. Furthermore, very recent trials support the use of these agents as first-line therapy in place of tamoxifen. CONCLUSIONS: The roles of the selective aromatase inhibitors in the prevention of breast cancer and in the neoadjuvant and adjuvant treatment of early-stage breast cancer are the focus of several planned and ongoing large-scale clinical trials. These trials will answer some of the many questions that remain regarding optimal hormonal therapy for hormone-dependent breast cancer.     

Landscape of combination therapy trials in breast cancer brain metastasis

Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional and therapeutic clinical trials involving combination therapy for BCBM, without limiting for date or location. Information on trial characteristics was collected. Combination therapies used in trials were analyzed and explored in line with evidence from the medical literature. Sixty-five combination therapy trials were selected (n = 65), constituting less than 0.7% of all breast cancer trials. Most trials (62%) combined ≥2 chemotherapeutic agents. Chemotherapy with radiation was main-stay in 23% of trials. Trastuzumab was mostly used in combination (31%), followed by lapatinib (20%) and capecitabine (15%). Common strategies involved combining tyrosine kinase inhibitors with thymidylate synthase inhibitors (6 trials), dual HER-dimerization inhibitors (3 trials), microtubule inhibitors and tyrosine kinase inhibitors (3 trials), and HER-dimerization inhibitors and tyrosine kinase inhibitors (3 trials). The combination of tucatinib and capecitabine yielded the highest objective response rate (83%) in early phase trials. The triple combination of trastuzumab, tucatinib and capecitabine lowered the risk of disease progression or death by 52% in patients with HER2-positive BCBM. Combining therapeutic agents based on biological mechanisms is necessary to increase the effectiveness of available anti-cancer regimens. Significant survival benefit has yet to be achieved in future combination therapy trials. Enhancing drug delivery through blood–brain barrier permeable agents may potentiate the overall therapeutic outcomes.     

The challenges of individualized care for older patients with localized breast cancer

Individualized care is achieved when the appropriate screening and/or evaluative tests are used, the treatment plan is driven by evidence-based data and the patient’s functional ability, physical and mental health, preference and social situation are incorporated into treatment decisions. Breast cancer is a disease of aging; yet, the management of breast cancer in older women in most cases lacks evidence from prospective randomized clinical trials (i.e., level 1 evidence) to support treatment recommendations. Older women are underrepresented in therapeutic clinical studies, even though studies show that selected fit older women enrolled on clinical trials derive similar benefits as younger women. Very few studies have focused on the distribution and biological behavior of different molecular subtypes of breast cancer in older women making it difficult to conclude whether old age adds extra biological complexity. A comprehensive geriatric assessment that includes a multidimensional process designed to assess functional ability, physical health, cognitive and mental health, social issues and environmental situation of elderly person should be an integral part of individualized care for older patients with breast cancer. However, incorporation of this tool into standard oncology practice is very slow despite the expected steep increase in older individuals with cancer projected over the next 25 years. All of the factors mentioned above hinder progress in delivering individualized care to older patients with breast cancer. This article provides an overview on progress and challenges of individualized and personalized health care in older women with breast cancer.     

Should women be advised to take prophylactic endocrine treatment outside of a clinical trial setting?

Epidemiological, experimental and clinical data strongly support the possibility that breast cancer can be prevented by using anti-estrogenic interventions in healthy women. Four trials involving over 25,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer, and several trials utilizing raloxifene or aromatase inhibitors are underway. Interim analyses of the Royal Marsden tamoxifen trial and the Italian national trial showed no effect on the early incidence of breast cancer. The NSABP-P1 showed a 49% reduction in early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract and thromboembolism. The IBIS trial showed a 32% reduction with a two-fold increase in endometrial cancer and in thromboembolic events. Mortality rates of breast cancer in women receiving tamoxifen prophylactically should be monitored and further follow-up of these trials is needed to determine whether tamoxifen provides an overall health benefit or increase specific or overall survival of breast cancer. High-risk women should not be advised to take anti-estrogens outside of a clinical trial setting.     

Identification of accrual barriers onto breast cancer prevention clinical trials

BACKGROUND:

The purpose of this study was to examine factors influencing a woman's decision to participate in a breast cancer prevention clinical trial. Nine healthcare organizations in Massachusetts cooperated in the present project.

METHODS:

The authors performed a case‐control study to compare responses between the study group (Study of Tamoxifen and Raloxifene [STAR] trial eligible, but not enrolled) and the control group (STAR trial participants) on 12 factors previously identified as barriers to accrual for clinical trials. Eight hypotheses were tested using multiple logistic regression to estimate the strength of the association for each factor on the dependent variable (study participation).

RESULTS:

The study samples were similar to the general population of eligible breast cancer prevention clinical trial subjects in the counties where the participating organizations were located, the state of Massachusetts, and nationally published STAR trial data. Results of a mailed questionnaire showed that when adjusting for subject demographics, and in the presence of other questions, 4 factors significantly influenced a woman's decision to enroll onto a breast cancer prevention clinical trial more than other eligible subjects: 1) clinician expertise and qualifications (P = .012; odds ratio [OR], 4.903; 95% confidence interval [CI], 1.41‐17.04); 2) personal desire to participate (P = .033; OR, 3.16; 95% CI, 1.10‐9.06); 3) perceived value of the trial (P = .020; OR, 2.92; 95% CI, 1.18‐7.21); and 4) level of trial inconvenience (P = .002; OR, 0.10; 95% CI, 0.02‐0.44).

CONCLUSIONS:

Addressing these issues in the relationship between patients and clinicians should improve accrual to breast cancer prevention clinical trials. Cancer 2010. © 2010 American Cancer Society.     

Unequal allotment of patients in phase III oncology clinical trials

Patient enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls, however recently some clinical trials have utilized an unequal distribution between the case and control arms. Trends and proportion of phase 3 cancer clinical trials that have an unequal allocation between the years 2010 and 2019 were studied from data extracted from clinicaltrials.gov. 323 trials with two arms and 35 trials with 3 arms were identified as randomized control trials with the primary purpose of a cancer-related treatment that provided allocation data. Amongst the trials with two arms, 238 trials had equal allocation and 85 trials had unequal allocation. Therefore, cancer clinical trials with unequal allocation represent about one in four 2-arm phase 3 trials. Amongst the eligible trials with three arms, 26 trials had equal allocation and 9 trials had unequal allocation. There was no significant difference in the annual proportion of trials with unequal allocation from 2010 to 2019. The categories of cancer which had the highest number of unequally allotted two-arm clinical trials were: gastrointestinal, breast, and genitourinary malignancies. This shift may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs and lower statistical power attached to this method.     

A commentary on the role of the surgeon in primary breast cancer

Summary The function of the surgeon remains the same relative to the management of primary breast cancer. What has changed is our perception of the biology of the disease and our understanding of data evaluation and analysis. This presentation provides an overview of some of the more important findings which have altered our understanding of breast cancer and which have led to a reassessment of the basis for cancer surgery. It also emphasizes why controlled clinical trials are necessary for obtaining credible data. To most succinctly summarize the author's position regarding a number of critical controversies related to primary breast cancer surgery, answers are presented to ten of the questions most frequently posed by surgeons regarding surgical therapy.     

Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer: cochrane review

The published literature comparing surgery, with or without adjuvant endocrine therapy, with endocrine therapy alone in older women with operable breast cancer was systematically reviewed.The design used is Cochrane review. Randomised controlled trials retrieved from the Cochrane Breast Cancer Group Specialised Register on 29 June 2005. Eligible studies recruited women aged 70 years or over with operable breast cancer, fit for surgery under general anaesthia. The studies compared surgery (either mastectomy or wide local excision, with or without endocrine therapy) to endocrine therapy alone. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Double data extraction and quality assessment were undertaken. Seven eligible trials were identified of which six had published time-to-event data. The quality of the allocation concealment was adequate in three studies and unclear in the remainder. In each case the endocrine therapy used was tamoxifen. When surgery alone was compared to endocrine therapy alone, there was no significant difference in OS (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.74-1.30, P=0.9), but a significant difference in PFS (HR 0.55, 95% CI 0.39-0.77, P=0.0006). When surgery with adjuvant endocrine therapy was compared to endocrine therapy alone, there was no significant difference in OS (HR 0.86, 95% CI 0.73-1.00, P=0.06), but a significant difference in PFS (HR 0.65 (95% CI 0.53-0.81, P=0.0001) for surgery plus endocrine therapy vs primary endocrine. The regimens have different side effect profiles with one study suggesting increased psychosocial morbidity at 3 months in the surgical arm, which resolves by 2 years. Primary endocrine therapy with tamoxifen is associated with inferior local disease control but non-inferior survival to surgery for breast cancer in older women. Trials are needed to evaluate appropriate selection criteria for its use in terms of patient co-morbidity and quality of life. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for this population.     

Informing breast cancer patients about clinical trials: a randomized clinical trial of an educational booklet.

BACKGROUND: To evaluate the impact of an educational booklet on women's knowledge of and willingness to participate in a randomized clinical trial of treatment for breast cancer. MATERIALS AND METHODS: Women undergoing surgery for newly diagnosed early stage breast cancer were randomized to receive, or not, an information booklet explaining the need for and manner in which randomized trials are conducted. RESULTS: Eighty-three women with newly diagnosed early stage breast cancer completed a questionnaire assessing attitudes to random clinical trials (RCTs) and were randomized to receive usual information treatment options provided from their oncologist, or the educational booklet in addition to usual information from their oncologist (42 usual information, 41 booklet). Fewer women who received the clinical trials booklet (40% versus 47%) would consider participating in the hypothetical clinical trial (P = 0.6). Mean knowledge scores increased for both groups; moreover, women who did not receive the booklet showed similar improvements to women who received the booklet [mean difference 0.09, 95% confidence interval (CI) -0.66 to 0.83]. In a multivariate analysis women who would consider participating in the clinical trial were more anxious [odds ratio (OR) 5.9, P = 0.02] had involved lymph nodes (OR 5.8, P = 0.02) and were less influenced by negative aspects of clinical trials (OR 7.7, P = 0.0001). After adjustment for these variables women who received the educational booklet were significantly less likely to consider trial participation (OR 0.22, P = 0.05). CONCLUSIONS: Educating women about clinical trials in this manner appears ineffective in improving recruitment to RCTs. Women appear to be more influenced by their perception of risk than understanding. This finding has ethical implications for communication of information about RCTs.     

Breast cancer adjuvant chemotherapy dosing in obese patients: dissemination of information from clinical trials to clinical practice

BACKGROUND: Substantial variation in adjuvant breast cancer chemotherapy dosing in obese women suggests that there is uncertainty about optimal practices. The purpose of this study was to investigate variations in dose determinations in clinical trial protocols and publications over the last 3 decades as potential sources of this uncertainty. METHODS: The National Cancer Institute database was used to identify protocols of breast cancer adjuvant chemotherapy conducted by cooperative groups between 1970-2000, and these protocols were then obtained directly from the cooperative groups. Dose determinations were categorized in each protocol and in published reports from each clinical trial. Fisher exact tests were used to compare the proportions of protocols that used full weight-based doses over time. RESULTS: Protocol-specified chemotherapy dosing was obtained for all of 44 eligible trials. A significant increase was identified in the use of full weight-based doses in the later time period compared with the earlier (P = .004; 2-sided Fisher exact test). A notable exception was 1 cooperative group that continues to require dose limitations for doxorubicin and cyclophosphamide in patients with a body surface area of more than 2.0 m(2). Regardless of publication date, published reports of clinical trials rarely provide information on use of full or limited weight-based doses. CONCLUSIONS: Variations in dose determinations among clinical trial protocols and lack of information on use of full weight-based doses in most publications are 2 likely sources of variation in chemotherapy dosing in obese women. Developing consensus and disseminating information on optimal chemotherapy dosing will likely reduce such variation and may improve survival among obese patients with breast cancer.     

Association between pharmaceutical involvement and outcomes in breast cancer clinical trials

BACKGROUND: Since 1992, pharmaceutical industry support has surpassed National Institutes of Health funding for clinical research in the United States. In this study, the authors sought to evaluate the impact of this shift in funding from public to private sponsors on the nature of published breast cancer clinical research. METHODS: All published breast cancer clinical trials from 2003, 1998, and 1993 were reviewed from 10 select English-language medical journals to evaluate pharmaceutical involvement over time and the association between sponsorship, trial design, and results. Clinical studies that reported disease-specific outcomes from medical therapy for breast cancer were eligible for analysis. Pharmaceutical involvement was defined as reported pharmaceutical industry funding, provision of drug, and/or authorship for each publication. RESULTS: In total, 140 eligible studies were identified, including 45 studies that were published in 1993, 39 studies that were published in 1998, and 56 studies that were published in 2003. Among those, 67 publications (48%) reported pharmaceutical industry involvement, 36 publications (26%) had at least >/=1 pharmaceutical industry author, And 100 publications (71%) were considered positive. Pharmaceutical involvement was identified in 44% of the studies published in 1993, in 38% of the studies published in 1998, and in 58% of the studies published in 2003. Pharmaceutical authorship was reported in 22% of the 1993 studies, in 21% of the 1998 studies, and in 34% of the 2003 studies. For studies that were published in 2003, those that reported pharmaceutical involvement were more likely to be positive (84% vs 54%; P = .02; Fisher exact test), to be single-arm studies (66% vs 33%; P = .03), and to evaluate metastatic disease (72% vs 46%; P = .06). CONCLUSIONS: Pharmaceutical involvement in published clinical breast cancer research may affect study design, focus, and results. Further research is warranted, including analysis of unpublished studies, to evaluate the impact of increasing pharmaceutical industry involvement on clinical research.     

组蛋白去乙酰化酶抑制剂治疗乳腺癌的临床研究

组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors,HDACIs）作为第一个成功用于癌症治疗的表观遗传学相关药物,能够有效解除对抑癌基因转录的阻滞,已成为极具潜力的抗癌药物。近年来,HDACIs在乳腺癌治疗领域中的临床研究逐渐开展,已有个别HDACIs在大型临床研究中表现出较强的抗癌活性。本文针对HDACIs在乳腺癌治疗领域开展的临床研究作一综述,有利于临床医师更好的了解HDACIs在乳腺癌治疗中的现状与进展。     

Do participants in adjuvant breast cancer trials reflect the breast cancer patient population?

AimTo describe the proportion of women in Tayside, Scotland diagnosed with early breast cancer who would have been eligible for influential adjuvant breast cancer trials.MethodsPhase III trials of adjuvant treatment for breast cancer referenced in five national guidelines were shortlisted by breast cancer specialists to identify the twelve considered most influential. Eligibility criteria were extracted from protocols and applied to a 16-year cohort of women who had received a diagnosis of breast cancer and the proportion meeting trial criteria calculated. The criteria used clinically in Tayside to make decisions about use of the trial treatments were also applied to the cohort. Finally, the proportion of women receiving adjuvant endocrine therapy as part of their care and who would have been eligible for the trial evaluating that therapy was calculated.ResultsOf the cohort’s 4811 women, 3535 (73%) were eligible for at least one trial but eligibility for an individual trial rarely exceeded 45%. There were substantial differences between the proportion of women meeting trial eligibility criteria and the proportion considered clinically eligible for the same treatment. The proportion of women receiving an endocrine therapy as part of their care who would also have been eligible for the trial evaluating that treatment ranged from 17% to 56%.ConclusionClinical eligibility criteria may be at variance with trial criteria. For adjuvant endocrine therapy, a substantial proportion of women who would have been ineligible for a trial nevertheless received the trial treatment as part of their care.     

Modelling the early detection of breast cancer.

A mathematical model was developed to predict the outcome of early detection clinical trials or programs targeted at evaluating mortality benefit from earlier diagnosis of breast cancer. The model was applied to eight randomized breast cancer trials, which were carried out to evaluate the benefits of mammography, physical examination or their combination. The model assumes that breast cancer is a progressive disease and any mortality benefit from earlier diagnosis is generated from a favorable shift in the stage at diagnosis relative to usual care. The model predicted the reduction in mortality for seven of the eight trials within the reported confidence intervals. Input data required by the models are: stage shift distribution, examination schedules, population age distribution, follow up time, and survival conditional on stage at diagnosis. Survival distributions were obtained from the 1973-82 SEER database whereas the remaining data was obtained for each of the trials. Information on sensitivity and stage was ordinarily available during the early phase of the trials. The theoretical model has the promise of being able to predict the long-term outcome of early detection trials or programs during the initial examination phase. The theoretical model is general and may be applied to other chronic diseases, which satisfy the basic assumptions.     

The AURORA initiative for metastatic breast cancer

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as ‘exceptional responders'' or as ‘rapid progressors'' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients.     

Quality of life assessment in patients receiving adjuvant therapy for breast cancer: The IBCSG approach

Background and purpose: The International Breast Cancer Study Group (IBCSG) has developed an approach for assessing the impact of adjuvant therapy on quality of life (QL) within the framework of international, multilingual clinical trials. The major steps are summarized. Conceptual, methodological and practical issues are discussed with reference to results of two trials closed to accrual (IBCSG VI, VII) and one subsequent ongoing trial (IBCSG IX).Patients and methods: QL was assessed in pre- and postmenopausal patients with operable breast cancer. Various single-item linear analogue self-assessment (LASA) scales were used as indicators of components of QL, including global indicators of well-being, functioning and health perception, and specific indicators of symptoms of disease and treatment. In trials VI and VII, QL was assessed at baseline, during adjuvant treatment and follow-up, and at recurrence. Based on this experience, the QL form was revised for subsequent trials and further investigated in a subsample of patients randomized into trial IX.Results: In trials VI and VII, the QL indicators were responsive to the impact of biomedical factors at baseline, various adjuvant treatments, changes over the first 18 months, and recurrence. In trial IX, the revised QL form was well accepted by patients and staff. Completing this form did not exceed five minutes. QL differences between on and off cytotoxic treatment strengthen the claim that these measures are responsive. Correlations and logistic regression analyses show the expected relationship among the various global and specific indicators.Conclusion: Results from two trials closed to accrual and an ongoing trial confirm the feasibility, validity and clinical relevance of the IBCSG approach for studying the impact of adjuvant breast cancer therapy on QL in international clinical trials.     

The Feasibility of Women at High Risk for Breast Cancer Participating in Chemoprevention Trials

Abstract

There is significant interest in developing chemoprevention trials for women at high risk for breast cancer, yet it is not clear how acceptable these strategies are. Results of clinical trials with tamoxifen have demonstrated a reduction in the incidence of breast cancer in women at increased risk, but rates of participation in such trials have been lower than expected. No previous studies have assessed the attitudes of high-risk women toward participating in chemoprevention trials using drugs causing ovarian suppression. All women who had attended a large familial cancer clinic in Sydney, New South Wales, between 1994 and 2000 who were eligible for the Raloxifene and Zoladex Research study being piloted in the United Kingdom at the time were approached. Telephone interviews were conducted with the 35 high-risk women willing to participate in this study. Almost half the women surveyed expressed willingness to participate in a randomized trial, and slightly fewer women considered participating in a nonrandomized trial. The women who would consider participating were younger than those who would not. The most frequently mentioned reasons for interest in participating in trials were to aid research, help others, and learn more, which indicates that altruism may have played a significant part in the women's willingness to participate. Most women interviewed were participating in risk reduction and early detection strategies and expressed high interest in research screening tests. Given the interest in randomized trials and the fact that women at high risk for breast cancer consider the side effects as mainly acceptable, undertaking such trials may be worthwhile.